bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Insights into the Mechanism of Methoxyflurane Nephrotoxicity and Implications for Anesthetic Development (Part 1)
Authors: Kharasch Evan D. , Schroeder Jesara L. , Liggitt H Denny , Park Sang B. , Whittington Dale , Sheffels Pamela 
Published: September 2006

Background
Methoxyflurane nephrotoxicity results from biotransformation; inorganic fluoride is a toxic metabolite. Concern exists about potential renal toxicity from volatile anesthetic defluorination, but many anesthetics increase fluoride concentrations without consequence. Methoxyflurane is metabolized by both dechlorination to methoxydifluoroacetic acid (MDFA, which may degrade to fluoride) and O-demethylation to fluoride and dichloroacetatic acid. The metabolic pathway responsible for methoxyflurane nephrotoxicity has not, however, been identified, which was the aim of this investigation.

Methods
Experiments evaluated methoxyflurane metabolite formation and effects of enzyme induction or inhibition on methoxyflurane metabolism and toxicity. Rats pretreated with phenobarbital, barium sulfate, or nothing were anesthetized with methoxyflurane, and renal function and urine methoxyflurane metabolite excretion were assessed. Phenobarbital effects on MDFA metabolism and toxicity in vivo were also assessed. Metabolism of methoxyflurane and MDFA in microsomes from livers of pretreated rats was determined in vitro.

Results
Phenobarbital pretreatment increased methoxyflurane nephrotoxicity in vivo (increased diuresis and blood urea nitrogen and decreased urine osmolality) and induced in vitro hepatic microsomal methoxyflurane metabolism to inorganic fluoride (2-fold), dichloroacetatic acid (1.5-fold), and MDFA (5-fold). In contrast, phenobarbital had no influence on MDFA renal effects in vivo or MDFA metabolism in vitro or in vivo. MDFA was neither metabolized to fluoride nor nephrotoxic. Barium sulfate diminished methoxyflurane metabolism and nephrotoxicity in vivo.

Conclusions
Fluoride from methoxyflurane anesthesia derives from O-demethylation. Phenobarbital increases in methoxyflurane toxicity do not seem attributable to methoxyflurane dechlorination, MDFA toxicity, or MDFA metabolism to another toxic metabolite, suggesting that nephrotoxicity is attributable to methoxyflurane O-demethylation. Fluoride, one of many metabolites from O-demethylation, may be toxic and/or reflect formation of a different toxic metabolite. These results may have implications for interpreting anesthetic defluorination, volatile anesthetic use, and methods to evaluate anesthetic toxicity.
New Insights into the Mechanism of Methoxyflurane Nephrotoxicity and Implications for Anesthetic Development (Part 2)
Authors: Kharasch Evan D. , Schroeder Jesara L. , Liggitt H Denny , Ensign Dustin , Whittington Dale 
Published: September 2006

Background
Methoxyflurane nephrotoxicity results from its metabolism, which occurs by both dechlorination (to methoxydifluoroacetic acid [MDFA]) and O-demethylation (to fluoride and dichloroacetic acid [DCAA]). Inorganic fluoride can be toxic, but it remains unknown why other anesthetics, commensurately increasing systemic fluoride concentrations, are not toxic. Fluoride is one of many methoxyflurane metabolites and may itself cause toxicity and/or reflect formation of other toxic metabolite(s). This investigation evaluated the disposition and renal effects of known methoxyflurane metabolites.

Methods
Rats were given by intraperitoneal injection the methoxyflurane metabolites MDFA, DCAA, or sodium fluoride (0.22, 0.45, 0.9, or 1.8 mmol/kg followed by 0.11, 0.22, 0.45, or 0.9 mmol/kg on the next 3 days) at doses relevant to metabolite exposure after methoxyflurane anesthesia, or DCAA and fluoride in combination. Renal histology and function (blood urea nitrogen, urine volume, urine osmolality) and metabolite excretion in urine were assessed.

Results
Methoxyflurane metabolite excretion in urine after injection approximated that after methoxyflurane anesthesia, confirming the appropriateness of metabolite doses. Neither MDFA nor DCAA alone had any effects on renal function parameters or necrosis. Fluoride at low doses (0.22, then 0.11 mmol/kg) decreased osmolality, whereas higher doses (0.45, then 0.22 mmol/kg) also caused diuresis but not significant necrosis. Fluoride and DCAA together caused significantly greater tubular cell necrosis than fluoride alone.

Conclusions
Methoxyflurane nephrotoxicity seems to result from O-demethylation, which forms both fluoride and DCAA. Because their co-formation is unique to methoxyflurane compared with other volatile anesthetics and they are more toxic than fluoride alone, this suggests a new hypothesis of methoxyflurane nephrotoxicity. This may explain why increased fluoride formation from methoxyflurane, but not other anesthetics, is associated with toxicity. These results may have implications for the interpretation of clinical anesthetic defluorination, use of volatile anesthetics, and the laboratory methods used to evaluate potential anesthetic toxicity.
Adding Bupivacaine to High-potassium Cardioplegia Improves Function and Reduces Cellular Damage of Rat Isolated Hearts after Prolonged, Cold Storage
Authors: Ross James D. , Ripper Richard , Law William R. , Massad Malek , Murphy Patricia , Edelman Lucas , Conlon Beth , Feinstein Douglas L. , Palmer June W. , DiGregorio Guido , Weinberg Guy L. 
Published: September 2006

Background
Bupivacaine retards myocardial acidosis during ischemia. The authors measured function of rat isolated hearts after prolonged storage to determine whether bupivacaine improves cardiac protection compared with standard cardioplegia alone.

Methods
After measuring cardiac function on a Langendorff apparatus, hearts were perfused with cardioplegia alone (controls), cardioplegia containing 500 microm bupivacaine, or cardioplegia containing 2 mm lidocaine; were stored at 4 degrees C for 12 h; and were then reperfused. Heart rate and left ventricular developed pressures were measured for 60 min. Maximum positive rate of change in ventricular pressure, oxygen consumption, and lactate dehydrogenase release were also measured.

Results
All bupivacaine-treated, four of five lidocaine-treated, and no control hearts beat throughout the 60-min recovery period. Mean values of heart rate, left ventricular developed pressure, maximum positive rate of change in ventricular pressure, rate-pressure product, and efficiency in bupivacaine-treated hearts exceeded those of the control group (P < 0.001 at 60 min for all). Mean values of the lidocaine group were intermediate. Oxygen consumption of the control group exceeded the other groups early in recovery, but not at later times. Lactate dehydrogenase release from the bupivacaine group was less than that from the control group (P < 0.001) but did not differ from baseline.

Conclusions
Adding bupivacaine to a depolarizing cardioplegia solution reduces cell damage and improves cardiac function after prolonged storage. Metabolic inhibition may contribute to this phenomenon, which is not entirely explained by sodium channel blockade.
Supraspinal Anesthesia
Authors: Jugovac Izabela , Imas Olga , Hudetz Anthony G. 
Published: September 2006

Background
Anesthetic endpoints of unconsciousness and immobility result from agent effects on both brain and spinal cord that are difficult to separate during systemic administration. To investigate cerebral mechanism of anesthetic-induced unconsciousness, the authors studied behavioral and electrophysiologic effects of four anesthetics infused intracerebroventricularly to conscious rats. The authors aimed to produce progressively increasing anesthetic depths, indicated by electro-encephalographic synchronization and behavioral change.

Methods
During anesthesia, rats were equipped with intracerebroventricular infusion catheters, hind-paw stimulation, and epidural electrodes to record the electroencephalogram from the somatosensory cortex. Silicone bolus was injected into the fourth ventricle to minimize drug distribution to the spinal cord. 60 min later, 50-min infusion of pentobarbital (6.0 mg/h), fentanyl (0.75 microg/h), propofol (3.0 mg/h), or midazolam (0.24 mg/h) was initiated. Vibrissal, olfactory, corneal, and tail-pinch responses were tested every 10 min.

Results
All agents depressed vibrissal, olfactory, and corneal responses; propofol and pentobarbital produced the strongest effect. All agents except propofol depressed tail-pinch response; fentanyl and pentobarbital produced the strongest effect. All agents except midazolam increased delta power. Pentobarbital enhanced theta power. All agents except fentanyl enhanced alpha and beta power. Pentobarbital and midazolam slightly increased, whereas fentanyl decreased, gamma power. Pentobarbital increased and midazolam decreased somatosensory evoked potential; these changes were small and apparently unrelated to behavior.

Conclusions
Alpha and beta power increase may reflect sedative component of anesthesia. Simultaneous delta, alpha, and beta power increase may correlate with loss of consciousness. Theta and delta power increase may reflect surgical anesthesia. Opioid-induced gamma power decrease may reflect suppression of pain perception. Pentobarbital-, fentanyl-, and midazolam-induced immobility to noxious stimulation may be mediated supraspinally.
Pain after Cardiac Surgery
Authors: Lahtinen Pasi , Kokki Hannu , Hynynen Markku 
Published: September 2006

Background
Persistent chest pain may originate from cardiac surgery. Conflicting results have been reported on the incidence of persistent poststernotomy pain with considerable discrepancies between the retrospective reports and the one prospective study conducted to assess this pain. Therefore, the authors conducted a follow-up survey for the first 12 months after cardiac surgery in 213 patients who had a sternotomy.

Methods
The authors performed a prospective inquiry of acute and chronic poststernotomy pain both before and after cardiac surgery. Two hundred thirteen coronary artery bypass patients received a questionnaire preoperatively, 4 days postoperatively, and 1, 3, 6, and 12 months postoperatively. All patients were asked about their expectations, their preferences, and the location and intensity of postoperative pain.

Results
The return rates for the postal questionnaires were 203 (95%) and 186 (87%) after 1 and 12 months, respectively. Patients experienced more pain postoperatively at rest than they had expected to preoperatively. At rest, the worst actual postoperative pain was 6 (0-10), and the worst expected pain as assessed preoperatively was 5 (0-10) (P = 0.013). The worst reported postoperative pain was severe (numeric rating scale score 7-10) in 49% at rest, in 78% during coughing, and in 62% of patients on movement. One year after the operation, 26 patients (14%) reported mild chronic poststernotomy pain at rest, 1 patient (1%) had moderate pain, and 3 patients (2%) had severe pain. Upon movement, persistent pain was even more common: 45 patients (24%) had mild, 5 patients (3%) had moderate, and 7 patients (4%) had severe pain. Patients who experienced moderate to severe acute postoperative pain also reported any chronic poststernotomy pain (numeric rating scale score 1-10) more frequently.

Conclusions
Although common, the incidence of persistent pain after sternotomy was lower than previously reported. Also, reassuringly, 1 year after surgery this pain was mostly mild in nature both at rest and on movement.
Antinociception by Spinal and Systemic Oxycodone: Why Does the Route Make a Difference?
Authors: Lemberg Kim K. , Kontinen Vesa K. , Siiskonen Antti O. , Viljakka Kaarin M. , Yli-Kauhaluoma Jari T. , Korpi Esa R. , Kalso Eija A. 
Published: September 2006

Background
The pharmacology of oxycodone is poorly understood despite its growing clinical use. The discrepancy between its good clinical effectiveness after systemic administration and the loss of potency after spinal administration led the authors to study the pharmacodynamic effects of oxycodone and its metabolites using in vivo and in vitro models in rats.

Methods
Male Sprague-Dawley rats were used in hot-plate, tail-flick, and paw-pressure tests to study the antinociceptive properties of morphine, oxycodone, and its metabolites oxymorphone and noroxycodone. Mu-opioid receptor agonist-stimulated GTPgamma[S] autoradiography was used to study G-protein activation induced by morphine, oxycodone, and oxymorphone in the rat brain and spinal cord. Spontaneous locomotor activity was measured to assess possible sedation or motor dysfunction. Naloxone and the selective kappa-opioid receptor antagonist nor-binaltorphimine were used to study the opioid receptor selectivity of the drugs.

Results
Oxycodone showed lower efficacy and potency to stimulate GTPgamma[S] binding in the spinal cord and periaqueductal gray compared with morphine and oxymorphone. This could relate to the fact that oxycodone produced only weak naloxone-reversible antinociception after intrathecal administration. It also suggests that the metabolites may have a role in oxycodone-induced analgesia in rats. Intrathecal oxymorphone produced strong long-lasting antinociception, whereas noroxycodone produced antinociception with very high doses only. Subcutaneous administration of oxycodone and oxymorphone produced thermal and mechanical antinociception that was reversed by naloxone but not by nor-binaltorphimine. Oxymorphone was more potent than oxycodone, particularly in the hot-plate and paw-pressure tests.

Conclusions
The low intrathecal potency of oxycodone in rats seems be related to its low efficacy and potency to stimulate mu-opioid receptor activation in the spinal cord.
Severe Toxic Damage to the Rabbit Spinal Cord after Intrathecal Administration of Preservative-free S (+)-Ketamine
Authors: Vranken Jan H. , Troost Dirk , de Haan Peter , Pennings Fritz A. , van der Vegt Marinus H. , Dijkgraaf Marcel G. W. , Hollmann Markus W. 
Published: September 2006

Background
Ketamine and S(+)-ketamine have been advocated for neuraxial use in the management of postoperative pain and severe intractable pain syndromes unresponsive to opioid escalation. Although clinical experience has accumulated with S(+)-ketamine, safety data on toxicity in the central nervous system after neuraxial administration of S(+)-ketamine are conflicting. In this study, neurologic and toxicologic effects on the spinal cord from repeated daily intrathecal administration of commercially available, preservative-free S(+)-ketamine were evaluated against placebo in a randomized, blinded design.

Methods
Eighteen white New Zealand rabbits were assigned to two groups receiving either 0.5 ml intrathecal S(+)-ketamine, 0.5% solution (12 rabbits), or 0.5 ml saline (6 rabbits) once a day for 7 consecutive days. During general anesthesia, an intrathecal catheter was placed between the fifth and sixth spinous processes (lumbar). Neurologic (according to Tarlov criteria) and histopathologic assessments were performed after 7 days of treatment.

Results
Postmortem investigation of the spinal cord and nerve roots revealed histopathologic lesions suggestive of toxic damage in 11 rabbits, from the group of 12 animals receiving S(+)-ketamine. These results were significantly different compared with 5 control animals (no histologic changes observed). There was no significant difference in neurologic status between the two groups after 7 days of intrathecal treatment.

Conclusions
The authors conclude that repeated intrathecal administration of preservative-free S(+)-ketamine in a clinically relevant concentration and dosage has, considering the extent and severity of the lesions, a toxic effect on the central nervous system of rabbits.
Silent night: adaptive disappearance of a sexual signal in a parasitized population of field crickets
Authors: Zuk Marlene , Rotenberry John T , Tinghitella Robin M 
Published: September 2006

Abstract

Sexual signals are often critical for mate attraction and reproduction, although their conspicuousness exposes them to parasites and predators. We document the near-disappearance of song, the sexual signal of crickets, and its replacement with a novel silent morph, in a population subject to strong natural selection by a deadly acoustically orienting parasitoid fly. On the Hawaiian Island of Kauai, more than 90% of male field crickets (
Teleogryllus oceanicus
) shifted in less than 20 generations from a normal-wing morphology to a mutated wing that renders males unable to call (flatwing). Flatwing morphology protects male crickets from the parasitoid, which uses song to find hosts, but poses obstacles for mate attraction, since females also use the males' song to locate mates. Field experiments support the hypothesis that flatwings overcome the difficulty of attracting females without song by acting as ‘satellites’ to the few remaining callers, showing enhanced phonotaxis to the calling song that increases female encounter rate. Thus, variation in behaviour facilitated establishment of an otherwise maladaptive morphological mutation.
Models of in warm, diffuse, molecular gas in the Galactic centre
Authors: Le Petit Franck , Roueff Evelyne 
Published: September 2006

Oka
et al
. (Oka
et al
. 2005
Astrophys. J
.
632
, 882–893) have recently observed a large column density of

in the Galactic centre. In one of the gaseous components, a column density of

in its metastable level (3,3) of approximately 4×10
14
cm
−2
is measured. From the excitation of

, they deduce a density below 50 cm
−3
and a temperature approximately 270 K. In this paper, we report results for this region from a new version of our PDR code which includes the

excitation. Models show it is unlikely that the mean temperature of the gas could be above 100 K. We also show that there is a possibility to produce hot

in C-shocks.
The biological and physical stability and resilience of a selection of Scottish soils to stresses
Authors: Kuan H. L. , Hallett P. D. , Griffiths B. S. , Gregory A. S. , Watts C. W. , Whitmore A. P. 
Published: September 2006

SummaryThe ability of soil to resist and recover from anthropogenic and environmental stresses defines stability and resilience, respectively; an understanding of this ability is critical to sustainable land‐use. In this study of 26 soils from across Scotland, we examine the influence of soil properties and antecedent conditions on physical and biological resilience to stress. The sites studied covered a wide range of soil types and land management, including serpentine soil from the Shetland Islands, a catena on the Highland Boundary Fault, and young aeolian sandy soils on the east coast. Biological resilience was measured as CO2 evolution from soil with added plant residues after either a transient (heat) or a persistent (copper) stress. Measures of physical resilience were: (i) compression and expansion indices following rapid uniaxial compression (to 50 kPa) and relaxation; and (ii) void ratio changes due to an overburden stress and subsequent cycles of wetting and drying. Evolution of CO2 from soil with added plant residues after heat or copper stress ranged from 23% to >100% that of the unperturbed soil, while the air‐filled void ratio after the overburden stress ranged from 70% to >100% that of the unperturbed soil. Soils were grouped into quartiles based on their resistance to and recovery after each of the four prescribed stresses. Soil organic carbon (SOC) content correlated strongly with resilience after biological and physical stresses, particularly resistance to Cu stress (r= 0.72) and recovery from compression (r= 0.67), whereas there were no strong correlations between resilience following heat and any of the measured soil characteristics, although both land use and soil class were helpful in separating the responses. Resistance to compression was negatively correlated with SOC (r=−0.63).
Effects of artificial ultraviolet‐B radiation on growth and fatty acid composition of duckweed (Lemna minor)
Authors: YOUNG D. L. W. , WIEGAND M. D. , LOADMAN N. L. , COLLINS S. A. , BALLEVONA A. J. , HUEBNER J. D. 
Published: September 2006

Summary1. Duckweed (Lemna minor), collected either in summer or early fall was exposed under laboratory conditions to control (photosynthetically active and UV‐A radiation) or experimental (control plus UV‐B radiation) conditions.2. Growth and survival were determined by counting the number of green, and brown/white fronds following 1–5 or 11 days of irradiation. Growth of duckweed was impaired by exposure to UV‐B radiation in the fall experiment but not in the summer.3. Fatty acid compositions were analysed following 5 or 11 days of irradiation and a recovery period of 0, 5, 29 or 40 h. Concentrations of the major fatty acids, palmitic, linoleic (LA) and α‐linolenic (ALA) acids were similar in the summer and fall duckweed collections, but the summer samples had higher concentrations of the desaturation products of LA and ALA.4. UV‐B exposure had small, but significant, and contrasting effects on duckweed fatty acid concentrations. In the summer experiment, duckweed exposed to UV‐B had slightly lower concentrations of major fatty acids than control duckweed, while the reverse was true in the fall experiments.5. These minor effects of UV‐B on concentrations of LA and ALA would be unlikely to have a major impact on the supply of these essential fatty acids from duckweed to freshwater food webs.
Carbon pathways to zooplankton: insights from the combined use of stable isotope and fatty acid biomarkers
Authors: PERGA MARIE‐ELODIE , KAINZ MARTIN , MATTHEWS BLAKE , MAZUMDER ASIT 
Published: September 2006

Summary1. Numerous studies have quantified the relative contribution of terrestrial‐ and phytoplankton‐derived carbon sources to zooplankton secondary production in lakes. However, few investigated the pathways along which allochthonous and autochthonous carbon (C) was actually conveyed to consumers.2. We suggest that the combined use of fatty acid and stable isotope biomarkers could solve this issue. We conducted a field study on two oligotrophic lakes, in which primary production increased significantly between 2002 and 2004. We used modelling to estimate the contribution of terrestrial‐ and phytoplankton‐derived C to particulate organic C (POC) and zooplankton production from their δ13C values in 2002 and 2004.3. According to the isotope model, phytoplankton‐derived C accounted for a major part of the POC pool in both lakes and supported more Daphnia sp. production in 2004 than in 2002. Fatty acid data revealed that increased contribution of algal‐C to Daphnia production, although common between both lakes, was achieved through C pathways that were different. In one lake, Daphnia grazed more intensively on phytoplankton, whereas in the other there was greater grazing on bacteria. In the latter case, the increased primary production resulted in greater release of algal‐derived dissolved organic C (DOC), which may have supported extra bacterial and eventually Daphnia, production.4. This is the first study illustrating that the combination of fatty acid and stable isotope biomarkers could further our understanding of the factors controlling the relative magnitude of food webs pathways conveying organic matter to zooplankton.