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PubMed1988

Anion regulation of [3H]strychnine binding to glycine-gated chloride channels is explained by the presence of two anion binding sites.

The effects of six monovalent anions (chloride, bromide, iodide, nitrate, perchlorate, and thiocyanate) on [3H]strychnine binding to glycine-gated chloride channels were examined. These anions have previously been shown to permeate glycine-gated chloride channels and stimulate [3H]strychnine binding. Whereas low concentrations (10-200 mM) of all these anions enhanced [3H]strychnine binding, higher concentrations (0.2-3 M) of thiocyanate, perchlorate, and iodide produced a robust inhibition of radioligand binding, and a more modest inhibition was observed with the same concentrations of nitrate and bromide. The presence of one binding site for anions at glycine-gated chloride channels can account for either the activation or the inhibition phase, but not both. However, these biphasic effects can be explained by the presence of two binding sites for anions at these channels. Two models with two anion binding sites were considered, the first assuming both allosteric activation and inhibition of the binding of the ligand, and the other explained by allosteric activation combined with competitive inhibition. Mathematical expressions for both models were formulated, and the equations obtained yielded satisfactory fitting to the results obtained with all anions tested in both concentration-response and saturation experiments. These equations also permitted the calculation of several parameters describing the interaction of the anions with these channels. The main difference in the behavior of these anions relates to the extent to which they produce activation of [3H]strychnine binding and to their cooperative interaction at the two putative anion binding sites. Thus, a strong negative cooperativity was observed for the simultaneous binding of two molecules of chloride, bromide, or nitrate, but not for the simultaneous binding of thiocyanate, perchlorate, or iodide. This latter property may be related to the conductance of these anions through glycine-gated chloride channels.

Allosteric Regulation↗

PubMedDate not supplied

Inflammatory atypia. An apparent link with subsequent cervical intraepithelial neoplasia explained by cytologic underreading.

A review of 5,752 cervical smears done on college students at a medium-sized midwestern university in a 24-month period showed 496 cytologic diagnoses of inflammatory atypia and 132 of dysplasia (cervical intraepithelial neoplasia: CIN). Further retrospective review of a nonselected cohort (178 cases) of the 496 patients with inflammatory atypia showed that their subsequent cytologic smears were more likely to show CIN than could be explained by chance alone. Only ten cases accounted for this difference, and a case-controlled blind review of the original cytologic smears of these ten patients resulted in the reclassification to CIN (mild dysplasia) of seven who had subsequently "progressed" from inflammatory atypia to dysplasia. Only one control smear was reclassified. In this population, underreading of a small number of cervical smears explained a strong statistical apparent correlation between inflammatory atypia and the subsequent development of CIN.

Adult↗

PubMed1995

Structural basis for explaining open-channel blockade of the NMDA receptor.

The open-channel structure of the N-methyl-D-aspartate (NMDA) receptor was investigated to explain apparently conflicting interpretations about ionic interactions within the pore. Patch-clamp techniques were applied to tissue-cultured rat hippocampal neurons from the CA1 region. A wide range of ammonium derivatives was studied to learn about the structure of the pore from permeability and open-channel blocking characteristics. We conclude that the pore is asymmetric, having high-affinity binding for organic cations from the outside and having a larger external entrance. The minimum cross-sectional area of the pore is rectangular (approximately 0.45 x 0.57 nm) and is the single-occupancy binding site(s) for small permeant cations. The narrow region extending from this minimum cross section is short, and its shape underlies the voltage dependencies of blocking cations. While occupying the blocking site, some open-channel blockers can interact with permeant cations at their binding site in the minimum cross section. A structurally based hypothesis is presented, explaining that the electrostatic interactions between the blocking site and permeant-ion site produce a high voltage dependence for blockade by some cations.

Animals↗

PubMed1995

[A theory explaining the relation between "egorrhea symptoms" and "symptoms of being influenced" more efficiently than the existing theories--from the viewpoint of "experiencial type" as opposed to symptomatological direction].

Fujinawa, A. and his co-researchers have categorized symptoms of ego disorder into two opposing symptoms; "egorrhea symptoms" having the direction of "Inside to Outside" in their symptomatological structure and "symptoms of being influenced" having the direction of "Outside to Inside". They have also proposed, for ideal cases, the following: (1) "Egorrhea symptoms" are schizophrenic ego disorders. (2) These two types of symptoms are independent and opposing series of ego disorder. (3) There exists a new entity named "egorrhea type of schizophrenia" which is mainly characterized by "egorrhea symptoms" and opposed to the common type of schizophrenia which is mainly characterized by "symptoms of being influenced". The author, however, indicated several faults in their propositions and revised them from their same viewpoint. The author then proposed, from the viewpint of intentionality, the following: (1) Any symptom exhibits one of two opposite direction of intentionality; one exhibits intentionality to an object ("object experiencial type") and the other exhibits intentionality to the subject itself ("subject experiencial type"). (2) Symptoms of each "experiencial type" are related to each other and therefore make the state be composed mainly of them. The author attempted to compare his theory with Fujinawa. A. and his co-researchers theory and the revised one. 58 hallucinatory-delusional cases (29 schizophrenic cases, 29 non-schizophrenic cases) were examined. Some results were as follows: (1) "Egorrhea symptoms" are not peculiar to schizophrenia. (2) A special type of auditory hallucination, which occurs when the patient sees others, is statistically related to "egorrhea symptoms". (3) The other common type of auditory hallucination, which occurs when the patient cannot see others, is statistically related to "symptoms of being influenced". The theory proposed by the author explains these results satisfactorily compared with the former two theories. That is, (1) is not against the theory, and (2) is considered to be caused by the relation between the special type of auditory hallucination and "egorrhea symptoms" having the same object experiencial type of symptoms, and (3) is considered to be caused by the relation between the common type of auditory hallucination and "symptom of being influenced" having the same subject experiencial type of symptoms. The author further deduced the developmental series of symptoms and states from his theory and examined them with the data from the above 58 cases and other cases reported by other researchers. As a result, much of the data was successfully explained by his theory.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1994

Interdependence of form and function in cognitive systems explains perception of printed words.

Perception is described within a complex systems framework that includes several constructs: resonance, attractors, subsymbols, and design principles. This framework was anticipated in J. J. Gibson's ecological approach (M. T. Turvey & C. Carello, 1981), but it is extended to cognitive phenomena by assuming experiential realism instead of ecological realism. The framework is applied in this article to explain phonologic mediation in reading and a complex array of published naming and lexical decision data. The full account requires only two design principles: covariant learning and self-consistency. Nonetheless, it organizes and explains a vast empirical literature on printed word perception.

Cognition↗

PubMed1994

Explaining information technology use with the usefulness scale: a comparison with user age.

Understanding and predicting the use of information technology is an important problem in healthcare management. The relationships among user characteristics and information technology have generally been weak. This paper describes a recently developed scale that measures perceived usefulness of information technology. Following this description, the scale is compared with user age in ability to explain information technology use. The results suggest perceived usefulness explains a significant proportion of the variance in use (r2 = .13, p < or = 0.0001), while age was not a significant predictor. Implications and suggestions for use of the usefulness scale are discussed.

Adult↗

PubMed1994

Can the increasing weight of Australians be explained by the decreasing prevalence of cigarette smoking?

In Australia there has been a recent increase in the body mass index (BMI) of the population and a decrease in smoking prevalence. Data from the three risk factor prevalence surveys conducted by the National Heart Foundation of Australia in 1980, 1983 and 1989 were analysed to determine if the increase in BMI could be explained by the decrease in smoking. For men in all age groups and for women aged 50 years or over, there were parallel increases in mean BMI for current smokers, ex-smokers and never smokers. For women under 50 years, the pattern of increasing BMI over time was less clear. Mean BMI increased over time within each five-year age group and in age 'cohorts' and the pattern was independent of smoking status. For men and for both groups of women there were similar changes in mean BMI over time for most categories of employment status, education and physical activity. Thus the increase in body weight cannot be explained by the decrease in smoking rate, or by the other factors investigated in this paper.

Adult↗

PubMed1993

Enhanced Na-K ATPase activity in the aorta may explain the unaltered contractile responses to KCl in diabetes mellitus.

Sodium-potassium ATPase activity and transmembrane calcium influx in the aortic smooth muscle from control and diabetic rats were assessed indirectly through the measurement of KCl relaxation and contractile responses to CaCl2 in attempts to explain the contractile responses to KCl following streptozotocin-induced diabetes mellitus. There were no significant changes in the maximum contractile responses of the aortas from 4 and 12 week diabetic rats to KCl even when significant increases in calcium influx were demonstratable. On the other hand, the diabetic aortas were significantly (P < 0.05) more sensitive to KCl-induced relaxations than the controls. This provides an indirect evidence for increased activity of the sodium-postassium ATPase enzyme in the aortas from streptozotocin diabetic rats. This may, atleast in part, explain the inability of KCl to produce greater than normal contractions of the aortas from diabetic rats.

Animals↗

PubMedDate not supplied

The difference between benign and malignant tumours explained with the 4-mutation paradigm for carcinogenesis.

In recent years a 4-mutation paradigm for carcinogenesis was developed for mutations in tumour suppressor genes. The major tenet of this paradigm is that transformation of a normal cell into a malignant cell is the result of an accumulation of a set of 4 specific cancer mutations. In this paper we show that this paradigm can explain the characteristic differences between benign and malignant tumours. We surmise that benign tumour cells are due to 2 or 3 specific cancer mutations, whereas malignant tumour cells contain 4 specific cancer mutations and 1-3 tumour progression mutations. The following characteristics, essential for differentiating benign and malignant tumours, are explained by our paradigm: (a) differentiation--anaplasia, (b) rate of growth, (c) encapsulation--invasion, (d) metastasis, and (e) the differences in size of benign epithelial and mesenchymal tumours and the relation between tumour size and malignancy.

Animals↗

PubMed1993

Response to mail surveys: effect of a request to explain refusal to participate. The ARIC Study Investigators.

As part of a mailed health survey, we investigated the effect on the response rate of a request to explain refusal to participate. Subjects (N = 1,240) were randomized either to receive or not to receive, with the first mailing, a letter requesting an explanation of their decision not to fill out the questionnaire, if they chose that option. There was a slightly higher cumulative response during most of the study from subjects who had been sent the request, but little difference between the two study groups in the ultimate response rate [80% from the intervention group vs 83% from the control group; response rate difference = -3%; 95% confidence limits (CL) = -7%, 1%]. Of 209 individuals who were sent the request and did not return the questionnaire, only 15 (7%) sent back an explanation. A request to explain a refusal to participate in a mail survey neither jeopardized the response rate nor enhanced it.

Cooperative Behavior↗

PubMed1996

Do severity measures explain differences in length of hospital stay? The case of hip fracture.

OBJECTIVE: To examine whether judgments about hospital length of stay (LOS) vary depending on the measure used to adjust for severity differences. DATA SOURCES/STUDY SETTING: Data on admissions to 80 hospitals nationwide in the 1992 MedisGroups Comparative Database. STUDY DESIGN: For each of 14 severity measures, LOS was regressed on patient age/sex, DRG, and severity score. Regressions were performed on trimmed and untrimmed data. R-squared was used to evaluate model performance. For each severity measure for each hospital, we calculated the expected LOS and the z-score, a measure of the deviation of observed from expected LOS. We ranked hospitals by z-scores. DATA EXTRACTION: All patients admitted for initial surgical repair of a hip fracture, defined by DRG, diagnosis, and procedure codes. PRINCIPAL FINDINGS: The 5,664 patients had a mean (s.d.) LOS of 11.9 (8.9) days. Cross-validated R-squared values from the multivariable regressions (trimmed data) ranged from 0.041 (Comorbidity Index) to 0.165 (APR-DRGs). Using untrimmed data, observed average LOS for hospitals ranged from 7.6 to 23.9 days. The 14 severity measures showed excellent agreement in ranking hospitals based on z-scores. No severity measure explained the differences between hospitals with the shortest and longest LOS. CONCLUSIONS: Hospitals differed widely in their mean LOS for hip fracture patients, and severity adjustment did little to explain these differences.

Aged↗

PubMed1996

Do differences in the prevalence of risk factors explain the higher mortality from sudden infant death syndrome in New Zealand compared with the UK?

AIMS: To compare the prevalence of risk factors for the sudden infant death syndrome (SIDS) in New Zealand (SIDS mortality 3.53/1000) with that in the South West Thames (SWT) region of the United Kingdom (SIDS mortality 1.36/1000). METHODS: The methodology of the study was essentially identical in New Zealand and SWT. The subjects in both countries were randomly selected from all births in the study regions. The subjects were randomly allocated an age at which to be interviewed using the same questionnaire in the two study areas. Obstetric records were also examined. Eighteen hundred subjects were selected in New Zealand and 700 subjects in SWT. RESULTS: Younger and unmarried mothers were slightly more common in New Zealand than in SWT. The prevalence of maternal smoking, prone sleeping position and infants' sharing of beds with another person were all higher in New Zealand than SWT, thus increasing the risk of SIDS (maternal smoking in pregnancy: 31.0% vs 23.8% respectively, chi 2 = 11.6, p = 0.001; prone sleeping position: 32.9% vs 25.9%, chi 2 = 18.9, p < 0.001; bed sharing: 10.5% vs 6.8%, chi 2 = 6.0, p = 0.14). However, New Zealand infants were breast fed more frequently and for longer than infants in SWT, which would tend to reduce the risk of SIDS in the New Zealand population. In combination the differences in the prevalences of these four risk factors explain only 20% of the excess risk of SIDS in New Zealand. CONCLUSIONS: The high SIDS mortality rate in New Zealand is not simply explained by a high prevalence of known and modifiable risk factors for SIDS.

Breast Feeding↗

PubMed1997

Unconventional structure of tRNA(Lys)SUU anticodon explains tRNA's role in bacterial and mammalian ribosomal frameshifting and primer selection by HIV-1.

Transfer RNA(Lys)SUU, with a 5-modified-2-thiouridine at wobble position 34, facilitates -1 frameshifts for correct translation of the Escherichia coli DNA polymerase gamma subunit and retroviral polymerases. Peptidyl-tRNA(Lys)SUU prematurely terminates translation more often than other tRNAs. In order to determine if the anticodon structures of bacterial and mammalian tRNA(Lys)SUU species explain these observations, oligonucleotides corresponding to the anticodon regions of mammalian and E. coli tRNA(Lys)SUU were synthesized and their physicochemical properties compared with that of E. coli tRNA(Glu)SUC. The anticodon region of tRNA(Lys)SUU was stabilized by an unusual interaction between the side chains of the 5-modified-s(2)U34 and N-6-threonylcarbamoyl-adenosine-37 (t(6)A37), a combination of modified nucleosides unique to tRNA(Lys)SUU species. This first observation of modified nucleoside side-chain interactions is analogous to the interactions of amino acid side chains in proteins. The tRNA(Lys)SUU anticodon structure was determined from NMR restraints on model oligonucleotides. With only two of three anticodon bases available for codon pairing, this unconventional anticodon structure is a reasonable explanation for the bacterial and mammalian tRNA(Lys)SUU tendency to frameshift. A two-out-of-three reading of coding triplets also explains the increased rate at which peptidyl-tRNA(Lys)SUU prematurely terminates translation. In addition, modified nucleoside interaction distorts the anticodon loop. The distorted loop is a possible structural determinant for the preferential selection of tRNA(Lys3)SUU as primer of HIV-1 reverse transcriptase in vivo.

Anticodon↗

PubMed1997

[To what degree can patient satisfaction be explained? An analysis of a retrospective study].

A retrospective survey comprising 1198 randomly chosen former surgical patients was carried out on average ten months after treatment. The goal of the research project was to investigate the associations between global satisfaction with treatment and issues that might influence how the treatment was experienced. There were no significant differences between the 610 responders and the sample of 1198 patients with respect to age, sex, length of treatment and diagnosis. The following five variables explained together 36.2% of the variance in global treatment satisfaction: Subjective health at time of investigation, the personality dimension conscientiousness, the "degree of severity of the illness", "contact with doctors and nurses" and "conveyed information and supervision". "Contact with doctors and nurses" alone explained 25.1% of the variance.

Female↗

PubMed1997

Low-dose radiation sensitivity and induced radioresistance to cell killing in HT-29 cells is distinct from the "adaptive response" and cannot be explained by a subpopulation of sensitive cells.

Several reports using two different improved assays of clonogenicity have indicated the presence of a hypersensitive region in the radiation survival response at low doses, followed by an increase in radioresistance, in many mammalian cell lines. Mathematical modeling of these responses has suggested that it is unlikely that this effect can be explained by the presence of a small subpopulation of sensitive cells; however, this possibility cannot be excluded solely on the basis of those results. A second explanation has been offered which hypothesizes that a radiation-induced mechanism causes an increase in cellular radioresistance. This proposal has led to speculation that the substructure observed at low doses in these cell lines is related to the adaptive response, which hypothesizes the induction of a repair mechanism after a small priming dose of radiation which can protect cells against a larger second dose given several hours later. We have investigated these proposals with a study of priming doses using human tumor HT-29 cells, which we have previously shown to exhibit low-dose hyper-radiosensitivity. Our results provide significant evidence that this effect cannot be explained by a subpopulation of sensitive cells. However, the results also suggest that the radiation-induced increase in radioresistance observed in this cell line is distinct from the adaptive response.

Adenocarcinoma↗

PubMed1998

Physiological red blood cell kinetic model to explain the apparent discrepancy between adenosine breakdown inhibition and nucleoside transporter occupancy of draflazine.

A physiological red blood cell (RBC) kinetic model is proposed for the adenosine (ADO) transport into erythrocytes and its subsequent intracellular deamination into inactive inosine (INO) and further breakdown into hypoxanthine (HYPO). The model and its parameters were based on previous studies investigating the kinetics of the biochemical mechanism of uptake and metabolism of ADO in human erythrocytes. Application of the model for simulations of the breakdown of ADO in a RBC suspension revealed that the predicted adenosine breakdown inhibition (ABI) of draflazine corresponded well with the ABI measured ex vivo. The model definitely explained the apparent discrepancy between the ex vivo measured ABI and the nucleoside transporter occupancy of draflazine. Intracellular deamination of ADO rather than its transport by the nucleoside transporter is the rate-limiting step in the overall catabolism of ADO. Consequently, at least 90% occupancy of the transporter by draflazine is required to inhibit adenosine breakdown ex vivo substantially. Simulations on basis of the validated model were performed to evaluate the ABI for different experimental conditions and to mimic the clinical situation. The latter may be very helpful for the design of optimal dosing schemes of draflazine. It was demonstrated that the short half-life of released ADO was prolonged substantially in a dose-related manner after a continuous infusion of draflazine. Finally, the previously found different sigmoidal Emax relationships between the measured ABI and the concentrations of draflazine in plasma and whole blood could be explained by the ADO transport and breakdown RBC kinetic model and the capacity-limited specific RBC binding characteristics of draflazine.

Adenosine↗

PubMed1998

A developmental hypothesis to explain the multicentricity of breast cancer.

In this article the author proposes that the multicentricity of breast cancer might be explained by a developmental hypothesis. Genetic alterations ("hits") occurring in epithelial stem cells during the development of the breast may be transmitted to populations of daughter cells during growth. As a result, areas of the breast may be predisposed to malignant transformation with the occurrence of further genetic hits. Areas with the same predisposition should be anatomically connected, and earlier hits during breast development should result in larger areas of predisposition. The multicentricity of breast cancer would be explained if multiple lesions--monoclonal for the predisposing genetic hit and polyclonal for subsequent hits--developed within a predisposed area. Multiple lesions arising from the spread of disease by extension would be expected to share many genetic hits. The author discusses the implications that further evidence supporting the developmental hypothesis would have for the prevention and treatment of breast cancer.

Breast↗

PubMed1999

Measurement error does not explain the persistence of a body mass index association with endometrial cancer after adjustment for endogenous hormones.

Identified risk factors for endometrial cancer are accepted as operating through estrogen exposure. In a recent analysis, the effect of risk factors such as body mass index (BMI) was not explained by circulating estrogen concentrations. In the present analysis, we correct for measurement error associated with obtaining only one blood sample per subject. Applying regression calibration ideas, we found that error correction of log estrone had little impact on estimates of the BMI effect, suggesting that hormone measurement error does not account for the residual importance of BMI. The biologic mechanism for the increased risk associated with BMI remains to be explained.

Bias↗