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Biomedical subjects

A M Walker

Publications and source records attributed to A M Walker.

At least 19 recordsLinked to original sources
PubMed1996

Pleural and pericardial pressures limit fetal right ventricular output.

BACKGROUND: The chest wall, lungs, and pericardium limit diastolic filling of the left ventricle in the fetus, neonate, and adult. To determine the effect that these tissues have on the fetal right ventricle (RV), we studied six fetal lambs (142 days of gestation) METHODS AND RESULTS: Pregnant ewes were anesthetized (ketamine and alpha-chloralose), and the fetuses were partially delivered by cesarean section. Fetuses were instrumented to record RV stroke volume, RV end-diastolic pressure (Prved), intrapericardial pressure (Pip), and pleural pressure. Prved was varied between 2 and 20 mm Hg under three conditions: initially with a closed chest and a closed pericardium (CCCP); subsequently with an open chest (chest wall and lungs retracted) and a closed pericardium (OCCP); and finally after the chest wall, lungs, and pericardium were retracted (OCOP). At equal Prved, stroke volume increased substantially when the chest wall and lungs were retracted from the heart and increased further on subsequent retraction of the pericardium (eg, at Prved of 9 mm Hg, stroke volume increased from 1.2 +/- 0.2 mL [mean +/- SEM] in the CCCP condition to 2.9 +/- 0.4 and 4.2 +/- 0.3 mL in the OCCP and OCOP conditions, respectively, P < or = .05). The limitation of stroke volume in the CCCP and OCCP conditions occurred because Pip increased in an almost one-to-one fashion as Prved increased; as a consequence, RV preload (RV end-diastolic transmural pressure, Prved minus Pip) was relatively unchanged. CONCLUSIONS: The chest wall-lung combination and the pericardium each significantly constrain the fetal RV and together limit RV stroke volume.

Animals↗
PubMed1996

Cigarette smoking and pancreas cancer: a case control study of the search programme of the IARC.

A multi-centre case-control study of pancreas cancer, designed to be population-based, to use a random sample of local populations as controls and to use a common protocol and core questionnaire, was conducted as the first study of the SEARCH programme of the International Agency for Research on Cancer. "Ever-smokers" were found to be at increased risk for pancreas cancer compared with "never-smokers" consistently in all strata of gender, response status and centre. Risk of pancreas cancer was found to increase with increasing lifetime consumption of cigarettes, the relative risk rising to 2.70 (95% C.I. 1.95 to 3.74) in the highest intake category. The overall trend in risk was highly significant and the association was found consistently in each stratum of gender, response status and centre. Fifteen years had to pass from quitting cigarette smoking until the risk fell to a level compatible with that in never-smokers among the heaviest group of smokers; among the 2 lowest tertiles this happened within 5 years. Further, reported smoking habits more than 15 years before diagnosis appeared to have no influence on pancreas-cancer risk, irrespective of amount smoked. The results are consistent with a causal role for cigarette smoking in the aetiology of pancreas cancer and illustrate that ceasing to smoke cigarettes can lead to reductions in the elevated risk of pancreas cancer produced by this habit.

Case-Control Studies↗
PubMed1996

Effect of lung liquid volume on respiratory performance after caesarean delivery in the lamb.

1. The volume of liquid in the lungs of the fetal lamb is reported to fall in the final days of gestation and during labour itself. We aimed to test the hypothesis that this fall in liquid volume adapts the lungs for air breathing and pulmonary gas exchange. 2. In twelve chronically catheterized fetal lambs we measured lung liquid volume at 140 days gestation (term is 147 days) and then delivered the fetuses by Caesarean section under maternal spinal anaesthesia. In five fetuses we removed approximately half the liquid contained in the lungs just before delivery (experimental group) while the remaining seven fetuses were delivered without change to their lung liquid (control group). 3. Lambs born with reduced lung liquid volume improved their arterial blood gas and acid-base status more quickly than lambs born without alteration to lung liquid. 4. Carotid arterial blood gas values in the first 60 min of postnatal life were significantly related to the volume of liquid present in the lungs at birth, with higher arterial partial pressure of oxygen (Pa,02) and arterial oxygen saturation (Sa,02) and lower arterial partial pressure of carbon dioxide (Pa,CO2) levels being associated with lower lung liquid volumes. 5. We conclude that postnatal gas exchange is enhanced by a reduction in the volume of liquid remaining in the lungs when breathing starts.

Animals↗
PubMed1996

Identification of the major site of rat prolactin phosphorylation as serine 177.

Phosphorylation of prolactin by endogenous protein kinases within isolated secretory granules was shown to result in the production of both phosphoserine and phosphothreonine residues. The majority of the radiolabel was determined to be present in the C terminus of the molecule after specific cleavage with glandular kallikrein. Glandular kallikrein cleaves in three places at the C terminus, liberating three small peptides, only one of which contains a phosphorylatable residue. Sequencing of this phosphopeptide showed it to be Arg175-Lys185. Thus the major site of prolactin phosphorylation was determined to be serine 177. Using a synthetic peptide equivalent to this region of the molecule (Ser161-Val180), serine 177 was demonstrated to be a substrate for protein kinase A as well as for one of the endogenous granule kinases. Inclusion of the synthetic peptide in an endogenous granule phosphorylation reaction resulted in competition for the kinase and reduced phosphorylation of prolactin. Protein kinase A phosphorylation of purified prolactin resulted in the production of only phosphoserine and primarily the most abundant (monophosphorylated) variant. We conclude that serine 177 is the major in vivo phosphorylation site of rat prolactin and that phosphorylation of this site can be reproduced by protein kinase A in vitro. The minor threonine phosphorylation site was demonstrated by two-dimensional tryptic peptide mapping and mass analysis to be either threonine 58 or 63, both of which are contained within a single peptide.

Amino Acid Sequence↗
PubMed1996

Manduca sexta lipid transfer particle: synthesis by fat body and occurrence in hemolymph.

Lipid transfer particle (LTP) is present in hemolymph of the tobacco hornworm Manduca sexta. Biosynthesis of LTP, occurrence in hemolymph, and the role of LTP-apoproteins in the lipid transfer reaction were investigated using antibodies specific for LTP or for each of the apoproteins. In vitro protein synthesis followed by immunoprecipitation demonstrated that LTP is synthesized by the fat body and secreted into the medium. In contrast to apolipophorin III, an exchangeable apoprotein of lipophorin (the major lipid transport protein in hemolymph), apoLTP-III could not be detected free in hemolymph. LTP concentrations in the hemolymph were measured by a sandwich ELISA using a mouse monoclonal antibody against apoLTP-III as capturing antibody and rabbit polyclonal antibody against apoLTP-I as detecting antibody. LTP concentration increased during the late fifth instar larval stage, followed by a decrease in the wandering stage. Subsequently, LTP concentrations were strongly increased in hemolymph of adult moths. The role of the three apoproteins of LTP in the lipid transfer reaction was analyzed using apoprotein-specific antibodies. All three, apoLTP-I, -II, and -III, appeared to be important for lipid transfer activity, as shown by inhibition of lipid transfer by antibodies specific for each of the three apoproteins.

Animals↗
PubMed1996

Japanese and American reports of randomized trials: differences in the reporting of adverse effects.

We sought to identify differences in the description of adverse drug experiences in reports of randomized clinical trials (RCTs) from the United States and Japan, using diclofenac and simvastatin as test drugs. Reports were identified in Medline (Index Medicus 1966-1990), EMBASE (Excerpta Medica 1974-1990), JAPICDOC (1979-1990), and JOIS-III (JMEDICINE 1980-1990). In each search keywords describing study design were paired with the drugs' generic names, chemical names, and development numbers. Twenty-seven U.S. reports (18 for diclofenac and 9 for simvastatin) and 22 Japanese reports (17 for diclofenac and 5 for simvastatin) identified in these four databases were selected for review. For each paper we identified the relation of the article to the data (preliminary, primary, and secondary reports, reviews), the means of identifying adverse reactions, the principal outcomes of the trials, and a variety of descriptive measures relating to study design, authorship, and elements of presentation. With few exceptions, Japanese reports were not indexed in English-language databases, and studies from the United States were not carried out in the Japanese databases. The Japanese literature consisted exclusively of primary reports of clinical trials, whereas the U.S. literature was dominated by review articles and secondary reports of data from trials not fully published elsewhere. Japanese reports contained more detail on adverse experiences but reported principally those attributed to the drugs by attending clinicians. U.S. reports by contrast offered little detail but tended to include all adverse experiences, whether or not clinically attributed to drugs. A preponderance of U.S. articles reported significant differences between drugs in safety or treatment efficacy, whereas only one third of the Japanese articles did so for the same agents. Reports from both countries offered few details of the methods used to gather information on adverse drug experiences, and as a result the reported absolute frequencies of such events are difficult to compare between trials or to generalize to other settings. In conclusion, the reporting of adverse reactions in clinical trials is inadequate in both the United States and Japanese literature. The shortcomings are complementary in that reports of U.S. trials contain insufficient detail and Japanese reports do not interpret or synthesize experience. Clinical research into drug safety in both countries could be improved through the adoption of simple standards of clarity and consistency in the monitoring and reporting of drug adverse effects.

Adverse Drug Reaction Reporting Systems↗
PubMed1996

Estrogen replacement therapy and the development of osteoarthritis.

Recent studies have indicated that estrogen users have a lower than expected rate of concurrent osteoarthritis. We assessed the association between estrogen replacement therapy and incident symptomatic osteoarthritis, using a nested case-control design. We identified all incident cases of hand, hip, and knee osteoarthritis in women members of the Fallon Community Health Plan, age 20-89 years, from January 1, 1990, to December 31, 1993. For each case, we selected a control woman matched by closest date of birth. We used pharmacy records to classify women as new users, past users, ongoing users (past and new users), and never-users of estrogen replacement therapy. There were 60 informative case-control pairs. After controlling for obesity and health care utilization, we found that new use of estrogen replacement therapy was a predictor of new osteoarthritis diagnosis. Past use was inversely associated with risk of osteoarthritis [adjusted odds ratio = 0.7; 95% confidence interval (CI) = 0.3-1.9]. For ongoing use of estrogen replacement therapy and osteoarthritis, the adjusted odds ratio was 1.4 (95% CI = 0.6-3.3). The associations between osteoarthritis and both new use of estrogen replacement therapy and utilization of services suggest that frequent medical care increases the likelihood of diagnosis of osteoarthritis.

Adult↗
PubMed1996

Nitric oxide modulates regional blood flow differences in the fetal gastrointestinal tract.

We studied the role of endogenous nitric oxide (NO) in the regulation of gastrointestinal (GI) circulation in 11 chronically instrumented and unanesthetized late-gestation fetal sheep. Systemic and GI blood flows were measured by the radiolabeled microsphere technique. Mean arterial pressure (MAP), heart rate, blood flows, oxygen delivery, and vascular resistance were determined before and after infusion of the specific NO synthase inhibitor, N omega-nitro-L-arginine (L-NNA), to cumulative doses of 10 and 25 mg/kg. At both L-NNA doses, MAP increased, and combined ventricular output and heart rate decreased. GI blood flow and oxygen delivery decreased and vascular resistance increased for the stomach, all segments of the small intestine, and proximal colon and cecum but were unchanged in the middle and distal colon and rectum. Because blood flow reduction in the small intestine was pronounced (from 176 to 107 ml.min-1.100 g-1, P < 0.001) and blood flow in the large intestine was unchanged, distribution of intestinal blood flow became more uniform. Overall, blood flow reduction was proportionally greater in GI circulation than in the remainder of fetal circulation. In three additional animals we established that L-NNA reduced blood flow to the mucosal-submucosal layer (P < 0.02) but not to the muscularis serosa of the small intestine. In the same animals, L-arginine (250 mg/kg) restored systemic hemodynamics and partially restored small intestinal blood flow. Our results suggest that NO is an important differential regulator of vascular tone in the developing GI circulation.

Animals↗
PubMed1996

Interrelation between ventricular function, myocardial blood flow, and O2 consumption changes at birth in lambs.

We studied the interrelation of changes in ventricular external work, myocardial blood flow, and O2 consumption at birth. Eleven fetal sheep were instrumented under general anesthesia at 133-134 days gestation with arterial, peripheral venous, and left atrial catheters, and in five fetuses, a catheter was also inserted into the coronary sinus. Fetal left ventricular (LV) and right ventricular (RV) outputs and myocardial blood flows (radioactive microspheres), hemodynamics, and LV O2 consumption were measured 1 wk later. Fetuses were delivered by cesarean section, and measurements were repeated 1 and 4 h after birth. RV minute work (mmHg.l.kg-1) was greater in fetuses (10.8 +/- 0.5 vs. 15.6 +/- 1.0 P < 0.001), but because of increased LV minute work (to 20.9 +/- 1.4, P < 0.005) and unchanged RV minute work, this pattern was reversed by 1 h after birth. RV myocardial blood flow (ml.min-1.100 g-1) was predominant in fetuses (234 +/- 25 vs. 306 +/- 27, P < 0.001), but this also reversed in lambs; this reversal was related to unchanged 1-h (248 +/- 16) and lower 4-h LV myocardial blood flow (199 +/- 9, P < 0.05) and a progressive fall in RV myocardial blood flow (1 h: 245 +/- 20, P < 0.05; 4 h: 174 +/- 12, P < 0.005). LV O2 consumption (ml.min-1.100 g-1) increased between fetal (8.1 +/- 0.6) and 1-h lambs (18.9 +/- 1.3, P < 0.005) because of a rise in the LV arteriovenous O2 content difference (3.6 +/- 0.4 vs. 7.5 +/- 0.6 ml/dl, P < 0.005). External work performed per unit myocardial blood flow (mmHg.l.ml-1) in the LV increased between fetal and 1-h lambs (1.92 +/- 0.14 to 3.33 +/- 0.15, P < 0.001) and, in the RV, between fetal and 4-h lambs (2.09 +/- 0.18 to 2.92 +/- 0.24, P < 0.01). The proportion of consumed O2 converted to external work was, however, similar in fetal (34.6 +/- 3.1%) and 1-h (31.3 +/- 2.9%) and 4-h lambs (34.5 +/- 3.6%). These findings indicate that 1) a switch from a fetal RV to a newborn LV dominance is due to increased LV pumping performance, 2) an associated switch in LV and RV myocardial blood flow patterns is mainly related to a fall in RV myocardial blood flow, 3) a postnatal rise in LV O2 consumption results from enhanced LV arteriovenous O2 extraction, not increased LV myocardial blood flow, 4) ventricular external work per unit myocardial blood flow increases postnatally, particularly in the LV, and 5) LV mechanical efficiency is not altered after birth.

Animals↗
PubMed1996

Prolactin (PRL) is a zinc-binding protein. I. Zinc interactions with monomeric PRL and divalent cation protection of intragranular PRL cysteine thiols.

PRL in secretory granules is osmotically inert. Previous studies by us and others have suggested that this is due in part to hormone oligomerization. Data suggest intermolecular disulfide bridges and/or intermolecular ionic interactions, as thiols, urea, and chelators increase monomerization of the majority of granule PRL. Because of the inhibitory effect of zinc on PRL release from isolated granules and the effects of zinc on the specific packing of PRL within granules, we examined the possibility that zinc contributed to the stability and/or oligomerization of intragranular PRL. To do this, we first analyzed zinc binding to purified monomeric rat PRL in solution. Zinc binding was demonstrated using the chromogenic chelator 5,5'-nitrilodibarbituric acid (murexide) and was confirmed by matrix-assisted, time of flight mass analysis. Because these spectrophotometric methods were not applicable for intragranular PRL studies, we tested the influence of zinc on granule PRL indirectly. As hormone free thiols were potentially formed during PRL oligomerization and storage, these were possible sites for hormone-divalent cation interactions. By derivatization of thiols with 4-vinyl pyridine and isolation of the carboxyterminal region of granule PRL, we found that a proportion of the cysteines 189 and 197 occurred as thiols and not disulfides. These thiols were only detectable when EDTA was present in the granule incubations. It is proposed that binding of zinc stabilizes the intermolecularly bonded storage form of PRL, in part by protection of hormone free thiols. Removal of the divalent cation and exposure of free thiols could be what initiates the thiol-disulfide interchange necessary for conversion of intermolecular to intramolecular disulfide bonds before exocytosis. Experimentally, both urea and EDTA could remove zinc, thus initiating monomerization and explaining how these agents as well as thiols achieve monomerization.

Amino Acid Sequence↗
PubMed1995

Patient factors associated with strut fracture in Björk-Shiley 60 degrees convexo-concave heart valves.

BACKGROUND: Previously established predictors of outlet strut fracture in Björk-Shiley convexo-concave (CC) valves include larger valve size, larger opening angle (70 degrees versus 60 degrees), younger age at implant, and date of manufacture. We sought to identify patient characteristics that might be predictive of strut fracture and to refine the estimates associated with previously identified predictors. METHODS AND RESULTS: We conducted a case-control study of CC60 degrees valves implanted in the United States and Canada and manufactured between January 1, 1979, and March 31, 1984. Cases included all valves with verified outlet strut fractures reported to the manufacturer from January 1979 through January 1992. Up to 10 controls were selected for each case. Control valves were matched according to implanting surgeon and were required to have been functioning at least as long as their matched case valves. Case and control medical records were reviewed for information on patient medical history before the valve implant. There were 96 case and 634 control valves for which clinical data were available. Patient age and valve size and implant position were confirmed as important determinants of fracture. There was a strong inverse gradient of risk with age. The risk of fracture was 42% lower for each 10-year increment of patient age at time of implant. Large mitral valves were at greatest risk of strut fracture, with the largest mitral valves (33 mm) estimated to be 33 times more likely to fracture than the smallest (21 to 25 mm) aortic valves. Date of manufacture was also associated with risk; valves welded from mid-1981 through March 1984 were more likely to fracture than those manufactured in 1979 and 1980. Body surface area < 1.5 m2 was associated with 1/16 the risk of body surface area > or = 2.0 m2. No other patient factor was strongly associated with the risk of strut fracture. CONCLUSIONS: Few patient features identifiable in the implant record are predictive of strut fracture. Our analysis supports previous work in identifying valve size, patient age, and date of manufacture as predictors of fracture and adds body surface area. A number of these associations suggest that conditions associated with higher cardiac output may also place patients at increased risk.

Adult↗
PubMed1995

Peptic ulcer and gastrointestinal hemorrhage associated with nonsteroidal anti-inflammatory drug use in patients younger than 65 years. A large health maintenance organization cohort study.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an elevated risk of peptic ulcer and upper gastrointestinal hemorrhage, but published reports have lacked information on rates of outpatient disease, have concentrated on the elderly, and have not provided comparisons of rates for specific types of NSAIDs. METHODS: We compared incidence rates of peptic ulcer and upper gastrointestinal hemorrhage in 68 028 people younger than 65 years who used diclofenac sodium, naproxen, piroxicam, or sulindac, and who were members of a network of health maintenance organizations. We reviewed automated insurance claims data and medical records to ascertain cases and included conditions treated on an outpatient basis. RESULTS: Medical claims data were adequate for crude identification of potential cases, but review of medical records led to rejection of 63% of these, representing either no abnormality or diseases other than peptic ulcer or upper gastrointestinal hemorrhage. Of the total 112 cases, 64 (57%) were treated as outpatients. The crude incidence rate per 1000 person-years in users of any current, recent, or past NSAID was 2.2 and in distant-past users of NSAIDs was 0.75. For diclofenac, naproxen, piroxicam, and sulindac, we found a consistent pattern of decreasing NSAID effects from current to recent to past exposure. The risk of peptic ulcer or upper gastrointestinal hemorrhage was 1.6 cases per 1000 people using NSAIDs. CONCLUSIONS: Combining use of automated claims records with review of medical records promotes efficiency while maintaining specificity of case ascertainment. This study, with 57% of cases treated as outpatients, had results consistent with other published reports that were based on hospitalized patients. Within the limits of statistical error, the incidence rates of peptic ulcer and upper gastrointestinal hemorrhage appeared to be similar for the various NSAIDs studied.

Adult↗
PubMed1995

Discontinuation of antihyperlipidemic drugs--do rates reported in clinical trials reflect rates in primary care settings?

BACKGROUND: Discontinuation rates for drugs used to treat chronic conditions may affect the success of therapy. However, the discontinuation rates reported in clinical trials may not reflect those in primary care settings. METHODS: We conducted a cohort study using computerized research files and medical records on 2369 new users of antihyperlipidemic therapy at two health maintenance organizations (HMOs) from 1988 through 1990. The rates of drug discontinuation in these primary care settings were compared with the rates reported in clinical trials published from 1975 through 1993, located with the Medline data base. RESULTS: In the HMOs, the one-year probability of drug discontinuation was 41 percent for bile acid sequestrants (95 percent confidence interval, 38 to 44 percent), 46 percent for niacin (95 percent confidence interval, 42 to 51 percent), 15 percent for lovastatin (95 percent confidence interval, 11 to 19 percent), and 37 percent for gemfibrozil (95 percent confidence interval, 31 to 43 percent). For the bile acid sequestrants, niacin, and gemfibrozil, the risks of discontinuation were substantially higher in the HMOs than in randomized clinical trials, in which the summary estimates of this risk were 31 percent, 4 percent, and 15 percent, respectively, for trials of one year or longer. The rates of discontinuation in open-label studies were similar to those in the HMOs. CONCLUSIONS: The discontinuation rates reported in randomized clinical trials may not reflect the rates actually observed in primary care settings. The effectiveness and tolerability of antihyperlipidemic medications should be studied further in populations that typically use the agents.

Adult↗