Biomedical subjects

J Atkinson

Publications and source records attributed to J Atkinson.

At least 127 records · Page 7Linked to original sources

PubMed1996

Small intestinal absorption during endotoxemia in swine.

We studied the effects of systemic endotoxemia on small intestinal absorption in an in vivo animal model. Seven adolescent Yorkshire swine underwent creation of 25 cm distal ileal Thiry-Vella fistulae. After 1 week recovery, the fistulae were perfused with a solution of glucose and electrolytes labeled with 14C-PEG, and net absorption of water, Na+, Cl-, and glucose was calculated. Animals were studied under three different conditions: (1) Basal fasting state, (2) immediately after intravenous injection of E. coli lipopolysaccharide (LPS; 250 micrograms/kg), and (3) 24 hours after LPS. Water, Na+, and Cl- absorption was significantly reduced 2 hours after LPS, but recovered to baseline values by the third hour after LPS. Twenty-four hours after LPS water, Na+, and Cl- absorption was significantly decreased below baseline values. Glucose absorption after LPS paralleled that of water and electrolytes, except that the transient early recovery was not observed. Histological studies of the ileum after LPS showed marked epithelial inflammation at 6 hours, villous atrophy at 24 hours, and signs of recovery at 7 days. Intestinal absorption of water, electrolytes, and glucose is adversely affected in the immediate and early periods after an endotoxemic episode, but the histological epithelial injury secondary to endotoxemia is reversible.

Animals↗

PubMed1996

Widespread HIV counseling and testing linked to a community-based tuberculosis control program in a high-risk population.

The aim of the work reported here was to evaluate community-wide screening for HIV infection that was linked to a tuberculosis control program in a population at high risk for both infections. Between May 1990 and August 1992, adults in Cité Soleil, Haiti, were recruited by community health workers at their homes and in clinics for individual, clinic-based counseling and testing for HIV and tuberculosis. All of the screened subjects were offered post-test HIV counseling. Those with active tuberculosis received treatment, while those with latent tuberculosis and HIV infection were offered an opportunity to participate in a trial of antituberculosis chemoprophylaxis. The 10,611 individuals screened for HIV represented 10.0% of the adult population in Cité Soleil. HIV infection was detected in 1,629 (15.4%) and active tuberculosis in 242 (2.3%). Latent M. tuberculosis infection was found in 4,800 (67.5%) of 7,309 community residents who completed tuberculosis screening, 781 (16.3%) of whom were coinfected with HIV. The high prevalence of HIV infection found in this screened population, as compared to other groups undergoing HIV screening in the same community, suggests that people at high risk for HIV infection selectively sought or accepted tuberculosis clinic screening. Also, many people with active tuberculosis were identified earlier in the course of their disease than they would have been in the absence of a screening program. Overall, the results indicate that community-based screening for HIV infection within a tuberculosis control program can result in effective targeting of screening for both infections.

Adolescent↗

PubMed1996

Zotepine: preclinical tests predict antipsychotic efficacy and an atypical profile.

Zotepine, an atypical antipsychotic structurally similar to clozapine, is in Phase III clinical trials in the United States and Europe for the treatment and management of acute and chronic schizophrenia. Zotepine's pharmacological profile has been compared with those of the atypical antipsychotic clozapine, and the typical neuroleptics haloperidol and chlorpromazine in preclinical tests that predict antipsychotic efficacy and extrapyramidal symptoms (EPS). Because zotepine causes potent, long-lasting inhibition of dopaminergic behavioral responses in animals, it may have an efficacious prolonged antipsychotic action in humans. In contrast, it induces little catalepsy, indicating that it should cause minimal motor side effects, such as EPS. Like clozapine but unlike the typical neuroleptics, zotepine's affinities for cloned human D1 and D2 receptors are very similar. Since a stimulation imbalance favoring D1 over D2 receptors has been suggested to induce dyskinesias, zotepine's reduced EPS profile in humans may derive, in part, from balanced inhibition of these receptors.

Animals↗

PubMed1995

Effect of aging and chronic angiotensin I converting enzyme inhibition on the endothelial function of the mesenteric arterial bed of the rat.

Endothelial function was studied in perfused mesenteric arterial bed preparations removed from 6, 12, 24, or 30 month-old, male, normotensive rats. Half of the animals were treated with a hypotensive dose of an angiotensin I converting enzyme (ACE) inhibitor (perindopril, 1 mg/kg/day, p.o.) from 6 months onwards. Disruption of endothelium produced a fall in baseline perfusion pressure in all animals except 30-month old controls, suggesting that the maintenance of baseline tone by endothelial vasoconstrictor(s) is impaired with age. Physiologic antagonism of norepinephrine-induced vasoconstriction by the muscarinic agonist carbachol was impaired in 30-month old controls. Norepinephrine-induced vasoconstriction increased following disruption of endothelium, suggesting that norepinephrine-induced release of endothelium-derived relaxing factor attenuates vasoconstriction. This mechanism was impaired in 30-month old controls. Chronic ACE inhibition postponed the age-related decrease in vasodilator and vasoconstrictor endothelial functions, either directly or indirectly via the hypotensive action of such treatment.

Aging↗

PubMed1995

Severity of hypoxia predicts response to nitric oxide in a porcine pulmonary hypertension model.

Although inhaled nitric oxide (NO) has been variably successful in resolving pulmonary hypertension in neonates, children, and adults, no parameters predictive of response to this therapy have been elucidated. We conducted an animal study to determine if severity of hypoxia can predict magnitude and sustenance of response to inhaled NO therapy. Seven Yorkshire swine weighing 11 to 20 kg underwent 16 experiments, each consisting of four phases: Phase 1: Control period of ventilation on FIO2 .3; phase 2: Hypoxic period on FIO2 .10 to .15, establishing pulmonary hypertension; phase 3: Treatment period with NO starting at five parts per million (ppm), doubling dose every 10 min to 80 ppm; phase 4: Posttreatment observation period after discontinuation of NO while maintaining hypoxia for 1 hour or until circulatory failure or pulmonary hypertension of pre-NO magnitude developed. Each animal underwent a maximum of three experiments in random order of hypoxia severity before sacrifice with pentobarbital overdose. Continuous hemodynamic parameters, intermittent cardiac output and pulmonary capillary wedge pressure, and intermittent arterial blood gas analyses were obtained through pulmonary and systemic artery catheters placed by femoral cutdown. Pulmonary and systemic vascular resistances (PVR and SVR) were calculated by standard formulas. Experiments were divided into two groups (n = 8 in each): group 1 with severe hypoxia (PaO2, 25 to 35) and group 2 with moderate hypoxia (PaO2, 36 to 65). Data for all hemodynamic parameters were expressed as mean percentage change from baseline (phase 1) +/- SEM under each set of conditions, and the two groups were compared by two-way analysis of variance and covariance adjusted for order of experimentation.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

PubMed1995

Reduction of infant myopia: a longitudinal cycloplegic study.

Changes of cycloplegic retinoscopy refraction from 8.5 to 38.5 months of age were compared in two infant groups in the Cambridge population: "infant myopes", having at least one myopic axis (0 to -3.5 D inclusive), and a second, "control" group with low hyperopia (< or = +3.5 D). Cycloplegia eliminated the variable accommodation of infants. The myopic group showed a significant emmetropization of the mean spherical equivalent towards low hyperopia by 3 yr. There was no significant change in the control group's mean spherical equivalent power. Both groups showed a significant reduction in astigmatism with age. Analysis of the vertical and horizontal powers showed significant "emmetropization" of these meridians, in both groups, towards low hyperopia from 8.5 to 38.5 months. These meridional emmetropization changes were significant for both With-the-Rule and Against-the-Rule astigmatism.

Aging↗

PubMed1995

Intracellular concentrations of fura-2 and fura-2/am in vascular smooth muscle cells following perfusion loading of fura-2/am in arterial segments.

A new method for the determination of tissue concentrations of Fura-2 and Fura-2/AM was developed based upon acetonitrile extraction followed by RP-HPLC separation (using tetrahexylammonium as counter-ion), post-column alkaline hydrolysis of Fura-2/AM, and fluorimetric detection. The detection limit was 1.2 nM and 1 nM for Fura-2 and Fura-2/AM, respectively. When this technique was applied to perfusion-loaded segments of the rat tail artery, intracellular concentrations of Fura-2 determined by tissue disruption were 10 times those obtained by comparing the increase in fluorescence at the isoemissive point (following loading), with a calibration curve for Fura-2. Loading conditions of 90 min at [Fura-2/AM]e = 5 microM were optimal in terms of [Fura-2]i which attained a concentration not significantly different from [Fura-2/AM]e. Under such conditions, however, Fura-2/AM also accumulated in the arterial wall. Although incompletely de-esterified, Fura-2/AM metabolites produced by in vitro incubation of Fura-2/AM with pig liver esterases could be easily detected, fluorescent forms of Fura-2 with a different sensitivity for calcium were not detected in arterial extracts.

Animals↗

PubMed1995

Context effects on misreading and suppression at UAG codons in human cells.

The effect of the 3' codon context on the efficiency of nonsense suppression in mammalian tissue culture cells has been tested. Measurements were made following the transfection of cells with a pRSVgal reporter vector that contained the classical Escherichia coli lacZ UAG allele YA559. The position of this mutation was mapped by virtue of its fortuitous creation of a CTAG MaeI restriction enzyme site. Determination of the local DNA sequence revealed a C-->T mutation at codon 600 of the lacZ gene: CAG-->TAG. Site-directed mutagenesis was used to create a series of vectors in which the base 3' to the nonsense codon was either A, C, G, or U. Suppression of the amber-containing reporter was achieved by cotransfection with genes for human tRNA(Ser) or tRNA(Gln) UAG nonsense suppressors and by growth in the translational error-promoting aminoglycoside drug G418. Nonsense suppression was studied in the human cell lines 293 and MRC5V1 and the simian line COS-7. Overall, the rank order for the effect of changes to the base 3' to UAG was C < G = U < A. This study confirms and extends earlier findings that in mammalian cells 3' C supports efficient nonsense suppression while 3' A is unsympathetic for read-through at nonsense codons. The rules for the mammalian codon context effect on nonsense suppression are therefore demonstrably different from those in E. coli.

Animals↗

PubMed1995

Effect of chronic ANG I-converting enzyme inhibition on aging processes. V. Intracellular calcium-vasoreactivity coupling.

Age-related changes in intracellular calcium ([Ca2+]i)-vasoreactivity coupling efficiency (i.e., perfusion pressure divided by [Ca2+]i) were studied in vitro in tail arteries of male, normotensive, WAG/Rij rats aged 6, 12, 24, or 30 mo; one-half of these were chronically treated with the angiotensin I-converting enzyme inhibitor (ACEI) perindopril (1 mg.kg-1.day-1 orally) from 6 mo onward. Arterial segments were perfused at a constant flow rate (perfusion pressure taken as an index of arterial tone) and loaded with the acetoxymethyl ester of fluorescent dye fura 2 (fura 2-AM). Increases in [Ca2+]i were measured simultaneously with vasoconstriction after stimulation with a depolarizing hyperkalemic solution or the agonists norepinephrine or serotonin. Age had no effect on increases in [Ca2+]i vasoconstrictor responses, or electromechanical coupling efficiency (hyperkalemic solution). Increases in [Ca2+]i after agonists were similar in all groups, but vasoconstrictor responses and pharmacomechanical coupling efficiency decreased with age. ACEI had no effect on vasoconstriction or [Ca2+]i signals. In conclusion, coupling efficiency after agonist stimulation decreased with age; ACEI had no effect on coupling efficiency.

Aging↗

PubMed1995

Aortic stiffness and left ventricular mass in a rat model of isolated systolic hypertension.

We tested whether cardiac mass can be related to decreased aortic stiffness in an original rat model of isolated systolic hypertension. Increased aortic stiffness was produced by calcium overload of elastic arteries after vitamin D3 plus nicotine treatment. Half of the animals were chronically treated with the angiotensin-converting enzyme inhibitor perindopril (1 mg/kg per day PO). Rats were pithed, and lower body vascular resistance was measured. Blood pressure was then increased by phenylephrine infusion, and carotidofemoral pulse wave velocity was measured. This value together with those for thoracic aorta internal diameter and medial thickness (determined after in situ fixation and histomorphometry) were used to calculate elastic modulus. Vitamin D3 plus nicotine treatment produced parallel increases in cardiac mass and elastic modulus, with a significant correlation between the two. There was no significant change in resistance. Treatment with perindopril reversed the changes in cardiac mass and elastic modulus but had no effect on resistance after calcium overload of the elastic arteries. In this model of isolated systolic hypertension, we showed that cardiac mass is related to arterial elasticity.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1995

Ontogeny of membrane cofactor protein: phenotypic divergence in the fetal heart.

Human adult cells are protected from complement-induced damage in part by membrane cofactor protein (MCP, CD46). To examine fetal characteristics which might influence autoantibody-mediated diseases acquired in utero, such as heart block in neonatal lupus, the tissue expression of MCP was studied. Using a high ratio of acrylamide:bisacrylamide, immunoblots of tissues from six fetuses (aged 19-24 weeks) probed with rabbit anti-MCP antibodies revealed a band at 60 KD in addition to the known 65 KD and 55 KD isoforms which comprise the codominant allelic system of MCP. Five fetuses expressed the most common MCP polymorphism (predominance of the 65 KD isoform, upper band alpha-phenotype) in the kidney, spleen, liver and lung. In contrast, all hearts from these five fetuses demonstrated a different pattern in which there was a marked decrease in the intensity of the 65 KD band and accentuation of the lower molecular weight bands. In a sixth fetus, which expressed the second most common polymorphism (equal expression of the 65 KD and 55 KD MCP isoforms, alpha beta-phenotype), the heart was similar to the other tissues. These studies confirm the expression of MCP in early gestational life. Preferential expression of the MCP beta-isoform in the majority of fetal hearts irrespective of the phenotype of other organs, suggests tissue-specific RNA splicing or post-translational modification which may relate to autoantibody-mediated injury in diseases such as neonatal lupus.

Antigens, CD↗

PubMed1995

A comparison of laparoscopic versus open splenectomy in children.

Laparoscopic operative procedures are gaining wider acceptance in pediatric patients. Although laparoscopic splenectomy is being performed more frequently, no studies to date have compared this procedure with the standard open technique with respect to operative outcomes. We performed a case control study of seven laparoscopic splenectomies and 14 open splenectomies. Two-tailed t test was used to compare the two groups for mean operative time, mean hospital stay, mean interval before tolerating a regular diet, and total parenteral narcotic dose in morphine equivalents. Operative time was significantly longer in the laparoscopic group (221 minutes vs 59 minutes, P < 0.001). Hospital stay, interval before tolerating a regular diet, and postoperative narcotic dose did not differ significantly between the two groups. In the laparoscopic group, one operation was converted to an open procedure secondary to bleeding complications. Three patients required mini-laparotomies for removal of extremely large spleens after completion of the dissection. Pediatric laparoscopic splenectomy does not appear to have advantages over the traditional method with regard to operative time, hospital stay, postoperative ileus, or postoperative pain. Larger studies, including cost analysis, are needed before major proposed advantages of laparoscopic splenectomy can be accepted.

Adolescent↗

PubMed1995

Alcohol and liver fibrosis--pathobiochemistry and treatment.

In Western societies roughly 50% of all cases of liver cirrhosis are related to alcohol abuse. The oxidative metabolite of ethanol, acetaldehyde, often in conjunction with viral or metabolic liver disease, is implicated as the major cause for liver fibrogenesis. Acetaldehyde damages cell membranes, initiates lipid peroxidation and forms noxious protein adducts, resulting in the activation of Kupffer cells and perisinusoidal lipocytes/portal fibroblasts. The activation of lipocytes and fibroblasts to a proliferative and collagen-producing myofibroblast-like phenotype is triggered by the release of fibrogenic factors such as platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) from the activated Kupffer cells. Due to the socioeconomic burden inflicted by cirrhosis, antifibrotic treatment is urgently needed. Strategies to prevent or reverse cirrhosis must interrupt the continuous process of pathological wound healing in the liver. An antifibrotic effect has been demonstrated for the interferons, prostaglandins E and relaxin. Polyunsaturated lecithin, silymarin and ursodeoxycholic acid, agents with a high hepatotropism and a good safety-profile, appear to have antifibrotic properties. Targeted approaches include the specific removal of matrix-bound fibrogenic growth factors and the induction of stress-relaxation of the activated mesenchymal cells by biologically active matrix-peptides and their stable analogues. Since serum tests for the non-invasive assessment of collagen synthesis and degradation in the liver are now available, rapid progress in the development and clinical application of antifibrotic drugs can be anticipated.

Acetaldehyde↗

PubMed1994

Crystallization and preliminary X-ray analysis of a mutant duck delta II crystallin.

A duck delta II crystallin mutant, where histidine 178 has been replaced by an aspartic acid residue, has been purified from a bacterial expression system and subsequently crystallized. The crystals grow as flat plates, with unit cell dimensions a = 94.1 A, b = 99.9 A, c = 108.7 A and beta = 102 degrees. The crystals exhibit the symmetry of space group P2(1) and diffract to a minimum d-spacing of 2.8 A resolution. On the basis of density calculation four monomers (one tetramer) are estimated to be present in the asymmetric unit (Vm = 2.5 A3/Da). Self-rotation functions clearly show the presence of 222 non-crystallographic symmetry.

Animals↗

PubMed1994

Evidence for a tropic role of brain-derived neurotrophic factor in transplanted embryonic retinae.

Developing retinal axons must follow a stereotypic course directing them to the subcortical visual centres which on arrival they must recognise. Transplantation studies suggest that local substrate cues close to the surface of the brainstem and diffusible factors emanating from the target region are important. To test a role for diffusible factors, we transplanted retinae to the cerebral cortex and have shown that outgrowth can be promoted by BDNF secreting fibroblasts.

Animals↗

PubMed1994

Mutations to nonsense codons in human genetic disease: implications for gene therapy by nonsense suppressor tRNAs.

Nonsense suppressor tRNAs have been suggested as potential agents for human somatic gene therapy. Recent work from this laboratory has described significant effects of 3' codon context on the efficiency of human nonsense suppressors. A rapid increase in the number of reports of human diseases caused by nonsense codons, prompted us to determine how the spectrum of mutation to either UAG, UAA or UGA codons and their respective 3' contexts, might effect the efficiency of human suppressor tRNAs employed for purposes of gene therapy. This paper presents a survey of 179 events of mutations to nonsense codons which cause human germline or somatic disease. The analysis revealed a ratio of approximately 1:2:3 for mutation to UAA, UAG and UGA respectively. This pattern is similar, but not identical, to that of naturally occurring stop codons. The 3' contexts of new mutations to stop were also analysed. Once again, the pattern was similar to the contexts surrounding natural termination signals. These results imply there will be little difference in the sensitivity of nonsense mutations and natural stop codons to suppression by nonsense suppressor tRNAs. Analysis of the codons altered by nonsense mutations suggests that efforts to design human UAG suppressor tRNAs charged with Trp, Gln, and Glu; UAA suppressors charged with Gln and Glu, and UGA suppressors which insert Arg, would be an essential step in the development of suppressor tRNAs as agents of human somatic gene therapy.

Codon↗

PubMed1994

Cytokines modulate interleukin-6 production by human salivary gland cell line.

The ability of HrTNF-alpha, HrIL-1 beta, and HrIFN-gamma to modulate IL-6 production by cultured human salivary cell line (HSG) was examined. IL-6 activity was measured by the hybridoma growth factor biologic activity. HrTNF-alpha had a significant dose-dependent effect, whereas HrIL-1 beta and HrIFN-gamma had moderate and minor effects, respectively. Maximal effect (920 units) was noted when cytokines were applied in combination (1000 units HrIFN-gamma and 20 units HrTNF-alpha) and incubated with human salivary gland cells for 72 hr. The same combination of cytokines had also a marked inhibitory effect (70% of control) on human salivary gland cell growth. This is the first report of these concomitant phenomena in a human cell line originating from salivary tissue.

Cell Division↗

PubMed1994

Estimation of myocardial interstitial norepinephrine release after brain death using cardiac microdialysis.

Brain death is a pathophysiological condition associated with major hemodynamic changes, temporary myocardial ischemia, and histological damage of the heart. These modifications could be related to a major local release of norepinephrine from myocardial sympathetic nerve endings leading to norepinephrine cardiotoxicity. This study was designed to evaluate the utility of cardiac microdialysis to measure interstitial myocardial norepinephrine release resulting from brain death. The dialysis probe consisted in a 10 x 0.20-mm dialysis fiber with a 18,000 mol wt cutoff. Dialysis probes were implanted into the right and left ventricular walls of the beating heart in anesthetized pigs and perfused with Ringer solution at 2 microliters/min. Dialysate norepinephrine concentration was measured using HPLC with electrochemical detection. The relative recovery rate of norepinephrine in vivo was 34 +/- 4%. Interstitial fluid concentrations were obtained using the following formula: [C]interstitium = [C]dialysate/Recovery in vivo. After brain death, a transient increase in interstitial norepinephrine concentration was observed (from 0.74 +/- 0.20 to 4.50 +/- 0.60 ng/ml and 0.76 +/- 0.20 to 6.2 +/- 0.9 ng/ml in left and right ventricle, respectively, P < 0.01) which far exceeded plasma level increase (from 0.50 +/- 0.10 ng/ml to 0.91 +/- 0.20 ng/ml, P < 0.05). This increase in myocardial norepinephrine was, moreover, biphasic, with a second peak occurring 40 min after brain death. The present study confirms the onset of a dramatic increase in cardiac norepinephrine release from myocardial nerve endings following brain death, and demonstrate the utility of the new cardiac microdialysis technique to assess changes in interstitial fluid content.

Animals↗