Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses

BACKGROUND: To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N-methyl-D-aspartate subtype of excitatory amino acid receptor. METHODS: Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured. RESULTS: Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4-hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure. CONCLUSIONS: These data indicate that N-methyl-D-aspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.     

Differential assembly of coexpressed glutamate receptor subunits in neurons of rat cerebral cortex

In the rat, subunits of the glutamate receptor family fall into three pharmacologically distinct groups: alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid preferring receptors (Glu R1-4), kainate preferring receptors (Glu R5-7, KA 1, KA 2), and N-methyl-D-aspartate preferring receptors (NMDA R1, NMDA R2A-2D). In the present study, we demonstrate immunocytochemically that the majority of neurons in rat cerebral cortex coexpress members of all three groups of glutamate receptor subunits, Glu R2/3, Glu R5/6/7, and NMDA R1. Using immunoaffinity purified or immunoprecipitated alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, kainate and N-methyl-D-aspartate receptors, we show that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors containing Glu R1-4, kainate receptors containing Glu R6, Glu R7, and KA 2 and N-methyl-D-aspartate receptors containing NMDA R1 each form distinct protein complexes that do not share subunits. Our data indicate that a mechanism exists which allows for the specific assembly of selected glutamate receptor subunits into functionally and structurally distinct heteromeric receptors.     

Production of inflammatory mediators by human macrophages obtained from ascites

Ascites is a readily available source of human macrophages (M phi), which can be used to study M phi functions in vitro. We characterized the mediators of inflammation produced by human peritoneal M phi (hp-M phi) obtained from patients with portal hypertension and ascites. The production of the cytokines interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) was found to be lipopolysaccharide (LPS) concentration dependent (0-10 micrograms/ml) with a maximal production at 10 micrograms/ml and also dependent on the time of exposure to the stimulus (0-36 h). IL-1 beta, IL-6 and TNF-alpha production after LPS administration reached a plateau at 24 h. In vitro stimulation for 24 h with LPS does not influence the eicosanoid production from endogenous arachidonate. 13 min of exposure of the cells to the calcium ionophore A23187 gives a significant increase in eicosanoid production from both exogenous and endogenous arachidonate. The main eicosanoids produced are the 5-lipoxgenase products LTB4 and 5-hydroxyeicosatetraenoic acid (HETE). The increase in production of the other eicosanoids is not significant. The eicosanoid production depends on the stimulus concentration. The optimal A23187 concentration is 1 microM. Oxygen radical production was measured in the M phi by a flowcytometric method. The fluorescence intensity of phorbol 12-myristate 13-acetate stimulated and dihydro-rhodamine 123 loaded hp-M phi increases significantly after 15 min. We conclude that LPS stimulation of hp-M phi from liver disease results in similar production of IL-1 beta, IL-6 and TNF-alpha, but that the profile of the eicosanoid production of these M phi stimulated with LPS and A23187 differs from M phi of other origin and species.     

Factors influencing functional outcome in supraglottic laryngectomy

BACKGROUND: The relationship between preoperative pulmonary function tests (PFTs) and postoperative aspiration and deglutition complications in supraglottic laryngectomy (SL) has not been adequately analyzed. The effects of numerous other variables are either controversial or have not been studied. METHODS: A retrospective chart review was performed on 46 SL patients, analyzing preoperative PFTs and arterial blood gases, demographic factors, stage of disease, extended resections, cricopharyngeal myotomy, hyoid preservation, neck dissection, and postoperative radiotherapy with regards to aspiration and deglutition problems. RESULTS: Eighteen (39%) patients had no problems, 15 (33%) had moderate problems, and 13 (28%) had severe problems; of these, 39 (85%) were ultimately successful with no further swallowing dysfunction, whereas seven (15%) suffered intractable aspiration difficulties. Decreasing FEV1/FVC was significantly correlated with a poorer outcome, as was a greater number of pack-years of smoking. The effect of FEV1/FVC was shown to be independent from pack-years, whereas the converse was not clearly demonstrated. Extensions of the standard procedure did not correlate significantly with increased problems. CONCLUSIONS: An FEV1/FVC less than 50% signifies a greater risk for severe aspiration and deglutition complications, although it must be regarded as one factor among many in determining operability. With careful attention to reconstruction, extensions of the standard SL procedure can be safely performed.     

Bilateral hyperplastic nephromegaly, nephroblastomatosis, and renal dysplasia in a newborn: a variety of universal nephroblastomatosis

A preterm boy was born at 34 weeks. Prenatal ultrasonography showed oligohydramnios, fetal ascites, large kidneys, and small thorax. He died 21 h after birth of respiratory insufficiency. Autopsy revealed Potter's-like facies, hypoplastic lungs, ascites, and bilateral nephromegaly (renal weight almost 10 times normal). The kidneys were finely nodular externally, solid, and cerebriform on cut section. Histologically, they showed a diffusely distorted architecture of jumbled lobules, hyperplasia of cortical-type tissue with inconspicuous proximal tubules, relative hypoplasia of medullary tissue, tubulointerstitial dysplasia, and perilobar nephrogenic rests. The renal features represent a variety of the universal or panlobar (also called pancortical or infantile) type of nephroblastomatosis. To our knowledge, this is only the third such case reported. In the brain, each lateral ventricle contained a yellow gelatinous mass. Histologically, the masses consisted of a pseudomyxoid matrix with delicate fibers and focal adipocyte clusters, all confined within choroid plexus. We consider these lesions fibrolipomatous hamartomas.     

Isolation and structure/activity features of halomon-related antitumor monoterpenes from the red alga Portieria hornemannii

Ten halogenated monoterpenes (2-6 and 8-12) related to the novel antitumor compound halomon (1) or to the carbocyclic analog 7 have been isolated from different geographic collections of the red alga, Portieria hornemannii. Structures were assigned to the basis of spectral analyses (primarily NMR and MS). The absolute configuration of isohalomon (2) was further established by X-ray crystallography. The compounds were comparatively evaluated alongside 1 and 7 in the U.S. National Cancer Institute's in vitro human tumor cell line screening panel. The results provide some interesting initial insights into the structure/activity relationships in this series.     

Wallerian degeneration of peripheral nerve. Age-dependent loss of nerve lipids

The age-dependent loss of the major peripheral nerve lipids (cholesterol, phospholipid, and total galactolipid) was quantitated over a period of 9 weeks of Wallerian degeneration induced by surgical transection of rabbit sciatic nerves in animals of several ages. Proportionate losses of these lipids were determined by calculating the content of each lipid on a per nerve and on a per gram fresh weight basis remaining after a given period of Wallerian degeneration as a percent of original normal values at several time following surgery. The proportionate loss of each lipid from the distal stump was the most prompt and the most complete in nerves transected at 2 weeks of age, and the least in nerves transected at 20 weeks of age. The prompter clearance of these lipids from younger than older degenerating nerve gives convincing evidence that the suggestion from light-microscopic studies of faster clearance of neural debris in younger than in older animals is correct. A possible relationship between these biochemical findings and the phenomenon of greater functional recovery from peripheral nerve injury in younger than in older subjects is discussed.     

Search for resistances controlling canine gastric emptying of liquid meals

Previous work has indicated that a chemoselective resistance controls gastric emptying. By use of meals of glucose or oleate, which were shown to empty spontaneously from dogs' stomachs half as fast as saline, we sought to locate this resistance by studying flow under controlled pressures in various regions of the gastrointestinal tract. In intact dogs, gastric outflow of glucose or oleate rose one-third as fast as outflow of saline as gastric pressure was raised, and this increased resistance to outflow of nutrients was unaffected by truncal vagotomy and pyloroplasty. In fistula dogs, gastroduodenal outflow rose linearly with gastroduodenal pressure gradients; outflow was markedly inhibited in a dose-related manner by intestinal oleate but not glucose. Inhibition by oleate was abolished by pyloroplasty. Glucose or oleate flowed into the small bowel from a barostat only slightly slower than saline. However, there was a strong inhibition of intestinal inflow of all three meals by gastric distension, an effect unaltered by truncal vagotomy. The findings suggest that gastric emptying is controlled by complex interactions among pressures and resistances, both within and beyond the stomach.     

Related donor marrow transplant for chronic myeloid leukemia: patient characteristics predictive of outcome

This article presents health expectancy calculations from Bulgaria for 1976-1992. The calculations are based on mortality statistics and data from a national information system from the Expert Medical Commissions on Working Capacity about loss of working capacity. Following internationally accepted terminology, the most appropriate term for the health expectancies presented here is "occupational handicap-free life expectancy' (OHFLE). Life expectancies were calculated as partial life expectancies from ages 16 to 59. Health expectancy calculations followed Sullivan's cross-sectional method with age and sex specific prevalence data on occupational handicap. Around 1985 a three- to four-fold increase in these prevalences occurred. The distribution of occupational handicaps over sexes, age groups and severity levels, however, remained fairly constant. The results show a decrease both in partial life expectancy within the age range 16-59 and in OHFLE at the age of 16 for men. For women a more or less stable partial life expectancy and a decrease in OHFLE at the age of 16 was found around 1985. The introduction of more incentives for people who successfully registered probably caused the decrease around 1985. Major social changes may have acted as confounding factors for the fluctuations after 1985. On the other hand the findings may reflect real changes in population health due to an increasing incidence in some major disease categories. The nation-wide system for assessment and registration of health related working incapacity has proved a useful source for an attempt to calculate OHFLE. Given uncertainties about the population health underlying these changes in OHFLE, however, it is recommended that health interview and health examination surveys should be considered as alternative routes for achieving a more comprehensive picture of population health in Bulgaria.