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The D-SPECT is a dedicated cardiac camera that incorporates a solid-state semiconductor detector. This camera differs greatly from conventional SPECT/CT systems, resulting in significant differences in patient imaging. This continuing education article focuses on the specifications of both SPECT/CT and D-SPECT systems, radiopharmaceutical dosing requirements, imaging workflows, and some disadvantages of using each camera system. When used properly, the D-SPECT system can provide high-quality cardiac images with lower doses and faster exam times than conventional SPECT/CT systems.

Lack of diversity among genomic research participants results in disparities in benefits from genetic testing. To address this, the Alabama Genomic Health Initiative employed community engagement strategies to recruit diverse populations where they lived. In this paper, we describe our engagement techniques and recruitment strategies, which resulted in significant improvement in representation of African American participants. While African American participation has not reached the representation of this community as a percentage of Alabama's overall population (26%–27%), we have achieved an overall representation exceeding 20% for African Americans. We believe this demonstrates the value of engagement and recruitment where diverse populations reside.

Early measurements of tissue viability after myocardial infarction (MI) are essential for accurate diagnosis and treatment planning but are challenging to obtain. Here, manganese, a calcium analogue and clinically approved magnetic resonance imaging (MRI) contrast agent, is used as an imaging biomarker of myocardial viability in the first hours after experimental MI. Safe Mn2+ dosing is confirmed by measuring in vitro beating rates, calcium transients, and action potentials in cardiomyocytes, and in vivo heart rates and cardiac contractility in mice. Quantitative T1 mapping‐manganese‐enhanced MRI (MEMRI) reveals elevated and increasing Mn2+ uptake in viable myocardium remote from the infarct, suggesting MEMRI offers a quantitative biomarker of cardiac inotropy. MEMRI evaluation of infarct size at 1 h, 1 and 14 days after MI quantifies myocardial viability earlier than the current gold‐standard technique, late‐gadolinium‐enhanced MRI. These data, coupled with the re‐emergence of clinical Mn2+‐based contrast agents open the possibility of using MEMRI for direct evaluation of myocardial viability early after ischemic onset in patients., Early measurements of tissue viability after myocardial infarction (MI) are essential for accurate diagnosis and treatment planning. Here, the safety and efficacy of manganese‐enhanced magnetic resonance imaging (MEMRI) in vitro in cardiomyocytes and in vivo in mouse models of MI are evaluated. It is demonstrated that MEMRI offers a novel biomarker of myocardial viability in the first hours after MI.

PURPOSE: The Alabama Genomic Health Initiative (AGHI) is a state-funded effort to provide genomic testing. AGHI engages two distinct cohorts across the state of Alabama. One cohort includes children and adults with undiagnosed rare disease; a second includes an unselected adult population. Here we describe findings from the first 176 rare disease and 5369 population cohort AGHI participants. METHODS: AGHI participants enroll in one of two arms of a research protocol that provides access to genomic testing results and biobank participation. Rare disease cohort participants receive genome sequencing to identify primary and secondary findings. Population cohort participants receive genotyping to identify pathogenic and likely pathogenic variants for actionable conditions. RESULTS: Within the rare disease cohort, genome sequencing identified likely pathogenic or pathogenic variation in 20% of affected individuals. Within the population cohort, 1.5% of individuals received a positive genotyping result. The rate of genotyping results corroborated by reported personal or family history varied by gene. CONCLUSION: AGHI demonstrates the ability to provide useful health information in two contexts: rare undiagnosed disease and population screening. This utility should motivate continued exploration of ways in which emerging genomic technologies might benefit broad populations.

Background The epicardium, the most external layer of the heart, is composed of a layer of epithelial cells and underlying connective tissue. Following myocardial infarction, epicardial cells are activated and provide a source of paracrine factors and progenitor cells. In the border zone of the ischaemic tissue, the activated epicardial cells support cardiac and vascular regeneration by releasing pro-angiogenic and pro-survival factors, and by differentiating towards multiple cell lineages. During this process, activated epicardial cells migrate to the site of injury where they contribute to both post-ischemic remodelling and fibrosis. There is limited knowledge of the cellular and molecular regulation of these processes in large animals and humans, in part due to the lack of robust and representative models. Purpose In this project, we developed an ex vivo 3D organotypic model derived from porcine hearts, amenable to culture, which enables structural, molecular and cellular studies of the epicardium. Methods Thin epicardial/cardiac tissue slices (EpCardio-TS) were obtained by using a vibratome to cut the first layer of tissue from the epicardial side of porcine heart cubes. Slices were cultured for up to 72h in a bioreactor that uses a 3D printed chamber connected to a control system that allows maintenance and adjustment of culture conditions, and ensures continuous media flow. Local intracellular delivery of fluorescent quantum-dots (Qdots) was performed using nanoneedle chips to track epicardial cells, whilst cell fate is visualised in 3D by performing immunofluorescence on decolourised slices. Results Intact EpCardio-TS obtained from porcine heart included a viable epicardium, expressing typical epicardial markers (wt-1, mesothelin, uroplakin), and an electrically active myocardium. Live/dead staining showed epicardial (67.8±16.2%, N=5) and myocardial (40.8±28.6%, N=3) viability, and TUNEL assay confirmed low levels of apoptosis (6.3±5.1% of wt-1+ epicardial cells N=1). Moreover, the presence of proliferating epicardial cells (PCNA+), the increase in wt-1+ cells, and the increase in epicardial gene expression (Tbx18 and TCF21) suggested that cells maintain their progenitor phenotype and undergo activation in culture. Nanoinjection of fluorescent Qdots to EpCardio-TS localized them to the wt-1+ cells on the slice surface, presenting a strategy to mark the epicardial layer. This, combined with the successful decolourisation of the slices, provides an in vitro platform to track the role of epicardial cells in cardiac remodelling and fibrosis. Conclusions EpCardio-TS represents a robust ex vivo model merging the complexity of a 3D organotypic culture with the simplicity of the in vitro culture. EpCardio-TS are amenable to culture and cell tracking, and can therefore find application in toxicology and gene therapy screening for the modulation of epicardial interactions with myocardial and non-myocardial cells of the heart.

Objective Examine the association of duration of therapeutic coma (TC) with seizure recurrence, morbidity, and mortality in refractory status epilepticus (RSE). Define an optimal window for TC that provides sustained seizure control and minimizes complications. Methods Retrospective, observational cohort study involving patients who presented with RSE to the University of Alabama at Birmingham or the University of California at San Francisco from 2010 to 2016. Relationship of duration of TC with primary and secondary outcomes was evaluated using two-sample t tests, simple linear regression, and chi-square tests. Multivariable linear and logistic regression models were used to identify independent predictors. Predictive ability of TC for seizure recurrence was quantified using a receiver-operating characteristic curve. Youden index was used to determine an optimal cutoff value. Results Multivariable analysis of clinical and treatment characteristics of 182 patients who were treated predominantly with propofol as anesthetic agent showed that longer duration of the first trial of TC (27.2 vs 15.6 hours) was independently associated with a higher chance of seizure recurrence following the first weaning attempt (P = 0.038) but not with poor functional neurologic outcome upon discharge, in-hospital complications, or mortality. Furthermore, higher doses of anesthetic utilized during the first trial of TC were independently associated with fewer in-hospital complications (P = 0.003) and associated with a shorter duration of mechanical ventilation and total length of stay. Duration of TC was identified as an independent predictor of seizure recurrence with an optimal cutoff point at 35 hours. Significance This study suggests that a shorter duration yet deeper TC as treatment for RSE may be more effective and safer than the currently recommended TC duration of 24-48 hours. Prospective and randomized trials should be conducted to validate these assertions.

An ex-vivo cardiac model able to accurately predict the benefits and side-effects of new treatments could reduce the large number of flawed treatments entering in vivo testing. We have previously shown that cardiac tissue slices are a promising experimental platform as they retain structural and functional properties of the native heart, while allowing control over interventions and straightforward observations. Porcine hearts share anatomical, physiological and electrical characteristics with human hearts and are readily available from veterinary laboratories and abattoirs. The aim of this study was therefore to establish an ex-vivo model of porcine myocardium using organotypic slices from easily accessible porcine hearts and assess their electrophysiological and calcium handling properties. Vibratome-cut myocardial slices (300–350 μm thick) were prepared from the sub-epicardial region of the left ventricle of porcine hearts (by-product from porcine carcasses provided by the Pirbright Institute). Slices were point-stimulated at cycle lengths (CL) ranging from 500 ms to 4000 ms, and analysed using a multi-electrode array system. Conduction velocity (CV) and field potential duration (FPD), an index of action potential duration, were measured. Ca2 +cycling was assessed using Fluo-4 AM and optical mapping, during field-stimulation at 500–4000 ms CL. Ca2 +transient duration at 50% recovery (CaTD50) and 75% recovery (CaTD75) were measured at each pacing CL. Data was analysed using one-way ANOVA and presented as mean ± SEM. CV was 46 ± 10 cm/s along muscle fibre orientation and 14 ± 1 cm/s perpendicular to fibre orientation, with an anisotropic ratio of 3:1 (n=4 slices). Mean FPD was 316 ± 11 ms at 1000 ms CL (n=5 slices), similar to previously reported data using ventricular wedges. All slices displayed FPD restitution, with FPD prolongation at longer pacing cycle lengths (CL 500 ms: 239 ± 6 ms; CL 1500 ms: 351 ± 21 ms; CL 2000 ms: 367 ± 14 ms; CL 4000 ms: 412 ± 13 ms; n=4–5, ANOVA p Our results show that myocardial slices prepared from porcine hearts maintain electrical and calcium cycling properties of the native myocardium and provide a novel ex-vivo multicellular preparation with potential applications in cardiac preclinical research.

The heart is a complex organ composed of multiple cell types, including cardiomyocytes and different non-myocyte populations, all working closely together to determine the hearts properties and maintain normal cardiac function. Connexins are abundantly expressed proteins that form plasma membrane hemichannels and gap junctions between cells. Gap junctions are intracellular channels that allow for communication between cells, and in the heart they play a crucial role in cardiac conduction by coupling adjacent cardiomyocytes. Connexins are expressed in both cardiomyocytes and non-myocytes, including cardiac fibroblasts, endothelial cells, and macrophages. Non-myocytes are the largest population of cells in the heart, and therefore it is important to consider what roles connexins, hemichannels, and gap junctions play in these cell types. The aim of this review is to provide insight into connexin-based signalling in non-myocytes during health and disease, and highlight how targeting these proteins could lead to the development of novel therapies. We conclude that connexins in non-myocytes contribute to arrhythmias and adverse ventricular remodelling following myocardial infarction, and are associated with the initiation and development of atherosclerosis. Therefore, therapeutic interventions targeting these connexins represent an exciting new research avenue with great potential.

BACKGROUND: Little data is available in the literature about the role of end tidal oxygen in critically ill patients. We sought to identify the association between the level of respiratory oxygen and clinical outcomes in critically-ill ventilated trauma and burn patients. METHODS: A retrospective cohort of 55 trauma and burn patients from 2010 to 2016 was collected. Exposures of interest included a) expiratory end tidal oxygen (ETO2) and b) the difference between FiO(2) and ETO2 ( uptake ). Associations of clinical characteristics with ETO2 and oxygen uptake were examined using a Spearman correlation. The relationships between discharge status, demographics, injury type, severity, and clinical characteristics were examined using chi-square (or Fisher’s exact) tests and two-sample t-tests. Multivariable analyses using linear and logistic regression were performed to determine whether expiratory end tidal oxygen or oxygen uptake was an independent predictor of clinical outcomes. RESULTS: Mean age for the patients was 46.3 ± 18.2 years with 41 (74.6%) male and 34 (61.8%) white. In the cohort, 27 (49.1%) of patients had burns and 28 (50.9%) blunt trauma. Oxygen uptake was negatively correlated with lactic acid, minute ventilation, total ICU days, and ventilator days (p < 0.05). Patients who died demonstrated lower oxygen uptake than those alive, oxygen uptake remained significantly associated with discharge status after adjusting for potential confounders (p = 0.028). CONCLUSION: A narrowed difference between ETO(2) and inspiratory oxygen is associated with increased mortality in a cohort of ventilated trauma and burn patients. Future research is needed to further elucidate the role of respiratory oxygen level in larger, prospective studies.

Paroxetine is a selective serotonin reuptake inhibitor commonly prescribed for the treatment of depression, obsessive-compulsive disorder, panic disorder, social anxiety disorder and post-traumatic stress disorder. While the use of paroxetine is considered relatively safe, negative side effects, including nausea, drowsiness, insomnia and dizziness, can adversely affect a pilot's ability to safely operate an aircraft. The use of paroxetine may increase suicidal behavior and suicidal ideation. When relying on postmortem specimens for toxicological evaluation, a general understanding of drug distribution throughout postmortem specimens is important. This laboratory has determined the distribution of paroxetine in postmortem tissues and fluids from nine aviation accident fatalities. Specimens were processed using an n-butyl chloride liquid/liquid extraction followed by gas chromatographic/mass spectrometeric analysis. Blood paroxetine concentrations obtained from these cases ranged from 0.019 to 0.865 µg/mL. The distribution of paroxetine, expressed as mean specimen/blood ratio, was 1.67 ± 1.16 urine (n = 4), 0.08 ± 0.04 vitreous humor (n = 6), 5.77 ± 1.37 liver (n = 8), 9.66 ± 2.58 lung (n = 9), 1.44 ± 0.57 kidney (n = 8), 3.80 ± 0.69 spleen (n = 8), 0.15 ± 0.04 muscle (n = 8), 4.27 ± 2.64 brain (n = 7) and 1.05 ± 0.43 heart (n = 8). The large standard deviations associated with the paroxetine distribution coefficients suggest that paroxetine can experience significant postmortem concentration changes.

Zinnia elegans Jacq. plants are infected by a fungus that causes dark red spots with necrosis on leaves, particularly in late spring to the middle of summer in the Mid-South of the United States. This fungal disease causes the leaves to wilt and eventually kills the plant. The fungus was isolated, cultured in potato dextrose broth, and identified as Nigrospora sphaerica by molecular techniques. Two major lactone metabolites (phomalactone and catenioblin A) were isolated from liquid culture of N. sphaerica isolated from Z. elegans. When injected into leaves of Z. elegans, phomalactone caused lesions similar to those of the fungus. The lesion sizes were proportional to the concentration of the phomalactone. Phomalactone, but not catenioblin A, was phytotoxic to Z. elegans and other plant species by inhibition of seedling growth and by causing electrolyte leakage from photosynthetic tissues of both Z. elegans leaves and cucumber cotyledons. This latter effect may be related to the wilting caused by the fungus in mature Z. elegans plants. Phomalactone was moderately fungicidal to Coletotrichum fragariae and two Phomopsis species, indicating that the compound may keep certain other fungi from encroaching into plant tissue that N. sphaerica has infected. Production of large amounts of phomalactone by N. sphaerica contributes to the pathogenic behavior of this fungus, and may have other ecological functions in the interaction of N. sphaerica with other fungi. This is the first report of isolation of catenioblin A from a plant pathogenic fungus. The function of catenioblin A is unclear, as it was neither significantly phyto- nor fungitoxic.

The analysis of designer drugs, including those in the synthetic cathinone and piperazine classes, may be complicated by the poor stability of these compounds in biological specimens. The stability of four of these compounds was investigated: 3,4-methylenedioxypyrovalerone, 4-methyl-N-methylcathinone (mephedrone), N-benzylpiperazine and 1-[3-(trifluoromethyl)phenyl]piperazine. Compound stability was monitored in three different biological matrices when each matrix was stored under three different conditions. These matrices and conditions included human whole blood, human serum and human urine, each stored at -20, 4 and 22°C for a period of 14 days in the dark in a sealed glass container. Analysis by liquid chromatography-tandem mass spectrometry was performed on Day 1 to establish the initial concentration for each drug in each specimen type, and then the samples were divided into three parts for storage under the various conditions. Analysis was performed in triplicate on Days 2, 4, 7 and 14 for each specimen type under each storage condition and the results were compared to those obtained on Day 1. Following analysis of the data, it became clear that mephedrone was not stable, and that care must be taken following specimen receipt to ensure minimal degradation.

e18578Background: Inadequate recruitment of patients represents a major impediment to successful completion of precision oncology clinical trials. Rapid and efficient identification of all potentia...

INTRODUCTION: Pilots are subject to the same temptations as the general population, but due to the demands of flying, the use of ethanol or other impairing substances are more likely to have severe consequences. The Federal Aviation Administration (FAA) requires pilots to report all adverse legal actions involving their use of ethanol and/or other drugs. The purpose of this study was to evaluate fatal civil aviation accidents between the years 2000 and 2007 in which ethanol was present in the pilot and the pilot had a record of previous drug and/or alcohol offenses. METHODS: Case histories and accident information for the period under study were obtained from the National Transportation Safety Board (NTSB). Toxicological information was obtained from the Civil Aerospace Medical Institute's Forensic Toxicology Research Laboratory. RESULTS: During the examined period 215 of the 2391 pilot specimens received for toxicological analysis had documented alcohol or drug related offenses. Of the 215 pilot specimens received, 23 showed evidence of ethanol consumption prior to the fatal incident and 16 of those had ethanol concentrations above the FAA's legal limit of 40 mg x dl(-1). DISCUSSION: These results confirm earlier reports that pilots with previous alcohol and/or drug offenses are more likely than others to engage in repeated substance abuse in association with flying with resultant fatal accidents. These findings support the NTSB's recommendation that the FAA implement more thorough verification of alcohol and drug offenses as a means of identifying pilots at increased risk of causing accidents. Language: en

The purpose of this study was to determine the agreement between angular measures of cervical spinal motion obtained from radiographs and from measures recorded by the OSI CA 6000 Spine Motion Analyzer (OSI SMA) in asymptomatic subjects. Fourteen subjects performed each of the following motions two times while wearing the OSI SMA: cervical flexion, extension, side bending to the right and left. Each motion was performed once for the cervical radiograph. The difference between the values obtained by the two methods was plotted against the average of those values for each subject to illustrate the level of agreement of the two methods. The plotted points were widely scattered, with a large range between the limits of agreement. Range of motion values taken from the OSI SMA were not similar to those obtained from radiographs for the motions of the cervical spine.

Two separate cases of drowning with extended periods underwater (2 and 4 weeks) are reported. The postmortem ethanol concentrations were 260 and 280 in central blood, 50 and 80 in vitreous, and 330 and 320 in urine (mg/100 mL) for cases 1 and 2, respectively. Determination of the urine 5-hydroxytryptophol/5-hydroxyindole-3-acetic acid ratios produced results of 713 and 41 pmol/nmol, respectively. The serotonin metabolite ratios support the explanation of diffusion of ethanol from the vitreous fluid into the surrounding water, rather than postmortem production of ethanol in blood, as the primary reason for the blood-vitreous ethanol differences.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that was introduced in 1986. Certain side effects of this medication-drowsiness, dizziness, abnormal vision, diarrhea, and headache-could affect pilot performance and become a factor in an aviation accident. Our laboratory has determined the distribution of fluoxetine and its desmethyl metabolite, norfluoxetine, in various postmortem tissues and fluids from 10 fatal aviation accident cases. When available, 11 specimen types were analyzed for each case, including blood, urine, vitreous humor, bile, liver, kidney, skeletal muscle, lung, spleen, heart muscle, and brain. Blood fluoxetine concentrations in these 10 cases ranged from 21 to 1480 ng/mL. The distribution coefficients for both fluoxetine and norfluoxetine, expressed as specimen/blood ratios, were determined. The distribution coefficients for fluoxetine were determined to be 0.9 +/- 0.4 for urine, 0.10 +/- 0.03 for vitreous humor, 9 +/- 1 for bile, 38 +/- 10 for liver, 60 +/- 17 for lung, 9 +/- 3 for kidney, 20 +/- 5 for spleen, 2.2 +/- 0.3 for muscle, 15 +/- 3 for brain, and 10 +/- 2 for heart. To our knowledge, this is the first report presenting the distribution of fluoxetine in humans at therapeutic concentrations.

Our laboratory was interested in epidemiological and toxicological findings from aircraft-assisted pilot suicides. Between 1993-2002 there were 3,648 fatal aviation accidents. The NTSB determined that 16 were aircraft-assisted suicides; 15 from intentional crashing of an aircraft and 1 from exiting the aircraft while in-flight. All pilots involved in these aircraft-assisted suicides were male, with a median age of 40 years. Seven of the 14 pilots for which specimens were available were positive for disqualifying substances. Based on the few cases conclusively attributed to suicide, death by the intentional crashing of an aircraft appears to be an infrequent and uncommon event.

Purpose This phase I study was conducted to determine the toxicities, pharmacokinetics, and recommended doses of pemetrexed in cancer patients with normal and impaired renal function. Patients and Methods Patients received a 10-minute infusion of 150 to 600 mg/m2 of pemetrexed every 3 weeks. Patients were stratified for independent dose escalation by measured glomerular filtration rate (GFR) into four cohorts ranging from ≥ 80 to less than 20 mL/min. Pemetrexed plasma and urine pharmacokinetics were evaluated for the first cycle. Patients enrolled after December 1999 were supplemented with oral folic acid and intramuscular vitamin B12. Results Forty-seven patients were treated with 167 cycles of pemetrexed. Hematologic dose-limiting toxicities occurred in vitamin-supplemented patients (two; 15%) and nonsupplemented patients (six; 18%), and included febrile neutropenia (four patients) and grade 4 thrombocytopenia (two patients). Nonhematologic toxicities included fatigue, diarrhea, and nausea, and did not correlate with renal function. Accrual was discontinued in patients with GFR less than 30 mL/min after one patient with a GFR of 19 mL/min died as a result of treatment-related toxicities. Pemetrexed plasma clearance positively correlated with GFR (r2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m2 was tolerated by patients with a GFR ≥ 80 mL/min, whereas patients with a GFR of 40 to 79 mL/min tolerated a dose of 500 mg/m2. Conclusion Pemetrexed was well tolerated at doses of 500 mg/m2 with vitamin supplementation in patients with GFR ≥ 40 mL/min. Additional studies are needed to define appropriate dosing for renally impaired patients receiving higher dose pemetrexed with vitamin supplementation.

Specimens from fatal aviation accident victims are submitted to the FAA Civil Aerospace Medical Institute for toxicological analysis. During toxicological evaluations, ethanol analysis is performed on all cases. Care must be taken when interpreting a positive ethanol result due to the potential for postmortem ethanol formation. Several indicators of postmortem ethanol formation exist; however, none are completely reliable. The consumption of ethanol has been shown to alter the concentration of two major serotonin metabolites, 5-hydroxytryptophol (5-HTOL) and 5-hydroxyindole-3-acetic acid (5-HIAA). While the 5-HTOL/5-HIAA ratio is normally very low, previous studies using living subjects have demonstrated that the urinary 5-HTOL/5-HIAA ratio is significantly elevated for 11-19 h after acute ethanol ingestion. Recently, our laboratory developed and validated an analytical method for the simultaneous determination of both 5-HTOL and 5-HIAA in forensic urine samples using a simple liquid/liquid extraction and LC/MS/MS and LC/MS/MS/MS. In this previous work a 15 pmol/nmol serotonin metabolite ratio cutoff was established in postmortem urine, below which it could be conclusively determined that no recent antemortem ethanol consumption had occurred. In the current study this newly validated analytical method was applied to five ethanol-positive aviation fatalities where the origin of the ethanol present could not previously be conclusively determined. In four of the five cases examined the detected ethanol was demonstrated to be present due to postmortem microbial formation, and not consumption, even though some indication of ethanol consumption may have been present.

During the investigation of aviation accidents, postmortem samples obtained from fatal accident victims are submitted to the FAA's Civil Aerospace Medical Institute (CAMI) for toxicological analysis. During toxicological evaluations, ethanol analysis is performed on all cases. Many species of bacteria, yeast, and fungi have the ability to produce ethanol and other volatile organic compounds in postmortem specimens. The potential for postmortem ethanol formation complicates the interpretation of ethanol-positive results from accident victims. Therefore, the prevention of ethanol formation at all steps following specimen collection is a priority. Sodium fluoride is the most commonly used preservative for postmortem specimens. Several studies have been published detailing the effectiveness of sodium fluoride for the prevention of ethanol formation in blood and urine specimens; however, our laboratory receives blood or urine in approximately 70% of cases. Thus, we frequently rely on tissue specimens for ethanol analysis. The postmortem tissue specimens received by our laboratory have generally been subjected to severe trauma and may have been exposed to numerous microbial species capable of ethanol production. With this in mind, we designed an experiment utilizing unadulterated tissue specimens obtained from aviation accident victims to determine the effectiveness of sodium fluoride at various storage temperatures for the prevention of microbial ethanol formation. We found that without preservative, specimens stored at 4 degrees C for 96 h showed an increase in ethanol concentration ranging from 22 to 75 mg/hg (average 42 +/- 15 mg/hg). At 25 degrees C, these same specimens showed an increase ranging from 19 to 84 mg/hg (average 45 +/- 22 mg/hg). With the addition of 1.00% sodium fluoride, there was no significant increase in ethanol concentration at either temperature.

Cocaine (COC) is one of the most widely abused illicit drugs in America. COC abuse transcends all social, racial, and economic boundaries. Following the introduction in the mid-1980s of a new form of cocaine called crack, cocaine use has been on the rise. Because of its intense high, crack smoking has become very popular. Despite its popularity, crack smoking is a particularly dangerous form of COC use. Additionally, COC and ethanol are frequently used together, resulting in the formation of a biologically active molecule that is nearly as psycoactive as COC but produces a longer lasting and toxic effect. Demonstrating the presence or absence of COC and COC-related molecules in postmortem fluids and/or tissues can have serious legal consequences and may help determine the cause of impairment and/or death. We have developed a simple method for the simultaneous determination of COC and the COC metabolites benzoylecgonine, norbenzoylecgonine, ecgonine methyl ester, ecgonine, and norcocaine, as well as anhydroecgonine methyl ester (a unique byproduct of COC smoking), cocaethylene (a molecule formed by the concurrent use of COC and ethanol) and their related metabolites, anhydroecgonine, norcocaethylene, and ecgonine ethyl ester. This method incorporates a Zymark RapidTrace automated solid-phase extraction system, gas chromatography/mass spectrometry, and PFP/PFPA derivatives. The lower limits of detection ranged from 0.78 - 12.5 ng/mL, and the linear dynamic range for most analytes was 0.78 3200 ng/mL. The extraction efficiencies were from 26 - 84%, with the exception of anhydroecgonine and ecgonine, which were from 1 - 4%. We applied this method to 5 aviation fatalities. This method has proven to be simple, robust, and accurate for the simultaneous determination of COC and 11 COC metabolites in postmortem fluids and tissues.

The establishment of the Web application as a successful application model may be attributed to its adherence to open standards, to the powerful J2EE™ application framework for the execution of business and process logic, and to its integration with heterogeneous external systems, transactional processes, and Web technologies. In addition, effective tool support has enabled rapid development and deployment, powerful processes composed from components, and access to a steadily increasing range of function. Many Web applications are designed for high performance, scalability, and highly reliable utilization and are capable of extending modes of usage and growing throughput. Successful application development in these environments involves bridging the gap between exercising available programming specifications and the proper design, coding, and life-cycle management of the application. This paper addresses issues, transactional and nontransactional, in application development that are important for the successful deployment and execution of enterprise Web applications in production environments. These issues are based on experience with deployments of Web applications in various customer environments and are not new, but are either fundamental to previous transactional systems or have appeared in other classes of applications. Understanding these issues is essential both to building effective tooling to support the runtimes and to the evolution and definition of the runtimes themselves.

During the investigation of aviation accidents, postmortem specimens from accident victims are submitted to the Federal Aviation Administration's Civil Aerospace Medical Institute (CAMI) for toxicological analysis. A case recently received by CAMI screened positive for the anticonvulsant medication carbamazepine (Tegretol ) by gas chromatography/mass spectrometry (GC/MS). The carbamazepine found during the routine screening procedure was subsequently confirmed using a carbamazepine-specific GC/MS procedure. Concurrently, it was discovered that the accident victim had been prescribed oxcarbazepine (Trileptal ). Oxcarbazepine is nearly structurally identical to carbamazepine and is metabolized by cytosolic enzymes in the liver to the active compound 10,11-dihydro-10-hydroxycarbamazepine. The carbamazepine initially found in this case was present due to the breakdown of the active oxcarbazepine metabolite in the GC/MS injector port. In the current study, this conversion is investigated, the percentage of carbamazepine formed at various injector port temperatures is determined, and these three compounds are quantified in nine fluid and tissue specimens from the case in question. Finally, liquid chromatography/mass spectrometry (LC/MS) was used to demonstrate the absence of carbamazepine, and its formation, in the same specimens.

This double-masked, randomized, placebocontrolled study was conducted in healthy adult male and female volunteers with no clinically relevant baseline electrocardiographic (ECG) abnormalities to assess the cardiac tolerability margin of sparfloxacin (as measured by the effect on QT c interval) under conditions of potential overdose at up to 4 times the usual therapeutic loading dose. The 23 enrolled volunteers received a sequence of single doses of sparfloxacin (400, 800, 1200, and 1600 mg), 1 dose in each of 4 study periods. Six volunteers received placebo during each period. A 14-day washout separated the periods. Serial blood samples and ECG measurements were collected in each period to determine the pharmacokinetic and pharmacodynamic characteristics of sparfloxacin. The area under the concentration-time curve from time zero to infinity (AUC 0–∞ ) exhibited dose proportionality. The maximum plasma concentration (C max ) after the 1200-and 1600-mg doses was lower than would be expected for a linear dose relationship. This was also the case with the mean increase and mean maximum increase in QT c interval. Increases in the QT c interval correlated well with C max but not with AUC 0–∞ . The time to reach C max showed a slight tendency to increase with dose, as did the terminal elimination half-life. Changes in QT c -interval dispersion were similar for both placebo recipients and sparfloxacin-treated volunteers and were of no clinical consequence. At supratherapeutic doses, the extent of sparfloxacin's absorption (AUC 0–∞ ) was dose independent; however, the rate of absorption was dose dependent, with C max increasing substantially less than proportionally to the administered dose. This limited the C max of sparfloxacin at supratherapeutic doses and thus the increase in QTC c interval. Rechallenge demonstrated that only 2 of 8 subjects had the same degree of QT c -interval prolongation, emphasizing the marked variability in the QT c interval.

Sparfloxacin, a broad-spectrum, oral fluoroquinolone antimicrobial agent, has a long elimination half-life that permits once-daily administration. Antibiotics may increase the oral bioavailability of digoxin, leading to increases in its plasma concentration. Since patients treated with sparfloxacin may be receiving concurrent treatment with digoxin, the possibility of an interaction between sparfloxacin and digoxin was examined in a doublemasked, placebo-controlled, multipledose, two-way crossover study in 24 healthy male volunteers between 20 and 49 years of age. All subjects were given digoxin 0.3 mg once daily throughout the 20-day study. Sparfloxacin (or placebo) was given as a 400-mg loading dose on day 1, followed by single 200-mg daily doses for 9 days, with crossover to the alternate treatment on days 11 through 20. Plasma levels of digoxin were analyzed by validated radioimmunoassay, and plasma levels of sparfloxacin were analyzed by validated high-performance liquid chromatography. Concomitant administration of sparfloxacin and digoxin was generally well tolerated. Mean values for steady-state area under the concentration-time curve over 24 hours for the 2 treatments were virtually identical: 28.4 ng/h per mL −1 for digoxin administered with placebo and 28.9 ng/h per mL −1 for digoxin administered concomitantly with sparfloxacin. Mean steady-state maximum plasma concentrations were 3.91 and 3.59 ng/mL for digoxin with placebo and digoxin with sparfloxacin, respectively. Mean steady-state trough plasma digoxin concentrations for the 2 treatments were 0.87 and 0.89 ng/mL, respectively. Mean times to steady-state maximum plasma concentrations were identical at 0.89 hours for both treatments. Mean steady-state oral clearance was 10.6 L/h for digoxin alone and 10.4 L/h for digoxin with sparfloxacin. Thus administration of sparfloxacin in combination with digoxin did not alter the pharmacokinetics of digoxin in healthy male volunteers aged 20 to 49 years. Steady-state plasma sparfloxacin concentrations were consistent with those obtained in other multiple-dose phase I studies, suggesting that digoxin does not alter the steady-state pharmacokinetics of sparfloxacin.

Sparfloxacin is a broad-spectrum oral fluoroquinolone antimicrobial agent with a long elimination half-life (t(1/2)). Concurrent treatment with antacids has demonstrated a reduction in the oral absorption of many quinolones. This study was undertaken to determine an optimal time for dosing antacids in relation to sparfloxacin administration to minimize antacid-induced reduction in sparfloxacin bioavailability. This open-label, single-dose, randomized, four-way crossover study was conducted in 20 healthy male volunteers between the ages of 18 and 38 years. Treatments consisted of single 400-mg oral doses of sparfloxacin alone and with Maalox 30 mL given 2 hours before, 2 hours after, and 4 hours after oral administration of sparfloxacin. All 20 subjects completed the study. A 400-mg single oral dose of sparfloxacin was well tolerated both given alone and with Maalox. Maalox given 4 hours after sparfloxacin administration was the only regimen that did not cause a statistically significant reduction in the rate and extent of sparfloxacin absorption. The 90% confidence intervals comparing sparfloxacin alone with the preceding regimen in terms of area under the concentration-time curve from zero to infinity (AUC(0-infinity)) and maximum plasma concentration (Cmax) were within the range 80% to 125%. Administration of Maalox 2 hours before, 2 hours after, and 4 hours after sparfloxacin caused mean decreases in AUC(0-infinity) of 23%, 17%, and 5%, respectively. Corresponding decreases in mean Cmax values were 29% with Maalox administered 2 hours before sparfloxacin and 13% with Maalox administered 2 hours after sparfloxacin. The mean Cmax value was un affected when Maalox was administered 4 hours after sparfloxacin administration. The 90% confidence intervals for these comparisons with sparfloxacin alone were outside the 80% to 125% range and did not include 100%. Time to Cmax and t(1/2) were similar for all four regimens. The elimination rate of sparfloxacin was unaffected by concomitant administration with Maalox in healthy male volunteers.

SUMMARY. The aims of this investigation were firstly to determine the level of agreement between angular measures of lumbar spinal motion recorded by the OSI CA 6000 Spine Motion Analyzer (OSI SMA) and measures obtained from X-rays of subjects without lumbar symptoms, and secondly to determine the intra-rater reliability of measures of lumbar spinal range of motion using the OSI SMA on individuals with lumbar symptoms. To fulfill the first aim 13 asymptomatic subjects (mean age = 28.6 years; SD = 7.1) performed the motions of lumbar flexion, extension, side bending to the right, and side bending to the left twice while wearing the OSI SMA, and once for the exposure of the X-ray. The difference between the measures obtained by the two methods was plotted against the average of those measures for each subject to illustrate the level of agreement of the two methods. Differences between measures that were within one standard deviation of the mean were as follows: for flexion, 7 out of 10 showed less than 8 degrees difference; for extension, 7 out of 10 showed less than 7 degrees difference; for side bending to the right, 11 out of 13 showed less than 6 degrees difference; and for side bending to the left, 10 out of 13 showed less than 5 degrees difference. For asymptomatic subjects, measures obtained from the OSI SMA appear to provide good agreement with measures of lumbar spinal motion in the sagittal and frontal planes as determined by X-rays. To fulfil the second aim of the investigation thirty subjects with lumbar symptoms (mean age = 35.9 years; SD = 14.2) performed four trials of lumbar motion to their maximum for flexion, extension, side bending to the right and left, and rotation to the right and left. The OSI SMA hardware was then completely removed and replaced by the same examiner, and the trials were repeated. ICC values were 0.903 or higher for all motions. These results suggest that active range of motion measures obtained with the OSI SMA in subjects with lumbar symptoms are consistent over repeated trials. Copyright 1997 Harcourt Publishers Ltd.

Sertraline (Zoloft) is a selective serotonin reuptake inhibitor that is a commonly prescribed drug for the treatment of depression, obsessive-compulsive disorder, panic disorder, social anxiety disorder, premenstrual dysphoric disorder and post-traumatic stress disorder. Although the use of sertraline is relatively safe, certain side effects may negatively affect a pilot’s performance and become a factor in an aviation accident. The authors’ laboratory investigated the distribution of sertraline and its primary metabolite, desmethylsertraline, in various postmortem tissues and fluids obtained from 11 fatal aviation accident cases between 2001 and 2004. Eleven specimen types were analyzed for each case, including blood, urine, vitreous humor, liver, lung, kidney, spleen, muscle, brain, heart and bile. Human specimens were processed utilizing solid-phase extraction, followed by characterization and quantitation employing gas chromatography – mass spectrometry. Whole blood sertraline concentrations obtained from these 11 cases ranged from 0.005 to 0.392 mg/mL. The distribution coefficients of sertraline, expressed as specimen/ blood ratio, were as follows: urine, 0.47+ 0.39 (n 5 6); vitreous humor, 0.02+ + 0.01 (n 5 4); liver, 74+ 59 (n 5 11); lung, 67+ + 45 (n 5 11); kidney, 7.4+ + 5( n 5 11); spleen, 46+ + 45 (n 5 10); muscle, 2.1+ + 1.3 (n 5 8); brain, 22+ + 14 (n 5 10); heart, 9+ 7 (n 5 11); and bile, 36+ 26 (n 5 8). Postmortem distribution coefficients obtained for sertraline had coefficients of variation ranging from 47– 99%. This study suggests that sertraline likely undergoes significant postmortem redistribution.

Objective To audit routine measurement of alpha-fetoprotein (AFP) and acetylcholinesterase in amniotic fluid (AF) samples obtained at second-trimester amniocentesis. Methods We reviewed retrospectively 1737 consecutive AF specimens obtained for cytogenetic evaluation over a 4-year period and routinely assayed for AFP and acetylcholinesterase. In all instances, high-resolution ultrasonography was performed before amniocentesis. Details of pregnancy outcome of all cases with AF AFP levels greater than 2.0 multiples of the median and a positive or faint acetylcholinesterase band were obtained. Results There were 31 abnormal results (1.8%, 1 of 56). Of these, 25 cases had elevated AF AFP and/or positive acetylcholinesterase. Ultrasonography correctly identified all 18 fetuses with anomalies associated with abnormal levels of these biochemical markers, including open neural tube defects and/or anterior abdominal wall defects (17 cases) and fetal hydrops (one). In the remaining seven, no fetal anomalies were detected, and all neonates were structurally normal after birth. In addition, six pregnancies with faint acetylcholinesterase and normal AF AFP showed no fetal abnormalities at ultrasonographic examination and postdelivery. Conclusions High-resolution Ultrasonography was more accurate than AF biochemistry in the detection of congenital anomalies associated with elevated AFP levels and acetylcholinesterase in the AF. Routine measurement of these biochemical markers in AF samples obtained for cytogenetic analysis appears to have a very low yield and would therefore not be cost-effective in practices where high-resolution Ultrasonography is performed before amniocentesis.

Because spinal range of motion (ROM) is assessed routinely in clinical and research settings, a technique is needed that can be performed comfortably, quickly, and reliably. The purpose of this study was to determine if ROM data from asymptomatic subjects measured with the OSI CA 6000 Spine Motion Analyzer (OSI SMA) are reliable within and between observers. Thoracolumbar ROM, from approximately T7 to S2, was measured in all three planes in eight male and 13 female asymptomatic adult subjects (mean age = 29.7 years, SD = 5.6; mean height = 1.7 m, SD = 3.4, mean weight = 78.25 kg, SD = 34.6). A standardized protocol was used to fit each subject with appropriate hardware. Foot placement at a comfortable foot angle was standardized by the use of a template. Subjects performed three practice trials of flexion, extension, right and left sidebending, and right and left rotation. During testing, subjects performed four trials of each maximal pain-free motion. The hardware was completely removed and replaced by the same examiner, and ROM trials in all three planes were repeated. The same procedure was completed by a second examiner. Repeated measures analysis of variance and intraclass correlation coefficients (ICC [2,1] were used to analyze intra- and interobserver data. Intraobserver ICCs were 0.89 or higher for all motions. Interobserver ICCs were 0.85 or higher for all motions. Measurements of thoracolumbar ROM using the OSI SMA are sufficiently reliable within and between observers for clinical assessment and research purposes.

Blends of hydroxyethylcellulose (HEC) and sodium carboxymethylcellulose (NaCMC) were used to achieve zero order release of chlorpheniramine maleate (CM) from hydrophilic matrix capsules. Dynamic swelling/erosion and response surface measurements were made to provide an insight into the drug release behavior. The drug to total polymer and the HEC to NaCMC ratio influences the rate of drug release. NaCMC appears to influence water uptake and erosion of the matrix mixture. The factors by which zero-order drug release is achieved may include synchronization of the rates of water uptake and polymer erosion even though a constant diffusional pathlength may not be maintained. The combined mixture factorial design presented in this study allows for the characterization and optimization of the drug release profiles.

Magnetic resonance spectroscopy has been a particularly powerful tool for probing the structure and dynamical behavior of fullerenes. NMR and EPR studies of native and modified fullerenes are reported here.

Magnetic resonance spectroscopy has been a particularly powerful tool for probing the structure and dynamical behavior of fullerenes. NMR and EPR studies of native and modified fullerenes are reported here.

This article reports on a study that investigated the role of antiemetics and sedatives in civil aviation pilot fatalities between 2000 and 2006. The authors note that although many of these compounds are considered disqualifying by the FAA, their use occurs and some pilots may be unaware of the danger of combining compounds from these two drug classes. The authors collected epidemiological, toxicological, and aeromedical findings. Case histories, accident information, and the probable cause of the aviation accidents were obtained from the National Transportation Safety Board (NTSB). Toxicological information was obtained from the Civil Aerospace Medical Institute's (CAMI's) Forensic Toxicology Research Laboratory. Their investigation found that of the 2,184 fatal aviation accidents over this time period, 26 were found positive for compounds from both the antiemetic and the sedative drug classes. All of the pilots were male and 21 tested positive for a disqualifying substance that may have affected their ability to control the aircraft. Ethanol was detected in eight of the pilots, of whom three had also taken dephenhydramine, marijuana was detected in three pilots, chlorpheniramine was detected in two, and five of the cases tested positive for diazepam or one of its active metabolites. The article includes four case histories that consist of brief descriptions; readers are referred to an Office of Aerospace Medicine Technical report for detailed information about each of the 26 cases. The authors conclude that although the percentage of accidents in which the pilot tests positive for a compound from each class is small, it is important for all pilots to understand the dangers of self-medicating and concomitant use of such substances. Ongoing pilot education is the key to preventing inadvertent drug-drug interactions.

Background We have shown earlier that inhaled nitric oxide (iNO) administered by oxygen hood reduces pulmonary hypertension in an animal model (J Perinatol 2002; 22:50-6). Our objective in this study was to determine feasibility of iNO by oxygen hood in neonates with elevated alveolar-arterial oxygen gradients (A-aDO2). Methods/Principal Findings Masked randomized controlled pilot trial. Inclusion criteria were: gestation≥34 weeks, age100 torr, while oxygenation was unchanged in the controls. Methemoglobinemia and other adverse effects were not noted in any infant. Environmental levels of NO and NO2 were minimal (0.3 m from the hood. Conclusions Administration of iNO by oxygen hood is feasible. Larger randomized controlled trials are required to measure the efficacy and determine an appropriate target population for this technique. Trial Registration ClinicalTrials.gov NCT00041548

The objective of this research was to examines the effect of CNBr immobilization on the kinetics and thermostability of the protease from T. fusca and the evaluate the proteolytic and esterolytic activity of the immobilized enzyme toward various substrates

Vardenafil (Levitra) is one of the most widely prescribed treatments for erectile dysfunction. This report presents a rapid and reliable method for the identification and quantification of vardenafil in postmortem fluids and tissues, applies this method to a postmortem case, and describes the distribution of vardenafil in various fluids and tissues. This procedure utilizes sildenafil-d 8 , which is structurally closely related to vardenafil, as an internal standard for more accurate and reliable quantitation. The method incorporates solid-phase extraction and liquid chromatography-tandem mass spectrometry (MS) and MS-MS-MS utilizing an atmospheric pressure chemical ionization ion trap MS in the positive chemical ionization mode. Solid-phase extraction proved to be exceptionally efficient providing recoveries that ranged from 94% to 97%. The limit of detection for vardenafil was determined to be 0.19 ng/mL. The linear dynamic range for this compound was 0.39-200 ng/mL. This method was successfully applied to postmortem fluid and tissue specimens obtained from an aviation accident victim. The distribution of vardenafil in various fluids and tissues and the unusually high concentration of vardenafil in the victim's blood are examined.

We present an automated approach to generate functional conformance tests for semantic Web services. The semantics of the Web services are defined using the inputs, outputs, preconditions, effects (IOPEs) paradigm. For each Web service, our approach produces testing goals which are refinements of the Web service preconditions using a set of fault models. A novel planner component accepts these testing goals, along with an initial state of the world and the Web service definitions to generate a sequence of Web service invocations as a test case. Another salient feature of our approach is generation of verification sequences to ensure that the changes to the world produced by an effect are implemented correctly. Lastly, a given application incorporating a set of semantic Web services may be accessible through several interfaces such as 1) direct invocation of the Web services, or 2) a graphical user interface (GUI). Our technique allows generation of executable test cases which can be applied through both interfaces. We describe the techniques used in our test generation approach. We also present results which compare two approaches: an existing manual approach without the formal IOPEs information and the IOPEs-based approach reported in this paper. These results indicate that the approach described here leads to substantial savings in effort with comparable results for requirements coverage and fault detection effectiveness.

Opiates are some of the most widely prescribed drugs in America and are often abused. Demonstrating the presence or absence of opiate compounds in postmortem fluids and/or tissues derived from fatal civil aviation accidents can have serious legal consequences and may help determine the cause of impairment and/or death. However, the consumption of poppy seed products can result in a positive opiate drug test. We have developed a simple method for the simultaneous determination of eight opiate compounds from one extraction. These compounds are hydrocodone, dihydrocodeine, codeine, oxycodone, hydromorphone, 6-monoacetylmorphine, morphine, and thebaine. The inclusion of thebaine is notable as it is an indicator of poppy seed consumption and may help explain morphine/codeine positives in cases where no opiate use was indicated. This method incorporates a Zymark ® RapidTrace™ automated solid-phase extraction system, gas chromatography/mass spectrometry, and trimethyl silane (TMS) and oxime-TMS derivatives. The limits of detection ranged from 0.78 to 12.5 ng/mL. The linear dynamic range for most analytes was 6.25–1600 ng/mL. The extraction efficiencies ranged from 70 to 103%. We applied this method to eight separate aviation fatalities where opiate compounds had previously been detected.

Hypertension is a growing medical concern in the United States. With the number of Americans suffering from hypertension increasing, the use of antihypertensives such as beta-blockers is increasing as well. In fact, three beta-blockers – atenolol, metoprolol and propranolol – were among the 200 most prescribed medications in the United States in 2003. Pilots that successfully manage their hypertension can remain certified to fly. The Federal Aviation Administration currently designates approximately 8% of active pilots as “hypertensive with medication”. The Civil Aerospace Medical Institute (CAMI) performs toxicological evaluation on victims of fatal aviation accidents. At CAMI beta-blockers are analyzed using gas chromatography with mass spectrometric detection. We have, however, recently developed a liquid chromatography with mass spectrometric detection (LC/MS) method for the simultaneous quantitation of three commonly prescribed beta-blockers, atenolol, metoprolol and propranolol. One advantage of our LC/MS method is the specificity provided by an ion trap MS. Utilizing an ion trap MS, we were able to conduct MS/MS and MS/MS/MS on each analyte. This method also eliminates the time-consuming and costly derivitization step necessary during GC/MS analysis. Additionally, by utilizing this novel method, any concerns about beta-blocker metabolite and/or sample matrix interference are eliminated. The limits of detection for this method ranged from 0.39 to 0.78 ng/mL and the linear dynamic range was generally 1.6–3200 ng/mL. The extraction efficiencies for each analyte ranged from 58% to 82%. This method was successfully applied to postmortem fluid and tissue specimens obtained from victims of three separate aviation accidents.

BACKGROUND Pemetrexed disodium (Alimta [Eli Lilly and Company, Indianapolis, IN], LY231514, multitargeted antifolate) is a new multitargeted antifolate agent that inhibits multiple enzymes in the folate pathway. Phase II trials showed single-agent response rates of 16% and 23% in untreated patients with nonsmall cell lung carcinoma (NSCLC). This study was undertaken to determine the response to pemetrexed disodium given in combination with cisplatin. METHODS Previously untreated patients were eligible if they had Stage IIIB or IV NSCLC, performance status 0, 1, or 2, adequate hematology and biochemistry and bidimensionally measurable lesions. Patients with brain metastases or neuropathy higher than Grade 2 were excluded. Pemetrexed disodium 500 mg/m2 was given over 10 minutes, and cisplatin 75 mg/m2 with hydration and mannitol diuresis was administered on Day 1 of each 21-day cycle. Dexamethasone 4 mg was taken orally once every 12 hours starting 24 hours before treatment and continuing for 6 doses after treatment. Four patients had detailed pemetrexed disodium pharmacokinetic analysis performed. RESULTS Between May 1998 and June 1999, 31 patients were treated on the study. There were 20 males and 11 females; median age was 60 years (range, 35–75 years); there were 5 Stage IIIB, 26 Stage IV, 26 performance status 0 or 1, and 5 performance status 2. In 29 patients evaluable for response, there were 13 partial responses (PRs; overall response rate [ORR], 95%; confidence interval [CI]: 26–64%) of median duration 6.1 months (1.6–7.8 months). Three of four evaluable patients with performance status 2 achieved PR, and 11 of 24 evaluable Stage IV patients responded (ORR, 45.8% in Stage IV). Eighteen patients died. The median survival rate was 8.9 months (range, 1–15+ months). A total of 160 courses were delivered (median, 6 for both cisplatin and pemetrexed disodium). Grade 3 and 4 anemia was observed in 5 and 1 patients, respectively, and Grade 3 and 4 granulocytopenia in 7 and 4 patients, respectively. Grade 3 nausea and emesis occurred in only 2 patients, Grade 3/4 diarrhea in 3 patients, and 2 patients had Grade 3 motor neuropathy. Nine patients had Grade 2 infections, and there was one case of febrile neutropenia. Pharmacokinetic results showed Cmax, clearance and Vss values to be similar to data from single-agent pemetrexed disodium given in the same dose. CONCLUSIONS The combination of pemetrexed disodium and cisplatin is active against advanced NSCLC and is a well-tolerated convenient outpatient regimen. It deserves further study to compare it with other standard regimens for NSCLC. Cancer 2001;92:595–600. © 2001 American Cancer Society.

Sparfloxacin is a fluoroquinolone antimicrobial agent with a broad spectrum of activity and long elimination half-life. Because its single-dose pharmacokinetics are altered by renal impairment, the present study was undertaken to determine the effects of moderate or severe renal insufficiency on the multidose pharmacokinetic characteristics of and tolerance to sparfloxacin. The pharmacokinetic characteristics of sparfloxacin were assessed in 32 subjects (15 men, 17 women) with (1) normal renal function (creatinine clearance [CLcr]> or = 250 mL/min per 1.73 m2) and a mean age of 52.6 years and mean weight of 70.4 kg; (2) moderate renal insufficiency (CLcr 30-49 mL/min per 1.73 m2) and a mean age of 54.4 years and mean weight of 67.8 kg; and (3) severe renal insufficiency (CLcr 10-29 mL/min per 1.73 m2) and a mean age of 50.8 years and mean weight of 73.1 kg. The first 2 groups received a 400-mg loading dose on day 1 followed by 200 mg once daily for 9 days; subjects with severe renal insufficiency received a 400-mg loading dose on day 1 followed by 200 mg every 48 hours on days 3, 5, 7, and 9. The plasma and urinary pharmacokinetics of sparfloxacin and its glucuronide metabolite were determined after the last dose. All subjects were monitored for changes in the corrected QT (QTc) interval and for adverse events. Renal insufficiency altered the steady-state pharmacokinetic variables of sparfloxacin and its glucuronide metabolite, reducing their renal clearances and increasing both maximum plasma concentration and area under the plasma concentration-time curve. Mean steady-state plasma sparfloxacin concentrations in subjects with severe renal insufficiency (48-hour dosing interval) were comparable to those in subjects with normal renal function (24-hour dosing interval). However, mean plasma sparfloxacin concentrations in patients with moderate renal insufficiency were 2 to 3 times greater than the corresponding concentrations in subjects with normal renal function receiving the same dosage regimen. The QTc interval was slightly increased in all groups (the greatest increases were 14, 14, and 6 milliseconds in the groups with normal renal function and moderately and severely impaired renal function, respectively, at 5.5 hours post-dose on day 9 or 10) but similar among subjects with normal renal function or with renal insufficiency. Sparfloxacin was well tolerated. Thus sparfloxacin clearance is reduced and plasma concentrations raised by moderate or severe renal insufficiency. These increases do not appear to augment drug effects on the QTc interval or enhance the risk for adverse events. These results suggest that alternate-day dosing (48-hour dosing interval) following a double loading dose on day 1 should be used in patients with severe renal insufficiency and may be appropriate for patients with moderate renal insufficiency.

Sparfloxacin, a fluoroquinolone with a broad antimicrobial spectrum and long elimination half-life, is indicated for the treatment of community-acquired pneumonia and acute bacterial exacerbations of chronic bronchitis in adult patients. The present study was undertaken to determine the effects of skim milk and a high-fat breakfast without milk on the single-dose pharmacokinetic characteristics of this antibiotic. The pharmacokinetics of a single 200-mg dose of sparfloxacin were assessed in a 3-way crossover study that included 23 healthy male volunteers who had fasted, had ingested 240 mL of skim milk, or had consumed a standard high-fat breakfast. The subjects' mean age and weight were 26.5 years and 73.2 kg, respectively; 17 were white, 5 Hispanic, and 1 black. Neither skim milk nor the high-fat breakfast had a statistically significant effect on sparfloxacin absorption, as reflected in the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC). Ninety percent confidence limits for logarithmically transformed AUC from time zero to infinity and Cmax were within the 80% to 125% range, demonstrating that the rate and extent of sparfloxacin absorption with skim milk or a high-fat breakfast were not different from those under fasted conditions. As indicated by an increase in the time to Cmax from 3.6 to 5.4 hours, the high-fat breakfast slightly delayed the onset of sparfloxacin absorption. Skim milk and the high-fat breakfast did not significantly affect the elimination kinetics of sparfloxacin. Sparfloxacin was well tolerated in all 3 treatment groups. Despite the apparent delay in the onset of absorption, the bioavailability of sparfloxacin in the healthy male subjects in this study population was not affected by concomitant administration with skim milk or a high-fat meal. Accordingly, the results suggest that sparfloxacin can be administered without regard to the ingestion of milk or meals.

The chest radiographs of 24 patients with documented Legionnaires' disease were evaluated. Twenty-two of the 24 patients had positive findings for the disease initially. There was unilateral involvement in 68% and the most common lung shadows were poorly marginated round opacities (46%), diffuse patchy (25%) and peripheral opacities (21%). At peak, 70% of patients had a lobar shadow. Pleural effusions were present in 39% of cases but could be explained by underlying congestive heart failure or renal failure in 7 of the 9. Although the findings are not specific, the radiologist should consider this diagnosis in a patient with compatible clinical history, a pneumonia of obscure etiology, and these radiographic manifestations.

The studies described in this report were initiated in an effort to elucidate the mechanism of action of the sulfonylurea compounds. It seemed to us that a broad clinical investigative approach, involving the study of a large number of conditions in which the metabolism of carbohydrate is disturbed, was most likely to eliminate quickly a number of possible modeg of action and to define more sharply the areas upon which further effort should be concentrated. Thus, extensive metabolic-balance studies and numerous individual testing procedures have been performed before, during, and following the administration of carbutamide (BZ-55) and/or tolbutamide (Orinasei) in the following subjects: (1) healthy young men; (2) three middle-aged, obese, stable diabetics; ( 3 ) an unstable diabetic of normal weight; (4) a patient with lipo-atrophic diabetes; ( 5 ) a totally depancreatized woman; (6) patients with coexisting diabetes mellitus and Addison’s disease, familial diabetes and Cushing’s syndrome, and diabetes and panhypopituitarism; and (7) an acromegalic with mild diabetes. Although the data reported below do not define a specific mode of action of the sulfonylurea compounds, they eliminate from consideration a number of important possibilities. Results

Any condition which reduces available insulin activity in the diabetic may precipitate diabetic ketoacidosis.Important factors in prognosis include duration of ketoacidosis and coma, patient's age and vascular status, and associated complications.The incidence of serious complications and the mortality in this condition have been reduced by earlier and individualized treatment and improved management of late complications of therapy.