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Biomedical subjects

A M Walker

Publications and source records attributed to A M Walker.

At least 91 records · Page 5Linked to original sources
PubMed1998

Development of recombinant human prolactin receptor antagonists by molecular mimicry of the phosphorylated hormone.

Previous studies have demonstrated that naturally phosphorylated PRL antagonizes the growth-promoting effects of unmodified PRL in two different PRL-responsive cell lines. In this study our aim was to produce a molecular mimic of phosphorylated PRL by substituting a fairly bulky, negatively charged amino acid (glutamate or aspartate) for the normally phosphorylated serine [serine 179 in human PRL (hPRL)]. In addition, because of the marked effect of phosphorylation on biological activity, we investigated the importance of the unmodified serine in the growth-promoting activity of PRL. hPRL complementary DNA was obtained from the American Type Culture Collection and subcloned into pT7-SCII after site-directed mutagenesis using the deoxyuridine approach. Proteins were expressed in Escherichia coli BL21 (DE3) and were primarily found in inclusion bodies. Agonist and antagonist activities of each serine 179 mutant were assessed using the Nb2 bioassay. Compared with standard hPRL, the recombinant wild-type was more active in the Nb2 assay, attesting to both the absence, or low level, of endotoxin contamination in preparations from these cells and the appropriate folding of the molecule. The aspartate and glutamate mutants had no intrinsic agonist activity, but both antagonized the growth-promoting activity of wild-type PRL, with the aspartate mutant proving to be a very effective antagonist. Two hundred picograms per ml of the aspartate mutant negated 75% of the growth response to 400 pg/ml wild-type PRL. When serine 179 was mutated to alanine or valine, mutant PRLs with 0% and 14% of the biological activity of wild-type PRL, respectively, were produced. These results demonstrate 1) that molecular mimicry of the phosphorylated hormone does produce a PRL antagonist, and 2) that the serine at position 179 is crucial to the growth-promoting activity of PRL. The aspartate mutant can now be used to study many aspects of the physiology of PRL.

Amino Acid Sequence↗
PubMed1998

Prolactin receptor antagonists.

Most prolactin (PRL) in the circulation is produced by the pituitary. However, a wide variety of traditional target tissues of the hormone have also been shown to produce their own prolactin. The amount produced per cell is low, but may well be sufficient for autocrine/paracrine activity. Although dopamine agonists allow one to study the target tissue effects of pituitary PRL, other agents, such as PRL receptor (PRLR) antagonists, are needed to analyze autocrine/paracrine loops. With PRLR antagonists, it should be possible to dissect out the role of extrapituitary prolactin in both the normal physiology, and the pathophysiology of various tissues. In tissues where the locally produced PRL may promote disease, such antagonists have the potential to be important therapeutics. This article briefly, but critically, reviews current understanding of PRL-receptor interactions and initial signaling, and describes the development of both growth hormone (GH) and PRL antagonists within that context. In the final section, results with a very potent PRL antagonist further one theme of the article, which is whether the simple receptor dimerization model explains all signal transduction following PRLR binding.

Animals↗
PubMed1998

Estrogen replacement therapy and urinary tract infections in postmenopausal women aged 45-89.

OBJECTIVE: An elevated risk of urinary tract infections (UTIs) in postmenopausal women has been attributed to an increase in the vaginal pH. Estrogen replacement therapy (ERT) helps restore the vaginal milieu and may have a beneficial effect on risk of infection. Studies examining the association between ERT and UTIs have been inconsistent. We conducted a nested case control study to clarify this relationship in women aged 45-89. DESIGN: For each case, we selected up to five control women, matched by year of birth. We used pharmacy records to classify women as new users, past users, ongoing users (past and new users), and never users of ERT. There were 254 cases and 1,268 controls. RESULTS: The risk ratio for UTI was 1.02 [95% confidence interval (CI) 0.74, 1.40] for any use versus never use, after adjustment for health care utilization. The risk ratio for the association between new use and UTI was 1.13 (95% CI 0.46, 2.77). For ongoing users the risk ratio was 1.08 (95% CI 0.76, 1.54), whereas the risk ratio for past use was 0.77 (95% CI 0.39, 1.48). CONCLUSIONS: Our results do not support a protective effect of ERT on the risk of UTIs.

Aged↗
PubMed1997

Oxygen transport and utilization during feeding in the young lamb.

1. Five lambs (19-27 days old) were studied to determine the effects of feeding on cardiorespiratory function. 2. Each lamb was instrumented to record cardiac output, aortic and pulmonary artery pressure and arterial and mixed venous oxyhaemoglobin saturations (Sa,O2 and Sv,O2). 3. During feeding, arterial haemoglobin desaturated and resaturated sequentially during the periods of sucking and non-sucking. The nadir of these Sa,O2 desaturations (83 +/- 2%, mean +/- S.E.M.) was significantly lower than the baseline value (92 +/- 2%, P < or = 0.05, ANOVA). Sa,O2 returned to the baseline level between periods of sucking. Sv,O2 also decreased (55 +/- 3% baseline, 46 +/- 3% sucking, P < or = 0.05) but, in contrast to Sa,O2, it remained significantly lower than baseline levels in the pauses between periods of sucking. 4. Arterial pressure increased during feeding (94 +/- 4 mmHg baseline, 113 +/- 6 mmHg feeding, P < or = 0.05), while heart rate and cardiac index did not change. 5. Total body oxygen consumption rose during the pauses between sucking periods (10.9 +/- 1.1 ml O2 min-1 kg-1 baseline, 13.9 +/- 1.2 ml O2 min-1 kg-1 non-sucking, P < or = 0.05) and was provided for by a significant increase in total body oxygen extraction as systemic oxygen transport was unchanged. 6. Our results reveal that during feeding in young lambs oxygen consumption increases and body stores of oxygen (e.g. Sv,O2) become depleted; this combination may promote rapid arterial desaturation and cyanosis during feeding.

Analysis of Variance↗
PubMed1997

Epidemiologic aspects of gallbladder cancer: a case-control study of the SEARCH Program of the International Agency for Research on Cancer.

BACKGROUND: There are few previous epidemiologic studies of gallbladder cancer, a rare but nearly always lethal gastrointestinal cancer with a demonstrated greater frequency in adult women and older subjects of both sexes, and also in the members of populations throughout central and eastern Europe and certain racial groups such as native American Indians. Unfortunately, the prospects for the prevention of this form of cancer are poor. PURPOSE: Our purpose in conducting this study was to investigate possible new risk factors for gallbladder cancer and to strengthen our understanding of established causal agents that may be involved in this disease. METHODS: A large, collaborative, multicenter, case-control study of cancer of the gallbladder was conducted in five centers located in Australia (Adelaide), Canada (Montreal and Toronto), The Netherlands (Utrecht), and Poland (Opole) from January 1983 through July 1988. Case subjects with gallbladder cancer were accrued by the centers from hospital pathology records and from reports to regional cancer registries. Cancer diagnosis was confirmed by either biopsy, cholecystectomy, or at the time of autopsy. Control subjects were randomly assigned at each center from the population. The pooled analysis included 196 case subjects and 1515 control subjects (who did not report previous cholecystectomy). Ninety-eight percent of the subjects were white. Personal interviews of case subjects, control subjects, and surrogates (spouse or next of kin) were conducted by trained personnel. RESULTS: After adjusting for potential confounding factors (age, sex, center, type of interview, years of schooling, alcohol intake, and lifetime cigarette smoking), a history of gallbladder symptoms requiring medical attention (e.g., reduced bile secretion from the gallbladder into the small intestine due to obstructions of the common bile or cystic ducts) was the major risk factor associated with this form of cancer (odds ratio [OR] = 4.4; 95% confidence interval [CI] = 2.6-7.5). This association was present even in subjects who had their first gallbladder examination because of symptoms present more than 20 years earlier (OR = 6.2; 95% CI = 2.8-13.4). Other variables associated with gallbladder cancer risk included an elevated body mass index, high total energy intake, high carbohydrate intake (after adjustment for total energy intake), and chronic diarrhea. All of these risk factors have been previously associated with gallstone disease. CONCLUSIONS: These findings are consistent with a major role of gallstones, or risk factors for gallstones, in the cause of gallbladder cancer. Additional information on whether or not screening high-risk subjects for gallstones or gallbladder cancer is needed.

Adult↗
PubMed1997

Risk factors for postherpetic neuralgia.

BACKGROUND: The risk factors for postherpetic neuralgia (PHN), the most common complication of herpes zoster, have not been well established. OBJECTIVE: To elucidate the risk factors for PHN. METHODS: Automated medical, claims, and pharmacy records of a health maintenance organization were used to identify cases of PHN and obtain data on risk factors. A case-base design was used to assess the impact of various patient, disease, and treatment factors on the prevalence of PHN 1 and 2 months after developing zoster. RESULTS: There were 821 cases of herpes zoster that met all eligibility criteria. The prevalence of PHN more than 30 days after onset of zoster was 8.0% (95% confidence interval [CI], 6.3%-10.1%) and 4.5% (95% CI, 3.2%-6.2%) after 60 days. Compared with patients younger than 50 years, individuals aged 50 years or older had a 14.7-fold higher prevalence (95% CI, 6.8-32.0) 30 days and a 27.4-fold higher prevalence (95% CI, 8.8-85.4) 60 days after developing zoster. Prodromal sensory symptoms and certain conditions associated with compromised immunity were also associated with PHN. Systemic corticosteroids before zoster and treatment of zoster with acyclovir or corticosteroids did not significantly affect the prevalence of PHN. CONCLUSIONS: Increased age and prodromal symptoms are associated with higher prevalence of PHN 1 and 2 months after onset of zoster. Overall, systemic acyclovir appears not to confer any protection against PHN, although benefit among elderly patients cannot be excluded.

Acyclovir↗
PubMed1997

Quantitative studies of the risk of serious hepatic injury in persons using nonsteroidal antiinflammatory drugs.

OBJECTIVE: To quantify the risk of symptomatic hepatic injury associated with nonsteroidal antiinflammatory drugs (NSAIDs). METHODS: Five population-based studies were summarized to evaluate information on more than 1,000,000 patients using NSAIDs. RESULTS: The risk of clinically apparent liver injury was approximately 1 case per 10,000 patient-years of NSAID use. Only sulindac, associated with a 5-10-fold higher incidence of hepatic injury, differed significantly from other NSAIDs. Patients using diclofenac showed no higher incidence of serious liver disease than did patients using other NSAIDs. CONCLUSION: Symptomatic hepatic effects attributable to most NSAIDs are extremely rare and usually mild.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Resource utilization and cost of care for rheumatoid arthritis and osteoarthritis in a managed care setting: the importance of drug and surgery costs.

OBJECTIVE: To describe the frequency and costs of medical services for patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in a managed care setting. METHODS: Individual utilization records of medical and pharmacy services for OA and RA patients were obtained from a group-model health maintenance organization (HMO). Estimates were made for costs of drugs and medical services for arthritis from July 1, 1993 to June 30, 1994 using Medicare reimbursement schedules and average wholesale drug prices. Calculated rates for each population were expressed as counts of events or as dollars per person-year. RESULTS: The average individual cost rate of arthritis-related care for 365 RA patients was $2,162 per year, and the total cost of RA care to the HMO was $703,053. Prescription medications accounted for 62% ($436,440) of the total cost of RA care, while ambulatory care accounted for 21% ($150,938), and hospital visits accounted for 16% ($115,674). With regard to 10,101 OA patients, the average individual cost rate was $543 per year, and total cost to the HMO was $4,728,425. Hospital care accounted for 46% ($2,170,890) of the total cost of OA care, medications accounted for 32% ($1,509,637), and ambulatory care accounted for 22% ($1,047,898). CONCLUSION: RA care, in the setting of this study, was characterized by intensive treatment, especially frequent use of medications that were delivered to most patients. Although the cost of RA care per patient was high, cost to the managed care provider was relatively low, owing to the rarity of RA. OA care tended to be infrequent, and the largest component of cost was hospital care for a small proportion of patients (5%). Owing to the greater prevalence of OA, care of OA was nearly 7 times more costly to the managed care provider than was care of RA.

Aged↗
PubMed1997

Estrogen replacement in ovariectomized rats results in physiologically significant levels of circulating progesterone, and co-administration of progesterone markedly reduces the circulating estrogen.

Estrogen and progesterone replacement in ovariectomized rats in an often-used experimental system for determination of the specific effects of these hormones. In this study, two different delivery systems and two different dosage levels of estrogen, progesterone or a combination of the two have been used. Estrogen and progesterone in the circulation have been measured in response to each treatment. It is reported that estrogen treatment (237.2 +/- 49.2 pg/mL) results in physiologically significant levels of circulating progesterone (11.1 +/- 1.3 ng/mL). Also, co-administration of progesterone (23.7 +/- 2.0 ng/mL) with estrogen decreases the level of estrogen over that seen with estrogen alone (96.7 +/- 19.2 pg/mL with progesterone vs 237.2 +/- 49.2 pg/mL without progesterone). Thus, contrary to expectations, estrogen replacement therapy is not specific to estrogen and some of the antagonistic effects of progesterone are the result of a decrease in circulating estrogen, and not a specific effect on a target tissue. Whereas the mechanism of these effects has not been determined, obvious artifactitous phenomena have been excluded as being their cause. These results could have a major impact on the interpretation of past and future experiments of this kind.

Animals↗
PubMed1997

Cardiomyopathy: a late complication of hemolytic uremic syndrome.

This report describes a child who presented with classic hemolytic uremic syndrome (HUS) and 4 months later developed a life-threatening but reversible cardiomyopathy with global cardiac dysfunction and a left ventricular ejection fraction of 14%. There was no evidence of electrolyte abnormalities, anemia, hypertension, severe fluid overload, or viral infection. Endomyocardial biopsies were consistent with a dilated cardiomyopathy. This paper highlights the importance of considering the diagnosis of associated cardiomyopathy when presenting with late-onset edema following HUS.

Cardiomyopathies↗
PubMed1997

International trends in sales of inhaled fenoterol, all inhaled beta-agonists, and asthma mortality, 1970-1992.

To evaluate the hypothesis that fenoterol or all inhaled beta-agonists caused an epidemic of asthma mortality in New Zealand from the late 1970s to the mid-1980s, we examined trends from 1970 to 1992 in per capita sales of inhaled fenoterol, inhaled beta-agonists, and asthma mortality in New Zealand and nine other countries that marketed fenoterol. During the last two decades, there has been a large and widespread increase in sales of inhaled beta-agonists, including fenoterol. Asthma mortality in most countries, however, has been relatively stable. Only New Zealand experienced an epidemic of asthma mortality. In addition, sales rates of fenoterol similar in magnitude to those in New Zealand near the peak of the epidemic also occurred in Belgium, Austria, and Germany, while asthma mortality in these countries remained low. Also, sales rates of all beta-agonists in Australia were similar to those in New Zealand, but no epidemic of asthma mortality occurred in Australia. Therefore, the difference between asthma mortality rates in New Zealand and other countries is not explained by differences in per capita sales of fenoterol or all beta-agonists. Within New Zealand, the beginning and end of the epidemic correlated with a rise and fall in sales of all beta-agonists, including fenoterol. From 1980 to 1989, however, sales of fenoterol and all beta-agonists doubled in New Zealand while asthma mortality declined by 40%. International data on medication sales and asthma mortality, therefore, do not point to a relation between asthma mortality and beta-agonists in general nor fenoterol in particular.

Administration, Inhalation↗
PubMed1997

Mortality in current and former users of clozapine.

Clozapine (Clozaril), a tricyclic dibenzodiazepine, causes fewer extrapyramidal side effects than do other antipsychotic drugs. Because it can induce agranulocytosis, however, clozapine is indicated only for schizophrenia that is not responsive to other therapies. To describe the drug's effects on mortality, we compared rates of various causes of death in 67,072 current and former clozapine users. We linked data from a national registry of clozapine recipients to the National Death Index and Social Security Administration Death Master Files, obtained death certificates, and calculated mortality rates for underlying causes of death using standardization to adjust for age, sex, and race. During 1991-1993, there were 396 deaths in 85,399 person-years for patients ages 10-54 years. Mortality was lower during current clozapine use than during periods of non-use. Mortality from suicide was decreased in current clozapine users by comparison with past users [rate ratio (RR) = 0.17; 95% confidence interval (CI) = 0.10-0.30]. During clozapine use, there were elevations in mortality rates for less common causes of death, including pulmonary embolism (RR for current exposure compared with past clozapine use = 5.2) and respiratory disorders (RR = 2.9). Clozapine appears to reduce mortality in severe schizophrenics, mostly by decreasing suicide rates.

Adolescent↗
PubMed1997

Efficacy of a two-component acellular pertussis vaccine in infants.

OBJECTIVE: This case-control study investigated the protective efficacy against pertussis of three doses of a two-component acellular pertussis vaccine (manufactured by Biken in Japan) combined with diphtheria and tetanus toxoids (manufactured by Connaught Laboratories in the US) in infants. METHODS: A case-control study was performed in 63 pediatric practices in Germany. Prospective recruitment of 16,780 infants ages 6 to 17 weeks took place between February, 1993, and July, 1994. According to parental choice infants received either Biken acellular pertussis vaccine combined with diphtheria and tetanus toxoids (DTacP) (74.6%) at approximately 2, 4 and 6 months of age, or a licensed German diphtheria-tetanus toxoids-whole cell pertussis vaccine (10.9%), diphtheria-tetanus toxoids vaccine (12.5%) or no vaccine (2.0%). Prospective surveillance of pertussis cases between February, 1993, and May, 1995, was accomplished by culturing all infants < or =2 years of age presenting with cough > or = 7 days. A pertussis case was defined as any cough of 21 days or longer plus a positive Bordetella pertussis culture or household contact exposure. RESULTS: We identified 241 pertussis cases prospectively by 11,017 B. pertussis cultures and 949 controls matched for age were selected from the same pediatric practices. Medical history and demographic and vaccine status data were collected from each case and for four controls. Data were analyzed through conditional logistic regression taking into account individual matching and adjusting for potential confounding variables. DTacP combined with diphtheria and tetanus toxoids vaccine was 82% protective (95% confidence interval, 68 to 90), diphtheria-tetanus toxoids-whole cell pertussis vaccine was 96% protective (95% confidence interval, 78 to 99). Protection against typical B. pertussis infection characterized by paroxysmal cough lasting > or =21 days was 96% (95% confidence interval, 87 to 99) for DTacP and was 97% (95% confidence interval, 79 to 100) for diphtheria-tetanus toxoids-whole cell pertussis vaccine. Adjustment for potentially confounding variables did not change the results significantly. CONCLUSIONS: Three doses of the two-component acellular pertussis vaccine protected infants against pertussis disease during the period before the recommended booster vaccination. For typical pertussis disease as defined by the WHO efficacy was high and similar to that of a licensed German diphtheria-tetanus toxoids-whole cell pertussis vaccine.

Case-Control Studies↗
PubMed1997

Left ventricular norepinephrine and epinephrine kinetics at birth in lambs.

Little is known about the changes in the left ventricular (LV) kinetics of the catecholamines norepinephrine and epinephrine occurring at birth and their relationship to perinatal alterations in LV function and whole-body catecholamine kinetics. To address this issue, whole-body and LV catecholamine kinetics (radiotracer dilution methodology) and fetal LV output and myocardial blood flow (radioactive microspheres) were measured in chronically instrumented near-term fetuses and in the same animals 1 and 4 hours after birth. Between fetal and 1-hour lambs, LV external work increased 115% (P<.005); carotid arterial plasma norepinephrine concentration, 148% (P<.01); carotid arterial plasma epinephrine concentration, 546% (P<.005); LV norepinephrine spillover, a measure of LV sympathetic activity, 4.1-fold (P<.005); LV epinephrine spillover, 3-fold (P<.05); total-body spillover of norepinephrine, 52% (P<.025); and total-body spillover of epinephrine, 460% (P<.005). Arterial catecholamine concentrations and total-body catecholamine spillovers were unchanged between 1- and 4-hour lambs, but LV external work fell (P<.05) to a level still 77% greater than in fetal lambs (P<.005); LV norepinephrine spillover returned to near-fetal levels, and LV epinephrine spillover became undetectable. These results suggest that (1) a transient increase in LV sympathetic activity occurs at birth and may contribute to the immediate postnatal augmentation of LV performance, (2) organ differences in the pattern of sympathetic activation occur at birth, and (3) birth-related increases in LV sympathetic activity are accompanied by release of epinephrine from the heart.

Animals↗
PubMed1997

5-Aminosalicylates, sulfasalazine, steroid use, and complications in patients with ulcerative colitis.

OBJECTIVES: The choice between sulfasalazine and 5-aminosalicylate (5-ASA) drugs in the management of patients with ulcerative colitis often depends on idiosyncrasies of drug tolerance and control of the disease in individual patients. We sought to evaluate whether there were population differences in the effect of 5-ASA and sulfasalazine on the occurrence of clinically recognized adverse events. We also attempted to determine whether there were differences in the use of concomitant steroids and in the rates of hospitalization. METHODS: We reviewed a large computerized database drawn from general practices in the United Kingdom. There we found records of 2894 patients in whom general practitioners had diagnosed ulcerative colitis, and who were receiving ongoing medical therapy specific to ulcerative colitis. The period of data availability ran from the beginning of 1990 to the latter part of 1993. The average duration of observation was 2.1 yr per patient. Patient histories were categorized into distinct periods according to the dose of 5-ASAs and sulfasalazine, steroids, and immunosuppressants, and were further separated according to the activity of ulcerative colitis. Within these categories, we examined the initiation and discontinuation of steroids, incidence of new hospitalizations for ulcerative colitis, and clinical mention of adverse events. RESULTS: New clinical mentions of hepatic, pancreatic, renal, and hematological events other than anemia were similar among the 5-ASAs and were very infrequent overall. Hospitalizations for ulcerative colitis occurred with similar frequency (about 15 hospitalizations per 100 patients per year) among users of those drugs. Patients receiving sulfasalazine had lower rates of initiation of prednisolone than did patients receiving 5-ASA, but sulfasalazine was used proportionately less often in patients who had been recently hospitalized, and it may be that sulfasalazine patients were somewhat less sick, overall, than were 5-ASA-using patients. The choice of drug did not affect discontinuation rates for prednisolone among established users. CONCLUSIONS: In the United Kingdom, during the period of this study, serious adverse reactions to drugs were not an important aspect of the management of patients with ulcerative colitis. Renal and pancreatic complications of sulfasalazine and 5-ASA therapy were extremely rare. Sulfasalazine and 5-ASA drugs have similar steroid-sparing properties. Disease-specific hospitalizations are approximately 100 times more common in ulcerative colitis patients than are serious adverse drug effects. Considerations of drug efficacy should therefore dominate the choice between therapeutic agents.

Adolescent↗
PubMed1997

Shop order fracture rate as a risk factor for strut fracture in Björk-Shiley CC60 degrees heart valves.

BACKGROUND AND AIMS OF THE STUDY: Previous studies have implicated a number of characteristics that predict strut fracture in Björk-Shiley convexo-concave heart valves, including valve size and position, opening angle, and weld date. This study examines whether the specific batch (shop order) with which a valve is associated during manufacture is related to the risk of fracture. MATERIAL AND METHODS: Our case-control study of CC60 degrees valves obtained detailed information on the manufacturing characteristics of 147 case and 1094 control valves used. Shop order fracture rate for each valve (percentage of other valves in the same shop order with a fracture) was obtained from the research database maintained by the valve manufacturer. RESULTS: Shop order was associated with fracture risk. Valves originating from shop orders with the highest two categories of fracture rate were at approximately twice the risk of fracture as other valves, after accounting for the effect of known risk factors. CONCLUSIONS: Shop order information may provide additional data for assessing the likelihood of valve fracture in individuals being considered for prophylactic explant of heart valves.

Analysis of Variance↗