Metabolism and disposition of a potent group II metabotropic glutamate receptor agonist, in rats, dogs, and monkeys.

Metabolism and disposition of MGS0028 [(1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate], a potent group II metabotropic glutamate receptor agonist, were examined in three preclinical species (Sprague-Dawley rats, beagle dogs, and rhesus monkeys). In rats, MGS0028 was widely distributed and primarily excreted in urine as parent and as a single reductive metabolite, identified as the 4R-isomer MGS0034 [(1R,2S,4R,5S,6S)-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]-hexane-2,6-dicarboxylic acid]. MGS0028 had a low brain to plasma ratio at efficacious doses in rats and was eliminated more slowly in rat brain than in plasma. Exposure increased proportionally (1--10 mg/kg p.o.) in rats, with bioavailability>60% at all doses. However, bioavailability was only approximately 20% in monkeys, and MGS0034 was found in relatively high abundance in plasma. In dogs, oral bioavailability was >60%, and the metabolite was not detected. In vitro metabolism was examined in liver subcellular fractions (microsomes and cytosol) from rat, dog, monkey, and human. Reductive metabolism was observed in rat, monkey, and human liver cytosol incubations, but not in dog liver cytosol incubations. No metabolism of MGS0028 was detected in incubations with liver microsomes from any species. Similar to in vivo results, MGS0028 was reduced in cytosol stereospecifically to MGS0034. The rank order of in vitro metabolite formation (monkey > rat approximately human > dog) was in agreement with in vivo observations in rats, dogs, and monkeys. Based on the observation of species difference in reductive metabolism, rat and monkey were recommended to be the preclinical species for further characterization prior to testing in humans. Finally, allometric scaling predicts that human pharmacokinetic parameters would be acceptable for further development.     

Development of functional connections between thalamic fibres and the visual cortex of the wallaby revealed by current source density analysis in vivo

Functional development of thalamic input to the cortex in anaesthetised wallaby pouch young between postnatal day 25 (P25) and P153 has been studied by electrical stimulation of the optic nerve, current source density (CSD) analysis, and histologic identification of recording sites. Conduction in the optic nerve was recorded prior to P39, by which time responses from the superior colliculus appeared. No evoked potential of cortical origin was recorded until P46, even though thalamic fibres grew into the cortical plate from P15. The first cortical synaptic responses were recorded at the margin of the subplate and the developing cortical plate, where cells that later comprise the adult layer 6 settle. At about P66, an additional short-latency, superficial response appeared, coinciding with the formation of layer 4. The deep response was retained in layer 6. Evoked activity in the presumed layer 4 was found progressively deeper in the cortex over the next few weeks, which would be expected from the addition of layer 3 above it. By P113, a new sink was added superficial in the cortex. Thalamocortical connections follow the same deep-to-superficial order in development as the cellular layers of the cortex.     

Pharmacokinetics of dopamine in healthy male subjects

BACKGROUND: Dopamine is an agonist of alpha, beta, and dopaminergic receptors with varying hemodynamic effects depending on the dose of drug being administered. The purpose of this study was to measure plasma concentrations of dopamine in a homogeneous group of healthy male subjects to develop a pharmacokinetic model for the drug. Our hypothesis was that dopamine concentrations can be predicted from the infusion dose using a population-based pharmacokinetic model. METHODS: Nine healthy male volunteers aged 23 to 45 yr were studied in a clinical research facility within our academic medical center. After placement of venous and arterial catheters, dopamine was infused at 10 microg x kg(-1) x min(-1) for 10 min, followed by a 30-min washout period. Subsequently, dopamine was infused at 3 microg x kg(-1) x min(-1) for 90 min, followed by another 30-min washout period. Timed arterial blood samples were centrifuged, and the plasma was analyzed by high-performance liquid chromatography. Mixed-effects pharmacokinetic models using NONMEM software (NONMEM Project Group, University of California, San Francisco, CA) were used to determine the optimal compartmental pharmacokinetic model for dopamine. RESULTS: Plasma concentrations of dopamine varied from 12,300 to 201,500 ng/l after 10 min of dopamine infusion at 10 microg x kg(-1) x min(-1). Similarly, steady-state dopamine concentrations varied from 1,880 to 18,300 ng/l in these same subjects receiving 3-microg x kg(-1) x min(-1) infusions for 90 min. A two-compartment model adjusted for body weight was the best model based on the Schwartz-Bayesian criterion. CONCLUSIONS: Despite a homogeneous population of healthy male subjects and weight-based dosing, there was 10- to 75-fold intersubject variability in plasma dopamine concentrations, making standard pharmacokinetic modeling of less utility than for other drugs. The data suggest marked intraindividual and interindividual variability in dopamine distribution and/or metabolism. Thus, plasma dopamine concentrations in patients receiving dopamine infusion at identical rates may vary profoundly. Our data suggest that dosing dopamine based on body weight does not yield predictable blood concentrations.     

超声造影剂SOnoVue(R)

超声造影剂(UCA)是一种用外壳固定气体的微泡,它可以大大增强超声的背向散射,从而增强血流的回波信号和血流在血管中的多普勒信号.超声造影剂已经普遍应用于超声诊断,而超声仪器的最新进展结合造影剂已使显示微循环和组织灌注成为可能.     

Reorganizing the system of care surrounding laparoscopic surgery: a cost-effectiveness analysis using discrete-event simulation.

PURPOSE: To determine the cost-effectiveness of a proposed reorganization of surgical and anesthesia care to balance patient volume and safety. METHODS: Discrete-event simulation methods were used to compare current surgical practice with a new modular system in which patient care is handed off between 2 anesthesiologists. A health care system's perspective, using hospital and professional costs, was chosen for the cost-effectiveness analysis. Outcomes were patient throughput, flow time, wait time, and resource use. Sensitivity analyses were performed on staffing levels, mortality rates, process times, and scheduled patient volume. RESULTS: The new strategy was more effective (average 4.41 patients/d [median = 5] v. 4.29 [median = 4]) and had similar costs (average cost/ patient/d = 5327 dollars v. 5289 dollars) to the current strategy with an incremental cost-effectiveness of 318 dollars/additional patient treated/d. Surgical mortality rate must be >4% or hand-off delay >15 min before the new strategy is no longer more effective. CONCLUSION: The proposed system is more cost-effective relative to current practice over a wide range of mortality rates, hand-off times, and scheduled patient volumes.     

Law as a Tool for Preventing Chronic Diseases: Expanding the Spectrum of Effective Public Health Strategies

Law, which is a fundamental element of effective public health policy and practice, played a crucial role in many of public health's greatest achievements of the 20th century. Still, conceptual legal frameworks for the systematic application of law to chronic disease prevention and control have not been fully recognized and used to address public health needs. Development and implementation of legal frameworks could broaden the range of effective public health strategies and provide valuable tools for the public health workforce, especially for state and local health department program managers and state and national policy makers. In an effort to expand the range of effective public health interventions, the Centers for Disease Control and Prevention will work with its partners to explore the development of systematic legal frameworks as a tool for preventing chronic diseases and addressing the growing epidemic of obesity, heart disease, stroke, and other chronic diseases and their risk factors.     

Nasal carriage of methicillin-resistant Staphylococcus aureus in an American Indian population.

BACKGROUND AND OBJECTIVE: Although reports of methicillin-resistant Staphylococcus aureus (MRSA) infections without healthcare exposure are increasing, population-based data regarding nasal colonization are lacking. We assessed the prevalence of and risk factors for community-associated MRSA nasal carriage in patients of a rural outpatient clinic. DESIGN: A cross-sectional population survey was conducted through random sample and stratification by community of residence. Recent healthcare exposure (ie, hospitalization, dialysis, or healthcare occupation) and other risk factors for MRSA carriage were assessed. Cultures of the nares were performed. Community-associated MRSA was defined as MRSA carriage without healthcare exposure. SETTING: A predominantly American Indian community in Washington. PATIENTS: Those receiving healthcare from an Indian Health Service clinic. RESULTS: Of 1,311 individuals identified for study, 475 (36%) participated. Unsatisfactory culture specimens resulted in exclusion of 6 participants. In all, 128 (27.3%) of 469 participants had S. aureus. Nine (1.9%) of 469 had MRSA carriage; of these, 5 had community-associated MRSA (5 of 469; overall community-associated MRSA carriage rate, 1.1%). MRSA carriage was associated with antimicrobial use in the previous year (risk ratio [RR], 7.2; P = .04) and residence in a household of more than 7 individuals (RR, 4.5; P = .03). Pulsed-field gel electrophoresis indicated that 5 (55%) of 9 MRSA carriage isolates were closely related, including 3 (60%) of 5 that were community associated. CONCLUSIONS: Prevalence of community-associated MRSA colonization was approximately 1% in this rural, American Indian population. Community-associated MRSA colonization was associated with recent antimicrobial use and larger household.     

Defining acidosis in postoperative cardiac patients using Stewart's method of strong ion difference.

OBJECTIVE: To define the true incidence and nature of acidosis in pediatric patients postcardiac surgery, using Stewart's direct method of measuring strong ion difference. We also wished to compare the ability of standard indirect methods (base deficit, lactate, anion gap, and corrected anion gap) to accurately predict tissue acidosis. DESIGN: A single-center prospective observational study. SETTING: A pediatric intensive care unit in a tertiary referral center. PATIENTS: Pediatric patients who had undergone cardiac surgery were studied in the immediate postoperative period. Patients who had undergone both open and closed cardiac surgery were included. INTERVENTIONS: Routine arterial blood gas analysis and laboratory electrolyte measurements were made in patients immediately on admission to the pediatric intensive care unit (PICU) after cardiac surgery and each morning until discharge from the PICU. MEASUREMENTS AND MAIN RESULTS: Figge's equations were used to calculate strong ion difference and total tissue acids (unmeasured acids and lactate). These direct methods then were compared to indirect measurements: base deficit, lactate anion gap, and anion gap corrected for albumin. We collected 150 samples from 44 patients. Tissue acidosis occurred overall in 60 of 150 samples. This was due to raised unmeasured acids alone in 44 of 60 (73.3%), raised lactate alone in six of 60 (10%), and a combination of the two in ten of 60 (16.6%). Hyperchloremia occurred in 19 of 150 samples overall and 12 of 25 (48%) samples immediately after cardiopulmonary bypass. Measured base deficit showed a poor correlation with true tissue acidosis (r = -.48, p <.001) and the worst discriminatory ability (area under the curve, 0.72; 0.62-0.82). Anion gap corrected for albumin had the best correlation (r =.95, p <.001) and highest area under the curve (0.90; 0.85-0.95). CONCLUSIONS: Metabolic acidosis occurs frequently postcardiac surgery and is largely due to raised unmeasured acids and less commonly raised lactate. Hyperchloremia is common, particularly after cardiopulmonary bypass. Base deficit correlates poorly with true tissue acidosis, and corrected anion gap offers the most accurate bedside alternative to Stewart's method of tissue acid calculation.     

Parents' reports of barriers to care for children with special health care needs: development and validation of the barriers to care questionnaire.

OBJECTIVE: To describe the development and validation of the Barriers to Care Questionnaire (BCQ). METHODS: The 39-item BCQ was developed through review of the literature, focus groups, and cognitive interviews of Spanish- and English-speaking parents of children with chronic health conditions. Barriers to care are conceptualized as a multidimensional construct consisting of pragmatics, health knowledge and beliefs, expectations about care, skills, and marginalization. The BCQ was field tested in 3 samples of children with special health care needs (CSHCN). RESULTS: Response rate for the field test was 77.2%. There were minimal missing data (0.08%), no floor effects, and minimal ceiling effects (3.8%, total scale). Internal consistency reliability (alpha) for the BCQ total scale was.95 and subscale alpha ranged from.75 to.91. The BCQ total scale and subscales correlated in the expected direction with validated measures of primary care characteristics and health-related quality of life. BCQ scores were higher (fewer barriers) for children with a primary care physician and for those who reported no problems getting care or foregone care. CONCLUSION: The BCQ is a feasible, reliable, and valid instrument for measuring barriers to care for CSHCN. Its use may inform efforts to support consumer choice, enhance provider accountability, and spur quality improvement.