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An isocratic HPLC method is described. It allows the simultaneous determination of debrisoquine and 4-hydroxydebrisoquine in urine. Sample preparation involves a rapid and simple (one step) liquid-liquid extraction without derivatization. Separation, followed by UV-detection, is carried out on a nitrile column in reversephase mode with a binary, aqueous mobile phase. This rapid assay uses a new internal standard (guabenxane) and allows the determination of urinary concentrations with good precision and appropriate sensitivity.

A rapid, selective and sensitive isocratic reversed-phase high-performance liquid chromatographic method for the determination of ganciclovir in plasma samples was developed. This method, which was applied to the analysis of plasma ganciclovir from heart transplant patients under ganciclovir therapy for cytomegalovirus infections, represents a suitable analytical tool for drug monitoring and pharmacokinetic investigations.

The purposes of the 'Lawrence Livermore National Laboratory Environmental Report 2007' are to record Lawrence Livermore National Laboratory's (LLNL's) compliance with environmental standards and requirements, describe LLNL's environmental protection and remediation programs, and present the results of environmental monitoring at the two LLNL sites--the Livermore site and Site 300. The report is prepared for the U.S. Department of Energy (DOE) by LLNL's Environmental Protection Department. Submittal of the report satisfies requirements under DOE Order 231.1A, Environmental Safety and Health Reporting, and DOE Order 5400.5, Radiation Protection of the Public and Environment. The report is distributed electronically and is available at https://saer.lln.gov/, the website for the LLNL annual environmental report. Previous LLNL annual environmental reports beginning in 1994 are also on the website. Some references in the electronic report text are underlined, which indicates that they are clickable links. Clicking on one of these links will open the related document, data workbook, or website that it refers to. The report begins with an executive summary, which provides the purpose of the report and an overview of LLNL's compliance and monitoring results. The first three chapters provide background information: Chapter 1 is an overview of the location, meteorology, and hydrogeology of themore » two LLNL sites; Chapter 2 is a summary of LLNL's compliance with environmental regulations; and Chapter 3 is a description of LLNL's environmental programs with an emphasis on the Environmental Management System including pollution prevention. The majority of the report covers LLNL's environmental monitoring programs and monitoring data for 2007: effluent and ambient air (Chapter 4); waters, including wastewater, storm water runoff, surface water, rain, and groundwater (Chapter 5); and terrestrial, including soil, sediment, vegetation, foodstuff, ambient radiation, and special status wildlife and plants (Chapter 6). Complete monitoring data, which are summarized in the body of the report, are provided in Appendix A. The remaining three chapters discuss the radiological impact on the public from LLNL operations (Chapter 7), LLNL's groundwater remediation program (Chapter 8), and quality assurance for the environmental monitoring programs (Chapter 9). The report uses Systeme International units, consistent with the federal Metric Conversion Act of 1975 and Executive Order 12770, Metric Usage in Federal Government Programs (1991). For ease of comparison to environmental reports issued prior to 1991, dose values and many radiological measurements are given in both metric and U.S. customary units. A conversion table is provided in the glossary.« less

In this high performance liquid chromatographic method described for the analysis of diltiazem and its metabolites, the compounds of interest are separated with high efficiency and selectivity on a Nucleosil C18 column, 3 μm particle size. Stability assay shows a significant degradation of diltiazem and its metabolites in blood samples and only a significant degradation of the major metabolite, N-demethyldiltiazem in plasma when samples are kept at room temperature. This observation shows the necessity of observing rigorous conditions during collection, transport and treatment of blood samples. This method is applied to the analysis of plasma samples from patients under diltiazem therapy.

Raytheon IRCOE has developed a family of uncooled microbolometer FPAs. These FPAs have been designed to address commercial and high-performance military applications. The SB-211 and SB-151 are high-sensitivity 320/spl times/240 FPAs with 50 /spl mu/m pixels. These FPAs have been integrated into a variety of prototype sensors including the Raytheon Long-Wavelength Staring Sensor (LWSS). The LWSS is a low power, lightweight sensor that has achieved excellent sensitivity and imaging with f/2.1 optics. Raytheon is applying the outstanding demonstrated uncooled FPA performance to the Thermal Emission imaging System IR Sensor (THEMIS) mission requirements to fabricate a nine-band multispectral imaging spectrometer to be flown on the Mars 2001 Orbiter. THEMIS is a compact, lightweight, low-power instrument that uses a 320/spl times/240 50 /spl mu/m uncooled microbolometer FPA. The instrument will be used to map Martian surface mineralogy. The FPA package incorporates a precision aligned stripe filter assembly with nine bands covering the infrared spectrum between 6.2 /spl mu/m and 15.5 /spl mu/m. The sensor also incorporates drive and signal processing electronics that have been qualified for both total dose radiation and single-event upset. The THEMIS IR sensor utilizes the FPA, vacuum package, electronics designs developed for low-cost commercial and tactical military applications in order to minimize development costs. This sensor demonstrates the ability to produce a new-generation of low-cost, IR sensors for space applications. We will also report on a significant breakthrough in the performance of uncooled FPAs.

Small gap Micromegas detectors ( < 50 μm) are expected to be optimal for high pressure applications. Combining the microbulk manufacturing technique with a small gap can result in attractive detectors for rare event detection, in particular double beta decay or dark matter searches. We present novel results obtained with small gap microbulks (25 and 12.5 μm) that have been manufactured recently. For the first time for this type of detectors, we show experimentally that for each amplification gap there is an optimal pressure and that smaller gaps are more suitable for higher pressures.

The CMS GEM collaboration is performing a feasibility study to install triple-GEM detectors in the forward region of the muon system (1.6 < vertical bar eta vertical bar < 2.4) of the CMS detector at the LHC. Such micro-pattern gas detectors are able to cope with the extreme particle rates that are expected in that region during the High Luminosity phase of the LHC. With their spatial resolution of order 100 micron GEMs would not only provide additional benefits in the CMS muon High Level Trigger, but also in the muon identification and track reconstruction, effectively combining tracking and triggering capabilities in one single device. The present status of the full project will be reviewed, highlighting all importants steps and achievements since the start of the R& D in 2009. Several small and full-size prototypes were constructed with different geometries and techniques. The baseline design of the triple-GEM detector for CMS will be described, along with the results from extensive test measurements of all prototypes both in the lab and in test beams at the CERN SPS. The proposed on-and off-detector electronics for the final system will be presented.

The calcium-sensing receptor (CaSR) is a member of a growing family of heptahelical receptors with an unusually large extracellular domain. To further delineate its functions in neurons and glia, we have investigated the expression pattern of CaSR transcripts in the postnatal and adult rat brain, spinal cord and dorsal root ganglia by in situ hybridization. CaSR-expressing cells were spatially and temporally regulated in myelinated structures with a caudo-rostral pattern that paralleled that of myelin basic protein, a marker of myelination, with a downregulation observed in the adult. Double-labelling studies demonstrated that CaSR mRNA colocalizes with myelin basic protein-expressing cells within fibre tracts, suggesting that CaSR is expressed by mature oligodendrocytes. In cultured rat oligodendrocytes, Ca2+ induced stimulation of phosphatidylinositol hydrolysis with an EC50 of 1.4 mM and increased intracellular calcium. NPS R-568 (1 microM), a calcimimetic, significantly stimulates the inositol phosphate response, whereas a less potent stereoisomer, NPS S-568 (1 microM), was without effect. These data suggest that a functional CaSR is expressed in mature oligodendrocytes with a potential role in myelination. CaSR expression was also developmentally regulated in neurons of the orbital cortex and in the CA2 region of the hippocampus, and present in olfactory nuclei, hypothalamic areas and in the area postrema through postnatal days to adulthood. This expression is consistent with a role of CaSR in olfactory or gustatory signal integration, and with the regulation of fluid and mineral homeostasis. CaSR expression in a subpopulation of small cells in dorsal root ganglia suggests additional roles for extracellular Ca2+ in sensory nerves.

To determine whether, in individuals in the general population with hand symptoms, there is a greater level of disability in those with objective evidence of delayed nerve conduction.A 19 item disability schedule relevant to hand function was developed for this survey. Subjects included 71 individual respondents to a random population survey who reported pain, tingling, numbness, or loss of sensation in the hands during an interview and who agreed to have nerve conduction studies. They were divided into those with (10) and without (61) delayed median nerve conduction.Those with delayed conduction were more likely to report disability for 14 of the 19 items assessed. Half those with delayed conduction reported disability in 7 or more items, compared with 18% of those with normal conduction (chi-squared = 7.49, p = 0.006). Disability items that showed the greatest disparity between the 2 groups were those that relied on hand, although not specifically fine hand, movements.Individuals with hand symptoms in the general population who have objective evidence of delayed nerve conduction have a greater degree of self-reported disability than those with normal conduction.

The negative conduction effect of quinidine on each of the successive phases of the ventricular depolarization was investigated using an original noninvasive method: the spatial velocity electrocardiogram of the QRS complex (SVECG-QRS). We performed a randomized placebo-controlled trial in 10 healthy subjects with a single oral dose of quinidine (330 mg) or placebo. Electrocardiographic acquisition and processing (220 recordings for the complete trial) were performed using the Lyon vectorcardiographic program. For each SVECG-QRS curve, the position of seven specific points from A (onset of QRS) to G (end of QRS) were determined precisely. The six successive time intervals between these points (AB-FG) and five velocity values (B-F) were then calculated. The QRS complex was longer under quinidine than placebo (102.4 +/- 1.6 vs. 100.3 +/- 1.5 ms). The difference was at the periphery of statistical significance (p = 0.05), and this lack of statistical difference may be mainly due to the low serum levels of quinidine obtained at the peak of the concentration (1.46 +/- 0.4 mg/1). All six QRS time intervals were longer under quinidine, but only the BC interval was significantly different (9.3 +/- 1.1 vs. 18.8 +/- 1.1 ms; p0.05) suggesting a more pronounced negative conduction effect at the onset of ventricular depolarization. No significant modifications were observed for the velocity values. We conclude that (1) the negative conduction effect of quinidine is heterogeneous, but a further study with a higher dose of quinidine (concentration-dependent effect) is required to confirm this hypothesis and (2) the spatial velocity electrocardiogram of the QRS complex allows a detailed analysis of the ventricular conduction phases. The results of the measurement were found to be reproducible. This noninvasive tool could be used in clinical practice to assess effects of antiarrhythmic drugs on successive ventricular depolarization phases.

BACKGROUND--Recent guidelines recommend that patients with obvious acute myocardial infarction receive thrombolysis, unless contraindicated, within 60-90 minutes of summoning assistance. If this target is to be achieved, an increasing number of general practitioners are likely to be involved in the administration of thrombolytic agents. AIM--This study aimed to assess the practicality and safety of thrombolysis with anistreplase when given by general practitioners. METHOD--An observational study was conducted in 805 general practices throughout the United Kingdom. Between March 1991 and September 1992, a total of 3383 patients with a clinical diagnosis of myocardial infarction were recruited--888 by 344 general practitioners who wished to include anistreplase in their management of myocardial infarction ('user' group) and 2495 by 776 general practitioners who did not wish to use anistreplase but who were willing to provide information about their cases ('comparison' group). RESULTS--More than half the patients were seen within two hours of onset of symptoms. A high frequency of contra-indications to thrombolysis, diagnostic uncertainty, and other, mainly practical, reasons limited the number of occasions on which anistreplase was administered. Thus, only 310 patients were given anistreplase in the community. The general practitioners in the study used anistreplase safely. Their diagnostic accuracy was high (of the 310 patients given anistreplase 69% had a definite, possible or probably myocardial infarction, 4% a definite non-cardiac diagnosis), the number of patients given anistreplase in spite of a documented contraindication was small (seven patients), and the doctors appeared to be aware of potential bleeding problems associated with thrombolysis. In all cases, the complications of acute myocardial infarction appeared to be managed appropriately. CONCLUSION--General practitioners can use anistreplase both appropriately and safely in the early management of acute myocardial infarction. Recognized contraindications to thrombolysis and practicalities of diagnosis and drug administration may, however, limit the number of occasions on which anistreplase is used.

Since the implementation of the 'Huriet law', drugs in phase IV clinical trials are handled by the pharmaceutical Department of the 'Hôpital Neuro-Cardiologique' (Lyon, France). The methodology of these trials is assessed by using a special assessment grid which enables a score for each protocol, with a maximal score of 20 and a minimal one of minus 20. Although many limitations could be advanced, results of this study show that, among 39 assessed trials, 13 trials had weak methodology (scoreor = 0), 16 are middle-quality trials (score between 0 and 10) whereas 10 trials only can be considered as having a strong methodology (score10). So, a fairly large number of the organized phase IV trials have debatable quality. Moreover, their objective is questionable, that is essentially promotional, in spite of the 'Huriet law' and Persons Protection Committees.

Diltiazem is often used to prevent myocardial ischaemia during the perioperative period of coronary artery bypass surgery. The purpose of this study was to investigate the effect of cardiopulmonary bypass (CPB) on plasma concentrations of diltiazem and of its two main and active metabolites (N-monodemethyldiltiazem (N-desmethyldiltiazem) and desacetyldiltiazem). The patients were administered their usual treatment during the preoperative days. The last dose was administered immediately before anaesthesia. At the onset of CPB, a significant decrease in the plasma concentrations of diltiazem and its metabolites was observed, whereas the variation was slight and not significant when the plasma concentrations were corrected for haemodilution. These results confirm that the decrease observed at the initiation of the bypass procedure can be ascribed to the haemodilution induced by the CPB. During CPB, the concentrations of diltiazem and its metabolites remained constant suggesting that the rate of metabolism and excretion of the drug was altered during the bypass procedure. At the end of CPB, there was no increase of drug plasma concentrations suggesting that no redistribution of diltiazem from tissues to plasma occurred. Furthermore, this study shows that only 33% of subjects have therapeutic levels of diltiazem before anaesthesia, and that all subjects have subtherapeutic levels during and after the CPB. These results suggest that a higher chronic oral dose of the drug should be given in patients undergoing cardiac surgery with CPB.

About a quarter to a third of patients receiving pinacidil, a new cyanoguanidine vasodilator, show ECG changes, in particular T-wave modifications that sometimes mimic myocardial ischemia. To investigate these changes, we performed a randomized placebo-controlled trial in 10 carefully selected, healthy subjects who received single oral doses of either pinacidil (25 mg), quinidine (330 mg), and placebo. Quinidine, which induces specific modifications to the surface ECG signal, was used as an internal control. The complete experimental design involved five consecutive administrations of the drugs in random order: pinacidil (twice), quinidine (twice), and placebo (once), separated by a week-long washout period. Electrophysiologic data acquisition and signal analysis were performed with the Lyon vectocardiographic processing system. Pinacidil decreased T-wave amplitude (-0.26 +/- 0.1 mV) significantly as compared with placebo (-0.14 +/- 0.06 mV), but did not change the duration of the T-wave. Although the cardiac rate increased with pinacidil, the QTc interval remained constant. Conversely, quinidine did not modify the RR interval but significantly increased duration of the T-wave (+67 +/- 20 ms) and QTc interval (+53 +/- 13 ms) as compared with placebo (+17 +/- 13 and +18 +/- 11 ms). In addition, no specific ischemic changes to the T-loop were observed with pinacidil. The modifications to the surface ECG signal caused by pinacidil appear to be drug-specific and related to its electrophysiologic properties rather than involving any ischemic mechanism. Such an approach may be useful for describing morphologic ECG changes caused by new drugs and identifying possible underlying electrophysiologic mechanism(s), which should then be confirmed in further studies.

Preoperative oral administration of calcium channel blocking agents has been found ineffective to prevent perioperative myocardial ischaemia. Our hypothesis was that low plasma concentrations may account for this inefficiency. Twenty-three male patients, scheduled for surgical myocardial revascularisation, were administered their usual anti-anginal treatment, including 180 to 360 mg of diltiazem since more than one week. The usual dosage was given at 8.00 p.m. on the day before surgery. On the morning of surgery, after withdrawal of a first blood sample, 60 mg of diltiazem were administered per month before the induction of anaesthesia. The anaesthesia was obtained with fentanyl, midazolam or flunitrazepam, pancuronium and isoflurane as required. The cardiopulmonary bypass (CPB) was associated with total haemodilution with Ringer's Lactate and a membrane oxygenator. A second blood sample was withdrawn after CPB. Plasma concentrations of diltiazem and its two active metabolites, N-monodemethyldiltiazem (MA) and desacetyldiltiazem (M1), were assessed by HPLC. Plasma diltiazem concentrations decreased from 78 +/- 66 (mean +/- SD) to 51 +/- 42 micrograms.l-1 (p0.05) with wide individual variations. These concentrations were under therapeutic levels in 18 out of 23 patients before (p0.05) with wide individual variations. These concentrations were under therapeutic levels in 18 out of 23 patients before induction and in 22 patients after CPB. The metabolite/diltiazem ratios remained constant. A dosage-plasma concentration relationship was observed preoperatively with diltiazem and MA. It is concluded that plasma concentrations of diltiazem should be optimized preoperatively in order to prevent myocardial ischaemia.

Using the rapid and sensitive high-performance liquid chromatographic (HPLC) method previously described for the analysis of ganciclovir in plasma, we have observed an interfering peak which co-elutes with the peak of ganciclovir in plasma samples from heart-transplant patients with severe renal insufficiency. A slight modification of this method allows the separation of the two peaks. The modified HPLC method, presented in this paper, is suitable for the accurate determination of ganciclovir in plasma from patients with severe renal impairment.

The pharmacokinetics of methohexital after intravenous bolus administration was studied during cardiovascular surgery with cardiopulmonary bypass. The effect of body temperature (normothermia and hypothermia) during cardiopulmonary bypass on methohexital pharmacokinetics was investigated. The pharmacokinetic data obtained were compared with those from vascular surgery without cardiopulmonary bypass. A marked decrease in plasma methohexital concentrations and therefore in area under curve and a significant increase in clearance and in volume of distribution were observed in the cardiopulmonary bypass groups compared to the vascular surgery group without cardiopulmonary bypass. However, the elimination half-life and the mean residence time were similar in the 2 groups. Furthermore, the study shows that body temperature during cardiopulmonary bypass does not influence methohexital pharmacokinetics.

Microscopy of wet-stained urinary sediment as an indicator of bacteriuria was evaluated in 418 consecutive primary care visits in a small community. Delivery of morning urine was encouraged and contributed to bladder incubation times of 4 or more hours in 79% of the visits; the overall culture positivity was about 80%. Bacteria or leukocytes alone or together as minimal requirements were suboptimal microscopy criteria for bacteriuria, whereas a minimum of moderate amounts of bacteria or 5 leukocytes per high-power field (x400) as a cutoff point yielded the best diagnostic accuracy. Optimization of urinary sediment microscopy in this way resulted in a desirable high sensitivity (97%) and efficacy (86%) in acutely symptomatic patients, as well as reasonably high efficacy (79%) in other patients, independent of sex or bladder incubation time. The method's simplicity and speed recommend it for use in primary care, particularly in patients with acute symptoms of urinary tract infection.