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Biomedical subjects

A M Walker

Publications and source records attributed to A M Walker.

At least 73 records · Page 4Linked to original sources
PubMed1999

Cerebral blood flow regulation in REM sleep: a model for flow-metabolism coupling.

The pattern of metabolic and circulatory changes occurring during REM sleep in the whole brain is also observed at a regional level in different instances of functional activation. This pattern is characterized by an increase in metabolic rate, blood flow, glucose and oxygen uptake, the increase in glucose uptake generally exceeding oxygen uptake. A model of interpretation is presented, based on the assumption that substantial limitation to oxygen diffusion exists in the brain. According to the model, microregions lying at mid-distance between capillaries may become hypoxic, depending on metabolic rate and blood-cell PO2 difference. At increasing metabolic rates, O2 consumption in pericapillary microregions increases and the PO2 drop becomes steeper. As a consequence, in microregions far from capillaries a decrease in O2 availability occurs, in concomitance with the increase in metabolic rate, so that non-oxidative glucose metabolism develops locally. A similar spatial PO2 pattern forms in the case of arterial hypoxia, when capillary PO2, and then blood-cell PO2 difference, is reduced. The hypoxic microregions are the source of vasodilatatory messages, the consequent vasodilatation increasing average capillary PO2 and then favoring O2 diffusion to the tissue. Oxygen thus appears to be a better candidate than glucose as a mediator of blood flow-metabolism coupling. This is supported by its higher extraction fraction and by the fact that, in physiologic conditions, arterial hypoxia (and not hypoglycemia) acts on cerebral blood flow. Moreover, the diffusion capacity of glucose in the brain is higher than that of oxygen, so that diffusion limitation is more likely to occur for oxygen. The present model allows consistent organization of the stereotyped changes in cerebral blood flow and glucose and oxygen uptake occurring both in REM sleep and in other instances of brain activation.

Animals↗
PubMed1998

Calcium channel blockers, cancer incidence, and cancer mortality in a cohort of U.S. women: the nurses' health study.

BACKGROUND: Some studies have suggested that the use of calcium channel blockers may increase the risk of cancer. A possible association of the use of calcium channel blockers with cancer incidence and cancer mortality was addressed using data from the Nurses' Health Study. METHODS: In this study, a total of 18,635 female nurses reported regularly taking at least 1 of 4 cardiovascular medications in 1988: diuretics, beta-blockers, calcium channel blockers, and/or angiotensin-converting enzyme (ACE) inhibitors. Cancer incidence and cancer deaths were ascertained until 1994. RESULTS: During 6 years of follow-up, 852 women were newly diagnosed with cancer and 335 women died of cancer. Women who reported the use of calcium channel blockers had no increased risk of newly diagnosed cancer compared with those taking other cardiovascular drugs (relative risk=1.02; 95% CI 0.83-1.26). The relative risk of dying from cancer associated with the self-reported use of calcium channel blockers was 1.25 (95% CI 0.91-1.72). Relative risks were adjusted for the following self-reported factors: age; weight; height; cholesterol level; systolic and diastolic blood pressure; smoking; alcohol intake; physical activity; menopausal status; postmenopausal hormone use; aspirin use; and history of diabetes, cancer, stroke, myocardial infarction, coronary artery bypass graft or percutaneous transluminal coronary angioplasty, angina, and hypertension. Regarding site specific cancer incidence and mortality, only lung cancer incidence was somewhat increased (RR=1.61; 95% CI 0.88-2.96). CONCLUSIONS: These data suggest no important increase in overall cancer incidence or cancer mortality related to the self-reported use of calcium channel blockers.

Adrenergic beta-Antagonists↗
PubMed1998

Repetitive hypoxia rapidly depresses arousal from active sleep in newborn lambs.

1. Arousal from sleep is an important protective mechanism that is depressed by repeated episodes of hypoxia. We aimed to determine how rapidly arousal depression occurs during repeated hypoxia and to determine if the depression is sleep state specific. 2. Three successive 12 h overnight sleep recordings were performed in six newborn lambs instrumented to record sleep state, blood pressure, heart rate and blood gases. The first (control) and third (recovery) nights were baseline studies (inspired oxygen fraction, FI,O2 = 0.21) to determine the spontaneous arousal probability. During the second (test) study night, lambs were exposed to a 60 s episode of isocapnic hypoxia (FI,O2 = 0.10; inspired carbon dioxide fraction, FI,CO2 = 0.03) during every epoch of sleep. 3. During quiet sleep (QS), the probability of arousing to hypoxia (56%) remained significantly higher than the probability of arousing spontaneously (18%) throughout the repeated hypoxic exposures (chi(2) = 81.5, P < 0.001). By contrast, during active sleep (AS) arousal rapidly became depressed with repetition of the hypoxic stimulus; the probability of arousal in hypoxia (52%) was significantly higher than the probability of spontaneous arousal (12%) during the first ten hypoxic exposures (chi(2) = 18.2, P < 0.001), but there was no difference thereafter. 4. We conclude that, when repeated, moderate hypoxia very rapidly becomes ineffective as an arousing stimulus in AS, but not in QS. These results suggest that the arousal mechanism is particularly vulnerable to failure during AS.

Animals↗
PubMed1998

Epidemiologic interpretation of artificial neural networks.

Multilayer neural networks have been faulted for functioning as "black boxes" and for failing to assess the relative importance of the input factors. The aim of this paper is to illustrate how neural networks can classify individuals. The authors investigated the role of weights in the formation of neural networks' decision surfaces and decision regions. The data used were from a case-control study. Two strong determinants of case status were used as input "neurons." Zero, three, and five hidden neurons were used to explore the effect of the number of hidden neurons on the decision surfaces and regions. Mapping of input and output spaces revealed that three hidden neurons were insufficient to fully discriminate cases from controls. Five hidden neurons may be optimal, but at the cost of possible over-fitting. The more complex neural networks were very effective at defining regions of uniform risk in the plane of the initial covariates, and at assigning risk levels. The authors speculate that neural networks will prove useful in epidemiologic problems that require pattern recognition or complicated classification techniques, and that they will be unfavorable in problems that involve distinct effects of distinguishable predictors.

Artificial Intelligence↗
PubMed1998

Prospective study of calcium channel blocker use, cardiovascular disease, and total mortality among hypertensive women: the Nurses' Health Study.

BACKGROUND: In several observational studies, patients prescribed calcium channel blockers had higher risks of cardiovascular diseases and mortality than those prescribed other antihypertensive medications. We explored these associations in the Nurses' Health Study. METHODS AND RESULTS: A total of 14 617 women who reported hypertension and regular use of diuretics, beta-blockers, calcium channel blockers, ACE inhibitors, or a combination in 1988 were included in the analyses. Cardiovascular events and deaths were ascertained through May 1, 1994. We documented 234 cases of myocardial infarction. Calcium channel blocker monodrug users had an age-adjusted relative risk (RR) of myocardial infarction of 2.36 (95% CI, 1.43 to 3.91) compared with those prescribed thiazide diuretics. Women prescribed calcium channel blockers had a higher prevalence of ischemic heart disease. After adjustment for these and other coronary risk factors, the RR was 1.64 (95% CI, 0.97 to 2.77). Comparing the use of any calcium channel blocker (monodrug and multidrug users) with that of any other antihypertensive agent, the adjusted RR was 1.42 (95% CI, 1.01 to 2.01). An association between calcium channel blocker use and myocardial infarction was apparent among women who had ever smoked cigarettes (covariate-adjusted RR, 1.81; 95% CI, 1.20 to 2.72) but not among never-smokers (RR, 0.94; 95% CI, 0.48 to 1.84). CONCLUSIONS: In analyses adjusted only for age, we found a significant elevation in RR of total myocardial infarction among women who used calcium channel blockers compared with those who did not. After adjustment for comorbidity and other covariates, the RR was reduced. Whether the remaining observed elevated risk is real, or a result of residual confounding by indication, or chance, or a combination of the above cannot be evaluated with certainty on the basis of these observational data.

Adult↗
PubMed1998

Prediction and cross-validation of neural networks versus logistic regression: using hepatic disorders as an example.

The authors developed and cross-validated prediction models for newly diagnosed cases of liver disorders by using logistic regression and neural networks. Computerized files of health care encounters from the Fallon Community Health Plan were used to identify 1,674 subjects who had had liver-related health services between July 1, 1992, and June 30, 1993. A total of 219 subjects were confirmed by review of medical records as incident cases. The 1,674 subjects were randomly and evenly divided into training and test sets. The training set was used to derive prediction algorithms based solely on the automated data; the test set was used for cross-validation. The area under the Receiver Operating Characteristic curve for a neural network model was significantly larger than that for logistic regression in the training set (p = 0.04). However, the performance was statistically equivalent in the test set (p = 0.45). Despite its superior performance in the training set, the generalizability of the neural network model is limited. Logistic regression may therefore be preferred over neural network on the basis of its established advantages. More generalizable modeling techniques for neural networks may be necessary before they are practical for medical research.

Algorithms↗
PubMed1998

A point mutation within CD45 exon A is the cause of variant CD45RA splicing in humans.

The leukocyte common antigen (CD45) is alternatively spliced, generating various isoforms expressed on hemopoietic cells. The splicing pattern of CD45 in T cells is altered in some individuals who show abnormal expression of high molecular weight isoforms containing exon A. The variant splicing pattern was shown to be associated with heterozygosity for a silent point mutation within CD45 exon A. This C to G transition is located 77 nucleotides downstream of the splice acceptor junction of exon A (198 bp total length). Here we report that this mutation is the cause of abnormal splicing. To isolate the mutant gene, somatic cell hybrids of lymphocytes with a CD45 splicing defect and a mouse lymphoid line were produced and clones expressing different isoforms of CD45 were isolated. Expression of the high molecular weight isoform containing exon A was associated with the mutation within exon A. All hybrids expressing the low molecular weight isoforms lacking exon A contained the normal allele of CD45 only. In addition, minigenes including this mutation were constructed and transfected into various cell lines (COS-7, HeLa, CHO). Semi-quantitative reverse transcription polymerase chain reaction showed an increase of more than tenfold in splicing to CD45RA (concomitant with a decrease in splicing to CD45RO) when compared with the normal minigene. Taken together, these results demonstrate a causal relationship between the mutation in CD45 exon A and the variant splicing pattern observed. The involvement of trans-acting splicing factors that interact with this region of CD45 pre-mRNA is currently under investigation.

Alleles↗
PubMed1998

Ketorolac use in outpatients and gastrointestinal hospitalization: a comparison with other non-steroidal anti-inflammatory drugs in Italy.

OBJECTIVE: To compare the risk of hospitalization for gastroduodenal ulcer associated with the use of ketorolac and other non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: A cohort and a nested case-control study were carried out. All residents in the region of Umbria (Italy), aged 35-84 years, who had been given at least one NSAID prescription in 1993 and 1994 were identified. Exposure to drugs was ascertained through a drug prescription database. We estimated rate ratios of hospitalization for gastroduodenal ulcer with or without complications in the current, recent or past period according to exposure to different NSAIDs. RESULTS: Rate ratio estimates, adjusted for age and sex, were 2.8 for any current NSAID and 1.4 for any recent NSAID. The highest rate ratios of lesions of any severity for current NSAID use were observed for piroxicam (RR: 4.6) and ketorolac (RR: 3.4). For gastrointestinal haemorrhage or perforation the highest rate ratios were those for ketorolac (RR: 5.9) and piroxicam (RR: 4.8). Rate ratio estimates did not change after adjustment for concomitant use of gastrotoxic drugs, use of gastroprotective agents not associated with NSAIDs and prior use of NSAIDs. CONCLUSION: Our study demonstrates the need to adhere to the restrictions relating to the indications and duration of use of ketorolac. At present piroxicam represents a greater public health concern since it is confirmed to be among the most gastrotoxic NSAIDs and is one of the most commonly prescribed NSAIDs in Italy.

Adult↗
PubMed1998

Massive decline in lung liquid before vaginal delivery at term in the fetal lamb.

OBJECTIVE: Our aim was to determine the volume of liquid remaining in the lungs of the fetal lamb just before a normal vaginal delivery at term to assess the extent to which an excess of liquid in the airspaces might contribute to the respiratory morbidity that accompanies elective cesarean delivery. STUDY DESIGN: The volume of liquid in the future airspace of the lungs was determined at the end of labor in eight fetal lambs at term from the dilution of an impermeable tracer (125I-labeled human serum albumin) mixed into the liquid. This volume was compared with that measured in a second group of 10 fetal lambs studied 7 days before the expected date of delivery (term = 147 days). RESULTS: The volume of lung liquid present at the end of labor was 6.8 +/- 1.0 ml x kg(-1) (n = 8) compared with 28.2 +/- 1.8 ml x kg(-1) (n = 10) in the second group of lambs studied before the onset of labor at 140 days of gestation. CONCLUSION: Our results indicate that the bulk (>75%) of the liquid that fills the lungs of the fetal lamb at 140 days of gestation is cleared at some time before normal term birth, suggesting that the adverse respiratory impact of elective cesarean delivery may be largely explained by denying the fetus this important adaptive mechanism.

Animals↗
PubMed1998

Newer oral contraceptives and the risk of venous thromboembolism.

Research on the relationship between venous thromboembolism and the progestagen content of combined oral contraceptives has pointed to an increase in risk associated with products containing desogestrel and gestodene. Although many biases must have been at play in these nonexperimental studies, the errors that have been suggested and examined are not of a sufficient magnitude to account for the observed results. The most plausible explanation of the available data is that combined oral contraceptives containing desogestrel and gestodene carry a very small risk of venous thromboembolism, which exceeds the even smaller risk carried by products containing levonorgestrel. The position of norgestimate is uncertain.

Contraceptives, Oral, Combined↗
PubMed1998

Comparative safety evaluation of non-narcotic analgesics.

Both spontaneous reports and single outcome studies may distort the overall safety evaluation of drugs. We identified epidemiologic studies, published from January 1970 to December 1995, that investigated the association of serious adverse effects with aspirin, diclofenac, acetaminophen, and dipyrone to determine and compare the excess mortality associated with short-term drug use. The estimated excess mortality due to community-acquired agranulocytosis, aplastic anemia, anaphylaxis, and serious upper gastrointestinal complications was 185 per 100 million for aspirin, 592 per 100 million for diclofenac, 20 per 100 million for acetaminophen, and 25 per 100 million for dipyrone. The estimates were largely influenced by the excess mortality associated with upper gastrointestinal complications. A relative risk estimate of 300 or more for the association of dipyrone with agranulocytosis would have been necessary for the excess mortality of dipyrone to be comparable to that of aspirin or diclofenac. Based on published epidemiologic evidence used to determine the excess mortality associated with short-term use of these four non-narcotic analgesics, the current regulatory ranking of the drugs appears inappropriate.

Acetaminophen↗
PubMed1998

Late incidence of cancer after metronidazole use: a matched metronidazole user/nonuser study.

In vitro mutagenic activity and carcinogenic potential of metronidazole in certain animals raised concerns about its possible carcinogenicity in humans. We studied the late incidence of cancer after metronidazole use among persons enrolled in the Group Health Cooperative of Puget Sound, Seattle, a health maintenance organization. Randomly selected nonusers were matched on a one-to-one basis for age, gender, and year of enrollment to persons who used metronidazole on an outpatient basis during the period January 1975 to December 1983; 5,222 metronidazole user/nonuser pairs, for whom the median follow-up was 12.6 years, were analyzed. Forty-nine percent, 39.2%, 9.8%, and 2% of users had 1, 2-4, 5-9, and > or = 10 prescriptions or refills of metronidazole filled, respectively. The late (after the first 7 years of follow-up) incidence of cancer was nearly identical among users and nonusers (652 and 662 per 100,000 person-years, respectively; relative risk, 0.98; 95% confidence interval, 0.80-1.20). Age-gender stratified analysis did not reveal any association between metronidazole use and cancer. These data support no association between short-term exposure to metronidazole and cancer in humans. Although the results are reassuring, they may not extend to subjects who have used metronidazole for prolonged periods; further epidemiological studies should focus on these individuals.

Adolescent↗
PubMed1998

Cerebral circulation in sleep: vasodilatory response to cerebral hypotension.

Little is known of the factors that regulate CBF in sleep. We therefore studied 10 lambs to assess the vasodilatory processes that underlie cerebral autoregulation during sleep. Lambs, instrumented to measure CBF (flow probe on the superior sagittal sinus), sleep state, and cerebral perfusion pressure (CPP), were rapidly made hypotensive by inflating a cuff around the brachiocephalic artery to reduce CPP to 30 mm Hg in each state. During control periods, cerebral vascular resistance (CVR in mm Hg/mL/min) was lower in active sleep (2.8 +/- 0.3, mean +/- SD, P < or = 0.001) than in wakefulness (3.9 +/- 0.6) and quiet sleep (4.3 +/- 0.6). The CVR decreased promptly in each state as CPP was lowered. The time (seconds) required for maximal cerebral vasodilation to occur was longer in active sleep (35 +/- 11) than in quiet sleep (20 +/- 6, P < or = 0.001) and wakefulness (27 +/- 11, P < or = 0.05). The CVR decreased less in active sleep (0.6 +/- 0.3, P < or = 0.001) than in quiet sleep (1.5 +/- 0.3), although the changes in CPP induced with brachiocephalic occlusion were equal in each state. In conclusion, our studies provide the first evidence that the vasoactive mechanisms that underlie autoregulation of the cerebral circulation function during sleep. Moreover, our data reveal that the speed and the magnitude of the vasodilatory reserves available for autoregulation are significantly less in active sleep than in quiet sleep.

Animals↗
PubMed1998

Dynamic changes in arousal threshold during sleep in the human infant.

Failure to arouse from sleep is a possible mechanism leading to sudden infant death. Using a controlled pulsatile air jet applied alternately to the nostrils we have made multiple measures of arousal threshold both between and within sleep states. Infants (n = 22) born at term were studied at 2-3 wk postterm (mean age 13 d, range 9-17 d, study 1) and again at 2-3 mo postterm (mean age 78 d, range 56-98 d, study 2). Arousal threshold (stimulus driving pressure, cm H2O) was determined in both active sleep (AS) and quiet sleep (QS). At both ages arousal threshold in QS was significantly higher (251 +/- 24 and 298 +/- 35) than in AS (163 +/- 19 and 144 +/- 29) (p < 0.001). In a morning sleep period, the first and second QS epochs were compared in each baby. In both study 1 and study 2, respectively, arousal thresholds were significantly higher in the second QS epoch (270 +/- 34 and 497 +/- 100) than in the first QS epoch (198 +/- 29 and 252 +/- 69) (p < 0.05 and p < 0.02). There was a significant correlation in individual infants between arousal thresholds in the two states at both ages (p < 0.005 and p < 0.007, respectively). Regression analysis showed no correlation between the length of time the infant had been in a particular sleep state and the arousal threshold in either state in study 1 or in AS in study 2; however, arousal threshold increased significantly (p < 0.01) with time in QS in study 2. This study has expanded on previous findings that arousability is sleep state-dependent by demonstrating that arousability in QS is also altered by the length of time that the infant has been asleep.

Activity Cycles↗
PubMed1998

Major vasodilator role for nitric oxide in the gastrointestinal circulation of the mid-gestation fetal lamb.

As nitric oxide (NO) may be a particularly important vasodilator in early life, we investigated its role in the regulation of the gastrointestinal (GI) circulation at mid-gestation. Cardiac output and GI blood flow were measured by the radioactive microsphere technique in eight chronically instrumented and unanesthetized mid-gestation fetal sheep. Mean arterial pressure (MAP), heart rate, blood flow, oxygen delivery, and vascular resistance were determined before and after infusion of the specific NO synthase inhibitor, Nomega-nitro-L-arginine (L-NNA) at doses of 10 and 25 mg/kg. In response to L-NNA infusion, MAP increased (p < 0.01) and combined ventricular output decreased (p < 0.001). GI blood flow and oxygen delivery decreased and vascular resistance increased in the stomach and all segments of the small and large intestine (all p < 0.001). The greatest reduction in blood flow was in the small intestine (p < 0.01) and the basal differential pattern of small intestinal blood flow exceeding large intestinal flow was completely abolished. These changes were much greater than those previously described in late-gestation fetuses. Our results suggest that, at mid-gestation, NO plays a major role in the regulation of blood flow and vascular tone across all segments of the fetal GI tract, with its effects being more pronounced than later in development.

Animals↗