Developmentally induced changes in rat lung malic enzyme activities.

To determine lung malic enzyme activity at varying stages of development, both cytosolic and mitochondrial enzyme activities were assayed in rat lungs at various stages from day 16 of fetal life to 2 months of postnatal life by measuring the production of 14CO2 from 14C-malate. Malic enzyme activities were significantly higher in the mitochondrial than in the cytosolic fractions at all ages studied. The mitochondrial malic enzyme activity was significantly higher in canalicular stage (days 19-20) stage of lung development when compared to the glandular stage (days 16-18). The mitochondrial fraction at day 19 exhibited biphasic kinetics: high affinity, Km = 0.45 mmol, Vmax = 10.04 nmol/mg protein/min; and low affinity, Km = 5.48 mmol, Vmax = 56.83 nmol/mg protein/min. The cytosolic malic enzyme activity of all fetal stages (saccular stage [days 16-18], canalicular stage [days 19-20], and glandular stage [days 21-22] were significantly higher when compared to postnatal levels (postnatal days 1-10, adult). In contrast to the mitochondrial fraction, at day 19, the cytosolic fraction showed a single Km of 0.23 mmol, Vmax = 12.32 nmol/mg protein/min. The increased mitochondrial malic enzyme activity during late gestation would suggest that, as we have previously demonstrated, anaplerotic substrates other than glucose, may provide a significant energy source in fetal lung. The increased cytosolic activity in the prenatal phases would suggest that the NADPH provided from malic enzyme is an important contributor to de novo fatty acid synthesis, leading to surfactant synthesis, critical to normal lung development in late gestation.

Ureaplasma urealyticum respiratory tract colonization is associated with an increase in interleukin 1-beta and tumor necrosis factor alpha relative to interleukin 6 in tracheal aspirates of preterm infants.

OBJECTIVE: To determine whether Ureaplasma urealyticum respiratory tract colonization in very low birth weight infants during the first week of life is associated with changes in tracheal aspirate concentrations of the cytokines interleukin 1-beta (IL-1-beta), tumor necrosis factor alpha (TNF-alpha) and IL-6. METHODS: Infants with birth weights < or =1250 g were prospectively enrolled. Samples were obtained from the endotracheal tube or nasopharynx on Day 1 and again between Days 7 and 10 for U. urealyticum culture. The concentrations of IL-1-beta, TNF-alpha and IL-6 were measured in tracheal aspirate samples by enzyme-linked immunosorbent assay. RESULTS: There were 18 positive cultures for U. urealyticum from 15 of 96 infants (15.6%). IL-1-beta in tracheal aspirates expressed as concentration per volume or as a ratio of IL-1-beta to IL-6 were 7- and 14.9-fold higher, respectively, in Ureaplasma-positive infants than in Ureaplasma-negative infants (P < 0.05). The TNF-alpha/IL-6 ratio was 18.9 and 15.5 times higher in the Ureaplasma-positive aspirates than in the Ure aplasma-negative aspirates on Day 1 and Days 7 to 10 (P < 0.05). Concentrations of IL-1-beta and TNF-alpha were significantly correlated on Day 1 and Days 7 to 10. Although there was no clinical association demonstrated between U. urealyticum colonization and the development of bronchopulmonary dysplasia (BPD) in this study, infants who developed BPD had significantly higher IL-1-beta concentrations and ratios of IL-1-beta to IL-6 in Day 1 aspirates than infants who did not develop BPD. Conclusions. Isolation of U. urealyticum from the respiratory tract is associated with increased IL-1-beta concentrations and IL-1-beta-IL-6 ratios on Day 1 and increased TNF-alpha-IL-6 ratios on Days 1 and 7 to 10 in tracheal aspirates of colonized infants. Infants who developed BPD had higher IL-1-beta concentrations and IL-1-beta-IL-6 ratios, suggesting that these may be early markers of lung inflammation.

Identification of severe right ventricular dysfunction by technetium-99m-sestamibi gated SPECT imaging.

An 84-yr-old man with previous anterior wall myocardial infarction presented with shortness of breath and palpitations. His symptoms were attributed to myocardial ischemia, and he was referred for a stress 99mTc-sestamibi SPECT imaging study with gating. The images showed minimal left ventricular ischemia, but a dilated and hypokinetic right ventricle suggested pulmonary pathology as the probable etiology of his presenting symptoms. A subsequent ventilation perfusion study was consistent with the diagnosis of multiple pulmonary emboli. Thus, 99mTc-sestamibi SPECT imaging with gating provides information about right ventricular perfusion and function, enhancing the clinical utility of stress myocardial perfusion imaging.

The role of glutamine and other alternate substrates as energy sources in the fetal rat lung type II cell.

Glucose has been thought to be the primary substrate for energy metabolism in the developing lung; however, alternate substrates are used for energy metabolism in other organs. To examine the role of alternate substrates in the lung, we measured rates of oxidation of glutamine, glucose, lactate, and 3-hydroxybutyrate in type II pneumocytes isolated from d 19 fetal rat lungs by measuring the production of 14CO2 from labeled substrates. Glutamine had a rate of 24.36 +/- 4.51 nmol 14CO2 produced/ h/mg of protein (mean +/- SEM), whereas lactate had a significantly higher rate, 40.29 +/- 4.42. 3-Hydroxybutyrate had a rate of 14.91 +/- 1.93. The rate of glucose oxidation was 2.13 +/- 0.36, significantly lower than that of glutamine. To examine the interactions of substrates normally found in the intracellular milieu, we measured the effect of unlabeled substrates as competitors on labeled substrate. This identifies multiple metabolic compartments of energy metabolism. Glucose, but not lactate, inhibited the oxidation of glutamine, suggesting a compartmentation of tricarboxylic acid cycle activity, rather than simple dilution by glucose. Glucose and lactate had reciprocal inhibition. Our data suggest at least two separate compartments in the type II cells for substrate oxidation, one for glutamine metabolism and a second for glucose metabolism. In summary, we have documented that glutamine and other alternate substrates are oxidized preferentially over glucose for energy metabolism in the d 19 fetal rat lung type II pneumocyte. In addition, we have delineated some of the compartmentation that occurs within the developing type II cell, which may determine how these substrates are used.

The role of glutamine as an energy source in the developing rat lung.

Because multiple substrates have been shown to play a role in the metabolic homeostasis of different tissues, a series of studies were initiated to examine the role of alternate substrates in the lung. In these studies, we measured rates of oxidation of glutamine, glucose, lactate and 3-hydroxybutyrate in fibroblasts isolated from d 19 fetal rat lungs by measuring the production of 14CO2 from labeled substrates and compared them with earlier studies of isolated Type II cells. The rate of glutamine oxidation was 16.04 nmol 14CO2 x mg protein(-1) x hr(-1) in the fibroblasts compared with 24.36 in Type II cells. Three-hydroxybutyrate had a rate of 10.75 in the fibroblasts and 14.9 in the Type II cells. Lactate oxidation in fibroblasts was similar to that of glutamine, with a rate of 18.49; however, in Type II cells the rate of lactate oxidation was significantly higher at 40.29. Glucose was oxidized at a rate significantly lower than the other three substrates. In the fibroblasts, that rate was 1.22 and in Type II cells it was 2.13. To examine the interactions of substrates normally found in the intracellular milieu, we measured the effect of unlabeled substrates as competitors on labeled substrate in the fibroblasts, similar to our studies with Type II cells that identified multiple metabolic compartments of energy metabolism in these cell populations. Glucose, but not lactate, inhibited the oxidation of glutamine, suggesting a compartmentation of tricarboxylic acid cycle activity rather than simple dilution by glucose. Glucose and lactate had reciprocal inhibition in the Type II cells. Our data suggest at least two separate compartments in developing lung cells for substrate oxidation: one for glutamine metabolism and a second for glucose metabolism. In summary, we have documented that glutamine and other alternate substrates are oxidized preferentially over glucose for energy metabolism in the d 19 fetal rat lung.

Malic enzyme activity in adult and newborn rat lung.

Using a sensitive technique measuring 14CO2 production from radiolabeled malate, we examined malic enzyme activity in both adult and newborn rat lung tissue and in L2 cells, a cell culture line of type II pneumocytes. Malic enzyme was present in both cytosolic and mitochondrial fractions. Time course experiments demonstrated a linear rate after the initial 10 min, up to 30 min. The optimal pH in the cytosolic fraction was 8.0, whereas maximal mitochondrial malic enzyme activity occurred at pH 7.0. The mitochondrial fraction exhibited biphasic kinetics over the 200-fold range of concentrations examined. The high-affinity Km was 0.16 mmol with Vmax of 7.11 nmol/mg protein/min. The low-affinity Km was 6.95 mmol, with Vmax of 31.82 nmol/mg protein/min. In the cytosol there was a single Km of 0.30 mmol and Vmax of 5.95 nmol/mg protein/min. In paired experiments examining differences between 1-d-old and adult rat lung, significantly higher total and mitochondrial malic enzyme activity occurred in the newborn as compared with the adult. Malic enzyme activity was also present in the L2 cells. The finding of malic enzyme activity in the lung suggests that cytosolic malic enzyme may play a role in generating NADPH needed in the lung for fatty acid synthesis. These findings of developmental differences in malic enzyme activity suggest that alternate substrates such as anaplerotic amino acids may be used in the young animal as energy substrates by way of the tricarboxylic acid cycle.

Training professional psychologists for the twenty-first century.

The continued growth and development of professional psychology may ultimately stand or fall on the integrity of the educational system that prepares future generations of practitioners. Currently, the educational enterprise is unduly hampered by several significant impediments. These impediments are identified and resolutions are proposed that would, if implemented, greatly enhance psychology's ability to assume its rightful place as a major autonomous profession that is properly positioned to address some of the nation's pressing social needs.

Effect of position on pulmonary mechanics in healthy preterm newborn infants.

Preterm infants are often placed in the supine position to facilitate care and observation. Prone positioning may positively affect later neurodevelopmental outcome, but it may also affect pulmonary function. Using a computerized system, we examined the effect of positioning on pulmonary mechanics in spontaneously breathing healthy preterm infants. Eleven infants with a mean birth weight (+/- SD) of 1523 +/- 171 gm and a mean gestational age (+/- SD) of 31.7 +/- 1.5 weeks were studied during the first 2 weeks of life. Pulmonary mechanic measurements were obtained in both supine and prone positions by mask pneumotachography and esophageal balloon technique. Respiratory rate and oxygen saturation were unaffected by positioning. There was a statistically, but not clinically, significant increase in heart rate in the prone position. However, there were no significant differences in tidal volume, minute ventilation, pulmonary resistance, or dynamic compliance between positions. The contribution of intrasubject variability of serial measurements was assessed in a separate group of four infants studied three times in the same position. There was no significant difference in respiratory rate, tidal volume, dynamic compliance per kilogram, or total pulmonary resistance in the same infant when studied in the same position over time (p > or = 0.24). The maximum variability (95% confidence limit) was 25.5% for tidal volume, 21% for dynamic compliance, and 44.3% for resistance. Because prone positioning did not adversely affect pulmonary mechanics or oxygen saturation in these healthy preterm infants, we suggest that prone position be used to facilitate the developmental needs of these infants.

Prescription privileges. Psychology's next frontier?

In the past 5 years there has been a growing interest among psychology practitioners in obtaining prescription privileges, and relevant policy documents have reflected increasing support from the APA. The nonphysician health manpower literature has demonstrated that a wide range of professionals can be trained to prescribe medications competently, while maintaining quality of care; within federal agencies, psychologists have legally prescribed medications. Ongoing debates in Hawaii and in the U.S. Department of Defense may be laying the foundation for psychology's training and practice agenda for the 1990s. Were psychologists to have this clinical privilege, many societal needs--including addressing the longstanding problems of excessive medication of elderly persons and quality care for the chronically mentally ill and for persons residing in rural areas--could be met.

Control of inspiratory duration in premature infants.

We used single-breath mechanical loads and airway occlusions in premature infants to determine whether maturation influences the reflex control of inspiratory duration. We measured flow, volume, airway pressure, and surface diaphragmatic electromyogram (EMG) in 10 healthy preterm infants [33 +/- 1 (SD) wk gestation], 2-7 days of age. Three resistive and two elastic loads and occlusions were applied to the inspiratory outlet of a two-way respiratory valve. Application of all loads resulted in inspired volumes significantly decreased from control (P less than 0.001), and these decreases were progressive with increasing loads. Inspiratory duration (TI) was prolonged from control by all loads and occlusions when measured from the diaphragmatic EMG (neural TI) and by all but the smaller elastic load when measured from the flow tracing (mechanical TI). Similar decreases in inspired volume at the end of neural TI produced by application of both elastic and resistive loads resulted in comparable prolongation of neural TI. In contrast, for comparable volume decrements, resistive loading prolonged mechanical TI more than elastic loading (P less than 0.001). Mechanical and neural TI values of the breath after the loaded breath were unchanged from control values. Comparison of the neural volume-timing relationship in premature infants with our data in full-term infants suggests that the strength of the timing response to similar relative decrements in inspired volume is comparable. We conclude that reflex control of neural TI in premature infants depends on the magnitude of inspired volume and is independent of the volume trajectory.(ABSTRACT TRUNCATED AT 250 WORDS)

Neonatal effects of maternal nadolol therapy.

Described is the case of an infant, exposed during gestation to the beta-blocker nadolol, who experienced cardiorespiratory depression, mild hypoglycemia, and growth retardation. The longer duration of action of nadolol and the fact that it is only 30% protein bound make it less desirable than propranolol for use as a beta-blocker during pregnancy.

Tumor models to investigate the therapeutic efficiency of immunomodulators.

The development of successful approaches to immunotherapy is dependent on the proper consideration of the pathobiology of metastasis and a better understanding of the principles of biological response modification. Immunomodulation as a therapeutic modality has not proven notably effective in animals with preexistent palpable disease, an observation in agreement with the results from clinical protocols. Therefore, rather than developing experimental immunotherapy models of immunoprophylaxis or models with minimal tumor burden, we believe it more appropriate to develop models based on preexistent metastatic disease in a tumor-conditioned host. The most rigorous test of a biological response modifier's efficiency prior to clinical trials will be provided from immunotherapeutic trials of palpable autochthonous tumors.

The distribution in the cat brain stem of neurones activated by vagal nonmyelinated fibres from the heart and lungs.

In anaesthetized cats, right cardiac vagal branches were electrically stimulated and recordings of evoked 'slow wave' and single neurone activity were made in the brain stem. Short-latency 'slow wave' and multi-neuronal activity evoked by excitation of myelinated vagal afferent fibres were recorded in the medial and lateral subnuclei of the nucleus tractus solitarius, the area postrema, the dorsal vagal motor nucleus, the lateral reticular formation and the nucleus ambiguus. Long-latency responses evoked by vagal non-myelinated fibres were recorded in the medial subnucleus of the nucleus tractus solitarius, the area postrema, dorsal vagal motor nucleus, the parahypoglossal area and the lateral reticular formation dorsal to the nucleus ambiguus. A specific study was made of seventy-two single neurones activated by non-myelinated afferent fibres in the cardiac branch. Thirty-four were shown to be synaptically activated, twenty-one were activated nonsynaptically and seventeen could not be classified. One neurone was also activated by myelinated cardiac afferent fibres, and two by thoracic vagal (including pulmonary) afferent fibres. Neurones were not spontaneously active. Indirect evidence suggests that the majority of the recordings of nonsynaptically activated neurones were likely to be from cell bodies. Neurones were located from the level of the obex to 3.0 mm rostral to it in the medial subnucleus of the nucleus tractus solitarius (45), and in the lateral subnucleus (2), the area postrema and its border with the medial subnucleus of the nucleus tractus solitarius (13), the dorsal vagal motor nucleus (9), the parahypoglossal area (1) and the lateral reticular formation dorsal to nucleus ambiguus (2). Recordings were made from fifteen neurones activated by myelinated fibres in the cardiac vagal branches, and twelve were excited synaptically. The neurones were located in the medial (8) and lateral (3) subnuclei of the nucleus tractus solitarius, the dorsal vagal motor nucleus (1) and the lateral reticular formation (1). Four neurones were also excited by vagal afferent fibres in the thoracic vagal nerve immediately caudal to the caudal cardiac branch.

The terminations and secondary projections of myelinated and non-myelinated fibres of the aortic nerve in the cat.

In anaesthetized cats the projection of myelinated and non-myelinated afferent fibres of the aortic nerve to the brain stem was studied by recording antidromic potentials evoked in the nerve by electrical stimulation of the medulla oblongata. Probable sites of termination of both myelinated and non-myelinated afferent fibres were found to be in the ipsilateral medial lateral subnucleus of the nucleus tractus solitarius, the ipsilateral area postrema, the commissural nucleus and the contralateral nucleus tractus solitarius about the level of the obex. No evidence for a projection of primary afferent fibres in the aortic nerve to the medial reticular formation was found. In a second series of experiments the aortic nerve was electrically stimulated and extracellular recordings were made from neurones in the medulla activated by afferent fibres in this nerve. Neurones activated by myelinated afferent fibres were located in the nucleus tractus solitarius, dorsal vagal motor nucleus, commissural nucleus, area postrema and lateral reticular formation including nucleus ambiguus. Neurones activated by non-myelinated afferent fibres were in or near the medial nucleus tractus solitarius, the area postrema, dorsal motor vagal nucleus and nucleus intercalatus. Few neurones appeared to be activated by both myelinated and non-myelinated afferent fibres and they were located in the medial nucleus tractus solitarius and nucleus ambiguus.

The effect of naloxone on the inhibition of nociceptor driven neurones in the cat spinal cord.

The functional role of the opiate receptors and enkephalins found in high concentration in the superficial dorsal horn of the spinal cord has not been ascertained but may be the modulation of transmission in nociceptive pathways. In cats anaesthetized with alpha-chloralose the nacrotic antagonist, nalozone, was tested on various types of inhibitory input to spinal cord neurones which responded to both noxious and non-noxious stimulation of their receptive fields (Class 2 neurones). Naloxone (0.3-2.0 mg/kg i.v.) failed to alter the response of these neurones to noxious radiant heat, to tonic descending inhibition or to inhibition evoked by stimulation of the dorsal columns or contralateral plantar nerve. Thus the endorphins do not appear to be involved in mediating the types of inhibition examined. On the other hand, i.v. morphine reduced the response of Class 2 neurones to noxious heating of the skin that was reversed by naloxone.