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Biomedical subjects

D R Brown

Publications and source records attributed to D R Brown.

At least 289 records · Page 16Linked to original sources
PubMed1991

Opiate binding sites in mucosa of pig small intestine.

Opiates such as morphine have profound antidiarrheal and constipating actions due in part to their ability to modify intestinal ion transport. This study was undertaken to examine the presence of opiate binding sites in the porcine distal jejunum, a gut segment analogous to the human ileum. Specific binding sites for the tritiated, mu-selective opioid agonist [D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) were localized to the basal portion of villous and crypt cells of the intestinal epithelium by receptor autoradiography. These binding sites may represent enkephalin receptors capable of modulating active electrolyte transport.

Animals↗
PubMed1991

Risk factors associated with kernicterus in the newborn infant: importance of benzyl alcohol exposure.

The prevalence of kernicterus in our neonatal intensive care unit (NICU) decreased from more than 2/1000 live births in 1980 to none in 1984. To clarify predictors of kernicterus, we examined the medical records of infants born during that time who died between 2 and 28 days of age. Infants were divided into three groups: those with kernicterus, all born before June 10, 1982 (n = 29); contemporaneous controls (n = 28); and infants born after June 10, 1982 (n = 32). Benzyl alcohol was not used after June 10, 1982. Kernicteric infants were more likely than contemporaneous controls to have seizures (p less than 0.001). Indices of pulmonary disease, arterial partial pressure of carbon dioxide and end-expiratory pressure on the ventilator were higher after 1982. However, exposure to benzyl alcohol was not different in kernicteric infants and contemporaneous controls, suggesting that benzyl alcohol exposure was not the explanation for the decrease in the prevalence of kernicterus in our NICU.

Analysis of Variance↗
PubMed1991

Replacement of bovine mitochondrial DNA by a sequence variant within one generation.

Inheritance of mitochondrial DNA (mtDNA) in Holstein cattle was characterized by pedigree analysis of nucleotide sequence variation. mtDNA was purified from leukocytes of 174 individuals representing 35 independent maternal lineages, and analyzed for nucleotide sequence variation by characterization of restriction fragment length polymorphism and direct sequence determination. These data revealed 11 maternal lineages in which leukocytes from some individuals seemingly were homoplasmic for the reference mtDNA sequence at nucleotide 364, whereas those from other individuals were homoplasmic for a sequence variant at this position. Both alternative alleles were detected in all branches of these 11 lineages, suggesting that mutation at nucleotide 364 and fixation of the variant sequence occurred frequently in independent events. Thirteen instances were detected of mother-daughter pairs in which leukocytes of each of the two animals seemingly were homoplasmic for a different allele at nucleotide 364, demonstrating the bovine mitochondrial genome can be replaced completely by a nucleotide sequence variant within a single generation. The two alternative sequences seemingly arose de novo at similar frequency, ruling out replicative advantage or other selective bias as the explanation for rapid fixation of mutations at nucleotide 364. Another instance of intralineage sequence variation was detected at nucleotide 5602. This variation was detected in only one of the lineages examined, and evidently arose within three generations.

Alleles↗
PubMed1991

Neonatal sensorineural hearing loss associated with furosemide: a case-control study.

Thirty-five neonates with sensorineural hearing loss (SNHL), identified by brainstem auditory evoked response (BAER), and 70 matched controls with normal BAERs were studied. All infants had had BAERs before discharge from hospital as part of a screening program for high-risk neonates. Infants with SNHL showed no response to a 60dBnHL click stimulus and all had these results confirmed on at least one occasion after hospital discharge. Based on the screening program results, over-all prevalence of non-hereditary hearing loss was estimated to be 0.93 per 1000 live births, and in neonates weighing less than 2000g at birth to be 15.54 per 1000 live births. Several factors, including seizures, exposure to anticonvulsant drugs, furosemide and kanamycin were associated with SNHL, but after multivariate analysis, only exposure to furosemide remained significant. Peak serum bilirubin concentration and benzyl alcohol exposure did not appear to be related to hearing loss.

Auditory Threshold↗
PubMed1991

SA nodal parasympathectomy delineates autonomic control of heart rate power spectrum.

The purpose of this study was to quantify the relative roles of the canine cardiac parasympathetic and sympathetic nerves in controlling the distribution of power within the heart rate (HR) power spectrum using a highly selective surgical technique to parasympathectomize the SA node. DAta were recorded in awake dogs (n = 6) before and after the selective denervation; the animals were isolated from human contact and their behavior carefully monitored during the measurements. The average amplitude in the high-frequency (approximately 0.32 Hz) peak in the HR power spectrum decreased from a predenervation control of 2.68 +/- 1.54 (mean +/- SD, arbitrary units) to 0.07 +/- 0.06 (P less than 0.05). Corresponding resting HR increased from 80 +/- 9 to 106 +/- 16 beats/min (P less than 0.05). The low-frequency peak (approximately 0.02 Hz) also decreased from a control of 2.45 +/- 1.18 to a postparasympathectomy value of 1.25 +/- 0.92 (P less than 0.05). beta-Adrenergic blockade (propranolol, 1 mg/kg) further decreased the latter peak to 0.59 +/- 0.52 (P less than 0.05). These data directly demonstrate that the high-frequency peak of the HR power spectrum 1) results from parasympathetic control of SA nodal automaticity, while 2) the low-frequency peak reflects activity in both divisions of the autonomic nervous system.

Adrenergic beta-Antagonists↗
PubMed1991

Angiotensin II does not contribute to rapid reflex control of arterial pressure.

Pharmacological blockade of the renin-angiotensin converting enzyme reportedly alters the heart rate (HR) power spectrum in conscious dogs, suggesting that these hormones contribute to the short-term regulation of arterial blood pressure. We tested this possibility using four independent procedures. First, HR power spectrum was determined in seven awake dogs before and after administration of enalaprilat (300 ng/kg), a converting-enzyme inhibitor. There were no significant changes in the average amplitude for the spectral peak between 0.003 and 0.1 Hz (i.e., the "low-frequency peak"). Second, the HR power spectrum was measured in 11 awake rabbits before and after treatment with deoxycorticosterone acetate (1 mg.kg-1.day-1) and salt (0.9% saline ad libitum) for 7 days to depress plasma renin levels. There were no significant changes in the amplitude of the HR power spectrum, although mean HR decreased from 206 +/- 3 to 184 +/- 4 beats/min after treatment. In the third experiment, another group of rabbits (n = 8) was tested after 2 wk on a low-salt diet to elevate plasma angiotensin levels and then after 2 wk on a normal salt diet. Once again there were no significant effects on the HR power spectrum. Finally, tranquilized dogs (n = 9) were subjected to sinusoidally varying lower body negative pressure at selected frequencies of 0.008-0.12 Hz. Tests were conducted in the control state and after administration of an angiotensin receptor antagonist (saralasin, 1 microgram.kg-1.min-1). Lower body negative pressure-induced fluctuations in arterial blood pressure were similar in both states. We find no evidence for the role of the renin-angiotensin system in the moment-to-moment regulation of arterial pressure and HR.

Angiotensin II↗
PubMed1991

Effect of cardiac denervation on cardiorespiratory responses to exercise in goats.

The purpose of this study was to determine whether intact cardiac innervation and a normal cardiovascular (CV) response are required for a normal ventilatory (VE) response to mild and moderate treadmill exercise in awake goats. Accordingly, we measured CV and respiratory responses to two levels of exercise in seven normal (N) and six cardiac-denervated (CD) goats. Evidence of surgical CD included 1) absence of a cardiac response during surgery when the left thoracic cardiac nerves, thoracic vagi, and right and left stellate ganglia were electrically stimulated, 2) total and 80% attenuation of baroreflex changes in heart rate (HR) when arterial blood pressure was raised or lowered, respectively, by infusion of vasoactive agents in awake goats, and 3) attenuation of the CV responses to exercise. At each level of exercise in the CD goats, the HR response was significantly reduced relative to the response observed before CD (P less than 0.05) and the recovery HR response was delayed. Cardiac index increased in a work rate-dependent manner in N and CD goats but was significantly lower in the CD animals (P less than 0.05). Hypotension was consistently observed during exercise following CD. There was no effect of CD on steady-state VE at any metabolic rate or on the VE-O2 uptake relationship (P greater than 0.05). The rest-to-work and work-to-work transition responses of arterial PCO2 were similar between N and CD goats, but there was a tendency toward greater hypocapnia at the exercise onset in CD goats at the highest work rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Ventilatory compensation for lactacidosis in ponies: role of carotid chemoreceptors and lung afferents.

We investigated changes in arterial PCO2 (PaCO2) and pulmonary ventilation (VE) in normal, carotid chemoreceptor-denervated, and hilar nerve-denervated ponies during intravenous lactic acid infusion at rest and treadmill exercise at 1.8 mph-5% grade (mild) and 1.8 mph-15% grade (moderate). Lactic acid, (0.5 M) infusion of 0.10, 0.13, and 0.20 ml.min-1.kg-1 at rest and mild and moderate exercise increased arterial [H+] linearly throughout the 10 min of acid infusion. At 10 min of infusion, arterial [H+] had increased approximately 20 nmol/l (0.2 pH units) for each condition and group. Under most conditions, the temporal pattern of PaCO2 during acid infusion was biphasic. At rest and during mild exercise in all groups, and in carotid chemoreceptor-denervated ponies during moderate exercise, PaCO2 increased approximately 2 Torr (P less than 0.05) during the first 2 min of acid infusion. However, in normal ponies during moderate exercise, PaCO2 was not changed from control in the first 2 min of infusion. Between 2 and 10 min of infusion at rest and mild and moderate exercise in all groups, there was a 5-Torr significant decrease in PaCO2, which did not differ (P greater than 0.10) between groups. VE increased between 15-30 s and 2 min of infusion, but VE changed minimally between 2 and 10 min of infusion at rest and exercise in all groups of ponies. We conclude that lactacidosis does increase VE at rest and submaximal exercise in the pony.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis, Lactic↗
PubMed1991

Insulin rapidly inhibits insulin-like growth factor-binding protein-1 gene expression in H4-II-E rat hepatoma cells.

The insulin-like growth factor-binding proteins (IGFBPs) are thought to determine the distribution of IGF-I and IGF-II between the blood and tissue compartments and to modulate their biological activities. A dynamic metabolic role for one of the IGFBPs, IGFBP-1, is suggested by the fact that plasma IGFBP-1 was increased after fasting and diabetes and rapidly decreased by refeeding or insulin treatment, respectively. IGFBP-1 mRNA also is increased in the livers of diabetic rats and decreased by insulin treatment. To understand the molecular basis for this regulation, we have examined the effects of insulin on IGFBP-1 and IGFBP-1 mRNA in the H4-II-E cell line derived from the well differentiated H35 rat hepatoma. IGFBP-1, identified by ligand blotting and immunoblotting, is the major IGFBP in H4-II-E cells. Incubation of H4-II-E cells with insulin for 24 h decreased IGFBP-1 in the culture medium by approximately 50%. Inhibition was observed at physiological concentrations of insulin (ED50, less than 0.5 nM), but not at higher concentrations of IGF-II. These results, together with the fact that H4-II-E cells do not possess IGF-I receptors with which insulin might cross-react, suggest that insulin acts via the insulin receptor. Insulin inhibited IGFBP-1 in the medium by 80% in the absence of glucose, suggesting that the inhibition is a direct effect of insulin; glucose exerted a smaller independent effect in the absence of insulin. Insulin decreased IGFBP-1 mRNA in H4-II-E cells by 50% within 1 h and by 90% after 2-12 h of incubation. Nuclear run-on transcription assays indicated a corresponding decrease in the rate of IGFBP-1 gene transcription. Pretreatment of H4-II-E cells with dexamethasone stimulated IGFBP-1 transcription and increased steady state IGFBP-1 mRNA; stimulation was abolished by insulin treatment, indicating that inhibition by insulin was dominant over induction by dexamethasone. Thus, insulin, acting through the insulin receptor, rapidly decreases the abundance of IGFBP-1 mRNA in H4-II-E cells. Regulation occurs at least in part at the level of gene transcription. We propose that regulation of IGFBP-1 synthesis is an important component of the regulation of IGFBP-1 by insulin in vivo.

Animals↗
PubMed1991

Neurohormonal regulation of ion transport in the porcine distal jejunum. Enhancement of sodium and chloride absorption by submucosal opiate receptors.

The actions of opiates in modulating ion transport across the porcine distal jejunal mucosa were examined in vitro. Opiate receptors were functionally characterized using [D-Pen2,D-Pen5]-enkephalin (DPDPE), [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]-benzeneacetamide), agonists selective for delta, mu and kappa receptor types, respectively. Serosal administration of opiate agonists produced concentration-dependent decreases in basal short-circuit current (Isc. DPDPE and DAMGO also increased tissue conductance (Gt). DPDPE (EC50 = 4 nM) was 7- and 86-fold more potent in decreasing basal Isc than DAMGO and U-50,488, respectively. U-50,488 displayed the greatest efficacy in decreasing Isc. Serosal naloxone decreased DPDPE and DAMGO potencies under basal conditions with Ke values of 11 and 6 nM, respectively. DPDPE- and DAMGO-induced decreases in basal Isc were associated with increases in net Cl absorption; in addition, DAMGO produced an increase in net Na absorption. 8-Bromocyclic AMP (0.3 mM) increased Isc, decreased Gt and inhibited net Na and Cl absorptive fluxes. Selective opiate agonists decreased cyclic AMP-induced elevations in Isc with a rank order of potency (DPDPE, EC50 = 3 nM) of DPDPE greater than DAMGO greater than U-50,488. DPDPE reversed the action of cyclic AMP on Isc and Cl absorption but had no effect on net Na transport. Cyclic AMP-induced decreases in Gt were not altered by DPDPE.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1991

Construction and characterization of genetically inactivated pertussis toxin.

Pertussis toxin has been shown to be an important virulence factor and an antigen which will probably be essential to a pertussis vaccine. Inactivation of the pertussis toxin was required due to the pharmacological properties associated with this toxin. However, chemical inactivation has the potential of altering important epitopes or of failing to inactivate the toxin. Cloning and sequencing of the pertussis toxin operon has permitted the introduction of specific mutations in the S1 gene which have been shown to have a profound effect on the subsequent enzyme activity. Various mutations were constructed, re-assembled into the pertussis toxin operon and returned to the Bordetella pertussis chromosome for expression. Pertussis toxin, with lysine substituted for arginine at position 9 in the S1 subunit (PTA-K9) was assembled and expressed to wild type levels. Substitution of codons for aspartic acid, glycine and glutamine, for that of glutamic acid at position 129 were incorporated into the PTA-K9 construction. Virulence of these constructed B. pertussis strains and ADP-ribosylation by their toxoids were greatly reduced relative to that found with the wild type. Additionally, PTA-K9 was found to have reduced leukocytosis promotion and histamine sensitization activities. Finally, PTA-K9 was shown to be a protective immunogen in both intracerebral and aeorosol challenge assays.

Animals↗
PubMed1991

28-day survival rates of 6676 neonates with birth weights of 1250 grams or less.

Survival rates specific for birth weight, gestational age, sex, and race are described for 6676 inborn neonates who weighed less than 1251 g at birth and were born during 1986 through 1987. Overall 28-day survival increased with gestational age and birth weight, from 36.5% at 24 weeks' gestation to 89.9% at 29 weeks' gestation, or from 30.0% for neonates of 500 through 599 g birth weight to 91.3% for neonates of 1200 through 1250 g. The expected birth weight-specific survival advantage for female neonates and black neonates diminished when the data were controlled for gestational age, showing that certain previously reported survival advantages are based on lower birth weight for a given gestational age. Multivariate analysis showed that all tested variables were significant predictors for survival, in order of descending significance: gestational age and birth weight, sex, race, single birth, and small-for-gestational-age status. The powerful effect of gestational age on survival highlights the need for an accurate neonatal tool to assess the gestational age of very low birth weight neonates after birth.

Black or African American↗
PubMed1991

Muscarinic cholinergic regulation of electrogenic chloride secretion in porcine proximal jejunum.

Acetylcholine is present in a majority of submucosal neurons which project to the intestinal epithelium. In this study, we examined the role of acetylcholine and the actions of cholinomimetic drugs, such as carbachol (CCH), on ion transport across muscle-stripped sheets of mucosa-submucosa from the proximal jejunum of weaned piglets. Serosal administration of CCH (10 nM-100 microM) produced rapid increases in short-circuit current (Isc) which were attributed to net Cl secretion. Acetylcholine, bethanechol and (4-hydroxy-2-butynyl)-1-trimethylammonium m-chlorocarbanilate chloride were partially effective in increasing Isc. Atropine and selective muscarinic cholinergic antagonists produced dextral shifts in the CCH concentration-effect relationship with an order of relative potency of 4-diphenylacetoxy-N-methyl piperidine methiodide (4-DAMP) greater than atropine much greater than pirenzepine greater than 11-[[[2-(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one(AF-DX116). The muscarinic receptor blocker [3H]quinuclidinyl benzilate (QNB) bound specifically and saturably to two sites in the mucosa-submucosa having equilibrium dissociation constants of approximately 10 +/- 3 and 890 +/- 120 pM and Bmax = 7 +/- 3 and 47 +/- 9 fmol/mg protein, respectively. Selective cholinergic antagonists competed for [3H]QNB binding with a rank order of affinity of 4-DAMP greater than hexahydrosiladifenidol much greater than AF-DX 116 greater than or equal to pirenzepine. Specific [3H]QNB binding sites were autoradiographically localized in the jejunal wall to the epithelium, submucosa, and muscularis propria. Electrical transmural stimulation (10-300 pulses/10 sec, 0.5 msec duration, 60 V stimulus strength) delivered to mucosal sheets produced tetrodotoxin-sensitive Isc elevations which were proportional to the number of impulses delivered. Mucosal Isc responses to electrical stimulation were attenuated by 10 microM hexamethonium, 1 microM atropine or autotachyphylaxis to CCH. Tetrodotoxin, at 0.1 microM, produced a 20-fold increase in the secretory potency of CCH. These results suggest that acetylcholine released from intramural neurons in porcine proximal jejunum produces transepithelial Cl secretion. Its effects may be mediated through interactions with two populations of muscarinic cholinergic receptors, located on neuronal and non-neuronal cells within the intestinal mucosa and submucosa, which serve to inhibit and promote Cl secretion respectively.

Acetylcholine↗
PubMed1990

Canine neurotensin, neurotensin6-13 and neuromedin N: primary structures and receptor activity.

Canine neurotensin (NT) and neuromedin N (NMN) were isolated from extracts of ileal mucosa using radioimmunoassay for detection. The structures determined were consistent with those predicted by earlier cDNA work. The molar ratio of NT to NMN was ca. 7, suggesting that the NT/NMN precursor, which contains one copy of each peptide, undergoes complex posttranslational processing or that other NT-precursors lacking NMN exist. In addition to NT, small quantities of NT6-13 and NT2-13 were obtained. Native and synthetic preparations of these peptides were indistinguishable in a radioreceptor assay employing rat brain membranes and 125I-labeled NT; NT6-13 was ca. 8-times more potent than NT and NMN was about one-sixth as potent as NT. NT6-13 was also ca. 10 times more potent than NT in inhibiting spontaneous contractile activity in longitudinally-oriented smooth muscle strips of porcine jejunum. Preparations of intestinal N-cells as well as N-cell vesicles also appeared to contain NT2-13 and NT6-13; however, it is not yet clear whether these peptides are utilized physiologically or simply represent metabolites of NT. These results suggest that further work on the processing of NT precursor and on biologic abilities of partial sequences of NT could be fruitful.

Amino Acid Sequence↗
PubMed1990

Compartmental and topographical specificity of reinnervation of the glutaeus muscle in the adult toad (Bufo marinus).

The extent to which the compartmental and topographical innervation patterns were re-established in the mature glutaeus muscle after nerve cut was determined by HRP retrograde labelling procedures and single motor unit glycogen depletion experiments. Glutaeus muscle axons normally cluster together along the length of the sciatic nerve and enter the triceps femoris nerve along with axons to the cruralis and tensor fasciae latae muscles. Glutaeus axons did not specifically reinnervate the glutaeus muscle after cutting the triceps femoris nerve. Axons within the glutaeus muscle nerve are grouped according to the primary nerve branch, and therefore muscle compartment, for which they are destined. When the glutaeus nerve was cut, regenerating axons lost their compartmental organization within the glutaeus nerve and nonspecifically reinnervated both glutaeus muscle compartments. In marked contrast, the topographical projection of spinal motoneurones to the ventral and dorsal halves of the glutaeus muscle was largely re-established after glutaeus nerve cut; that is, rostral motoneurones mostly reinnervated ventral muscle fibres, whereas caudal motoneurones reinnervated dorsally located muscle fibres. The relatively confined caudal projection was closely related to the sharp fibre type divisions within the glutaeus muscle. The results suggest that factor(s) present during development that determine the correct innervation of a muscle and its compartments no longer operate in the adult, although cues that direct motor terminals to their appropriate muscle region do, and these are most likely related to the topographical distribution of fibre types.

Animals↗
PubMed1990

Breath hydrogen excretion in the premature neonate.

We measured breath hydrogen excretion in 103 neonates from birth to as late as 2 months of age. The patients weighed less than 2000 g at birth and were part of a study of hydrogen excretion as a screening test for necrotizing enterocolitis. Hydrogen excretion in parts per million was normalized for the quality of the expired air by dividing by the Pco2 of the gas sample The rise in the H2/CO2 ratio was influenced by gestational age, energy intake, and antibiotic usage but not by the daily frequency of feeding. The mean +/- SD peak H2/CO2 ratio was 5.1 +/- 3.6 ppm per millimeter of mercury and occurred at 16.0 +/- 11.0 days of age. The age at which the peak H2/CO2 occurred varied with gestational age. Patients born between 23 and 28 weeks gestational age (n = 34) were 22.9 +/- 13.1 days of age when they experienced their peak H2/CO2 ratio, whereas those born between 29 and 34 weeks gestational age (n = 62) were 12.2 +/- 7.5 days of age. The age at which the peak H2/CO2 ratio occurred did not differ between these two groups when corrected for the age at which oral intake exceeded 420 kJ/kg per day. These results suggest that premature neonates require experience with ingesting more than 420 kJ/kg per day before bacteria and carbohydrates are present in large enough quantities to permit measurable hydrogen production. This information will be useful in future studies of premature gut development and physiology and in studying pathologic processes in which malabsorption may play a role.

Birth Weight↗