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.     

Tissue optical property measurements: overestimation of absorption coefficient with spectrophotometric techniques

We have cloned both human and murine complementary DNAs that are homologous to the Drosophila serine/threonine polo kinase and the recently cloned murine polo related kinase (PLK). Both the human and murine clones are about 2.1 kilobases with open reading frames of 1.8 kilobases, encoding proteins of 603 amino acids with a predicted size of 66 kilodaltons and an apparent size of 67 kilodaltons by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. During embryonic development of the mouse, the mRNA was expressed in all tissues examined, whereas in adult tissues, expression was limited to thymus and ovaries. All cell lines examined also expressed mRNAs of similar size. Microinjection of in vitro transcribed sense mRNA into serum-starved murine NIH3T3 cells induced tritiated thymidine incorporation, whereas microinjection of antisense RNA into growing NIH3T3 cells blocked tritiated thymidine incorporation. When PC12 rat cells were induced to differentiate with nerve growth factor, gene expression of PLK was greatly reduced. Together, these results suggest that PLK expression is restricted to, and is perhaps required by, proliferating cells.     

Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990

Information on the incidence of progressive supranuclear palsy (PSP) is limited; incidence rates for multiple system atrophy (MSA) are not available. We studied the incidence of PSP and MSA in Olmsted County, Minnesota, for the years 1976 to 1990. This study was part of a larger investigation of all forms of parkinsonism. We used the medical records-linkage system of the Rochester Epidemiology Project to identify all subjects whose records contained documentation of any from of parkinsonism, related neurodegenerative diseases, or tremor of any type. A nurse abstractor screened the records and, when applicable, a neurologist reviewed them to determine the presence or absence of parkinsonism. Cases of parkinsonism were classified using specified diagnostic criteria. Population denominators were derived from census data and were corrected by removing prevalent cases of parkinsonism. Over the 15 years of the study, we found 16 incident cases of PSP and nine incident cases of MSA. No cases of PSP or MSA had onset before age 50 years. The average annual incidence rate (new cases per 100,000 person-years) for ages 50 to 99 years was 5.3 for PSP and 3.0 for MSA. The incidence of PSP increased steeply with age from 1.7 at 50 to 59 years to 14.7 at 80 to 99 years, and was consistently higher in men. Median survival time from symptom onset was 5.3 years for PSP and 8.5 years for MSA. The incidence of PSP increases with age and is consistently higher in men at all ages. PSP and MSA are more common than previously recognized.     

Incidence of fatal pulmonary embolism after 1,390 knee arthroplasties without routine prophylactic anticoagulation, except in high-risk cases

OBJECTIVE: To determine whether the time of administration (morning vs. evening) of pantoprazole influences the effect of a 40 mg dose upon intragastric pH in healthy subjects. DESIGN: Randomized, double-blind, two-period crossover study to compare intragastric pH following treatment with pantoprazole, 40 mg once daily for 7 days, the drug being given as either a morning or an evening dose before meals. METHODS: Intragastric pH was measured for 24 h on three occasions. The baseline recording was made 2 days prior to the first treatment period and subsequent measurements were made on days 6 to 7 of each period. Adverse events were recorded and fasting laboratory variables measured. RESULTS: Twelve subjects were evaluable for efficacy. Increases in median pH over 24 h were observed in all subjects with both dosage regimens. There was a greater increase from baseline in 24-h median pH values following morning than evening administration of pantoprazole (P < 0.05). This difference was due to a greater effect on median daytime pH (07.00-19.00 h, P < 0.01) compared with that after evening administration. No adverse events were reported and there were no clinically significant changes in laboratory variables. CONCLUSION: The study supports the recommendation of a once-daily morning dosage regimen of pantoprazole 40 mg in the treatment of acid-related diseases.     

Nested PCR assay for detection of granulocytic ehrlichiae

A sensitive and specific nested PCR assay was developed for the detection of granulocytic ehrlichiae. The assay amplifies the 16S rRNA gene and was used to examine acute-phase EDTA-blood and serum samples obtained from seven humans with clinical presentations compatible with human granulocytic ehrlichiosis. Five of the seven suspected cases were positive by the PCR assay using DNA extracted from whole blood as the template, compared with a serologic assay that identified only one positive sample. The PCR assay using DNA extracted from the corresponding serum samples as the template identified three positive samples. The sensitivity of the assay on human samples was examined, and the limit of detection was shown to be fewer than 2 copies of the 16S rRNA gene. The application of the assay to nonhuman samples demonstrated products amplified from template DNA extracted from Ixodes scapularis ticks collected in Rhode Island and from EDTA-blood specimens obtained from white-tailed deer in Maryland. All PCR products were sequenced and identified as specific to granulocytic ehrlichiae. A putative variant granulocytic ehrlichia 16S rRNA gene sequence was detected among products amplified from both the ticks and the deer blood specimens.     

An electroencephalographic classification for coma

BACKGROUND: The assessment of thalamocortical function in comatose patients in the intensive care unit (ICU) can be difficult to determine. Since the electroencephalogram (EEG) affords such assessment, we have developed an EEG classification for comatose patients in our general ICU. METHODS: One hundred EEGs were classified in a blinded fashion by two EEGers, using our method and that of Synek. Interobserver agreement was assessed using kappa score determination. RESULTS: Kappa scores were 0.90 for our system and 0.75 for the Synek system. (The Kappa score represents the inter-rater agreement that is beyond chance; 0.90 is almost perfect agreement, while 0.75 is substantial agreement). CONCLUSION: Our system for classifying EEGs in comatose patients has a higher interobserver reliability than one that was previously published. This EEG classification scheme should be useful in clinical electrophysiological research involving ICU patients, allowing for internal consistency and comparisons among centres.     

Closed-chest cardiopulmonary bypass and cardioplegia: basis for less invasive cardiac surgery

BACKGROUND: We developed a method of closed-chest cardiopulmonary bypass to arrest and protect the heart with cardioplegic solution. This method was used in 54 dogs and the results were retrospectively analyzed. METHODS: Bypass cannulas were placed in the right femoral vessels. A balloon occlusion catheter was passed via the left femoral artery and positioned in the ascending aorta. A pulmonary artery vent was placed via the jugular vein. In 17 of the dogs retrograde cardioplegia was provided with a percutaneous coronary sinus catheter. RESULTS: Cardiopulmonary bypass time was 111 +/- 27 minutes (mean +/- standard deviation) and cardiac arrest time was 66 +/- 21 minutes. Preoperative cardiac outputs were 2.9 +/- 0.70 L/min and postoperative outputs were 2.9 +/- 0.65 L/min (p = not significant). Twenty-one-French and 23F femoral arterial cannulas that allowed coaxial placement of the ascending aortic balloon catheter were tested in 3 male calves. Line pressures were higher, but not clinically limiting, with the balloon catheter placed coaxially. CONCLUSIONS: Adequate cardiopulmonary bypass and cardioplegia can be achieved in the dog without opening the chest, facilitating less invasive cardiac operations. A human clinical trial is in progress.