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PubMed2005

Targeting the beta-catenin/APC pathway: a novel mechanism to explain the cyclooxygenase-2-independent anticarcinogenic effects of celecoxib in human colon carcinoma cells.

Celecoxib, a cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drug, is a new anticarcinogenic agent. Its antitumor effects depend on the one hand on its COX-2-inhibiting potency, but on the other hand on COX-2-independent mechanisms, which until now have not been fully understood. Here, we investigated whether celecoxib has an impact on the APC/beta-catenin pathway, which has been shown to play a pivotal role in the development of various cancers, especially of the colon. After only 2 h of treatment of human Caco-2 colon carcinoma cells with 100 muM celecoxib, we observed a rapid translocation of beta-catenin from its predominant membrane localization to the cytoplasm. Inhibition of the glycogen-synthase-kinase-3beta (GSK-3beta) by LiCl prevented this celecoxib-induced translocation, suggesting that phosphorylation of beta-catenin by the GSK-3beta kinase was essential for this release. Furthermore, the cytosolic accumulation was accompanied by a rapid increase of beta-catenin in the nuclei, starting already 30 min after celecoxib treatment. The DNA binding activity of beta-catenin time dependently decreased 2 h after celecoxib treatment. After this cellular reorganization, we observed a caspase- and proteasome-dependent degradation of beta-catenin after 8 h of drug incubation. Celecoxib-induced beta-catenin degradation was also observed in various other tumor cell lines (HCT-116, MCF-7, and LNCAP) but was not seen after treatment of Caco-2 cells with either the anticarcinogenic nonsteroidal anti-inflammatory drug R-flurbiprofen or the highly COX-2-selective inhibitor rofecoxib. These findings indicate that the anticarcinogenic effects of celecoxib can be explained, at least partly, by an extensive degradation of beta-catenin in human colon carcinoma cells.

Adenomatous Polyposis Coli Protein↗

PubMed1997

Pharmacodynamic modeling of vecuronium-induced twitch depression. Rapid plasma-effect site equilibration explains faster onset at resistant laryngeal muscles than at the adductor pollicis.

BACKGROUND: After bolus doses of nondepolarizing muscle relaxants, the adductor pollicis recovers from paralysis more slowly than the diaphragm and the laryngeal adductors, suggesting that the adductor pollicis is more sensitive than the respiratory muscles to effects of those drugs. In contrast, during onset, the respiratory muscles are paralyzed more rapidly than the adductor pollicis, suggesting that the respiratory muscles are more sensitive than the adductor pollicis. To reconcile these apparently conflicting findings, we determined vecuronium's pharmacokinetics and its pharmacodynamics at both the adductor pollicis and the laryngeal adductors. METHODS: Six volunteers were studied on two occasions during anesthesia with propofol. Mechanical responses to train-of-four stimulation were measured at the adductor pollicis and at the laryngeal adductors. Vecuronium (15-60 micrograms/kg) was given and arterial plasma samples were obtained from 0.5-60 min. Vecuronium doses differed by twofold on the two occasions. A pharmacokinetic model accounting for the presence and potency of vecuronium's 3-desacetyl metabolite and a sigmoid e-max pharmacodynamic model were fit to the resulting plasma concentration and effect (adductor pollicis and laryngeal adductors) data to determine relative sensitivities and rates of equilibration between plasma and effect site concentrations. RESULTS: The steady-state plasma concentration depressing laryngeal adductor twitch tension by 50% was approximately 1.5 times larger than that for the adductor pollicis. The equilibration rate constant between plasma and laryngeal adductor concentrations was about 1.5 faster than that between plasma and adductor pollicis concentrations. The Hill factor (gamma) that describes the steepness of the laryngeal adductor concentration-effect relation was approximately 0.6 times that of the adductor pollicis. CONCLUSIONS: More rapid equilibration between plasma and laryngeal adductor vecuronium concentrations explains why onset is more rapid at the laryngeal adductors than at the adductor pollicis. During recovery, both rapid equilibration and lesser sensitivity of the laryngeal adductors contribute to earlier recovery.

Adult↗

PubMed2002

Differences in systemic opioid use do not explain increased fever incidence in parturients receiving epidural analgesia.

BACKGROUND: It has been hypothesized that an increased incidence of fever in patients receiving epidural analgesia might result not from epidural per se, but rather from the antipyretic effect of opioids preferentially administered to women in the no-epidural group. If this were the case, then one would expect the incidence of fever in parturients who did not receive systemic opioids to be independent of whether they received epidural analgesia. METHODS: Using a cohort study design, the authors evaluated the records of 1,233 nulliparous patients whose labor analgesia was managed with (1) no medication (N = 170); (2) 10 mg intravenous systemic nalbuphine plus 10 mg intramuscular every 3 to 4 h as required (N = 327); (3) epidural analgesia with continuous infusion of 0.125% bupivacaine with 2 microg/ml fentanyl (N = 278); or (4) patients who received both systemic nalbuphine and epidural analgesia (N = 458). Fever was diagnosed if the maximum temperature during labor exceeded 100.4 degrees F (38 degrees C). RESULTS: The incidence of fever did not differ according to nalbuphine administration for women not receiving epidural analgesia (1% no nalbuphine, 0.3% with nalbuphine, P = 0.27) or for women receiving epidural analgesia (17% no nalbuphine, 17% with nalbuphine, P = 1.0). However, the incidence of fever differed significantly between patients who received no analgesia as compared to those who received epidural analgesia alone (1% vs. 17%, P = 10(-6)). Controlling for confounding did not alter these associations. CONCLUSIONS: Our findings suggest that an antipyretic effect of nalbuphine in patients who do not receive an epidural does not explain the greater incidence of fever observed in women who receive epidural analgesia for labor.

Adult↗

PubMed2002

Conventional mechanical ventilation is associated with bronchoalveolar lavage-induced activation of polymorphonuclear leukocytes: a possible mechanism to explain the systemic consequences of ventilator-induced lung injury in patients with ARDS.

BACKGROUND: Protective ventilatory strategies have resulted in a decreased mortality rate in acute respiratory distress syndrome, but the underlying mechanisms remain unclear. The authors hypothesized that (1) mechanical ventilation modulates activation of polymorphonuclear leukocytes (PMNs), (2) the consequent release of proteinases is correlated with a systemic inflammatory response and with multiple organ dysfunction, and (3) these deleterious effects can be minimized by a protective ventilatory strategy. METHODS: Human PMNs were incubated with bronchoalveolar lavage fluid obtained from patients at entry or 36 h after randomization to ventilation with either a conventional (control) or a lung-protective strategy. PMN oxidant production and surface expression of adhesion molecules and granule markers, including CD18, CD63, and L-selectin, were measured by flow cytometry. Extracellular elastase activity was quantified using a fluorescent substrate. RESULTS: Bronchoalveolar lavage obtained from both groups of patients at entry showed similar effects on PMN oxidant production and expression of surface markers. At 36 h, exposure of PMNs to bronchoalveolar lavage fluid from the control group resulted in increased PMN activation as manifested by a significant increase in oxidant production, CD18, and CD63 surface expression, and shedding of L-selectin. By contrast, these variables were unchanged at 36 h in the lung-protective group. There was a significant correlation between the changes of the variables and changes in interleukin-6 level and the number of failing organs. CONCLUSIONS: Polymorphonuclear leukocytes can be activated by mechanical ventilation, and the consequent release of elastase was correlated with the degree of systemic inflammatory response and multiple organ failure. This result may possibly explain the decreased mortality in acute respiratory distress syndrome patients treated with a lung-protective strategy.

Analysis of Variance↗

PubMed1992

Life-style factors do not explain racial differences in high-density lipoprotein cholesterol: the Minnesota Heart Survey.

We analyzed data from a population-based survey to determine whether serum high-density lipoprotein cholesterol (HDL-C) concentrations are different in blacks and whites after controlling for life-style characteristics. We studied a total of 741 white men, 453 black men, 786 white women, and 572 black women age 35-74 years. Age-adjusted HDL-C concentrations were higher in black than white men (48.6 vs 40.8 mg/dl) and in black than white women (56.1 vs 54.0 mg/dl). Life-style characteristics associated with HDL-C in women were exogenous hormone use, average number of cigarettes smoked per day, average ounces of alcohol consumed per week, body mass index, and use of beta-blockers. Life-style characteristics associated with HDL-C levels in men included age, average number of cigarettes smoked per day, average ounces of alcohol consumed per week, body mass index, and a self-reported history of diabetes. After adjustment for life-style characteristics, black men and women had HDL-C levels 7.0 and 5.3 mg/dl higher, respectively, than whites. Body mass index was a negative confounder in women; after adjusting for body mass and age, black women had HDL-C levels 4.6 mg/dl higher than white women. These data indicate that the measured life-style factors cannot fully explain the observed differences in HDL-C between blacks and whites. These findings, which are consistent with other reports, may reflect an inability to assess life-style factors accurately and/or genetic or cultural factors yet to be determined.

Adult↗

PubMed1995

Behavioral factors explaining the low risk for cervical carcinoma in Utah Mormon women.

We used data from a population-based case-control study conducted in Utah from 1984 to 1987 to determine whether the low incidence of cervical carcinoma in Mormon women can be explained by adherence to their religious teachings, which proscribe smoking and extramarital sexual relations. Mormon women had substantially lower risk for cervical carcinoma than non-Mormons [odds ratio (OR) = 0.39; 95% confidence interval (CI) = 0.28-0.54]; this low risk was confined to those who attended church frequently. The protective effect disappeared after controlling for differences in age, sexual behavior, and smoking (OR = 1.22; 95% CI = 0.80-1.87).

Adult↗

PubMed2001

A threshold explains modulation of neural responses to opposite-contrast stereograms.

Disparity-sensitive neurons respond to contrast-inverted stereograms (aRDS) that do not evoke depth percepts. This is in conflict with the idea that such neurons are the direct correlate of depth perception. However, the output of neurons responding to aRDS may be further processed: neurons at later processing stages show weaker responses to aRDS than early stage neurons. Here, we show that such a response hierarchy emerges in a three-layered neural network. A numerical analysis demonstrates that threshold operations can largely explain the network's behavior as well as the electrophysiological data. An extension of the energy neuron model for disparity-sensitive neurons predicts increased responses to aRDS for an identifiable sub-class of cells and can thus be tested in electrophysiological experiments.

Action Potentials↗

PubMed2004

Serological pattern 'anti-hepatitis B core alone' in HIV or hepatitis C virus-infected patients is not fully explained by hepatitis B surface antigen mutants.

We determined the frequency of hepatitis B virus (HBV) occult infection and studied S gene mutations in HIV or hepatitis C virus-co-infected patients with persistent pattern 'anti-hepatitis B core alone'. HBV DNA was particularly frequent in HIV-positive patients. Sequencing of the S gene showed that only two HIV-infected patients harboured mutants in the major hydrophilic loop; the absence of hepatitis B surface antigen detection could not be explained by diagnostic escape mutants.

AIDS-Related Opportunistic Infections↗

PubMed1997

Explaining different profiles in quality of life experiences in acute and chronic leukemia.

There is a need to understand and explain why quality of life (QOL) is experienced and viewed differently by those with acute and chronic leukemia. A total of 23 adults with either acute or chronic leukemia were interviewed about their experience of QOL. Adults with acute leukemia described QOL as a positive attitude to life, whereas those with chronic leukemia described QOL as life satisfaction. In order to elucidate why there are differences in their experience of QOL, a qualitative text analysis was used. The narrated interviews, tape-recorded and transcribed verbatim, were interpreted based on the following three questions: Why are there differences in these individuals' description of QOL? What are they talking about? Which phenomenon are they describing? The findings were interpreted, "a feeling of uncertainty," which made the difference to their experience of QOL. This uncertainty was expressed in different forms and could be seen in different degrees. Uncertainty is an important factor affecting the QOL of these adults. Nurses who work with these patients have a major role to play in minimizing uncertainty by offering coping skills to deal with feelings and improving QOL since QOL is one of the outcomes of nursing care.

Acute Disease↗

PubMed2001

Mathematical coupling does not explain the relationship between right ventricular end-diastolic volume and cardiac output.

OBJECTIVE: To evaluate the clinical significance of mathematical coupling on the correlation between cardiac output and right ventricular end-diastolic volume (RVEDV) through measurement of cardiac output by two independent techniques. DESIGN: Prospective, observational study. SETTING: Surgical intensive care unit in a level 1 trauma center. PATIENTS: Twenty-eight critically ill surgical patients who received mechanical ventilation and hemodynamic monitoring with a pulmonary artery catheter. INTERVENTIONS: A pulmonary artery catheter designed to measure right ventricular ejection fraction (RVEF) and cardiac output by the intermittent bolus thermodilution (TDCO) method and continuous cardiac output by the pulsed thermal energy technique was placed. A computerized data logger was used to collect data simultaneously from the RVEF/TDCO system and the continuous cardiac output system. MEASUREMENTS AND MAIN RESULTS: Two hundred forty-nine data sets from 28 patients were compared. There is statistical correlation between TDCO and continuous cardiac output measurements (r = 0.95, p < 0.0001) with an acceptable bias (-0.11 L/min) and precision (+/-0.74 L/min). The correlation was maintained over a wide range of cardiac outputs (2.3-17.8 L/min). There is a high degree of correlation between RVEDV and both TDCO (r = 0.72, p < 0.0001) and independently measured continuous cardiac output (r = 0.68, p < 0.0001). These correlation coefficients are not statistically different (p = 0.15). CONCLUSIONS: The continuous cardiac output technique accurately approximates cardiac output measured by the TDCO method. RVEDV calculated from TDCO correlates well with both TDCO and independently measured continuous cardiac output. Because random measurement errors of the two techniques differ, mathematical coupling alone does not explain the correlation between RVEDV estimates of preload and cardiac output.

Adult↗

PubMed1996

The development of auditory behavior (or what the anatomists and physiologists have to explain).

OBJECTIVE: Infants' and children's performance in detecting and discriminating between sounds is often poorer than that of adults. Behavioral immaturity often coexists with mature-looking morphology and physiological responses from the peripheral and brain stem structures that limit performance among adults. One interpretation of this pattern of results is that "hearing" is mature but some unnamed central process is immature. DESIGN: The approach to the problem taken here is to view auditory behavior as the process to be explained and physiological or anatomical measurements as giving us clues about the underlying processes. The development of four aspects of hearing-frequency resolution, detection, temporal resolution, and intensity resolution-is reviewed in this paper, and new data addressing these topics are presented. RESULTS: Frequency resolution, detection, temporal resolution, and intensity resolution all undergo development during infancy and childhood, although the mechanisms underlying development vary across capacity and developmental period. CONCLUSIONS: A coherent argument can be made that both primary auditory pathway maturation and maturation of specific central processes are involved in development. Both types of maturation continue into childhood, and both types of maturation can influence hearing directly.

Age Factors↗

PubMed1987

Alternatives to the BEIR relative risk model for explaining atomic-bomb survivor cancer mortality.

The apparent failure of the BEIR absolute risk model to explain the data on the Japanese atomic-bomb survivors does not imply that the BEIR relative risk model (RRM) is correct. RRM is objectionable in that it fits the data only in conjunction with an assumption not in accord with current knowledge and thinking. Contrary to what is widely believed, RRM is not a consequence of, or consistent with, initiator-promoter theories; models derived from initiator-promoter theories fit the data with fewer adjustable parameters and without requiring unpalatable assumptions. The preferable models give substantially lower radiation risks.

Age Factors↗

PubMed2000

Model of blood-brain transfer of oxygen explains nonlinear flow-metabolism coupling during stimulation of visual cortex.

The coupling between cerebral metabolic rate of oxygen (CMRO2) and blood flow (CBF) in response to visual stimulation was evaluated by means of a model of oxygen delivery. The model predicted a nonlinear relationship between stimulus-evoked changes of oxygen consumption and blood flow. The magnitude of the CMRO2/CBF ratio index (IO2) was used to indicate the degree of flow-metabolism coupling prevailing in specific areas of the brain during physiological stimulation. Therefore, the index provided a measure of the blood oxygenation level dependent (BOLD) magnetic resonance contrast. To evaluate the changes of IO2 in response to visual stimulation, the model was applied to the effect of a changing flicker rate of a visual stimulus on the magnitudes of CBF, CMRO2, and oxygen diffusion capacity, in the human brain. Positron emission tomography (PET) was used to measure the CBF and the CMRO2 in 12 healthy volunteers who viewed a cross-hair (baseline) or a yellow-blue annular checkerboard reversing at frequencies of 1, 4, or 8 Hz. The magnitude of CBF in the primary visual cortex increased as a function of the checkerboard reversal rate and reached a maximum at the frequency of 8 Hz (z=16.0), while the magnitude of CMRO2 reached a maximum at 4 Hz (z=4.0). Therefore, the calculated IO2 was lower at 8 Hz than at 1 and 4 Hz, in contrast to the oxidative metabolic rate that reached its maximum at 4 Hz. The model explained the increase of oxygen consumption as the combined effect of increased blood flow and increased oxygen diffusion capacity in the region of visual activation.

Adult↗

PubMed2000

Admixture with whole blood does not explain false-negative urease tests.

Rapid urease test sensitivity for Helicobacter pylori is reduced in the presence of active upper gastrointestinal bleeding. The aim of this study was to evaluate the in vitro effect of whole blood on rapid urease testing. Urease solution was added to normal saline, and heparinized whole blood both positive and negative for H. pylori antibody. The mixtures were then serially diluted in saline, and/or whole blood and added to three different rapid urease kits. The admixture of urease in H. pylori-seropositive whole blood diluted in either saline or whole blood enhanced performance in both kits fourfold compared with saline alone. No false-negative results were observed in either kit. Seronegative whole blood produced similar results. Undiluted saline or whole blood produced no positive rapid urease tests. Whole blood accelerates the urease reaction in vitro. Neither H. pylori antibody-positive nor -negative whole blood adversely impacted the rapid urease test. False-negative rapid urease test results in upper gastrointestinal bleeding cannot be explained by admixture with whole blood.

Clinical Enzyme Tests↗

PubMed1994

Explaining attitudes toward medication compliance among a seriously mentally ill population.

Data from a clinical trial of consumer-delivered case management services were used to construct an explanatory model for attitudes toward medication compliance, focusing on psychosocial factors. A regression model explaining attitudes toward medication compliance shows that more positive attitudes toward compliance are related to older age, fewer symptoms, and a broader array of daily activities involving social relations. Participation in social activities is a practical goal of psychosocial rehabilitation services that support compliance with medication regimens and psychiatric treatment.

Activities of Daily Living↗

PubMedDate not supplied

Positive inotropic and electrophysiological effects of APP 201-533 can be explained by an increase of cardiac cyclic AMP.

The possible mechanism of action of the positive inotropic agent APP 201-533 [3-amino-6-methyl-5-phenyl-2(1H)-pyridinone] was investigated. In guinea pig papillary muscles, APP 201-533 increased force of contraction concentration dependently at 10(-4)-10(-3) M. The effect was associated with an abbreviation of contraction and relaxation time. In guinea pig papillary muscles partially depolarized with 22 mM K+, APP 201-533 in concentrations of 10(-4) and 10(-5) M restored slow action potentials, which were not influenced by cimetidine, propranolol, and prazosin but were blocked by the Ca2+ antagonist PY 108-068 and by carbachol in an atropine-sensitive manner. The concentration-effect curve of histamine was shifted to the left in the presence of APP 201-533. These actions can be explained by the increase in cardiac cyclic AMP level that was found in rabbit papillary muscles and guinea pig left atria treated with APP 201-533 due to the known phosphodiesterase inhibitory effect of pyridinones. APP 201-533 increased the inotropic potency of dihydroouabain in guinea pig papillary muscles. It seems possible that this effect is based on an increased Ca2+ sensitivity of myocardial contractile structures as described previously for APP 201-533.

Action Potentials↗

PubMed1990

Explaining variability of cost using a severity-of-illness measure for ICU patients.

Factors related to hospital resource use by intensive care unit (ICU) patients, including severity of illness at admission and intensity of therapy during the first 24 ICU hours were explored in this study. Analysis was based on 2,749 patients admitted to the general medical-surgical ICU at Baystate Medical Center, Springfield, Massachusetts, between February 1, 1983 and January 10, 1985. Resource use was indexed by hospital length of stay (LOS) adjusted for differences between ICU and other hospital days. Severity of illness was measured by the Mortality Prediction Model (MPM0), a validated predictor of outcome but not previously used to analyze resource consumption. Intensity of therapy was measured using the Therapeutic Intervention Scoring System (TISS). The 10% of patients with longest ICU stays were significantly different from the other 90% with respect to previous ICU use, MPM probability, and TISS score. Variability in resource use was analyzed using four diagnosis-related groups (DRGs) accounting for large numbers of ICU patients. The relationship between severity of illness and resource was nonlinear: as severity increased from low levels, resource use increased at a decreasing rate, reached a plateau, and eventually declined. Within each DRG, MPM0 explained a statistically significant percentage of the variability in resource use.

Costs and Cost Analysis↗

PubMed1994

Does physician performance explain interspecialty differences in malpractice claim rates?

Physician specialty has been consistently associated with different malpractice claim rates, with neurosurgery, orthopedics, and obstetrics and gynecology having the highest rates. Whether these differences reflect physician performance or other aspects of patient care that are unique for each specialty is unclear. A retrospective cohort study was performed including 12,829 physicians involved in 8,221 closed cases from 1977 to 1991. For each case an assessment was made whether the plaintiff received an award and whether the physician care of the patient was indefensible. An award was made to the plaintiff in 42% of cases. Physician care was considered indefensible in 23% of the cases. The specialties with the highest award rates were anesthesiology (58.3%), obstetrics and gynecology (47.5%), and radiology (43.0%). Neurosurgery had the lowest rate of award (30.2%). The specialties with the highest indefensibility rates were radiology (36%), obstetrics and gynecology (27%), and anesthesiology (27%). Neurosurgery had the lowest indefensibility rate (10%). These results were unchanged after controlling for physician age, degree, site of training, certification status, and severity of patient injury. In conclusion, differences in award rate and indefensibility are present, but not large enough to explain the large variation in specialty claim rates. This suggests that the variation in malpractice rates results from factors other than a meaningful difference in physician performance.

Clinical Competence↗