A rational approach to anaesthetic premedication.

Rational use of premedication for anaesthesia must always be modified and updated to keep pace with the evolving fields of anaesthesiology and surgery, as well as to meet changing patient needs and preferences. It is no longer axiomatic that all patients require, and therefore should receive, premedication. Unfortunately, a variety of traditional reasons have been proposed to justify routine premedication in many institutions. Smoothing induction, decreasing reflexes and arrhythmias, decreasing nausea and vomiting, decreasing pain, decreasing secretions, and producing sedation and amnesia have all been claimed historically as beneficial results of premedication. Modern anaesthetic agents and techniques have come a long way towards eliminating the routine need for premedication. In the preoperative period, the goal of an anxiety-free patient who is physiologically uncompromised requires an individualised approach based on experience and an adequate knowledge of current pharmacology. As our knowledge of potential problems associated with anaesthesia has expanded, we have added other classes of drugs such as the H2-histamine receptor blockers and antacids to our premedicant armamentarium. Outpatient and short-stay patients have further challenged our preoperative goal of an anxiety-free patient by requiring individuals to be 'street ready' within a brief period of time after surgery. Even for in-house elective procedures, not every patient is a candidate for routine premedication. A frank preoperative discussion is all that is necessary to effectively allay anxiety in many persons. In these and other special situations, this article will hopefully guide the reader toward a more rational approach to premedicating patients.

A stereotaxic system for independent coordinated positioning of two or three microelectrodes.

This paper describes a straightforward, easily built and relatively inexpensive stereotaxic system that permits independent coordinated positioning of 2 or 3 microelectrodes. This system is ideally suited for situations where the ability to routinely place one electrode at a precise position relative to another is important. Resolution of relative position and interelectrode distance is +/- 50 micrometers. This system should prove useful for the study of local interactions in such neural aggregates as nuclei, motoneuron pools and within and between cortical columns.

Drug interactions in anesthesia.

The threat of adverse drug interactions increases daily as more and more drugs become available. All physicians should be familiar with the problems of drug interactions and their management. Careful preoperative evaluation and screening combined with limited prescribing can help to limit the magnitude of this problem.

R-Isovaline: a subtype-specific agonist at GABA(B)-receptors?

The R-enantiomer of isovaline, an analgesic amino acid, has a chemical structure similar to glycine and GABA. Although its actions on thalamic neurons are strychnine-resistant and independent of the Cl(-) gradient, R-isovaline increases membrane conductance for K(+). The purpose of this study was to determine if R-isovaline activated metabotropic GABA(B) receptors. We used whole-cell voltage-clamp recordings to characterize the effects of R-isovaline applied by bath perfusion and local ejection from a micropipette to thalamic neurons in 250 µm thick slices of rat brain. The immunocytochemical methods that we employed to visualize GABA(B1) and GABA(B2) receptor subunits showed extensive staining for both subunits in ventrobasal nuclei, which were the recording sites. Bath or local application of R-isovaline caused a slowly developing increase in conductance and outward rectification in 70% (54/77) of neurons, both effects reversing near the K(+) Nernst potential. As with the GABA(B) agonist baclofen, G proteins likely mediated the R-isovaline effects because they were susceptible to blockade by non-hydrolyzable substrates of guanosine triphosphate. The GABA(B) antagonists CGP35348 and CGP52432 prevented the conductance increase induced by R-isovaline, applied by bath or local ejection. The GABA(B) allosteric modulator CGP7930 enhanced the R-isovaline induced increase in conductance. At high doses, antagonists of GABA(A), GABA(C), glycine(A), µ-opioid, and nicotinic receptors did not block R-isovaline responses. The observations establish that R-isovaline increases the conductance of K(+) channels coupled to metabotropic GABA(B) receptors. Remarkably, not all neurons that were responsive to baclofen responded to R-isovaline. The R-isovaline-induced currents outlasted the fast baclofen responses and persisted for a 1-2-h period. Despite some similar actions, R-isovaline and baclofen do not act at identical GABA(B) receptor sites. The binding of R-isovaline and baclofen to the GABA(B) receptor may not induce the same conformational changes in receptor proteins or components of the intracellular signaling pathways.

GABA(B) receptor-mediated selective peripheral analgesia by the non-proteinogenic amino acid, isovaline.

Peripherally restricted analgesics are desirable to avoid central nervous system (CNS) side effects of opioids. Nonsteroidal anti-inflammatory drugs produce peripheral analgesia but have significant toxicity. GABA(B) receptors represent peripheral targets for analgesia but selective GABA(B) agonists like baclofen cross the blood-brain barrier. Recently, we found that the CNS-impermeant amino acid, isovaline, produces analgesia without apparent CNS effects. On observing that isovaline has GABA(B) activity in brain slices, we examined the hypothesis that isovaline produces peripheral analgesia mediated by GABA(B) receptors. We compared the peripheral analgesic and CNS effect profiles of isovaline, baclofen, and GABA (a CNS-impermeant, unselective GABA(B) agonist). All three amino acids attenuated allodynia induced by prostaglandin E2 injection into the mouse hindpaw and tested with von Frey filaments. The antiallodynic actions of isovaline, baclofen, and GABA were blocked by the GABA(B) antagonist, CGP52432, and potentiated by the GABA(B) modulator, CGP7930. We measured Behavioural Hyperactivity Scores and temperature change as indicators of GABAergic action in the CNS. ED(95) doses of isovaline and GABA produced no CNS effects while baclofen produced substantial sedation and hypothermia. In a mouse model of osteoarthritis, isovaline restored performance during forced exercise to baseline values. Immunohistochemical staining of cutaneous layers of the analgesic test site demonstrated co-localization of GABA(B1) and GABA(B2) receptor subunits on fine nerve endings and keratinocytes. Isovaline represents a new class of peripherally restricted analgesics without CNS effects, mediated by cutaneous GABA(B) receptors.

Isovaline causes inhibition by increasing potassium conductance in thalamic neurons.

The rare amino acid isovaline has analgesic properties in pain models and is a structural analogue of the inhibitory neurotransmitter glycine. Glycinergic inhibition is prevalent in pain pathways. In this paper, we examined the possibility that isovaline inhibits neurons by activating strychnine (Str)-sensitive glycine(A) receptors in ventrobasal thalamus. Sagittal brain sections containing ventrobasal nuclei were prepared from P10-P15 rats. Whole-cell recordings were made in current-clamp and voltage-clamp modes. R-isovaline (R-Iva) increased input conductance and hyperpolarized the membrane. The conductance increase shunted action potentials and low-threshold Ca(2+) spikes evoked by current pulse injection. Unlike the Cl(-)-mediated responses to glycine, isovaline responses were insensitive to Str antagonism and usually not reversible. The concentration-response curve was non-sigmoidal, rising to a maximum at approximately 100 microM, and thereafter declining in amplitude. Current-voltage relationships showed that isovaline increased inward and outward rectification. The isovaline current reversed polarity close to the K(+) equilibrium potential. The relationships were negligibly affected by tetrodotoxin (TTX), chelation of intracellular Ca(2+) or blockade of the hyperpolarization-activated current, I(h). Internal Cs(+) and external Ba(2+) or Cs(+) prevented isovaline responses. In conclusion, isovaline inhibited firing mainly by activating rectifying and possibly leak K(+) currents. Isovaline-induced changes shunted action potentials and suppressed rebound excitation in ventrobasal neurons, as expected for analgesic actions.

Isolation and characterization of 16 microsatellite loci in the mountain pine beetle, Dendroctonus ponderosae Hopkins (Coleoptera: Curculionidae: Scolytinae).

We isolated 16 polymorphic microsatellite loci in the mountain pine beetle (Dendroctonus ponderosae Hopkins) and developed conditions for amplifying these markers in four multiplex reactions. Three to 14 alleles were detected per locus across two sampled populations. Observed and expected heterozygosities ranged from 0.000 to 0.902 and from 0.100 to 0.830, respectively. Three loci deviated from Hardy-Weinberg equilibrium in one sampled population. One of these loci may be sex linked. These markers will be useful in the study of population structure in this important pest species.

A robust neural networks approach for spatial and intensity-dependent normalization of cDNA microarray data.

MOTIVATION: Microarray experiments are affected by numerous sources of non-biological variation that contribute systematic bias to the resulting data. In a dual-label (two-color) cDNA or long-oligonucleotide microarray, these systematic biases are often manifested as an imbalance of measured fluorescent intensities corresponding to Sample A versus those corresponding to Sample B. Systematic biases also affect between-slide comparisons. Making effective corrections for these systematic biases is a requisite for detecting the underlying biological variation between samples. Effective data normalization is therefore an essential step in the confident identification of biologically relevant differences in gene expression profiles. Several normalization methods for the correction of systemic bias have been described. While many of these methods have addressed intensity-dependent bias, few have addressed both intensity-dependent and spatiality-dependent bias. RESULTS: We present a neural network-based normalization method for correcting the intensity- and spatiality-dependent bias in cDNA microarray datasets. In this normalization method, the dependence of the log-intensity ratio (M) on the average log-intensity (A) as well as on the spatial coordinates (X,Y) of spots is approximated with a feed-forward neural network function. Resistance to outliers is provided by assigning weights to each spot based on how distant their M values is from the median over the spots whose A values are similar, as well as by using pseudospatial coordinates instead of spot row and column indices. A comparison of the robust neural network method with other published methods demonstrates its potential in reducing both intensity-dependent bias and spatial-dependent bias, which translates to more reliable identification of truly regulated genes.

The role of interleukin-4 in the regulation of mouse primordial germ cell numbers.

Interleukin-4 (IL-4), a pleiotropic cytokine, stimulates a dose-dependent increase in the number of mouse primordial germ cells in culture. Results from bromodeoxyuridine incorporation assays suggest that IL-4 acts as a survival factor rather than as a mitogen for primordial germ cells in this system. Studies on the embryonic expression patterns of IL-4 and its receptors, using RT-PCR and ELISA, show that IL-4 and its receptors are present at the correct time and place to influence PGC numbers in vivo.

Electroencephalographic quantitation of opioid effect: comparative pharmacodynamics of fentanyl and sufentanil.

The authors compared the pharmacodynamics of sufentanil with those of fentanyl using the electroencephalogram (EEG) as a measure of opioid drug effect. Sixteen patients were given a rapid infusion of sufentanil (18.75 micrograms/min) during EEG recording. To quantitate the opioid-induced slowing of the EEG, the authors analyzed its power spectrum and calculated the spectral edge. An inhibitory sigmoid Emax model of the maximal decrease in spectral edge produced by the opioid related spectral edge values to serum concentrations of sufentanil. The resulting data for the pharmacodynamic parameters of sufentanil were compared with fentanyl parameters that were obtained by reanalysis from an identically conducted, previously published study. The half-time of blood-brain equilibration (T1/2Keo) was not statistically different between sufentanil and fentanyl (6.2 +/- 2.8 vs. 6.6 +/- 1.7 min, mean +/- SD, respectively). The intrinsic potency of sufentanil, as measured by the serum concentration needed to cause half the maximal EEG slowing (IC50), was 12-fold greater (0.68 +/- 0.31 ng/ml) than that of fentanyl (8.1 +/- 2.2 ng/ml). The second part of the study verified the hypothesis that administration of equipotent bolus doses would produce equal onset times. Bolus injections of either 125 micrograms of sufentanil or 1,250 micrograms of fentanyl were given during EEG recording. The time from injection to 50% maximal EEG slowing (T50) was calculated for each patient. The values for T50 for the two groups did not differ. The authors conclude that fentanyl and sufentanil have similar pharmacodynamic profiles, the former being 12 times more potent than the latter.

Headache after lumbar puncture: review of the epidural blood patch.

The incidence of accidental dural puncture during epidural block is 2.9%; headache follows in as many as 76.5% of these patients. Treatment by injection of autologous blood into the epidural space has gained wide acceptance since its introduction in 1960, though it is contraindicated by blood dyscrasias, anticoagulant therapy, bleeding, and localized infection. The procedure is done by slowly injecting 15 to 20 ml of blood into the same interspace, no sooner than 24 hours after the original puncture. Serious complications are rare.

Testing computer-controlled infusion pumps by simulation.

The pharmacokinetic behavior of intravenous anesthetic drugs can be described by two- or three-compartment models. Rapid achievement and maintenance of steady plasma concentrations of these drugs requires a complicated delivery scheme, perhaps best controlled by a computer. The authors developed a method of simulating the performance of a computer-controlled infusion pump from the differential equations describing drug transfer between compartments. They also derived a mathematically simple and flexible approximate solution to these equations using Euler's numerical method. They incorporated this approximate solution into a computer-controlled infusion pump for intravenous drugs. They tested their pump by simulating the administration of fentanyl to a hypothetical patient whose fentanyl pharmacokinetics were described by a three-compartment model. The exact analytical solution served as the standard of comparison. The approximation technique, using a 15-s interval between model updates, had a maximum error of 0.35 ng.ml-1, and rapidly converged on the exact solution. The simulations revealed oscillations in the system. The authors suggest that such simulations be used to evaluate computer-controlled infusion pumps prior to clinical trials of these devices.

A 28 year old woman with ventricular tachycardia and an abnormal chest radiograph.

A 28 year old white woman with no medical history presented to the emergency room with symptomatic non-sustained ventricular tachycardia. She was asymptomatic up to a few days before presentation. Her physical examination was essentially normal and hence did not help with the differential diagnosis of the problem. Bronchoscopic transbronchial biopsy led to the final diagnosis of cardiac sarcoidosis.

Colloid oncotic pressure as a guide for the anesthesiologist in directing fluid therapy.

One useful but underused parameter of fluid replacement is colloid oncotic pressure. Colloid oncotic pressure (COP) is one of the Starling forces that maintain a balance between intravascular and extravascular fluid. Systemic and pulmonary circulations exhibit differences that limit the usefulness of COP manipulation in the treatment of pulmonary edema, especially that associated with hypoxic damage or pulmonary contusion. Systemic transcapillary fluid transport, however, is governed significantly by COP, and serial measurements of COP can serve as useful guides for colloid replacement. In this paper we present instances in which COP determinations were found to be clinically helpful, and discuss colloid replacement during surgery.

Regulation of loblolly pine (Pinus taeda L.) arginase in developing seedling tissue during germination and post-germinative growth.

After seed germination, hydrolysis of storage proteins provides a nitrogen source for the developing seedling. In conifers the majority of these reserves are located in the living haploid megagametophyte tissue. In the developing loblolly pine (Pinus taeda L.) seedling an influx of free amino acids from the megagametophyte accompanies germination and early seedling growth. The major component of this amino acid pool is arginine, which is transported rapidly and efficiently to the seedling without prior conversion. This arginine accounts for nearly half of the total nitrogen entering the cotyledons and is likely a defining factor in early seedling nitrogen metabolism. In the seedling, the enzyme arginase is responsible for liberating nitrogen, in the form of ornithine and urea, from free arginine supplied by the megagametophyte. In this report we investigate how the seedling uses arginase to cope with the large arginine influx. As part of this work we have cloned an arginase cDNA from a loblolly pine expression library. Analysis of enzyme activity data, accumulation of arginase protein and mRNA abundance indicates that increased arginase activity after seed germination is due to de novo synthesis of the enzyme. Our results suggest that arginase is primarily regulated at the RNA level during loblolly pine seed germination and post-germinative growth.

Selection of anesthesiology residents.

The large numbers of medical graduates seeking residency training in anesthesiology have created a logistical problem for many programs. This difficulty and the recurrent phenomenon of the misplaced physician have prompted a search for better selection criteria and more efficient evaluation systems. The literature does not provide a concise description of the ideal resident candidate, but it does contain several approaches taken by a few individual teaching centers to improve applicant review procedures. Computer-assisted resident candidate selection (CARCS) is a three-phase system of preinterview screening, interview evaluation, and final ranking. Based on faculty criteria, the entire process uses data management technology that provides automatic calculation of selection parameters, sorting on any data field or combination thereof, and maintenance of a concise information profile for each candidate. CARCS allows equitable consideration of all who apply, with significant cost savings to both program and applicants. This paper reviews traditional methods of selecting anesthesiology residents, describes the CARCS system, and previews the future of resident candidate selection.

Beyond career choice: the role of learning style analysis in residency training.

A recent article in this journal took an important step toward rethinking the utility of behavioural instruments designated as learning style tests (Jewett et al. 1987). The authors of that paper made much of a distinction between the terms 'learning style' and 'learning preference'. However, the results of their study do not seem to substantiate a marked difference between the function of the Rezler Learning Preference Inventory (LPI) and Kolb's Learning Style Inventory (LSI) with which it was contrasted. The most important aspect of their paper was that it rescued the concept of learning style analysis from the arena of career choice prediction at the undergraduate level and applied these ideas to doctors who had already made their specialty selections and were actively engaged in residency training. Clinical instructors in teaching institutions have, for the most part, little or no formal background in educational principles. For these individuals, an easily comprehensible model of resident-instructor psychology can be very useful on a daily basis. This article reviews the authors' experience with the LSI and describes their utilization of Kolb's Experimental Learning Model in the areas of resident counselling and residency curriculum design. The results of two recent studies are also presented in which learning style was examined as a predictor of success in residency, and teacher-resident learning style distributions were shown to exhibit parallel relationships at four different anaesthesiology residency training programmes.