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Biomedical subjects

B Davison

Publications and source records attributed to B Davison.

At least 19 recordsLinked to original sources
PubMed1996

Active interleukin-1 receptor required for maximal progression of acute pancreatitis.

OBJECTIVE: The authors' aim was to determine the requirement for an active interleukin (IL)-1 receptor during the development and progression of acute pancreatitis. SUMMARY OF BACKGROUND DATA: Interleukin-1 is a pro- inflammatory cytokine that has been shown to be produced during acute pancreatitis. Earlier animal studies of moderate and severe pancreatitis have shown that blockade of this powerful mediator is associated with attenuated pancreatic destruction and dramatic increases in survival. The exact role played by IL-1 and the requirement for activation of its receptor in the initiation and progression of pancreatitis is unknown. METHODS: Conventional and IL-1 receptor "knockout" animals were used in parallel experiments of acute pancreatitis induced by intraperitoneal injection of cerulean (50 microg/kg every 1 hour X 4). The conventional mouse strain had the IL-1 receptor blocked prophylactically by means of a recombinant IL-1 receptor antagonist (10 mg/kg injected intraperitoneally every 2 hours). The second mouse strain was genetically engineered by means of gene targeting in murine embryonic stem cells to be devoid of type 1 IL-1 receptor (IL-1 receptor knockout). Animals were killed at 0, 0.5, 1, 2, 4, and 8 hours, with the severity of pancreatitis determined by serum amylase, lipase, and IL-6 levels and blind histologic grading. Strain-specific controls were used for comparison. RESULTS: The genetic absence of the IL-1 receptor or its pharmacologic blockade resulted in significantly attenuated pancreatic vacuolization, edema, necrosis, inflammation, and enzyme release. Serum IL-6, a marker of inflammation severity, was dramatically decreased in both groups. CONCLUSIONS: Activation of the IL-1 receptor is not required for the development of pancreatitis but apparently is necessary for the maximal propagation of pancreatic injury and its associated inflammation.

Acute Disease↗
PubMed1996

Genotypic analysis of infant macaques infected transplacentally and orally.

The SIV-infected macaque provides an excellent model to study factors involved in maternal-fetal transmission of HIV. In our prenatal transmission studies, female macaques were inoculated intravenously during midgestation with either SIV/DeltaB670 or a combination of SIV/ DeltaB670 and the macrophage-tropic molecular clone SIV/17E-Fr. The females harbored a genetically diverse virus population at parturition, whereas a single genotype from the maternal quasispecies was identified in the infants. One of two variants was transplacentally transmitted to the infants, SIV/17E-Fr or B670-Cl 12, a genotype contained within the SIV/ DeltaB670 inoculum. Both of these variants have been identified in the central nervous system of macaques that have developed encephalitis and they replicate in vitro on primary rhesus macrophages. These results suggest a critical role for macrophages in fetal infection in utero. In our perinatal transmission studies we have evaluated the viral genotypes found in two newborn macaques infected orally with SIV/DeltaB670 and in one infant infected via amniotic inoculation in late gestation. More than one viral genotype was identified in each infant, moreover, each infant harbored different genotypes. These results suggest different mechanisms are responsible for viral infection via these routes.

Amino Acid Sequence↗
PubMed1995

Structural analysis of human and murine flt3 ligand genomic loci.

Both the murine and human genomic loci that encode flt3 ligand have been cloned. flt3 ligand is a hematopoietic growth factor that stimulates the proliferation of stem and progenitor cells. The portions of the murine and human flt3 ligand genomic loci encompassing the coding region of the protein are approximately 4.0 kb and 5.9 kb, respectively. The human genomic locus is larger as a result of the presence of repeated sequences within introns I, II, IV, V and VI. The transmembrane isoform of the murine and human flt3 ligand proteins are each encoded within seven exons (1-5 + 7 and 8). Analyses of flt3 ligand cDNA clones show that alternative splicing of a putative sixth exon results in the generation of a soluble form of the flt3 ligand protein. The sizes of each of the exons are well conserved between species. Murine and human flt3 genomic loci have a similar exon: intron structure compared to the genomic loci encoding Steel factor and colony stimulating factor 1. These proteins, which appear to be ancestrally related, are hematopoietic growth factors that stimulate cells via specific and structurally related tyrosine kinase receptors on the cell surface.

Alternative Splicing↗
PubMed1995

Distribution of SIV in lymph nodes of serially sacrificed rhesus monkeys.

Rhesus monkeys were inoculated with SIVDeltaB670 and sacrificed 2, 4, 8, and 24 weeks after inoculation or when moribund. Two monkeys predicted to have a rapid disease course and two predicted to have a slower disease course were sacrificed at each time point. Lymph nodes were studied by histopathology, immunohistochemistry, in situ hybridization, electron microscopy, flow cytometry for lymphocyte subsets, and mitogen responsiveness. A greater selective decrease in peripheral CD4+CD29+ (helper-inducer/memory) T cells occurred in monkeys with high antigenemia. Although the percentage of CD8+ lymphocytes was increased and the CD4+/CD8+ ratio decreased in all infected groups, there were no consistent differences between monkeys with high or low antigenemia in lymph node lymphocyte subsets. Blastogenic responses of lymph node lymphocytes to PHA, ConA, or PWM were not significantly altered in infected monkeys. A reticular pattern typical of antigen deposition within germinal center follicular dendritic cells was seen in three monkeys with atrophic lymph nodes, high serum antigenemia, and a low percentage of circulating CD4+/CD29+ cells. More individually stained cells were in monkeys with high serum antigen and in moribund animals. By in situ hybridization, most monkeys had signal in a reticular pattern of germinal centers. Animals with higher levels of serum antigenemia tended to have more infected cells and a more intense signal. Extracellular virions were found between the FDC foot processes in the germinal centers of lymph nodes. Disease course was already established 2 weeks after inoculation.

Animals↗
PubMed1995

Autonomic regulation of tissue resistance in the guinea pig lung.

Although the autonomic nervous system is known to influence airway tone and resistance in both the normal and inflamed lung, its effects on tissue resistance (Rti) have not been defined. To characterize autonomic neural control of Rti in the lung, we measured airway resistance (Raw) and Rti, lung elastance, and lung hysteresivity after adrenergic, cholinergic, and nonadrenergic noncholinergic (NANC) blockade in anesthetized mechanically ventilated guinea pigs by using the alveolar capsule technique. Five animals received 1 mg/kg i.v. phentolamine (alpha-blocker), eight received 1 mg/kg i.v. propranolol (beta-blocker), six received 0.1 mg/kg i.v. atropine (parasympatholytic), six had surgical bilateral vagotomy, and five were treated 14 days before study with 50 mg/kg sc capsaicin (peptidergic neurotransmitter depleter). Measurements were recorded at 5- to 10-min intervals for 120 min after pharmacological induction of autonomic blockade. Capsaicin treatment resulted in decreases in lung resistance (RL), Raw, and dynamic elastance (Edyn) compared with controls but Rti was not significantly affected. beta-Blockade resulted in significant increases in RL, Raw, and Edyn but did not affect Rti. alpha-Blockade and vagolytic maneuvers had no effect on RL, Raw, Rti, or Edyn. Furthermore, there was no effect of cholinergic, adrenergic, or NANC blockade on the relationship between Rti or elastance and breathing frequency or mean lung volume during tidal breathing. Our results suggest that, in the normal guinea pig lung, baseline Raw is modulated by both the beta-adrenergic and NANC nervous systems but Rti tone is largely independent of nervous system regulation.

Airway Resistance↗
PubMed1994

Effects of acute lung injury on dynamic tissue properties.

The dynamic properties of lung tissue after acute injury (ALI) were characterized by studying parenchymal strips prepared from guinea pigs endobronchially treated with hydrochloric acid. Forty-eight-hour samples (10 x 4 x 4 mm) from control (C), acid-damaged (D), and uninvolved (U) lungs of treated animals had elastance and resistance measured in a perfused organ bath system during uniaxial length oscillation at a mean force of 750 mg over a 1.5 (0.1-3 Hz)-fold decade frequency range and 5-fold (1-5%) strain amplitude range. Results were interpreted using a quasi-linear viscoelastic model with tissue stress expressed as an exponential function of strain. Among C strips, elastance increased linearly with the logarithm of frequency, whereas resistance decreased hyperbolically with frequency; both were strain amplitude independent. In contrast, elastance among D strips was uniformly greater (P < 0.0001) and was inversely strain amplitude dependent (P < 0.01); resistance was markedly elevated (P < 0.0001) but decreased hyperbolically with frequency similar to C strips. Resistance and elastance changes among U strips were intermediate between those for D and C strips. Histological grading of cellular infiltration, alveolar septal thickening, and hemorrhage correlated with functional changes. The frequency and amplitude dependencies and magnitude changes for resistance and elastance were similar to those previously observed in intact dog lungs after ALI. These findings suggest that ALI can affect the rheological properties of lung parenchyma independently of surfactant and that changes in lung mechanics after ALI may, in part, be determined at the parenchymal level.

Acute Disease↗
PubMed1994

BLOOD PRESSURE CONTROL IN THE ANTARCTIC FISH PAGOTHENIA BORCHGREVINKI

The mechanisms of cardiovascular control in the Antarctic fish Pagothenia borchgrevinki were investigated during rest and swimming exercise using pharmacological tools to reveal the nature of the control systems involved. Simultaneous and continuous recordings of ventral and dorsal aortic blood pressure, heart rate and ventral aortic blood flow (cardiac output) were made using standard cannulation procedures and a single-crystal Doppler flowmeter. Exercise produced a clear and consistent decrease in dorsal aortic blood pressure caused by a decrease in systemic vascular resistance. At the same time, ventral aortic blood pressure increased owing to the combined effects of a markedly increased cardiac output (by about 80 %) and branchial vasoconstriction. Judged from the effects of the alpha-adrenoceptor antagonist prazosin, control of the branchial vasculature involves an alpha-adrenoceptor-mediated vasoconstriction, in addition to more traditional cholinergic vasoconstrictor and ss-adrenoceptor-mediated dilatory mechanisms. The range of heart rates is large, from 3-4 beats min-1 in individual fish during hypertensive bradycardia to about 28 beats min-1 after atropine treatment. Both chronotropic and inotropic effects are responsible for a marked increase in cardiac output during exercise. The increase in blood pressure caused by adrenaline injection was due largely to an increase in cardiac output, while direct effects on the systemic vasculature were small and transient. The increase in cardiac output, in turn, was due solely to an adrenergic stimulation of stroke volume. A barostatic bradycardia, often seen in other vertebrates in response to adrenaline injection, was absent and it is possible that a decrease in heart rate was offset by direct adrenergic stimulation of the heart. Angiotensin II (Ang II) produced consistent hypertension by systemic vasoconstriction. In contrast to the effects of adrenaline injection, the hypertension caused by Ang II was accompanied by a marked bradycardia. This could be abolished by atropine, suggesting a cholinergic vagal reflex of the type found in other vertebrates. Angiotensin I also caused an elevated blood pressure, and this effect was abolished by the angiotensin converting enzyme inhibitor enalapril, demonstrating elements of an angiotensin-related cardiovascular control system.

Journal Article↗
PubMed1994

In vivo biological effects of recombinant soluble interleukin-4 receptor.

We investigated the role of soluble interleukin-4 receptor (sIL-4R) as a regulator of IL-4 mediated activities in vivo. Administration of recombinant sIL-4R to mice resulted in (i) prolonged survival of heterotopic cardiac allografts; (ii) decreased popliteal lymph node enlargement in response to allogeneic cells; and (iii) inhibition of IgE secretion in response to anti-IgD treatment. Transgenic mice constitutively expressing elevated levels of biologically active sIL-4R displayed prolonged cardiac allograft survival compared with control animals. However the sIL-4R transgenic mice were capable of mounting normal antigen-specific IgE responses despite the presence in serum of up to 3 micrograms/ml sIL-4R. Surprisingly, coadministration of IL-4/sIL-4R or IL-4/anti-IL-4 mAb complexes caused a superinduction of IgE secretion in anti-IgD-treated normal mice and subsequently in other IL-4-dependent biological activities. Thus, recombinant sIL-4R can not only antagonize functions mediated by endogenous IL-4, but also potentiate the biological activity of exogenously administered IL-4. These dual roles may have possible clinical implications for the recombinant molecule, as well as for natural sIL-4R immunoregulation.

Animals↗
PubMed1993

Tissue resistance in the guinea pig at baseline and during methacholine constriction.

Total lung resistance (RL), airway resistance (Raw), and tissue resistance (Rti) were measured in unconstricted and methacholine (MCh)-constricted guinea pigs while tidal volume, lung volume, and breathing frequency were varied. Measurements were made in tracheostomized ventilated guinea pigs with use of alveolar capsules. Relationships between Raw and Rti at different breathing frequencies, lung volumes, tidal volumes, and levels of constriction were compared with previously reported values in other species. Our results demonstrate that, at fixed tidal volume, Rti was inversely related to breathing frequency (Rti approximately f-0.64, where f is breathing frequency in Hz) and increased with increasing lung volume. Rti was a significantly greater percentage of RL after MCh administration (40-50%) than at baseline (15-35%), indicating a greater tissue than airway constrictor response. Rti was also 0.5 log dose more responsive to intravenous MCh than Raw on the basis of the dose required to produce 100% increase in resistance from baseline (PD100). These data show that, in the guinea pig, Rti changes with lung volume, breathing frequency, and constrictor tone in a manner similar to other species previously reported and that Rti can be an important determinant of lung dysfunction during constriction, even in species for which it is small in relation to Raw at baseline.

Airway Resistance↗
PubMed1992

Delayed allograft rejection in mice transgenic for a soluble form of the IL-4 receptor.

Accumulating evidence suggests that in serum and other biological fluids, cytokine binding is a property associated with soluble proteins, including a high-affinity soluble version of the IL-4 receptor (sIL-4R). While it is tempting to speculate that sIL-4R might act as a serum carrier protein or serve to inhibit or modulate IL-4 action, specific biological roles for sIL-4R remain to be established. To further assess the immunoregulatory and therapeutic potential of sIL-4R and other soluble receptors, we have created transgenic mice which constitutively express elevated levels of biologically active sIL-4R. Phenotypic characterization of lymphoid organs in sIL-4R transgenic mice revealed normal numbers of B and T cells and normal surface marker expression. Splenic lymphocytes displayed normal in vitro activities as measured by the PFC response and generation of cytotoxic T cells. In addition, antigen-specific IgE and IgG1 in vivo responses were similar in control and transgenic mice. Despite the apparent developmental normality of the sIL-4R transgenic mice, these animals were markedly deficient in the ability to reject cardiac allografts, suggesting that IL-4 is critical for the generation of alloreactivity. The results further suggest that the ability of sIL-4R to regulate IL-4 activities may be under the control of complex interactions that remain to be elucidated.

Amino Acid Sequence↗
PubMed1992

Development and testing of a PC-based system with menu-driven software for evaluating lung function in ICU patients.

This paper describes a portable PC-based system for measuring respiratory system resistance (Rrs) and dynamic lung compliance (Cdyn) in intubated and mechanically ventilated patients. A pneumotachometer placed immediately proximal to the endotracheal tube measures flow, and a pressure catheter with its tip at the distal end of the endotracheal tube measures lateral airway pressure. The software is menu driven and allows the user to select from options including patient information display and entry, data collection, data editing, and waveform display. Up to ten consecutive breaths can be analyzed per run. Rrs and Cdyn are calculated on a breath by breath basis. Results are displayed to the screen, output to the system printer, and written to a user-specified ACSII data file. The system was tested by measuring resistance and compliance in a model of the lung, and results compared with those calculated from analog signals. It was then used to make measurements in intubated post-operative patients. Results were comparable to those previously reported in intubated ICU patients without primary lung disease. We conclude that our system provides reliable measurements of lung mechanics in the intubated patient, and represents an inexpensive and more versatile alternative to microprocessor-based ventilator systems currently being marketed.

Intensive Care Units↗
PubMed1989

Assessment of the bioactivity of human and bovine thyrotrophin preparations using a porcine thyroid cell bioassay.

The biopotency of six preparations of thyrotrophin (TSH) has been compared in a highly sensitive in vitro porcine thyroid cell bioassay using iodide uptake as an endpoint. Three of these preparations were of human origin and three derived from bovine pituitary tissue. One human TSH preparation, the 2nd International Reference Preparation, 80/558, was used to calibrate the other five. The log dose-log response curves for all preparations were sigmoidal in shape. For the purpose of evaluation the central linear portions of the curves were compared. With all preparations the slopes in this region were very similar. The relative biopotencies of the bovine preparations (unit:unit) were at least five times those of the human standards when measured using the porcine thyroid cell bioassay. These findings emphasise the need to control the TSH standards employed in a variety of bioassays, particularly those used for between-laboratory comparison.

Animals↗
PubMed1986

Protein-A purified human immunoglobulins: a comparison of thyroid stimulating and thyrotrophin receptor binding activities in thyrotoxicosis.

Protein-A purified human thyroid stimulating immunoglobulins (TSIg) and thyrotrophin binding inhibiting immunoglobulins (TBIIg) were measured in euthyroid subjects and thyrotoxic patients by bioassay and TSH radioligand receptor assay respectively. Unextracted sera from euthyroid and thyrotoxic subjects inhibited both basal and TSH stimulated iodide uptake in the bioassay, which was based on iodide uptake in porcine thyrocytes. Similar effects were seen with Ig and TSIg extracted from sera using either polyethylene glycol or ammonium sulphate. However IgG and TSIg prepared using Protein-A Sepharose CL-4B from sera of euthyroid subjects had little effect in this system. The majority of Protein-A purified TSIg preparations from sera of thyrotoxic patients stimulated iodide uptake in procine thyrocytes in a dose-dependent manner and most (85%) diluted parallel to both bovine and human TSH. TSIg and TBIIg from 73 patients with thyrotoxicosis were assessed using the bioassay and receptor assay and compared to a control group of 35 euthyroid subjects. The median (and range) values for TSIg and TBIIg in the euthyroid group were 4.35 (0.8 to 7.5, % stimulation over control) and 2.7 (-9.3 to 8.6, TBII index) for the bioassay and radioreceptor assay respectively. A value of greater than 10.0 in both assays was taken as a positive result. Of the thyrotoxic patients 61 out of 73 were positive in the bioassay (83.6%) compared to 60 in the radioreceptor assay (82.2%). There was a positive correlation between the two assays (r = 0.821, P less than 0.001). Of the 73 thyrotoxic patients 40 were untreated, 18 had received carbimazole and 15 had been previously treated with iodine-131. TSIg levels in the untreated thyrotoxics were similar to those in either group of treated patients. However they were higher (P less than 0.05) in the iodine-131 group than in the patients treated with carbimazole. Similar results were obtained for TBIIg. The coupling of a specific extraction method for human serum IgG with a bioassay for TSIg has demonstrated a high prevalence of these immunoglobulins in patients with thyrotoxicosis. The agreement between this assay and a radioreceptor assay was good, indicating that TSH displacing and thyroid stimulating activities of these immunoglobulins are closely related.

Adult↗
PubMed1986

Effect of adrenocorticotrophin on cortisol and androstenedione secretion from dispersed cells of guinea-pig adrenal zonae fasciculata and reticularis.

We have studied cortisol and androstenedione secretion by dispersed cells of the outer zona fasciculata (ZF) plus zona glomerulosa, and the inner zona reticularis (ZR) plus medulla of the guinea-pig adrenal. The ZF and ZR were microdissected apart, the cells dispersed and incubated (200 000 cells/ml) for 90 min in the presence of adrenocorticotrophin (ACTH; 500 ng/l), dibutyryl cyclic AMP (dbcAMP; 1 mmol/l), pregnenolone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol and 21-deoxycortisol. The steroid concentrations were 5-25 mumol/l. Cortisol secretion was assayed by radioimmunoassay. There was no detectable cortisol secretion (less than 50 nmol/l) from the ZR in the controls (no additive) or after dbcAMP stimulation. Adrenocorticotrophin-stimulated cortisol secretion was also low (range less than 50-340 nmol/l). In contrast the ZF secreted 177-379 (control), 828-2052 (dbcAMP) and 2863-9735 (ACTH) nmol cortisol/l. There was no detectable (i.e. less than 2 nmol/l) cAMP production by ZR or ZF either basally (no ACTH) or after ACTH stimulation (500 ng/l). Challenge of the ZR cells with each cortisol precursor steroid (5 mumol/l) increased (P less than 0.05) cortisol secretion over that seen with the corresponding basal and ACTH-stimulated controls. Thus pregnenolone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol and 21-deoxycortisol (converted directly to cortisol by 21-hydroxylase) gave rise to (mean +/- S.D., n = 4) 406 +/- 86, 680 +/- 180, 1307 +/- 111, 1141 +/- 234 and 3160 +/- 419 nmol cortisol/l respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

17-alpha-Hydroxypregnenolone↗
PubMed1985

Murine leukemia virus long terminal repeat sequences can enhance gene activity in a cell-type-specific manner.

We tested the ability of sequences in the long terminal repeat (LTR) of a mink cell focus-forming (MCF) murine leukemia virus to function as an enhancer in a cell-type-specific manner. In a stable transformation assay, the MCF or Akv LTR and the simian virus 40 enhancer had similar activities in murine fibroblasts. In contrast, the MCF LTR had a significantly greater activity in murine T lymphoid cells than did either the simian virus 40 enhancer or the Akv LTR.

Animals↗
PubMed1985

Measurement of low concentrations of bovine thyrotrophin by iodide uptake and organification in porcine thyrocytes.

Thyrocytes isolated from porcine thyroids by mechanical and enzymatic dispersion and cultured in Eagle's minimal essential medium, supplemented with 5% (v/v) fetal calf serum, glutamine and cortisol, formed a continuous monolayer within 48 h. This monolayer was without cytochemical peroxidase and diaphorase (NADPH reoxidation) activity. In the presence of bovine thyrotrophin (bTSH; 50 mu./l) the cells developed a follicular-like architecture which was maximal at 4 days before reverting back to a uniform monolayer at 6 days. There were no detectable changes in the total DNA content over this period. The follicular structures had marked diaphorase and peroxidase activity, the latter being apically distributed. Concomitant with follicle formation bTSH induced uptake and organification of iodide presented to the cells during the last 6 h of culture. The extent of this process depended on the dose of bTSH and the duration of stimulation. The most sensitive effects for both iodide uptake and organification occurred with 1 mu. bTSH/l and were maximal with 100 mu./l. Uptake and organification were increased 20 +/- 8-fold and 9.6 +/- 2-fold (n = 10) respectively over the control with 100 mu./l and the doses of bTSH at which a half maximal response was seen (ED50) were 15 +/- 2 and 7 +/- 1 (S.D) mu./l (n = 10) respectively. On changing the culture medium to a serum-free system using HB101 culture medium the stimulation time for the most sensitive bTSH effect was reduced to 2.5 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗