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L Kandel

Publications and source records attributed to L Kandel.

11 recordsLinked to original sources
PubMed1998

Ethanol concentrations approaching minimum alveolar anesthetic concentration are required to suppress learning in a fear-potentiated startle paradigm in rats.

UNLABELLED: We previously demonstrated that desflurane and two nonimmobilizers dose-dependently decrease learning and memory in rats. This suggests that although they do not suppress movement in response to noxious stimuli, nonimmobilizers act like inhaled anesthetics in their effects on learning and memory. Like most conventional anesthetics, nonimmobilizers have a greater affinity for lipid than for aqueous phases. In the present study, we examined the effect of ethanol on learning and memory to test the hypothesis that a large part of the capacity of anesthetics to affect learning depends on an action on a lipid (nonpolar) phase. Unlike volatile anesthetics and nonimmobilizers, ethanol has a greater affinity for water than for lipids. Thus, if our hypothesis is correct, ethanol should be relatively less potent in its suppression of memory. Rats receiving various doses of ethanol were conditioned to fear a light followed by a footshock. Fear conditioning to the light was subsequently assessed by measurement of potentiation of the acoustic startle reflex in the presence, compared with the absence, of light. Ethanol up to 0.54 minimum alveolar anesthetic concentration (MAC) did not abolish fear, but 0.82 MAC ethanol did abolish learning. Expressed as a fraction of MAC or predicted MAC, ethanol is less potent than desflurane or the nonimmobilizer 1,2-dichlorohexafluorocyclobutane in suppressing learning. This finding is consistent with the hypothesis that the capacity of anesthetics and nonimmobilizers to impair learning and memory depends mostly on an action at a nonpolar site. IMPLICATIONS: Abolition of learning and memory is an important property of inhaled anesthetics. This effect primarily results from an action at a lipid (nonpolar) site, rather than a polar site or a water-lipid interface.

Anesthetics, Inhalation↗
PubMed1998

Septic arthritis of the glenohumeral joint. A report of 11 cases and review of the literature.

Eleven cases (6 adults and 5 pediatrics) of shoulder septic arthritis are described, and the English literature from 1960 to 1997 reviewed, for a total of 168 cases. Shoulder septic arthritis is an uncommon and difficult diagnosis requiring a high index of suspicion and early evaluation of the affected shoulder by the clinician. The disease usually involves very young infants or elderly patients (65-75 years old). Associated medical conditions were identified in 60% of the patients and include systemic disorders such as liver diseases, alcoholism, and malignancies in 46%; preceding chronic arthritic disorders in 24%; and associated infectious focus in 13% of the patients. Associated infections were more prevalent in the pediatric population. Intravenous drug abuse appears not to constitute a major risk factor; it was identified in less than 5% of patients. All patients presented with acute shoulder ache or with exacerbation of existing chronic pain in joints previously damaged. Elevated body temperature (over 38 degrees C) appeared in 67% of the adult patients and in over 90% of the pediatric patients. Shoulder arthritis was frequently accompanied by an accelerated erythrocyte sedimentation rate that may rise above 100 mm/hr. Increased white blood cell count was found in approximately 40% of patients. The initial X-rays were frequently normal, while ultrasonography supported the diagnosis in some cases by demonstrating accumulation of fluid inside the joint space. Aspiration of synovial fluid from the affected glenohumeral joint was necessary to evaluate the offending pathogen. False-negative Gram stain appeared in approximately 90% of the patients, whereas synovial fluid cultures demonstrated the pathogen in 88% of patients. Blood cultures were positive in 50% of adult patients and 90% of pediatric patients. The most common isolated pathogen was Staphylococcus aureus, which accounted for 41% of infections. Gram-negative bacilli, which accounted for about 20% of infections, are more prevalent in the pediatric population, especially the neonates. Pyogenic shoulder arthritis should first be treated with intravenous antibiotics, effective at least against staphylococcal infections, until the organisms and sensitivities are identified. Duration of antibiotic therapy should be 3-6 weeks. Unfortunately, our experience in addition to the literature summary does not allow statistical analysis and firm conclusions concerning the best therapeutic approach. However, it appears that in the adult population an operative draining procedure is preferred, whereas in the pediatric population, a closed needle aspiration, if needed at all, is the optimal treatment. With prompt antibiotic therapy and drainage of the shoulder, the patient can be expected to improve clinically, with no serious long-term debilitating effects from the disease.

Aged↗
PubMed1997

Anesthetic potencies of n-alkanols: results of additivity and solubility studies suggest a mechanism of action similar to that for conventional inhaled anesthetics.

The mechanism by which n-alkanols produce anesthesia and the characteristics relevant to those mechanisms (e.g., lipid solubilities versus potencies) remain unknown. Accordingly, we determined potencies (minimum alveolar anesthetic concentration [MAC]) and solubilities of normal methanol, ethanol, butanol, hexanol, and octanol. We also determined the additivity of these alkanols with a conventional anesthetic (desflurane) and the additivity of methanol with butanol. Finally, we determined whether alkanol metabolism influences alkanol potencies. MAC for methanol, ethanol, butanol, hexanol, and octanol (0.00200, 0.000989, 0.000133, 0.0000214, and 0.00000117 atm, respectively) increased with an increasing solubility in olive oil (olive oil/gas partition coefficients 48.6, 108, 1,650, 11,600, and 93,500, respectively) and octanol (octanol/gas partition coefficients 163, 1,150, 22,900, 135,000, and 4,140,000) to give a product of MAC x solubility for olive oil approximately 10 times less (values of 0.10-0.25) than that expected from the Meyer-Overton hypothesis (compared with conventional inhaled anesthetics). There was less deviation for octanol, but the results were more variable. Inhibition of methanol and butanol metabolism by 4-methylpyrazole did not alter MAC. Methanol, ethanol, butanol, hexanol, and octanol had approximately additive anesthetic effects with desflurane, with some small but statistically significant deviations both above and below additivity. In the presence of 0.5 MAC of desflurane, we needed to add 0.4-0.6 MAC of each alkanol to inhibit the movement of 50% of the rats in response to noxious stimulation. Similarly, the effects of methanol and butanol were additive (with each other). The saline/gas partition coefficient for each alkanol was high (3700, 2650, 1400, 900, and 709 for methanol through octanol), which indicates high polarity. We conclude that the potent anesthetic effects of normal alkanols may result from an affinity to both polar and nonpolar phases. Our finding of additivity of alkanols with each other is consistent with a common mechanism of action. Similarly, the finding of additivity or slight deviations from additivity for alkanols with desflurane is consistent with mechanisms of action that have much in common.

Alcohols↗
PubMed1996

Nonanesthetics can suppress learning.

Nonanesthetic gases or vapors do not abolish movement in response to noxious stimuli despite partial pressures and affinities for lipids that would, according to the Meyer-Overton hypothesis, predict such abolition. We investigated whether nonanesthetics depress learning and memory (i.e., provide amnesia). To define learning, we used a "fear-potentiated startle paradigm": rats trained to associate light with a noxious stimulus (footshock) will startle more, as measured by an accelerometer, when a startle-eliciting stimulus (e.g., a noise) is paired with light than when the startle-eliciting stimulus is presented alone. We imposed light-shock pairings on 98 rats under three conditions: no anesthesia (control); 0.20, 0.29, and 0.38 times the minimum alveolar anesthetic concentration (MAC) of desflurane; or two nonanesthetics (1,2-dichloroperfluorocyclobutane and perfluoropentane) at partial pressures predicted from their lipid solubilities to be between 0.2 and 1 MAC. Desflurane produced a dose-related depression of learning with abolition of learning at 0.28 MAC. Perfluoropentane at 0.2-predicted MAC had the same effect as 0.28 MAC desflurane. 1,2-Dichloroperfluorocyclobutane at 0.5- to 1-predicted MAC abolished learning. Because nonanesthetics suppress learning but not movement (the two critical components of anesthesia), they may prove useful in discriminating between mechanisms and sites of action of anesthetics.

Anesthetics, Inhalation↗
PubMed1996

Metabolism of compound A by renal cysteine-S-conjugate beta-lyase is not the mechanism of compound A-induced renal injury in the rat.

Compound A [CF2 = C(CF3)OCH2F], a vinyl ether produced by CO2 absorbents acting on sevoflurane, can produce corticomedullary junction necrosis (injury to the outer stripe of the outer medullary layer, i.e., corticomedullary junction) in rats. Several halogenated alkenes produce a histologically similar corticomedullary necrosis by converting glutathione conjugates of these alkenes to halothionoacetyl halides. To test whether this mechanism explained the nephrotoxicity of Compound A, we blocked three metabolic steps which would lead to formation of a halothionoacetyl halide: 1) we depleted glutathione by administering dl-buthionine-S, R-sulfoximine (BSO); 2) we blocked cysteine S-conjugate formation by administering acivicin (AT-125); and 3) we inhibited subsequent metabolism by renal cysteine conjugate beta-lyase to the nephrotoxic halothionoacetyl halides by administering aminooxyacetic acid (AOAA). These treatments were given alone or in combination to separate groups of 10 or 20 Wistar rats before their exposure to Compound A. We hypothesized that blocking these metabolic steps should decrease the injury produced by breathing 150 ppm of Compound A for 3 h. However, we found either no change or an increase in renal injury, suggesting that this pathway mediates detoxification rather than toxicity. Our findings suggest that the cysteine-S-conjugate-mediated pathway is not the mechanism of Compound A nephrotoxicity and, therefore, observed interspecies differences in the activity of this activating pathway may not be relevant in the prediction of the nephrotoxic potential of Compound A in clinical practice.

Aminooxyacetic Acid↗
PubMed1996

Factors affecting production of compound A from the interaction of sevoflurane with Baralyme and soda lime.

Various alkali (e.g., soda lime) convert sevoflurane to CF2=C(CF3)OCH2F, a vinyl ether called "Compound A, " whose toxicity raises concerns regarding the safe administration of sevoflurane via rebreathing circuits. In the present investigation, we measured the sevoflurane degradation and output of Compound A caused by standard (13% water) Baralyme brand absorbent and standard (15% water) soda lime, and Baralyme and soda lime having various water contents (including no water). We used a flow-through system, applying a gas flow rate relative to absorbent volume that roughly equaled the rate/volume found in clinical practice. Both absorbents, at similar water contents, temperatures, and sevoflurane concentrations, produced roughly equal concentrations of Compound A. Dry and nearly dry absorbents produced less Compound A early in exposure to sevoflurane, and more later, than standard absorbents. Increases in temperature and sevoflurane concentration increased output of Compound A. Both absorbents, especially when dry, also destroyed Compound A, the concentration exiting from absorbent resulting from a complex sum of production and destruction. We conclude that the variability of concentrations of Compound A found in clinical practice may be largely explained by the inflow rate used (i.e., by rebreathing), sevoflurane concentration, and absorbent temperature and dryness. The effect of dryness is complex, with fresh dry absorbent destroying Compound A as it is made, and with dry absorbent that has been exposed to sevoflurane for a period of time providing a sometimes unusually high output of Compound A.

Absorption↗
PubMed1996

Anesthetic and convulsant properties of aromatic compounds and cycloalkanes: implications for mechanisms of narcosis.

We examined the anesthetic and convulsant properties of 16 unfluorinated to completely fluorinated aromatic compounds, having six to nine carbon atoms (e.g., benzene to 1,3,5-tris(trifluoromethyl)benzene), and four cycloalkanes (cyclopentane to cyclooctane). Benzene, fluorobenzene, toluene, p-xylene, ethylbenzene, and cyclopentane caused excitation (twitching, jerking, and hyperactivity), and three aromatic compounds (perfluorotoluene, p-difluorotoluene and 1,3,5-tris(trifluoromethyl)benzene) and three cycloalkanes (cyclohexane, cycloheptane, and cyclooctane) produced convulsions. Cyclooctane and 1,3,5-tris(trifluoromethyl)benzene were nonanesthetics. Except for nonanesthetics and perfluorotoluene (too toxic to test for anesthetic potency), all compounds produced anesthesia or decreased the minimum alveolar anesthetic concentration of desflurane. Aromatic compounds were more potent and lipid-soluble than n-alkanes (data from previous report) and cycloalkanes. All three series increasingly disobeyed the Meyer-Overton hypothesis as molecular size increased. For a particular number of carbons (e.g., cyclohexane, n-hexane, and benzene), the deviation was cycloalkanes > or = normal alkanes > aromatic compounds. These results suggest that molecular shape (including "bulkiness") and size provide limited clues to the structure of the anesthetic site of action.

Anesthesia, Inhalation↗
PubMed1995

Carbon monoxide production from degradation of desflurane, enflurane, isoflurane, halothane, and sevoflurane by soda lime and Baralyme.

Anecdotal reports suggest that soda lime and Baralyme brand absorbent can degrade inhaled anesthetics to carbon monoxide (CO). We examined the factors that govern CO production and found that these include: 1) The anesthetic used: for a given minimum alveolar anesthetic concentration (MAC)-multiple, the magnitude of CO production (greatest to least) is desflurane > or = enflurane > isoflurane >> halothane = sevoflurane. 2) The absorbent dryness: completely dry soda lime produces much more CO than absorbent with just 1.4% water content, and soda lime containing 4.8% or more water (standard soda lime contains 15% water) generates no CO. In contrast, both completely dry Baralyme and Baralyme with 1.6% water produce high concentrations of CO, and Baralyme containing 4.7% water produces concentrations equaling those produced by soda lime containing 1.4% water. Baralyme containing 9.7% or more water and standard Baralyme (13% water) do not generate CO.3) The type of absorbent: at a given water content, Baralyme produces more CO than does soda lime. 4) The temperature: an increased temperature increases CO production. 5) The anesthetic concentration: more CO is produced from higher anesthetic concentrations. These results suggest that CO generation can be avoided for all anesthetics by using soda lime with 4.8% (or more) water or Baralyme with 9.7% (or more) water, and by using inflow rates of less than 2-3 L/min. Such inflow rates are low enough to ensure that the absorbent does not dry out.

Adsorption↗
PubMed1995

Nephrotoxicity in rats undergoing a one-hour exposure to compound A.

We previously demonstrated that rats experienced renal injury when exposed for 3-12 h to 50 ppm or more of a vinyl ether called Compound A [CF2 = C(CF3)OCH2F], a compound produced by CO2 absorbents acting on sevoflurane. These durations of exposure exceed the average duration of clinical anesthesia. We now report the effect of a 1-h exposure to 0, 100, 150, 200, 400, 600, or 800 ppm of Compound A in oxygen in 145 Wistar rats. Twenty-four hours after exposure, we obtained kidney and liver specimens for microscopic examination, applying hematoxylin and eosin, and (separately) an immunochemical marker (PCNA) for cell proliferation (regeneration). Compared with results from control rats (those breathing oxygen for 1 h), renal injury (defined as necrosis of the outer strip of the outer medullary layer or "corticomedullary junction necrosis") occurred at and above 200 ppm. Exposure to 150 ppm produced cell regeneration (i.e., stimulated cell proliferation). We conclude that the threshold concentrations for nephrotoxicity (i.e., minimal toxicity) for a 1-h exposure to Compound A exceed the maximum concentrations (particularly those at low inflow rates) reported in clinical practice by a factor of 2-3. If these threshold effects in rats apply to humans, one 1-h exposure to sevoflurane probably would not alter usual measures of renal function.

Animals↗
PubMedDate not supplied

Foreign-body synovitis mimicking septic arthritis of the knee.

Three cases are presented of recurrent synovitis of the knee in children caused by the presence of foreign material. There was no clear history of trauma. Arthroscopy is a useful method providing early diagnosis and simultaneous treatment of this condition.

Adolescent↗