Biomedical subjects
R A Mitchell
Publications and source records attributed to R A Mitchell.
Problems in assessing the possible disease-modifying effect of naproxen.
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Splanchnic and total body oxygen consumption differences in septic and injured patients.
The splanchnic and total body oxygen exchange and flow dynamics for injured patients (n = 7) and patients with sepsis and stable vital signs (n = 12) were studied. All patients were judged to be in the hyperdynamic phase of the stress response. In both patient groups 27% to 28% of the cardiac index was directed to the splanchnic circulation. However, in sepsis the splanchnic region consumed a significantly larger fraction (p less than 0.05) of the total body oxygen (43.8%) compared with that consumed in injury (30.2%). After injury, the regional splanchnic flow and oxygen consumption appeared to be well matched whereas in sepsis, a disproportionately higher oxygen consumption is found, which must be supplied by increasing blood oxygen extraction. This regional hypermetabolism of the splanchnic area probably results from the increased metabolic demand imposed by the various synthetic processes of this region. In addition, it is proposed that excessive discrepancy between splanchnic flow and oxygen demand may precipitate regional ischemia.
The architecture of nerves and ganglia of the ferret trachea as revealed by acetylcholinesterase histochemistry.
The goal of this study was to determine the architecture of the nerves and ganglia of the ferret trachea. Tracheas from four newborn ferrets and three adult ferrets were stained histochemically for acetylcholinesterase activity and analyzed in their entirety as whole mounts. The architecture consisted of one or two longitudinal nerve trunks overlying the posterior surface of the trachealis muscle, a dense plexus of nerves superficial to the trachealis muscle that interconnected these longitudinal nerve trunks, and, on the anterior surface, a plexus superficial to the submucosal glands and located between the cartilaginous rings. In addition, deep neural plexuses were associated with the trachealis muscle and with the submucosal glands. Ganglion cell bodies along the longitudinal nerve trunks were large (mean diameter +/- S.E. = 34.3 +/- 0.3 microns), were usually attached to the nerve trunk by a stalk, and were loosely clustered in groups of as many 38 cell bodies. By contrast, those cell bodies of the superficial muscle and gland plexuses were significantly smaller (mean diameter +/- S.E. = 24.2 +/- 0.3 microns), were never attached by a stalk, and were tightly clustered in ganglia of one to four cell bodies. We conclude that nerves and ganglia of the ferret trachea constitute one or two longitudinal nerve trunks containing ganglia with large cell bodies, two superficial nerve plexuses containing ganglia with small cell bodies overlying the smooth muscle and submucosal glands, respectively, and two deep nerve plexuses providing the terminal innervation to the muscle and glands.
The metabolic course of Reye's syndrome: distinction between survivors and nonsurvivors.
We compared the levels of hormones and metabolites in the plasma of 37 survivors of Reye's syndrome with the levels in 8 fatal cases, at four time periods within 72 hours of admission. The most prominent differences were found for norepinephrine (NE), which was significantly elevated in fatal cases compared with survivors at all periods. Lactate and dopamine were elevated in the earlier periods. Epinephrine and alpha-amino acid nitrogen were also elevated in fatal cases, but the differences usually were not significant. NE elevation may reflect an increased sympathoadrenal medullary output associated with brain edema, compounded by impaired hepatic clearance of monoamines. Skeletal muscle ischemia from NE-induced vasoconstriction may explain the association between lactic acidemia and the severity of encephalopathy.
A blitz of bends: decompression sickness in four students after hypobaric chamber training.
This paper reports three cases of type II and one case of type I decompression sickness occurring in a group of nine vigorously active US Army parachutists who took a hypobaric chamber HALO (high altitude-low opening) training flight to a maximum altitude of 9,908.5 m (32,500 ft). After the cases of decompression sickness were diagnosed and treated, the aviator mask regulators were checked and found to be functioning properly; the oxygen supply was analyzed and found to be pure. All cases fully recovered after treatment on US Navy Diving Table 6 and have returned to full military duty. This HALO training profile is not in use with either the US Navy or the US Air Force and should probably be considered unsafe for future use in training.
The relationship of insulin production to glucose metabolism in severe sepsis.
Basal glucose metabolism was evaluated in eight stable, infected patients by measuring hepatic glucose production rates in relation to stress endocrine profile and by comparing these data to five injured, noninfected patients. All patients exhibited normal total-body oxygen consumptions and cardiac indices. Fasting basal insulin values were similar in both groups (6 microU/cc) despite a significantly higher plasma glucose level in septic patients (106 +/- 14 mg/dL) compared to nonseptic patients (88 +/- 10 mg/dL). Septic patients exhibited splanchnic glucose production and calculated glucose clearance rates, 53% and 34% higher, than injured nonseptic patients, respectively. In addition, septic patients exhibited a decreased pancreatic insulin secretory response to an intravenous glucose tolerance test as evidenced by a significantly depressed peak insulin value (17 microU/cc) relative to injured patients (77 microU/cc). These findings indicate that insulin suppression is evident in sepsis even in the absence of shock and suggest that sepsis-related basal hyperglycemia does not appear to be associated with peripheral insulin resistance.
Prognosis and diagnosis of Reye syndrome by discriminant analysis.
Discriminant analysis was used to discriminate between Reye syndrome (RS) patients and non-RS cases based either on conventional blood chemistry data obtained upon admission, or on the activities of hepatic mitochondrial enzymes in biopsy or necropsy tissue. The control group for blood chemistry measurements contained children with upper respiratory tract infections, varicella, etc. who did not develop RS, as well as healthy children. Subjects with no liver disorder (e.g., accidental death, sudden infant death, etc.) or with non-RS liver disorders were used as controls for hepatic enzyme studies. Hepatic damage indicators (aspartate aminotransferase, AST; alanine aminotransferase, ALT; and bilirubin) correctly classified 86-96% of non-RS cases and 61-71% of RS. By contrast, AST and ALT had little prognostic value (63% overall correct). Ammonia effectively classified favorable outcome cases (95% correct) but not unfavorable (14% correct). However, when ammonia was included with stage of coma information 88% of the favorable and 85% of the unfavorable outcome cases were correctly classified. Discriminant analysis of hepatic enzymes (glutamate dehydrogenase and monoamine oxidase activity) for a RS and a non-RS group correctly classified 80% of non-RS and 95% of RS specimens. The function was suitable for the direct evaluation of RS-like mitochondrial enzyme changes in rat liver.
Inspiratory rhythm in airway smooth muscle tone.
In anesthetized paralyzed open-chested cats ventilated with low tidal volumes at high frequency, we recorded phrenic nerve activity, transpulmonary pressure (TPP), and either the tension in an upper tracheal segment or the impulse activity in a pulmonary branch of the vagus nerve. The TPP and upper tracheal segment tension fluctuated with respiration, with peak pressure and tension paralleling phrenic nerve activity. Increased end-tidal CO2 or stimulation of the carotid chemoreceptors with sodium cyanide increased both TPP and tracheal segment tension during the increased activity of the phrenic nerve. Lowering end-tidal CO2 or hyperinflating the lungs to achieve neural apnea (lack of phrenic activity) caused a decrease in TPP and tracheal segment tension and abolished the inspiratory fluctuations. During neural apnea produced by lowering end-tidal CO2, lung inflation caused no further decrease in tracheal segment tension and TPP. Likewise, stimulation of the cervical sympathetics, which caused a reduction in TPP and tracheal segment tension during normal breathing, caused no further reduction in these parameters when the stimulation occurred during neural apnea. During neural apnea the tracheal segment tension and TPP were the same as those following the transection of the vagi or the administration of atropine (0.5 mg/kg). Numerous fibers in the pulmonary branch of the vagus nerve fired in synchrony with the phrenic nerve. Only these fibers had activity which paralleled changes in TPP and tracheal tension. We propose that the major excitatory input to airway smooth muscle arises from cholinergic nerves that fire during inspiration, which have preganglionic cell bodies in the ventral respiratory group in the region of the nucleus ambiguus and are driven by the same pattern generators that drive the phrenic and inspiratory intercostal motoneurons.
Nicotine-induced respiratory effects of cigarette smoke in dogs.
We report that nicotine is responsible for both a blood-borne stimulation of the respiratory center and a direct effect on intrathoracic airway tone in dogs. We introduced cigarette smoke into the lungs of donor dogs and injected arterial blood obtained from them into the circulation of recipient dogs to show that a blood-borne material increased breathing and airway smooth muscle tone. Smoke from cigarettes containing 2.64 mg of nicotine was effective; that from cigarettes containing 0.42 mg of nicotine was not. Nicotine, in doses comparable to the amounts absorbed from smoke, also increased breathing and tracheal smooth muscle tension when injected into the vertebral circulation of recipient dogs. Finally, blockade of nicotine receptors in the central nervous system and in the airway parasympathetic ganglia inhibited the effects of inhaled cigarette smoke and intravenous nicotine on the respiratory center and on bronchomotor tone. We conclude that nicotine absorbed from cigarette smoke is the main cause of cigarette smoke-induced bronchoconstriction. It caused central respiratory stimulation, resulting in increased breathing and airway smooth muscle tension, and had a direct effect on airway parasympathetic ganglia as well.
Quantitative evaluation of the extent of hepatic enzyme changes in Reye syndrome compared with normal liver or with non-Reye liver disorders: objective criteria for animal models.
Five enzymes were measured in 50 liver specimens (18 normal liver, 20 Reye liver, 12 diverse liver disorders other than Reye syndrome). The enzymes were: glutamic dehydrogenase (E.C. 1.4.1.3), monoamine oxidase (E.C. 1.4.3.4), lactate dehydrogenase (E.C. 1.1.1.27), D-glucose-6-phosphate dehydrogenase (E.C. 1.1.1.49), catalase (E.C. 1.11.1.6). The Reye syndrome group showed significant decreases in glutamic dehydrogenase (56%) and monoamine oxidase (70%) compared to normal control tissue and these changes were not characteristic of the non-Reye liver disorder group as a whole. Neither catalase nor lactate dehydrogenase appeared to be altered significantly in the Reye or in the abnormal control group compared with normal controls. Thus, only the prominent decreases in the mitochondrial enzyme activities appeared to be highly characteristic of Reye syndrome. Paradoxically, the means of the five hepatic enzymes and the admission levels of two serum enzymes indicative of liver damage (alanine and aspartate aminotransferase) were remarkably similar for both survivors and nonsurvivors of Reye syndrome.
Absence of diffusible inhibitor of glutamate dehydrogenase in the hepatocytes of Reye syndrome patients.
Hepatic glutamate dehydrogenase (GDH) activity was measured in postmortem specimens obtained from two stage V Reye syndrome patients and in three postmortem specimens of normal human liver. The Reye syndrome specimens showed the hepatic mitochondrial enzyme deficits in GDH and monoamine oxidase activities that are characteristic of Reye syndrome. GDH activity was linear with the amount of supernatant fraction added, both for Reye and normal liver preparations: moreover, the activities of mixtures of Reye and control supernatant fractions were the sums of the activities of the individual components. This means that the activity difference between Reye and normal GDH activity is not due to a diffusible inhibitor in the Reye hepatocytes or to an activator of GDH in the normal control hepatocytes. Serum obtained from six Reye cases during neurologic deterioration was added to normal hepatic GDH preparations to test for a serum inhibitor of FDH. Highly variable effects were found, with two serum samples producing marked inhibition and others showing weak inhibition, no effect, or stimulation of GDH activity. The inhibitor was not removed by charcoal treatment and most of the activity was retained by a 10,000 dalton Diaflo membrane, signifying either that the compound had a high molecular weight or that it was bound to serum protein. We conclude that the decreased activity of GDH in Reye hepatocytes is not due to an intracellular diffusible inhibitor, and that serum effects are quite variable and are not directly related to intracellular changes in GDH activity.
Investigation of an animal model of a Reye-like syndrome caused by Margosa oil.
Following reports of a Reye-like syndrome in children resulting from Margosa oil (MO) ingestion, we administered MO to laboratory rats in an attempt to produce an animal model of Reye's syndrome. Male rats were injected intraperitoneally with either MO or corn oil and observed for clinical signs of a toxic response. After 15 h the animals were administered a second dose and the MO-treated animals developed florid neurological symptoms. The animals were then sacrificed and blood samples were analyzed for glucose, ammonia, aspartate aminotransferase, and alanine aminotransferase. Sections of liver, kidney, and brain were examined by light microscopy after Sudan black B, hematoxylin and eosin, and periodic acid-Schiff staining. Liver was additionally examined by electron microscopy. Liver samples were analyzed for hepatic enzyme levels and brain samples were analyzed for water content. There were greatly increased levels of ammonia, aspartate aminotransferase, and alanine aminotransferase and decreased glucose levels in the blood of MO-treated animals. Light microscopy of MO-treated livers revealed fatty infiltration, granularity of the cytoplasm with normal nuclei, and glycogen depletion; electron microscopy revealed mitochondrial pathology in the livers of MO-treated animals. There were no significant morphological changes in brain or kidney specimens although the kidneys did show some fatty infiltration. Hepatic mitochondrial enzyme levels were unchanged and there was no increase in brain water content in the MO-treated animals. Thus, many of the abnormalities seen in Reye's syndrome were seen in this model; however, there were no hepatic enzyme changes despite altered mitochondrial morphology and no evidence of cerebral edema despite a florid encephalopathy. Nonetheless, this model may have important implications for the understanding of the pathogenetic mechanisms of this Reye-like syndrome and, perhaps, Reye's syndrome.
Hepatic and encephalopathic components of Reye's syndrome: factor analysis of admission data from 209 patients.
Factor analysis of admission data from 209 Reye's syndrome patients yielded three factors. Factor 1 was associated with encephalopathy, blood ammonia, creatinine kinase (CK), uric acid and, to a lesser extent, bilirubin. This factor was linked to the encephalopathy and hypermetabolic changes in muscle, possibly prostaglandin-mediated proteolysis. Factor 2 was associated with serum alanine aminotransferase (AlaAT) and aspartate aminotransferase (AspAT), and was identified as a hepatic lesion component. These factors correspond to two etiologic components of Reye's syndrome. Salicylate was only weakly associated with neuropathic and hypercatabolic indicators and not at all associated with the hepatic damage indicators.
The significance of hypoalbuminemia following injury and infection.
Serum albumin and absolute hepatic albumin synthetic rates were measured in ten seriously ill injured and septic patients using the (14C) carbonate technique. Although it is commonly believed that serum albumin levels (SAL) reflect hepatic function and visceral protein status in hospitalized patients, no relationship was found between these two measured parameters in this patient population. A depressed mean serum albumin level of 1.98 +/- 0.50 gm/dl (range: 1.25-2.69 gm/dl) was associated with a supranormal mean albumin synthetic rate of 215 +/- 121 mg/kg/day (range: 21-447 mg/kg/d). No significant mean SAL and albumin synthetic rate differences were noted between injured nonseptic and septic patient populations. Since albumin synthesis was elevated in most of these stressed patients these findings support the view that extravascular protein redistribution and/or increased peripheral catabolism are the major factors responsible for hypoalbuminemia in critically ill patients.
Control of forward and reverse electron flow in mitochondria: thermodynamic versus kinetic considerations.
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The radiology of stillbirths and neonatal deaths.
Whole body radiographs were made in a consecutive series of 488 infants who were either stillborn or died within the first month of life; autopsies were done in 378. The radiographs were considered to have been useful, or diagnostic in 16% overall, in 100% of infants with dwarfism, in 40% where there were external malformations; and in 9% where there were no external malformations.
Cigarette smoke-induced bronchoconstriction in dogs: vagal and extravagal mechanisms.
We reassessed the severity of cigarette smoke-induced bronchoconstriction and the mechanisms involved in anesthetized dogs. To evaluate the severity of smoke-induced bronchoconstriction, we measured airway pressure and airflow resistance (Rrs, forced oscillation method). We studied the mechanisms in other dogs by measuring airway pressure, central airway smooth muscle tone in tracheal segments in situ, and respiratory center drive by monitoring phrenic motor nerve output, including the role of vagal and extravagal nerves vs. the role of blood-borne materials during inhalation of cigarette smoke. Rrs increased more than fourfold with smoke from one cigarette delivered in two tidal volumes. About half the airway response was due to local effects of smoke in the lungs. The remainder was due to stimulation of the respiratory center, which activated vagal motor efferents to the airway smooth muscle. Of this central stimulation, about half was due to blood-borne materials and the rest to vagal pulmonary afferents from the lungs. We conclude that inhalation of cigarette smoke in dogs causes severe bronchoconstriction which is mediated mainly by extravagal mechanisms.