Biomedical subjects
Publications and source records attributed to M Levitt.
Among 76 chronic schizophrenic patients, plasma amine oxidase activity was unrelated to paranoid/nonparanoid subtype, narrow/broad diagnostic criteria, prognosis, or age at onset. These clinical indices do not identify biological subtypes of schizophrenia with deviant plasma amine oxidase activity.
Quality of life research is an emerging science of particular relevance to clinical cancer research. The development and utilization of valid and reliable quality of life measures as outcome parameters may profoundly alter the clinical trials process. Such measures, contrary to prevailing opinion, may be as accurate and precise as conventional measures, but considerably more relevant to the trials process. However, lack of rigor in the evaluation of such indices and uncritical interpretation of results may seriously compromise the credibility of the concept. This overview of the current status of quality of life research is designed to provide a perspective from which to evaluate ongoing development.
Activity levels of platelet monoamine oxidase (MAO), plasma amine oxidase (PAO), erythrocyte catechol-o-methyltransferase, and dopamine-beta-hydroxylase were measured in 24 drug-free patients with Tourette's syndrome (TS) and in 24 normal control subjects matched for age and sex. Only MAO and PAO activity levels were significantly higher in patients than in controls. Activity of the four enzymes was uncorrelated with age, sex, age of onset of illness, severity of illness, family history of tics and Ts, and ethnic-religious background. The hypothesis that probands with heavily loaded pedigrees or with Ashkenazi ethnic-religious background would be more biochemically deviant was not supported.
To assess the pharmacologic and phenomenologic comparability of lactate-induced and naturally occurring panic attacks, patients meeting DSM-III criteria for panic disorder or agoraphobia with panic attacks were infused with 0.5M racemic sodium lactate before and after successful drug treatment. Lactate-induced and naturally occurring panic attacks were symptomatically similar. Following treatment, the patients' response to lactate did not differ from that of normal controls, whereas the pretreatment panic rate was much higher. These data suggest that lactate acts, by as yet unidentified mechanisms, to trigger the same panic attacks as occur spontaneously in vulnerable persons.
Concentrations of endogenous norepinephrine, dopamine and epinephrine in cerebroventricular perfusates were used to evaluate the effects of drugs on the availability of extracellular catecholamines in the intact rat brain. Administration of the antidepressant drugs imipramine, desmethylimipramine or tranylcypromine resulted in marked increases of both norepinephrine and dopamine concentrations while epinephrine levels were not affected. Treatment with a similar dose of carbamazepine - an anticonvulsant drug with antidepressant activity - resulted in a significant increase in dopamine concentrations without apparent effect on either norepinephrine or epinephrine. It is suggested that at the applied dose, carbamazepine may act to modify the uptake, release or metabolism of dopamine in brain areas adjacent to the cerebroventricular space without affecting the other catecholamines.
Platelet monoamine oxidase activity (MAO) was determined in 39 unmedicated chronic schizophrenic patients and 88 normal control subjects. Platelet MAO activity did not distinguish paranoid from nonparanoid patients or patients who met Taylor and Abrams criteria for narrowly defined schizophrenia from other schizophrenics. Enzyme activity was not related to either prognostic scores or age at onset of illness. MAO activity was decreased in patients compared to controls, and was lower in males than in females. Our findings indicate that clinical phenomenology, as defined in the present study, is of limited use in identifying biological subtypes of schizophrenia with deviant platelet MAO activity.
There are sound radiobiologic and suggestive clinical rationale for superfractionating the radiotherapeutic regimens employed for the therapy of rapidly growing malignancies. Oat cell carcinoma of the bronchus is such a tumor. We report our experience combining aggressive systemic combination chemotherapy with superfractionated radiotherapy for the treatment of "limited" oat cell carcinoma of the bronchus. Overall, patient tolerance was satisfactory and a complete remission rate of 74% was achieved. It remains to be proven, in a prospective randomized fashion, whether this approach is superior to current conventional management.
The authors determined the erythrocyte catechol O-methyltransferase (COMT) activity of 38 chronic schizophrenic patients, 69 of their first-degree relatives, and 39 normal controls. COMT activity did not distinguish patients from controls. Within families, COMT activity was not associated with schizophrenia spectrum disorders. The data suggest that COMT activity is not an indicator of vulnerability to schizophrenia.
Platelet monoamine oxidase (MAO) activity, determined in 102 patients with chronic schizophrenia, 223 first-degree relatives, and 88 normal control subjects, was shown to be a heritable and stable trait and was significantly lower in patients than in normal control subjects. Within families, MAO activity distinguished ill from well relatives. However, the considerable overlap in enzyme activity between affected and unaffected individuals limits the usefulness of low MAO activity as a major risk factor in schizophrenia.
The classical criteria for the evaluation of clinical trials in cancer reflect alterations in physical well-being, but are insensitive to other important factors, such as psychosocial state, sociability, and somatic sensation that may play a critical role in determining the patients' functional response to their illness and its treatment. The Functional Living Index-Cancer is designed for easy, repeated patient self-administration. It is a 22-item questionnaire that has been validated on 837 patients in two cities over a three-year period. Criteria for validity include stability of factor analysis, concurrent validation studies against the Karnofsky, Beck Depression, Spielberger State and Trait Anxiety, and Katz Activities of Daily Living scales, as well as the scaled version of The General Health Questionnaire and The McGill/ Melzack Pain Index. The index is uncontaminated by social desirability issues. The validation studies demonstrate the lack of correlation between traditional measures of patient response and other significant functional factors such as depression and anxiety (r = 0.33), sociability and family interaction, and nausea. These findings elucidate the frequently observed discrepancies between traditional assessments of clinical response and overall functional patient outcome. The index is proposed as an adjunct to clinical trials assessment and may provide additional patient functional information on which to analyse the outcome of clinical trials or offer specific advice to individual patients.
A large metastatic squamous carcinoma of the anterior chest wall was managed by en-bloc resection of the thoracic wall. The extensive defect resulting from the resection was bridged with Marlex mesh superimposed on an omental flap that served as recipient to partial-thickness skin grafts. This composite reconstruction restored an efficient bellows action to the chest cage, manifested by the lack of anterior flailing and postoperative spirometry values, measured at the bedside, that were 75% of those obtained preoperatively. During the initial postoperative period, however, mechanical ventilatory assistance was required to treat an adult respiratory distress syndrome that together with mild anterior flailing made early extubation impossible.
The ability of sodium lactate to precipitate panic attacks in vulnerable individuals has been repeatedly demonstrated, although its mechanism of action is unknown. Pitts and McClure hypothesized that the panicogenic effect of sodium lactate was due to its induction of a peripheral hypocalcemia via the complexing of infused lactate ions with extracellular ionized calcium. In the current study, serial ionized calcium measurements during lactate infusion are assessed for 22 panic patients who panicked during infusion, 11 panic patients who did not panic during the procedure, and 6 normal controls. Intravenous sodium lactate infusion was found to be associated with a significant decrease in ionized calcium in all groups. No specific association was found between the rate or magnitude of decrease in ionized calcium and the occurrence of a panic attack during the infusion.
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Native-like folded conformations of bovine pancreatic trypsin inhibitor protein are calculated by searching for conformations with the lowest possible potential energy. Twenty-five random starting structures are subjected to soft-atom restrained energy minimization with respect to both the torsion angles and the atomic Cartesian co-ordinates. The restraints used to limit the search include the three disulphide bridges and the 16 main-chain hydrogen bonds that define the native secondary structure. The potential energy functions used are detailed and include terms that allow bond stretching, bond angle bending, bond twisting, van der Waals' forces and hydrogen bonds. Novel features of the methods used include soft-atoms to make restrained energy minimization work, writhing numbers to classify chain threadings, and molecular dynamics followed by energy minimization to anneal the conformations and reduce their energies further. Conformations are analysed using writhing numbers, torsion angle distributions, hydrogen bonds and accessible surface areas. The resulting conformations are very diverse in their chain threadings, energies and root-mean-square deviations from the X-ray structure. There is a relationship between the root-mean-square deviation and the energy, in that the lowest energy conformations are also closest to the X-ray structure. The best conformation calculated here has a root-mean-square deviation of only 3 A and shows the same special threading found in the X-ray structure. The methods introduced here have wide ranging applications; they can be used to build models of protein conformations that have low energy values and obey a wide variety of restraints.
The motion of the atoms in the small protein bovine pancreatic trypsin inhibitor has been simulated for about 60 picoseconds using two different potential energy functions. In one known as HHL the hydrogen bond is purely electrostatic, in the other, known as L79, the hydrogen bond is a directional O . . . H interaction. The energy parameters and techniques used to obtain an accurate, well-equilibrated trajectory are described in detail. The trajectories calculated here with either potential are superior to those obtained in previous simulations on the same protein in that they treat hydrogen bonding realistically and remain closer to the native X-ray structure. Comparison of the two trajectories shows that the potential energy parameters have a significant effect on the shift from the X-ray structure, the distribution of (phi, psi) torsion angles, the pattern of hydrogen bonds and the accessible surface area of individual residues. The L79 potential with directional hydrogen bonds is used to simulate a longer 132 picosecond trajectory that is analysed in the accompanying paper.
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The 132 picosecond simulation of atomic motion in bovine pancreatic trypsin inhibitor protein generated in the accompanying paper is analysed here using a variety of different methods. Together, these techniques, many of which have been used before in analyses of protein co-ordinate refinement, give a complete and comprehensible description of the trajectory. Some highlights of the simulation are as follows. (1) The atoms vibrate about a time-averaged conformation that is close to the X-ray structure (within 1.1 A root-mean-square deviation for the main-chain of all residues except the first and last two). The vibration amplitude is least for main-chain atoms in alpha-helix or beta-sheet secondary structure and most for side-chain atoms in the charged polar side-chains (Asp, Glu, Lys and Arg). The overall extent and distribution of atomic motion is in agreement with the temperature factors derived from the X-ray refinement: the reorientation of bond vectors is much less than observed by nuclear magnetic resonance. (2) The protein explores four distinct regions of conformational space in the 132 picoseconds simulated. The conformational change from region III to IV and back again lasts 40 picoseconds and is of particular interest as it is reversible and involves an increase in the hydrogen bond energy. (3) The changes in main-chain torsion angles show the expected cooperativity of phi i + 1 and psi i; side-chains that are close in space also change their conformational angles in unison. (4) Hydrogen bonds are variable and many break and reform again in the 132 picoseconds. Certain hydrogen bonds are much less stable than others; with particular variability seen in the alpha-helices and at the ends of the beta-hairpin. Most noticeable are the co-operative changes of hydrogen bonds at both ends of the beta-hairpin that occur in going from region III to IV of the conformational space. (5) The overall solvent-accessible area remains close to that of the X-ray structure but polar charged residues become less exposed while non-polar hydrophobic residues become more exposed. Together these results give a conceptual model for protein dynamics in which the molecule vibrates about a particular conformation but then suddenly changes conformation, jumping over an energy barrier into a new region of conformational space.
Plasma amine oxidase (PAO) activity was studied in 52 chronic schizophrenics, 130 first-degree relatives, and 36 normal control subjects. Enzyme activity was shown to be a heritable and stable characteristic. Age and sex effects were not present. Patients had lower PAO activity than did control subjects, although the difference fell short of statistical significance. Within families, reduced PAO activity was associated with schizophrenia spectrum disorders.