bluuebunny/crossref_metadata_2025 huggingface dataset:
One Medical School’s Effort to Ready the Workforce for the Future: Preparing Medical Students to Care for Populations Who Are Publicly Insured
Authors: Turner Jane L. , Farquhar Lynda
Published: March 2009

This article describes the development, implementation, and evaluation of a curriculum project designed to prepare medical students to care for populations who have Medicaid or a low socioeconomic status (SES). The setting for the project was a community-based medical school, the College of Human Medicine (CHM) at Michigan State University. This article describes a four-year process of curriculum development and offers examples of specific changes that CHM made to courses and clerkships. CHM modified 25% of preclinical courses, five core clerkships of year three, and two clerkships (Senior Surgery and Senior Internal Medicine) of year four. The authors describe highlights of outcomes in student performance, course and clerkship ratings, attitudes, professional goals, student self-assessment of their skills, and feedback from residency program directors. The authors identified four items on the Association of American Medical Colleges (AAMC) Graduation Questionnaire as related to the project and tracked them as an outcome measure of student attitudes related to the social responsibility of physicians. Attitudes of the students who experienced the modified curriculum showed greater agreement with AAMC Graduation Questionnaire items than the previous class at CHM and than their classmates across the country. The majority of residency program directors rated CHM graduates as more skilled than their peers in applying cultural competence, working with patients who have Medicaid or a low SES, and using community resources. The authors discuss factors that contributed to the successful implementation of curricular changes as well as challenges to their implementation.
Role of CYP2B6 in Stereoselective Human Methadone Metabolism
Authors: Totah Rheem A. , Sheffels Pamela , Roberts Toni , Whittington Dale , Thummel Kenneth , Kharasch Evan D.
Published: March 2009

Background

Metabolism and clearance of racemic methadone are stereoselective and highly variable, yet the mechanism remains largely unknown. Initial in vitro studies attributed methadone metabolism to cytochrome P4503A4 (CYP3A4). CYP3A4 was also assumed responsible for methadone clearance in vivo. Nevertheless, recent clinical data do not support a primary role for CYP3A4 and suggest that CYP2B6 may mediate methadone clearance. Expressed CYP2B6 and also CYP2C19 N-demethylate methadone in vitro. This investigation tested the hypothesis that CYPs 2B6, 3A4, and/or 2C19 are responsible for stereoselective methadone metabolism in human liver microsomes and in vivo.

Methods

N-demethylation of racemic methadone and individual enantiomers by expressed CYPs 2B6, 2C19, and 3A4 was evaluated. Stereoselective microsomal methadone metabolism was quantified, compared with CYP 2B6 and 3A4 content, and probed using CYP isoform-selective inhibitors. A crossover clinical investigation (control, CYP2B6 and CYP3A4 induction by rifampin, CYP3A inhibition by troleandomycin and grapefruit juice) evaluated stereoselective methadone disposition.

Results

At clinical concentrations, methadone enantiomer N-demethylation by recombinant CYPs 2B6, 3A4, and 2C19 was S > R, S = R, and S < R. Greater stereoselective metabolism (S > R) occurred in livers expressing high levels of CYP2B6 compared with CYP3A4. Clopidogrel, troleandomycin, and (+)-N-3-benzyl-nirvanol, selective inhibitors of CYPs 2B6, 3A4, and 2C19, respectively, inhibited microsomal methadone metabolism by 50-60%, 20-30%, and less than 10%. Only inhibition by clopidogrel was stereoselective. Clinically, rifampin diminished both R- and S-methadone plasma concentrations, but troleandomycin and grapefruit juice altered neither R- nor S-methadone concentrations. Plasma R/S-methadone ratios were increased by rifampin but unchanged by CYP3A inhibition.

Conclusions

These results suggest a significant role for CYP2B6, but not CYP3A, in stereoselective human methadone metabolism and disposition.
Mouse Model of Fracture Pain
Authors: Minville Vincent , Laffosse Jean-Michel , Fourcade Olivier , Girolami Jean-Pierre , Tack Ivan
Published: March 2009

Background

The aim of this study was to validate a model of postfracture pain in mice, which was evaluated in the presence and the absence of morphine and ketoprofen.

Methods

The study was divided into two parts: protocol A, the effects of closed fracture; and protocol B, the effects of morphine and ketoprofen on fracture pain. In protocol A, mice were assigned to three groups: group 1, sham incision; group 2, sham pinning; or group 3, fracture. In protocol B, mice were randomly assigned to four groups to receive morphine (3 or 10 mg/kg body weight), ketoprofen (50 mg/kg body weight), or placebo (vehicle). Three tests were used to assess pain behavior: von Frey filament application, hot plate test, and a subjective pain scale.

Results

In protocol A, thermal nociception, mechanical nociception, and subjective pain were significantly modified in group 3 (fractured) compared with control groups 1 and 2 (sham groups). In protocol B, when tests were repeated for 240 min in morphine-treated animals and in ketoprofen-treated animals, reduction of mechanical nociception, thermal nociception, and subjective pain scale score were observed. Morphine and ketoprofen administration provided the same effect on behavioral testing on postoperative days 1 and 2.

Conclusion

This mouse model seems to be a reliable and reproducible tool to investigate the effect of closed bone fracture on several parameters, such as pain, remodeling, and recovery. Moreover, it allows studying the effects of various pharmacologic treatments as well as the involvement of various systems using different genetically modified strains of mice.
The Invention and Development of Enflurane, Isoflurane, Sevoflurane, and Desflurane
Authors: Terrell Ross C. , Warner David S.
Published: March 2009

Thirty-six halogenated Me Et ethers have been synthesized for evaluation as volatile anesthetics. Eleven of the ethers were too unstable to test, and, of the remaining 25, 13 had promising anesthetic properties in mice and are suitable for study in larger animals. Those ethers having one H with at least 2 halogens other than F or 2 or more H with at least one Br or Cl were the best anesthetics.
Autologous Transplantation of Endothelial Progenitor Cells Attenuates Acute Lung Injury in Rabbits
Authors: Lam Chen-Fuh , Liu Yen-Chin , Hsu Jen-Kuo , Yeh Pei-An , Su Ting-Ya , Huang Chien-Chi , Lin Ming-Wei , Wu Ping-Ching , Chang Pei-Jung , Tsai Yu-Chuan
Published: March 2009

Background

Acute lung injury (ALI) and end-stage acute respiratory distress syndrome (ARDS) are among the most common causes of death in intensive care units. Activation and damage of pulmonary endothelium is the hallmark of ALI/ARDS. Recent studies have demonstrated the importance of circulating endothelial progenitor cells (EPCs) in maintaining normal endothelial function as well as endothelial repairing after vascular injury. Here, the authors present the first study demonstrating the therapeutic potential of EPCs in a rabbit model of ALI/ARDS.

Methods

Circulating EPCs were obtained from rabbits using Ficoll centrifugation. One week after culturing, ALI was induced in rabbits by oleic acid (75 mg/kg, intravenous), and autologous EPCs were transplanted intravenously. Vasomotor function of isolated pulmonary artery and degrees of lung injury were assessed 2 days later.

Results

Endothelial dysfunction in the pulmonary artery was significantly attenuated in rabbits treated with EPCs, whereas the endothelium-independent relaxation responses were not different. Expression of inducible nitric oxide synthase was suppressed in the pulmonary artery of EPC-treated animals. Infiltration of leukocytes in the lung parenchyma was significantly reduced after EPC transplantation. EPCs also decreased water content, hyaline membrane formation, and hemorrhage in lungs.

Conclusion

The authors demonstrated that autologous transplantation of EPCs preserves pulmonary endothelial function and maintains the integrity of pulmonary alveolar-capillary barrier. Transplantation of EPCs can be a novel cell-based, endothelium-targeted therapeutic strategy for prevention and treatment of ALI/ARDS.
Incidence and Risk Factors for Perioperative Adverse Respiratory Events in Children Who Are Obese
Authors: Tait Alan R. , Voepel-Lewis Terri , Burke Constance , Kostrzewa Amy , Lewis Ian
Published: March 2009

Background

Consistent with the increasing prevalence of obesity in the United States and many countries worldwide, anesthesiologists are now presented with a greater number of adult and pediatric patients who are significantly overweight. This prospective study was designed to examine the relation between age-adjusted body mass index, preoperative comorbidities, and perioperative outcome in children.

Methods

Children aged 2-18 yr undergoing noncardiac elective procedures were classified as overweight or obese based on their age- and sex-adjusted body mass index. Information was elicited regarding patient demographics, presence of comorbidities, and anesthetic technique. Data regarding the incidence and severity of perioperative adverse events were collected prospectively.

Results

Two thousand twenty-five children comprised the sample (1,380 normal weight, 351 overweight, and 294 obese). Obese children had a significantly higher prevalence of comorbidities than nonobese children, including asthma, hypertension, sleep apnea, and type II diabetes. Furthermore, obese children had a higher incidence of difficult mask ventilation, airway obstruction, major oxygen desaturation (>10% of baseline), and overall critical respiratory adverse events. Logistic regression analysis revealed several risk factors for adverse events, including procedures involving the airway, obesity, age younger than 10 yr, and a history of obstructive sleep apnea.

Conclusions

These results suggest that children presenting for elective surgical procedures who are obese have a greater prevalence of preexisting comorbid medical conditions and an increased incidence of perioperative adverse respiratory events compared with normal-weight children. Identification and awareness of risk factors for perioperative complications will be important in optimizing the anesthetic management of these children.
Amnestic Concentrations of Sevoflurane Inhibit Synaptic Plasticity of Hippocampal CA1 Neurons through γ-Aminobutyric Acid–mediated Mechanisms
Authors: Ishizeki Junko , Nishikawa Koichi , Kubo Kazuhiro , Saito Shigeru , Goto Fumio
Published: March 2009

Background

The cellular mechanisms of anesthetic-induced amnesia are still poorly understood. The current study examined sevoflurane at various concentrations in the CA1 region of rat hippocampal slices for effects on excitatory synaptic transmission and on long-term potentiation (LTP), as a possible mechanism contributing to anesthetic-induced loss of recall.

Methods

Population spikes and field excitatory postsynaptic potentials were recorded using extracellular electrodes after electrical stimulation of Schaffer-collateral-commissural fiber inputs. Paired pulse facilitation was used as a measure of presynaptic effects of the anesthetic. LTP was induced using tetanic stimulation (100 Hz, 1 s). Sevoflurane at concentrations from amnestic (0.04 mm) to clinical concentrations (0.23-0.41 mm) were added to the perfusion solution.

Results

In the presence of 0.04 mm sevoflurane, the amplitude of population spikes was significantly depressed, and tetanic stimulation induced only posttetanic potentiation and then failure of LTP. These inhibitory effects were antagonized by bicuculline (10 microm), a gamma-aminobutyric acid type A receptor antagonist. Sevoflurane at 0.23-0.41 mm further depressed the amplitude of field excitatory postsynaptic potentials in a dose-dependent manner and completely blocked LTP. Bicuculline only partially antagonized 0.41 mm sevoflurane-induced profound inhibition of LTP. Sevoflurane at 0.23-0.41 mm, but not at 0.04 mm, significantly increased paired pulse facilitation, suggesting that sevoflurane has presynaptic actions to reduce glutamate release from nerve terminals.

Conclusions

The current study provides evidence that amnestic concentrations of sevoflurane inhibit LTP of hippocampal CA1 neurons through gamma-aminobutyric acid-mediated mechanisms, and these actions seem to account for the effects of amnestic sevoflurane on synaptic plasticity.
Isoflurane Reduces Excitability of Drosophila Larval Motoneurons by Activating a Hyperpolarizing Leak Conductance
Authors: Sandstrom David J.
Published: March 2009

Background

Mechanisms of anesthetic-mediated presynaptic inhibition are incompletely understood. Isoflurane reduces presynaptic excitability at the larval Drosophila neuromuscular junction, slowing conduction velocity and depressing glutamate release. Mutations in the Para voltage-gated Na channel enhance anesthetic sensitivity of adult flies. Here, the author examines the role of para in anesthetic sensitivity and seeks to identify the conductance underlying presynaptic inhibition at this synapse.

Methods

Neuromuscular transmission was studied using a two-electrode voltage clamp, with isoflurane applied in physiologic saline. The relation between ionic conductances and presynaptic function was modeled in the Neuron Simulation Environment. Motoneuron ionic currents were monitored via whole cell recordings.

Results

Presynaptic inhibition by isoflurane was enhanced significantly in para mutants. Computer simulations of presynaptic actions of anesthetics indicated that each candidate target conductance would have diagnostic effects on the relation between latency and amplitude of synaptic currents. The experimental latency-amplitude relation for isoflurane most closely resembled activation of a simulated hyperpolarizing leak. Simulations indicated that increased isoflurane potency in para axons resulted from reduced excitability of mutant axons. In whole cell recordings, isoflurane activated a hyperpolarizing leak current. The effects of isoflurane at the neuromuscular junction were insensitive to low pH.

Conclusions

The effects of isoflurane on presynaptic excitability are mediated via an acid-insensitive inhibitory leak conductance. para mutations enhance the sensitivity of this anesthetic-modulated neural pathway by reducing axonal excitability. This work provides a link between anesthetic-sensitive leak currents and presynaptic function and has generated new tools for analysis of the function of this synapse.
Effect of Nitrous Oxide on Neurologic and Neuropsychological Function after Intracranial Aneurysm Surgery
Authors: McGregor Diana G. , Lanier William L. , Pasternak Jeffrey J. , Rusy Deborah A. , Hogan Kirk , Samra Satwant , Hindman Bradley , Todd Michael M. , Schroeder Darrell R. , Bayman Emine Ozgur , Clarke William , Torner James , Weeks Julie
Published: March 2009

Background

Laboratory studies suggest that nitrous oxide augments brain injury after ischemia or hypoxia. The authors examined the relation between nitrous oxide use and outcomes using data from the Intraoperative Hypothermia for Aneurysm Surgery Trial.

Methods

The Intraoperative Hypothermia for Aneurysm Surgery Trial was a prospective randomized study of the impact of intraoperative hypothermia (temperature = 33 degrees C) versus normothermia (temperature = 36.5 degrees C) in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping. Anesthesia was dictated by a limited-options protocol with the use of nitrous oxide determined by individual anesthesiologists. All patients were assessed daily for 14 days after surgery or until hospital discharge. Neurologic and neuropsychological testing were conducted at 3 months after surgery. Outcome data were analyzed via both univariate tests and multivariate logistic regression analysis correcting for factors thought to influence outcome. An odds ratio (OR) greater than 1.0 denotes a worse outcome in patients receiving nitrous oxide.

Results

Outcome data were available for 1,000 patients, of which 373 received nitrous oxide. There was no difference between groups in the development of delayed ischemic neurologic deficit. At 3 months after surgery, there were no significant differences between groups in any outcome variable: Glasgow Outcome Score (OR, 0.84; 95% confidence interval [CI], 0.63-1.14; P = 0.268), National Institutes of Health Stroke Scale (OR, 1.29; 95% CI, 0.96-1.73; P = 0.087), Rankin Disability Score (OR, 0.84; 95% CI, 0.61-1.15; P = 0.284), Barthel Activities of Daily Living Index (OR, 1.01; 95% CI, 0.68-1.51; P = 0.961), or neuropsychological testing (OR, 1.26; 95% CI, 0.85-1.87; P = 0.252).

Conclusions

In a population of patients at risk for ischemic brain injury, nitrous oxide use had no overall beneficial or detrimental impact on neurologic or neuropsychological outcomes.
Cutaneous Amitriptyline in Human Volunteers
Authors: Dualé Christian , Daveau Julie , Cardot Jean-Michel , Boyer-Grand Anne , Schoeffler Pierre , Dubray Claude
Published: March 2009

Background

Amitriptyline is effective in relieving neuropathic pain. Its site of action is thought to be supraspinal and spinal, but a peripheral effect on fibers is also suggested.

Methods

This double-blind study examined the effects of transcutaneous amitriptyline diluted in hydroalcoholic solution in healthy young male volunteers. Six treatments were randomly applied on different areas of the skin of the back: amitriptyline at 0 (vehicle), 25, 50, and 100 mm; saline (control); and lidocaine-prilocaine cream as a positive control. Up to 24 h after application, mechanical thresholds for touch and nociception, and thermal thresholds for cold, warm, and heat sensation were recorded for each area. Blood samples were collected to assess plasma levels of amitriptyline. A late recording of the tactile thresholds was performed 1 and 3 weeks after the treatment session.

Results

The thresholds for all sensations did not differ between the vehicle and saline. Lidocaine-prilocaine cream displayed a short-lasting anesthetic effect for all sensations, although this was not significant for warm sensation. Amitriptyline, at the three concentrations studied, induced a mild and short-lasting increase of the tactile and mechanical nociceptive thresholds. It significantly decreased cold thresholds (down to 21.8 degrees C, P = 0.01 vs. 27.5 degrees C for control) and heat thresholds (down to 40.1 degrees C, P = 0.004 vs. 43.4 degrees C for control). These two effects were no longer significant after the fourth hour of observation. Amitriptyline did not change warm thresholds. There was no apparent systemic absorption effect of the drug.

Conclusion

It is hypothesized that amitriptyline has a differential effect on different fiber structures.
Isoflurane Preconditioning Reduces the Rat NR8383 Macrophage Injury Induced by Lipopolysaccharide and Interferon γ
Authors: Xu Xuebing , Feng Jifeng , Zuo Zhiyi
Published: March 2009

Background

Isoflurane exposure before an insult can reduce the insult-induced injury in various organs. This phenomenon is called isoflurane preconditioning. The authors hypothesize that isoflurane can precondition macrophages, cells that travel to all tissues and are important in the host defense and inflammation responses.

Methods

Rat NR8383 macrophages were pretreated with or without 1-3% isoflurane for 1 h at 30 min before they were incubated with or without 100 ng/ml lipopolysaccharide plus 50 U/ml interferon gamma for 24 h. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry was performed after cells were stained with annexin V and propidium iodide. Inducible nitric oxide synthase protein expression in macrophages was quantified by Western blotting.

Results

Lipopolysaccharide plus interferon gamma decreased cell viability by approximately 50%. This decrease was dose-dependently inhibited by aminoguanidine, an inducible nitric oxide synthase inhibitor. Lipopolysaccharide plus interferon gamma caused inducible nitric oxide synthase expression. This expression was inhibited by pretreatment with 2% but not 1% or 3% isoflurane. Isoflurane at 2% inhibited lipopolysaccharide plus interferon gamma-induced accumulation of nitrite, an oxidation product of nitric oxide. Pretreatment with 2% but not 1% or 3% isoflurane improved cell viability. Lipopolysaccharide plus interferon gamma increased the number of propidium iodide-positive staining cells. This increase was attenuated by 2% isoflurane pretreatment. The protective effect of 2% isoflurane was abolished by chelerythrine, calphostin C, or bisindolylmaleimide IX, protein kinase C inhibitors.

Conclusions

Lipopolysaccharide plus interferon gamma causes an inducible nitric oxide synthase-dependent macrophage injury. Isoflurane induces preconditioning effects that may be mediated by protein kinase C in macrophages.
Cardiac Arrests and Deaths Associated with Malignant Hyperthermia in North America from 1987 to 2006
Authors: Larach Marilyn Green , Brandom Barbara W. , Allen Gregory C. , Gronert Gerald A. , Lehman Erik B.
Published: March 2009

Background

The authors determined associated cardiac arrest and death rates in cases from Canada and the United States as reported to The North American Malignant Hyperthermia (MH) Registry and analyzed factors associated with a higher risk of poor outcomes.

Methods

The authors searched the database for AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports with inclusion criteria as follows: event date between January 1, 1987, and December 31, 2006; "very likely" or "almost certain" MH as ranked by MH Clinical Grading Scale; location in Canada or the United States; and one or more anesthetic agents given. The exclusion criterion was a pathologic condition other than MH independently judged by the authors. Severe MH outcomes were analyzed as regards clinical history and presentation, using Wilcoxon rank sum tests for continuous variables and Pearson exact chi-square tests for categorical variables. A Bonferroni correction adjusted for multiple comparisons.

Results

Of 291 events, 8 (2.7%) resulted in cardiac arrests and 4 (1.4%) resulted in death. The median age in cases of cardiac arrest/death was 20 yr (range, 2-31 yr). Associated factors were muscular build (odds ratio, 18.7; P = 0.0016) and disseminated intravascular coagulation (odds ratio, 49.7; P < 0.0001). Increased risk of cardiac arrest/death was related to a longer time period between anesthetic induction and maximum end-tidal carbon dioxide (216 vs. 87 min; P = 0.003). Unrelated factors included patient or family history, anesthetic management, and the MH episode.

Conclusions

Modern US anesthetic practice did not prevent MH-associated cardiac arrest and death in predominantly young, healthy patients undergoing low- to intermediate-risk surgical procedures.
Additive Interaction of the Cannabinoid Receptor I Agonist Arachidonyl-2-chloroethylamide with Etomidate in a Sedation Model in Mice
Authors: Meybohm Patrick , Brand Philipp-Alexander , Ufer Mike , Thiemann Florian , Steinfath Markus , Paris Andrea , Scholz Jens , Bein Berthold
Published: March 2009

Background

Both propofol and volatile anesthetics have been reported to interact with the endocannabinoid system. The purpose of this study was to evaluate the effect of selective agonists for cannabinoid receptor types 1 and 2 on etomidate-induced sedation.

Methods

A controlled, blinded, experimental study was performed in 20 mice that received intraperitoneal injections of etomidate, the cannabinoid1 receptor agonist arachidonyl-2-chloroethylamide (ACEA), the cannabinoid2 receptor agonist JWH 133 alone, and both ACEA and JWH 133 combined with etomidate. The cannabinoid1 receptor antagonist AM 251 and the cannabinoid2 receptor antagonist AM 630 were administered 10 min before the delivery of ACEA and JWH 133, respectively. Each drug combination was applied to 6-8 mice of these 20 study animals. Sedation was monitored by a Rota-Rod (Ugo Basile, Comerio, Italy). Isobolographic analysis was used for evaluation of pharmacologic interaction.

Results

Single drug administration of etomidate and ACEA produced dose- and time-dependent decreased time on the Rota-Rod (P < 0.05). No sedative effect was seen after JWH 133. Etomidate-induced sedation was significantly increased and prolonged with ACEA (P < 0.05), but not with JWH 133. Isobolographic analysis revealed an additive interaction between ACEA and etomidate that was antagonized by the cannabinoid1 receptor antagonist AM 251. The cannabinoid1 receptor antagonist had no effect on etomidate alone.

Conclusions

Etomidate-induced sedation was increased and prolonged by activation of the cannabinoid1 receptor, but not of the cannabinoid2 receptor, in mice. However, this interaction was only additive.
Inhaled Hydrogen Sulfide
Authors: Volpato Gian Paolo , Searles Robert , Yu Binglan , Scherrer-Crosbie Marielle , Bloch Kenneth D. , Ichinose Fumito , Zapol Warren M.
Published: March 2009

Background

Breathing hydrogen sulfide (H2S) has been reported to induce a suspended animation-like state with hypothermia and a concomitant metabolic reduction in rodents. However, the impact of H2S breathing on cardiovascular function remains incompletely understood. In this study, the authors investigated the cardiovascular and metabolic effects of inhaled H2S in a murine model.

Methods

The impact of breathing H2S on cardiovascular function was examined using telemetry and echocardiography in awake mice. The effects of breathing H2S on carbon dioxide production and oxygen consumption were measured at room temperature and in a warmed environment.

Results

Breathing H2S at 80 parts per million by volume at 27 degrees C ambient temperature for 6 h markedly reduced heart rate, core body temperature, respiratory rate, and physical activity, whereas blood pressure remained unchanged. Echocardiography demonstrated that H2S exposure decreased both heart rate and cardiac output but preserved stroke volume. Breathing H2S for 6 h at 35 degrees C ambient temperature (to prevent hypothermia) decreased heart rate, physical activity, respiratory rate, and cardiac output without altering stroke volume or body temperature. H2S breathing seems to induce bradycardia by depressing sinus node activity. Breathing H2S for 30 min decreased whole body oxygen consumption and carbon dioxide production at either 27 degrees or 35 degrees C ambient temperature. Both parameters returned to baseline levels within 10 min after the cessation of H2S breathing.

Conclusions

Inhalation of H2S at either 27 degrees or 35 degrees C reversibly depresses cardiovascular function without changing blood pressure in mice. Breathing H2S also induces a rapidly reversible reduction of metabolic rate at either body temperature.
Spinal Microglial and Perivascular Cell Cannabinoid Receptor Type 2 Activation Reduces Behavioral Hypersensitivity without Tolerance after Peripheral Nerve Injury
Authors: Romero-Sandoval Alfonso , Nutile-McMenemy Nancy , DeLeo Joyce A.
Published: March 2009

Background

Cannabinoids induce analgesia by acting on cannabinoid receptor (CBR) types 1 and/or 2. However, central nervous system side effects and antinociceptive tolerance from CBR1 limit their clinical use. CBR2 exist on spinal glia and perivascular cells, suggesting an immunoregulatory role of these receptors in the central nervous system. Previously, the authors showed that spinal CBR2 activation reduces paw incision hypersensitivity and glial activation. This study tested whether CBR2 are expressed in glia and whether their activation would induce antinociception, glial inhibition, central side effects, and antinociceptive tolerance in a neuropathic rodent pain model.

Methods

Rats underwent L5 spinal nerve transection or sham surgery, and CBR2 expression and cell localization were assessed by immunohistochemistry. Animals received intrathecal injections of CBR agonists and antagonists, and mechanical withdrawal thresholds and behavioral side effects were assessed.

Results

Peripheral nerve transection induced hypersensitivity, increased expression of CR3/CD11b and CBR2, and reduced ED2/CD163 expression in the spinal cord. The CBR2 were localized to microglia and perivascular cells. Intrathecal JWH015 reduced peripheral nerve injury hypersensitivity and CR3/CD11b expression and increased ED2/CD163 expression in a dose-dependent fashion. These effects were prevented by intrathecal administration of the CBR2 antagonist (AM630) but not the CBR1 antagonist (AM281). JWH015 did not cause behavioral side effects. Chronic intrathecal JWH015 treatment did not induce antinociceptive tolerance.

Conclusions

These data indicate that intrathecal CBR2 agonists may provide analgesia by modulating the spinal immune response and microglial function in chronic pain conditions without inducing tolerance and neurologic side effects.
Effects of Ropivacaine on Action Potential Configuration and Ion Currents in Isolated Canine Ventricular Cardiomyocytes
Authors: Szabó Adrienn , Szentandrássy Norbert , Birinyi Péter , Horváth Balázs , Szabó Gergely , Bányász Tamás , Márton Ildikó , Magyar János , Nánási Péter P.
Published: March 2009

Background

Despite the widespread clinical application of ropivacaine, there is little information on the cellular cardiac effects of the drug. In the current study, therefore, the concentration-dependent effects of ropivacaine on action potential morphology and the underlying ion currents were studied and compared with those of bupivacaine in isolated canine ventricular cardiomyocytes.

Methods

Action potentials were recorded from the enzymatically dispersed cells using sharp microelectrodes. Conventional patch clamp and action potential voltage clamp arrangements were used to study the effects of ropivacaine on transmembrane ion currents.

Results

Ropivacaine induced concentration- and frequency-dependent changes in action potential configuration, including shortening of the action potentials, reduction of their amplitude and maximum velocity of depolarization, suppression of early repolarization, and depression of plateau. Reduction in maximum velocity of depolarization was characterized with an EC50 value of 81 +/- 7 microm at 1 Hz. Qualitatively similar results were obtained with bupivacaine (EC50 = 47 +/- 3 microm). Under voltage clamp conditions, a variety of ion currents were blocked by ropivacaine: L-type calcium current (EC50 = 263 +/- 67 microm), transient outward current (EC50 = 384 +/- 75 microm), inward rectifier potassium current (EC50 = 372 +/- 35 microm), rapid delayed rectifier potassium current (EC50 = 303 +/- 47 microm), and slow delayed rectifier potassium current (EC50 = 106 +/- 18 microm).

Conclusions

Ropivacaine, similarly to bupivacaine, can modify cardiac action potentials and the underlying ion currents at concentrations higher than the usual therapeutic range. However, in cases of overdose, cardiac complications may be anticipated both during and after anesthesia due to the blockade of various ion currents.
Randomized Controlled Trial Comparing Adaptive-support Ventilation with Pressure-regulated Volume-controlled Ventilation with Automode in Weaning Patients after Cardiac Surgery
Authors: Gruber Pascale C. , Gomersall Charles D. , Leung Patricia , Joynt Gavin M. , Ng Siu Keung , Ho Ka-man , Underwood Malcolm J.
Published: March 2009

Background

Adaptive-support ventilation (ASV) is a minute ventilation-controlled mode governed by a closed-loop algorithm. With ASV, tidal volume and respiratory rate are automatically adjusted to minimize work of breathing. Studies indicate that ventilation in ASV enables more rapid weaning. The authors conducted a randomized controlled trial to determine whether ventilation in ASV results in a shorter time to extubation than pressure-regulated volume-controlled ventilation with automode (PRVCa) after cardiac surgery.

Methods

Fifty patients were randomly assigned to ASV or PRVCa after elective coronary artery bypass grafting. Respiratory weaning progressed through three phases: phase 1 (controlled ventilation), phase 2 (assisted ventilation), and phase 3 (T-piece trial), followed by extubation. The primary outcome was duration of intubation (sum of phases 1-3). Secondary outcomes were duration of mechanical ventilation (sum of phases 1 and 2), number of arterial blood gas samples, and manual ventilator setting changes made before extubation.

Results

Forty-eight patients completed the study. The median duration of intubation was significantly shorter in the ASV group than in the PRVCa group (300 [205-365] vs. 540 [462-580] min; P < 0.05). This difference was due to a reduction in the duration of mechanical ventilation (165 [120-195] vs. 480 [360-510] min; P < 0.05). There were no significant differences between the ASV and PRVCa groups in the number of arterial blood gas samples taken or manual ventilator setting changes made.

Conclusions

ASV is associated with earlier extubation, without an increase in clinician intervention, when compared with PRVCa in patients undergoing uncomplicated cardiac surgery.
Hyperglycemia and Acute Coronary Syndrome
Authors: Deedwania Prakash , Kosiborod Mikhail , Barrett Eugene , Ceriello Antonio , Isley William , Mazzone Theodore , Raskin Philip
Published: March 2009

Hyperglycemia is common and associated with markedly increased mortality rates in patients hospitalized with acute coronary syndromes (ACS). Despite the fact that several studies have documented this association, hyperglycemia remains underappreciated as a risk factor, and it is frequently untreated in ACS patients. This is in large part due to limitations of prior studies, and the remaining critical gaps in our understanding of the relationship between hyperglycemia and poor outcomes. The main objective of the present statement is to summarize the current state of knowledge regarding the association between elevated glucose and patient outcomes in ACS and to outline the most important knowledge gaps in this field. These gaps include the need to specifically define hyperglycemia, develop optimal ways of measuring and tracking glucose values during ACS hospitalization, and better understand the physiological mechanisms responsible for poor outcomes associated with hyperglycemia. The most important issue, however, is whether elevated glucose is a direct mediator of adverse outcomes in ACS patients or just a marker of greater disease severity. Given the marked increase in short- and long-term mortality associated with hyperglycemia, there is an urgent need for definitive large randomized trials to determine whether treatment strategies aimed at glucose control will improve patient outcomes and to define specific glucose treatment targets. Although firm guidelines will need to await completion of these clinical trials, the present statement also provides consensus recommendations for hyperglycemia management in patients with ACS on the basis of the available data.
Regulation of Apoptotic and Inflammatory Cell Signaling in Cerebral Ischemia
Authors: Giffard Rona G. , Han Ru-Quan , Emery John F. , Duan Melissa , Pittet Jean Francois
Published: March 2009

Although heat shock proteins have been studied for decades, new intracellular and extracellular functions in a variety of diseases continue to be discovered. Heat shock proteins function within networks of interacting proteins; they can alter cellular physiology rapidly in response to stress without requiring new protein synthesis. This review focuses on the heat shock protein 70 family and considers especially the functions of the inducible member, heat shock protein 72, in the setting of cerebral ischemia. In general, inhibiting apoptotic signaling at multiple points and up-regulating survival signaling, heat shock protein 70 has a net prosurvival effect. Heat shock protein 70 has both antiinflammatory and proinflammatory effects depending on the cell type, context, and intracellular or extracellular location. Intracellular effects are often antiinflammatory with inhibition of nuclear factor-kappaB signaling. Extracellular effects can lead to inflammatory cytokine production or induction of regulatory immune cells and reduced inflammation.
Lung Injury after In Vivo Reperfusion
Authors: Matot Idit , Einav Sharon , Weiniger Carolyn F. , Pearl Ron G. , Abramovitch Rinat , Joshi Balachandra V. , Jacobson Kenneth A.
Published: March 2009

Background

Although short-term findings after lung reperfusion have been extensively reported, in vivo animal studies have not described outcome beyond the immediate time period. Therefore, the authors evaluated lung injury 27 h after reperfusion. They also investigated whether attenuation of lung injury with the A3 adenosine receptor agonist MRS3558 was sustained beyond the immediate time period.

Methods

In intact-chest, spontaneously breathing cats in which the left lower lung lobe was isolated and subjected to 2 h of ischemia and 3 h of reperfusion, MRS3558 was administered before reperfusion. Animals were killed 3 or 27 h after reperfusion.

Results

When compared with 3 h of reperfusion, at 27 h the left lower lobe showed reduced apoptosis and no change in inflammation, but increased edema. Increased edema of the nonischemic right lung and hypoxemia were observed at 27 h after left lower lobe reperfusion. Increases in phosphorylated p38 levels were found at 3 h of reperfusion compared with control lung, with further increases at 27 h. The attenuation of injury observed with MRS3558 treatment at 3 h of reperfusion was sustained at 27 h.

Conclusions

Lung edema may worsen hours after the immediate postreperfusion period, even though lung apoptosis and inflammation are reduced or show no change, respectively. This was associated with further increases in phosphorylated p38 levels. The nonischemic lung may also be affected, suggesting a systemic response to reperfusion. In addition, early attenuation of injury is beneficial beyond the immediate period after reperfusion. Treatment aimed at inhibiting p38 activation, such as A3 receptor activation, should be further studied to explore its potential long-term beneficial effect.
New Strategies to Detect Alcohol Use Disorders in the Preoperative Assessment Clinic of a German University Hospital
Authors: Kip Miriam J. , Neumann Tim , Jugel Constanze , Kleinwaechter Robin , Weiss-Gerlach Edith , Guill Martin Mac , Spies Claudia D.
Published: March 2009

Background

Although alcohol use disorders (AUDs) have enormous public health consequences, the rate of diagnosis of AUDs remains unsatisfactorily low. The primary aim of this study was to compare the detection of AUDs by anesthesiologists in a large preoperative assessment clinic to that by computerized self-assessment of the Alcohol Use Disorder Identification Test. Secondary outcome measures were to compare the actions taken by anesthesiologists upon a finding of an AUD.

Methods

One thousand five hundred fifty-six patients were included. Before preoperative assessment, patients were asked to complete the Alcohol Use Disorder Identification Test (positive scores: men > or = 8, women > or = 5) using a computer. The authors performed a retrospective chart analysis of the anesthesiologists' actions upon a finding of an AUD. The anesthesiologists were blinded to the results of the computer-based assessment and to the subsequent chart analysis.

Results

The prevalence rate of AUDs determined by the anesthesiologists was 6.9% (107 of 1,556), whereas the proportion of patients positive for an AUD using the computerised Alcohol Use Disorder Identification Test was 18.1% (282 of 1,556) (P < 0.001). The detection rate by the anesthesiologists of AUDs among men was significantly higher than among women (P < 0.001) as well as in the elderly compared with younger patients (P < 0.001). Action taken by anesthesiologists was mainly based on evaluating quantity of alcohol consumption.

Conclusion

The computer-based self-assessment increases detection rates of AUDs in busy settings such as a preoperative assessment clinic. Prevalence rates of AUDs are underestimated. Best-practice guidelines for detection of AUDs are not implemented in the daily clinical routine. Barrier analysis is urgently required.
Pretreatment Swallowing Exercises Improve Swallow Function After Chemoradiation
Authors: Carroll William R. , Locher Julie L. , Canon Cheri L. , Bohannon Isaac A. , McColloch Nancy L. , Magnuson J Scott
Published: March 2009

Objectives/Hypothesis: Swallowing dysfunction is a devastating complication of chemoradiation therapy (CRT) for head and neck squamous cell carcinoma. We have previously demonstrated that pretreatment swallowing exercises improve posttreatment swallowing‐related quality of life. This study evaluates the effect of pretreatment swallowing exercises on posttreatment swallow function as measured by videofluoroscopy.

Study Design: Retrospective case control.

Methods: Eighteen patients with advanced squamous cell carcinoma of the oropharynx, hypopharynx, and larynx treated at University of Alabama at Birmingham with CRT were included in the study. Nine patients received pretreatment swallowing exercises prior to CRT, and nine patients received swallowing exercises during routine posttreatment management. Approximately 3 months after completing treatment, standard videofluoroscopy examinations were conducted. Outcomes measured by the videofluoroscopy examinations included hyoid elevation, epiglottis inversion, tongue base movement, cricopharyngeal opening, and Rosenbeck aspiration score. Percutaneous endoscopic gastrostomy (PEG) tube use was assessed at 12 months after treatment.

Results: Epiglottis inversion was better maintained (P = .05) in patients receiving pretreatment swallowing therapy. The position of the tongue base during swallowing was also significantly closer to the posterior pharyngeal wall (P = .025) for patients receiving pretreatment exercises. PEG tube removal rates did not significantly differ between groups.

Conclusions: Performing pretreatment swallowing exercises produces measurable improvements in posttreatment swallowing function in patients who undergo organ‐preservation CRT for head and neck cancer. This study provides an initial foundation for the development of noninvasive, cost‐effective, evidence‐based interventions in this group of vulnerable patients.
Ultrasound‐Guided Fine Needle Aspiration Biopsy of Thyroid Nodules Performed in the Office
Authors: Seiberling Kristin A. , Dutra Jose C. , Gunn James
Published: March 2009

Introduction: The majority of thyroid fine needle aspiration biopsies (FNAB) today are performed in the office freehand by palpation. Not infrequently, patients are sent to radiology for an ultrasound‐guided FNAB (USG‐FNB). Real‐time ultrasound (US) allows for continuous visualization of the needle during insertion and sampling. Historically, USG‐FNAB has been a procedure performed by a radiologist in a designated radiology suite. In more recent years, with the development of smaller more portable US machines, there has been a push for clinicians other than radiologists to perform the procedure.

Objective: To evaluate the accuracy and specimen adequacy of thyroid FNAB performed in the office under US guidance by one senior otolaryngologist.

Methods: Retrospective chart review of 203 patients who underwent ultrasound‐guided USG‐FNA of the thyroid gland between September, 2005, to February, 2007, in the office setting by one senior otolaryngologist. Specimens were reviewed onsite at the time of biopsy for cellular adequacy by a cytotechnologist.

Results: A total of 203 patients, 176 females and 27 males, underwent USG‐FNA of the thyroid gland. The average age of the females was 52 years, and 59.4 years for the males. A total of 271 FNA biopsies were performed. Two hundred and twenty FNAB were satisfactory specimens (81.2%), 26 were unsatisfactory (9.6%), and 25 (9.2%) were limited due to blood clotting or hypocellularity. Of the FNA specimens that had enough cells to evaluate, 159 were benign, 48 were indeterminate for malignacy, and 13 were positive for malignancy. Of the nodules biopsied, 143 were greater than 1.5 cm (average 2.59 cm, unsatisfactory rate 12.6%), and 128 were less than 1.5 cm (average 1.21 cm, unsatisfactory rate 6.3%).In 44 patients, one or more nodule was biopsied at the same office visit.

Discussion: Thyroid US is an indispensable tool in the workup and diagnosis of thyroid disease. It may be used to help identify pathology and physical features suspicious for malignancy and guide FNAB of suspicious nodules. The availability of an office US machine allows the referring physician to perform a service that is normally done in a different department. This ultimately frees up time for both the patient and physician and reduces health care costs by eliminating extra office visits. More importantly, it allows the primary physician to be more knowledgeable and hands on with the patient's overall care.

Conclusion: This study shows that a trained physician may perform a USG‐FNA of the thyroid gland in the office with results comparable to that in the radiology literature.
The Residency Experience in Pediatric Otolaryngology
Authors: Kerscher Kara , Tabaee Abtin , Ward Robert , Haddad Joseph , Grunstein Eli
Published: March 2009

Objectives: To assess the residency experience in pediatric otolaryngology, determine the impact of pediatric fellowship programs on residency training, and evaluate the need for fellowship training in pediatric otolaryngology.

Design: An anonymous, web‐based survey of chief residents in otolaryngology.

Methods: Respondents described their experience in pediatric otolaryngology using a 5‐point Likert scale and reported their comfort levels (yes/no) with various medical and surgical issues in pediatric otolaryngology.

Results: The survey was successfully completed by 70 respondents, representing a response rate of 26%. The majority of the respondents reported positive experiences with regard to the following aspects of pediatric otolaryngology training: didactics (81%), clinical research opportunities (78%), positive faculty role models (87%), career mentorship (74%), independent medical (84%) and surgical (81%) decision‐making, and overall comprehensive residency experience (87%). Basic science research opportunities (50%) were reported as less available than clinical research opportunities (78%) (P = .002). Compared with other surveyed issues, a lower comfort level was reported for management of craniofacial anomalies (P < .001), excision of large lymphatic malformations (P < .001), cochlear implantation (P < .001), laryngotracheal reconstruction (P < .001), and surgical correction of velopharyngeal insufficiency (P < .001). No statistically significant difference was noted in responses based on the presence of a fellowship program at the institution.

Conclusions: The residency experience in pediatric otolaryngology is perceived as comprehensive by graduating chief residents participating in this survey. The presence of a fellowship program does not appear to negatively impact the residency experience. Based on the reported comfort levels, the management of complex issues in pediatric otolaryngology may require additional training.