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Aneuploidy theory explains tumor formation, the absence of immune surveillance, and the failure of chemotherapy.

The autocatalyzed progression of aneuploidy accounts for all cancer-specific phenotypes, the Hayflick limit of cultured cells, carcinogen-induced tumors in mice, the age distribution of human cancer, and multidrug-resistance. Here aneuploidy theory addresses tumor formation. The logistic equation, phi(n)(+1) = rphi(n) (1 - phi(n)), models the autocatalyzed progression of aneuploidy in vivo and in vitro. The variable phi(n)(+1) is the average aneuploid fraction of a population of cells at the n+1 cell division and is determined by the value at the nth cell division. The value r is the growth control parameter. The logistic equation was used to compute the probability distribution for values of phi after numerous divisions of aneuploid cells. The autocatalyzed progression of aneuploidy follows the laws of deterministic chaos, which means that certain values of phi are more probable than others. The probability map of the logistic equation shows that: 1) an aneuploid fraction of at least 0.30 is necessary to sustain a population of cancer cells; and 2) the most likely aneuploid fraction after many population doublings is 0.70, which is equivalent to a DNA(index)=1.7, the point of maximum disorder of the genome that still sustains life. Aneuploidy theory also explains the lack of immune surveillance and the failure of chemotherapy.

Aneuploidy↗

Response disinhibition may be explained as an extinction deficit in an animal model of attention-deficit/hyperactivity disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is a disorder affecting between 2 and 12% of grade-school children disturbing social, academic, and occupational functioning. Problems related to social adjustment and functioning and/or psychiatric problems will exist in 50-70% of adolescents and young adults diagnosed with ADHD as children. It has been suggested that altered reinforcement and extinction processes may cause the symptoms of ADHD. The present study investigated extinction processes in spontaneously hypertensive rats (SHR), possibly the best-validated animal model of ADHD. Extinction was tested after either a variable interval (VI) or a fixed interval (FI) schedule of reinforcement with and without the presence of a conditioned reinforcer (light in the water cubicle). The results indicate a slower extinction process in the SHR compared to the normal controls, especially during the initial transition from scheduled reinforcement to extinction. Also, more responses were retained in the SHR during the later part of extinction. The extinction deficit in the SHR may be linked to reinforcer unpredictability and the presence of conditioned reinforcers, and may explain response disinhibition seen in children with ADHD.

Analysis of Variance↗

Psychrophilic enzymes: revisiting the thermodynamic parameters of activation may explain local flexibility.

Basic theoretical and practical aspects of activation parameters are briefly reviewed in the context of cold-adaptation. In order to reduce the error impact inherent to the transition state theory on the absolute values of the free energy (DeltaG(#)), enthalpy (DeltaH(#)) and entropy (DeltaS(#)) of activation, it is proposed to compare the variation of these parameters between psychrophilic and mesophilic enzymes, namely Delta(DeltaG(#))(p-m), Delta(DeltaH(#))(p-m) and Delta(DeltaS(#))(p-m). Calculation of these parameters from the available literature shows that the main adaptation of psychrophilic enzymes lies in a significant decrease of DeltaH(#), therefore leading to a higher k(cat), especially at low temperatures. Moreover, in all cases including cold-blooded animals, DeltaS(#) exerts an opposite and negative effect on the gain in k(cat). It is argued that the magnitude of this counter-effect of DeltaS(#) can be reduced by keeping some stable domains, while increasing the flexibility of the structures required to improve catalysis at low temperature, as demonstrated in several cold-active enzymes. This enthalpic-entropic balance provides a new approach explaining the two types of conformational stability detected by recent microcalorimetric experiments on psychrophilic enzymes.

Acclimatization↗

Dissecting affinity maturation: a model explaining selection of antibody-forming cells and memory B cells in the germinal centre.

Until recently, the relationship between apoptosis, selection in the germinal centre (GC) and production of high-affinity antibody-forming cells (AFCs) and memory B cells has been unclear. Here, Tarlinton and Smith present a model that accounts for the switch in GC production from high-affinity AFCs to memory B cells, and explain how Bcl-2, an inhibitor of apoptosis, can influence memory cells but not bone marrow AFCs.

Animals↗

Value measurement in cost-utility analysis: explaining the discrepancy between rating scale and person trade-off elicitations.

Previous studies have shown a discrepancy between common utility elicitation methods, such as rating scale (RS) elicitations, and person trade-off (PTO) elicitations. This discrepancy has generally been felt to be due to the fact that RS elicitations ask people to compare conditions to each other in terms of numbers on a visual rating scale, while PTO elicitations ask people to think in terms of numbers of people needing to be treated. However, there are three other cognitive differences between PTO and RS elicitations that might contribute to the discrepancy: In PTO elicitations, as opposed to RS elicitations: (1) people are asked to think about how conditions affect people other than themselves; (2) people are asked to think about the benefit of treating conditions; and (3) people are asked to chose who to treat among patients with different conditions. In this study, we attempt to determine whether any of three cognitive differences contribute to the discrepancy between RS and PTO utility elicitations. We randomized prospective jurors to receive one of several survey versions in which we manipulated the RS and PTO elicitations to reduce the differences between them, while preserving their underlying structure. In the RS-self survey, we asked subjects to rate a health condition on a scale from 0 to 100 as if they had the condition. In the RS-other survey, we asked people to rate the health condition as if someone else had it. In the RS-cure survey, we asked subjects to rate the benefits of curing someone else of the health condition. In the PTO-comparison survey, we asked people to determine equivalent numbers of people needing to be cured of two conditions in order to produce equal benefits. In the PTO-choice survey, we presented people with a budget constraint and asked them to determine equivalent numbers of people needing to be cured of two conditions to help decide which group should be treated within the budget constraint. Two hundred and twenty two subjects completed surveys. Median utilities for health conditions were higher in the two PTO elicitations than in the three RS elicitations. There were no differences in utilities across the two PTO surveys, nor across the three RS surveys. In addition, the PTO elicitations allowed people to make finer distinctions among non-life threatening conditions than did the RS elicitations. The discrepancy between RS and PTO elicitations cannot be explained by shifting subjects attentions from themselves to others, nor from conditions to the benefit of treating conditions. Instead, the discrepancy occurs because of the general format of RS and PTO elicitations.

Adult↗

Does the evolutionary history of aminoacyl-tRNA synthetases explain the loss of mitochondrial tRNA genes?

The importation of cytosolic tRNAs is required for protein synthesis in the mitochondria of the wide variety of eukaryotes that lack a complete set of mitochondrial tRNA genes. The evolutionary history of the process, however, is still enigmatic. The analysis presented here suggests that the loss of distinct mitochondrial tRNA genes was not random and that it might be explained by the differential capabilities of mitochondrial aminoacyl-tRNA synthetases to charge imported eukaryotic-type tRNAs with amino acid.

Amino Acyl-tRNA Synthetases↗

Computing measures of explained variation for logistic regression models.

The proportion of explained variation (R2) is frequently used in the general linear model but in logistic regression no standard definition of R2 exists. We present a SAS macro which calculates two R2-measures based on Pearson and on deviance residuals for logistic regression. Also, adjusted versions for both measures are given, which should prevent the inflation of R2 in small samples.

Computer Simulation↗

Putative leech dopamine1-like receptor molecular characterization: sequence homologies between dopamine and serotonin leech CNS receptors explain pharmacological cross-reactivities.

The biochemical characterization of a serotonin (5HT) receptor and the cloning of a dopamine (DA) receptor in the central nervous system (CNS) of the leech, Theromyzon tessulatum, is presented. Additionally, DA and 5HT binding sites were examined in the CNS by Scatchard analysis which showed a single, relatively high-affinity binding site with a Kd 1.1 nM and a Bmax 126+18 fmol/mg protein for [3H]DA and a Kd 2.1 nM and a Bmax 225 fmol/mg protein for [3H]5HT. The first 88 amino acids of the 5HT receptor, isolated by a 5HT-affinity column followed by anion exchange chromatography and C3 reverse-phase HPLC exhibited a 43% sequence homology with Lymnaea stagnalis 5HT-receptor. The isolated DA receptor revealed a single protein of 45 kDa with an anti-D1-R in Western blot. The first 80 N-terminal amino acid residues and a trypsin digested fragment of 31 residues were obtained, and based on these sequencing data, a molecular biology strategy using reverse transcriptase-polymerase chain reaction, was developed. An amplified 1-kb segment was obtained. The complete deduced sequence of 416 amino acid residues exhibited about 30.6% sequence homology with the vertebrate D1 receptor family. Moreover, we further demonstrate that the leech 5HT and DA receptors also exhibit 30% sequence identity with each other, explaining their pharmacological cross-reactivity. Finally, anti-D1-R immunocytochemistry revealed positive structures in the peripheral and central nervous system, e.g., neurons, sensory fibers and immune cells. This is the first biochemical and molecular characterization of a DA receptor in leeches.

Amino Acid Sequence↗

Under utilisation of evidence-based treatment partially explains for the unfavourable prognosis in diabetic patients with acute myocardial infarction.

AIMS: The prognosis after an acute myocardial infarction is worse for patients with diabetes mellitus than for those without. We investigated whether differences in the use of evidence-based treatment may contribute to the differences in 1-year survival in a large cohort of consecutive acute myocardial infarction patients with and without diabetes mellitus. METHODS: We included patients below the age of 80 years from the Register of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA), which included all patients admitted to coronary care units at 58 hospitals during 1995-1998. In all 5193 patients had the combination of acute myocardial infarction and diabetes mellitus while 20440 had myocardial infarction but no diabetes diagnosed. Multivariate logistical regression analyses were performed to evaluate the influence of diabetes mellitus on the use of evidence-based treatment and its association with survival during the first year after the index hospitalisation. RESULTS: The prevalence of diabetes mellitus was 20.3% (males 18.5%; females 24.4%). The 1-year mortality was substantially higher among diabetic patients compared with those without diabetes mellitus (13.0 vs. 22.3% for males and 14.4 vs. 26.1% for female patients, respectively) with an odds ratio (OR) (95% confidence interval (CI)) in three different age groups: <65 years 2.65 (2.23-3.16); 65-74 years 1.81 (1.61-2.04) and >75 years 1.71 (1.50-1.93). During hospital stay patients with diabetes mellitus received significantly less treatment with heparins (37 vs. 43%; p<0.001), intravenous beta blockade (29 vs. 33%; p<0.001), thrombolysis (31 vs. 41%; p<0.001) and acute revascularisation (4 vs. 5%; p<0.003). A similar pattern was apparent at hospital discharge. After multiple adjustments for dissimilarities in baseline characteristics between the two groups, patients with diabetes were significantly less likely to be treated with reperfusion therapy (OR 0.83), heparins (OR 0.88), statins (OR 0.88) or to be revascularised within 14 days from hospital discharge procedures (OR 0.86) while the use of ACE-inhibitors was more prevalent among diabetic patients compared to non-diabetic patients (OR 1.45). The mortality reducing effects of evidence-based treatment like reperfusion, heparins, aspirin, beta-blockers, lipid-lowering treatment and revascularisation were, in multivariate analyses, of equal benefit in diabetic and non-diabetic patients. INTERPRETATION: Diabetes mellitus continues to be a major independent predictor of 1-year mortality following an acute myocardial infarction, especially in younger age groups. This may partly be explained by less use of evidence-based treatment although treatment benefits are similar in both patients with and without diabetes mellitus. Thus a more extensive use of established treatment has a potential to improve the poor prognosis among patients with acute myocardial infarction and diabetes mellitus.

Adult↗

Could dual G-protein coupling explain [D-Met2]FMRFamide's mixed action in vivo?

In vitro studies have demonstrated that FMRFamide-related peptide receptors can be coupled to different G-proteins, mediating opposite stimulatory and inhibitory effects. The present study tested whether this duality might extend to effects in vivo. Antinociception in mice of ICV [D-Met2]FMRFamide, which produced agonist [ED50 = 36.3 micrograms (61.6 nmol)] and antagonist [ID50 = 0.72 microgram (1.22 nmol)] actions, was attenuated by 24-h pretreatment with ICV pertussis toxin (ID50 = 0.55 microgram) or cholera toxin (ID50 = 0.09 microgram), suggesting that [D-Met2]FMRFamide in vivo effects might also be explained by dual Gi/Gs, coupling.

Amino Acid Sequence↗

Oligoclonal expansions in the CD8(+)CD28(-) T cells largely explain the shorter telomeres detected in this subset: analysis by flow FISH.

We have previously reported that CD8(+)CD28(-) T cells have relatively shorter telomeres compared with CD8(+)CD28(+) T cells. Oligoclonal expansion is a common feature of CD8(+) T cells in human peripheral blood, and these expansions predominantly occur in the CD57(+)/CD28(-) population. We studied the telomere length in subsets of CD8(+) T cells using quantitative fluorescence in situ hybridization and flow cytometry (flow FISH). Our results confirm that CD8(+)CD28(-) T cells have shorter telomeres as compared with their CD28(+) counterpart cells. In addition, the oligoclonally expanded cells within the CD8(+)CD28(-) T cell subset generally have even shorter telomeres than the CD28(-) subset as a whole. We conclude that the presence of clonal expansions in the CD8(+)CD28(-) T cell population largely explain the shorter telomeres in this subset. These clonally expanded CD8(+)CD28(-) T cells generally have characteristics of terminally differentiated effector cells. Nevertheless, there is considerable individual variation in the degree of telomere shortening in these cells, which may reflect host genetic factors as well as the type and timing of the antigenic exposure.

CD28 Antigens↗

Using an interactive framework of society and lifecourse to explain self-rated health in early adulthood.

This paper presents an integrated model of the determinants of adult health combining lifecourse factors and contemporary circumstances. Using the 1958 British Birth Cohort, it operationalises lifecourse influences in terms of factors from birth to age 33, which might act through latent, pathway, or cumulative effects. Contemporary circumstances are represented by variables at different levels of social aggregation: macro (socio-economic circumstances); meso (involvement in civil society functions); micro (personal social support); and intersecting (job insecurity and life control). Multiple regression models were fitted, using self-rated health at age 33 as the health outcome. To allow for temporal ordering of events, early life factors were entered first in the final model, followed by later childhood factors and, finally current factors. Self-rated health was predicted by variables representing both early and later stage of the lifecourse and also contemporary societal-level factors. The effects of childhood factors were not removed by including contemporary factors, and conversely, contemporary factors contributed to the prediction of self-rated health over and above lifecourse factors. The factors were not collinear; supporting the notion that each dimension was distinct from the others. Although the model accounted for only 9% of the variance in self-rated health, the general conclusion is that both lifecourse and contemporary circumstances should be considered together in explaining adult health.

Adolescent↗

What explains rural-urban differentials in child mortality in Brazil?

This paper presents an analysis of differentials in child survival by rural-urban place of residence in Brazil and examines the hypothesis that observed mortality differentials by place of residence are merely manifestations of underlying differences in socioeconomic status and demographic and reproductive behavior. The child mortality data come from the 1986 Demographic and Health Survey of Brazil and supplementary community-level variables are obtained from a database assembled by the Brazilian federal statistical agency. Child mortality rates are substantially and significantly lower in urban areas of Brazil. Our results suggest, however, that the urban advantage does not simply reflect underlying differences in socioeconomic and behavioral characteristics at the individual and household levels; rather, community variables appear to play an independent and important role. We also find that the effects of community characteristics on child survival are moderated by household socioeconomic factors, especially maternal education. Differences in socioeconomic characteristics are therefore important in explaining rural-urban child mortality differentials, but not in the way hypothesized by previous researchers.

Adolescent↗

Explaining disablement in modern times: hand-injured workers' accounts of their injuries in Hong Kong.

In this paper, an attempt is made to explore how people respond to injuries at work among a group of hand-injured workers in the context of contemporary Hong Kong society. Qualitative research methods were adopted. A "focused interview" by means of open-ended questions was employed to investigate those workers who have suffered from work-related injury for over 10 years. Concerning the perceived cause of the injury, the industrial production process such as machine defects, piecework, limited working experience, and lack of supervision triggered the onset of the injuries which resulted in permanent disability. At the same time, respondents tellingly explained their injury in terms of magical-religious forces such as fate and luck. This kind of understanding is embraced in cultural beliefs that are commonly found among Chinese. Such understandings appear fatalistic but allow the individual to actively cope with such misfortune. The emphasis on harmony and stability among Chinese also affected what action they took against the employer for negligence. It was shown that in general many respondents were bound by kuan-hsi (personal relationship) and tended to preserve the harmony between themselves and their employer. In modern societies like Hong Kong, traditional values and modern practices are complementary to each other in coping with life stresses such as disablement. Modernity does not provide a solid means for people to have more control over their lives. Many people still stick to their habituated lifestyle as a guiding light in day-to-day matters. Concerning risk assessment in relation to work safety, workers' value systems and practices on the shopfloor should be taken into consideration.

Accidents, Occupational↗

Neuroprotective effect of mild hypothermia cannot be explained in terms of a reduction of glutamate release during ischemia.

An exogenous glutamate injection into the hypothermic hippocampal CA1 during 5-min ischemia produced the same extent of extracellular glutamate levels as observed in the normothermic CA1 during 5-min ischemia; however, neuronal death was not induced in the hypothermic CA1. Glutamate is released excessively into the extracellular space during ischemia, and is thought to induce brain injury by its neurotoxicity. It has been reported that the massive glutamate release is reduced by mild hypothermia, and it has been proposed that the reduction of ischemia-induced glutamate release exerts the neuroprotective effect on postischemic neuronal death. In the present study, to determine whether the neuroprotective effect of mild hypothermia on postischemic hippocampal CA1 neuronal death is due to the reduction of ischemia-induced glutamate release, gerbils were subjected to 5-min ischemia under hypothermic condition at 31 degrees C and were simultaneously injected exogenously with L-glutamate, so that the hypothermic CA1 around a microdialysis probe was exposed to the same extracellular glutamate levels as seen during normothermic ischemia, and the histological outcome was examined. An injection with 1 mM L-glutamate into the hypothermic CA1 during 5-min ischemia produced a similar extent of increased glutamate (17-fold increase) to that observed in the normothermic CA1 during 5-min ischemia (16-fold increase). However, neuronal death was not induced in the hypothermic CA1. This result indicates that the neuroprotective effect of mild hypothermia cannot be explained in terms of a reduction of glutamate release during ischemia.

Animals↗

Mycobacterial infections: are the observed enigmas and paradoxes explained by immunosuppression and immunodeficiency?

The enigmas and paradoxes observed in tuberculous patients, in Bacille Calmette-Guérin-vaccinated people and in Bacille Calmette-Guérin-treated cancer patients have been examined, in an attempt to explain them through the mechanisms of immunodeficiency and immunosuppression. A dual effect is postulated: an immunosuppression induced by the infecting mycobacteria that adds to a pre-existing or emerging state of immunodeficiency of the infected individual. The immunological cellular and humoral anergies observed at the beginning of a tuberculous therapy are usually lifted after the first two weeks of treatment. This restoration of immune responsiveness may be attributed to the destruction or to the growth inhibition of immunosuppressive mycobacteria. The observation that drugs cytocidal in vitro do not always sterilize the patients under treatment whereas bacteriostatic drugs do, may find an explanation in the dual immunosuppression induced by cytocidal drugs and mycobacteria. The fact that Bacille Calmette-Guérin applied as an immunotherapy to residual cancer has either a favorable or an unfavorable action may be due to the immunosuppressive activity attached to some Bacille Calmette-Guérin strains and to some cancers. The variable protective activity of Bacille Calmette-Guérin vaccines may be due to the immunological status of the vaccinated people and the compositional differences between strains. The protective activity of subunit vaccines in experimental models can be attributed to the elimination of immunosuppressive factors present in whole killed mycobacteria.

Animals↗

Signal transduction: specificity of growth factors explained by parallel distributed processing.

Mutations in proteins of receptor tyrosine kinase signalling pathways might change signalling properties and contribute to the progression towards neoplasia. Ligands for these receptors (growth factors) which elicit the same signal transducing cascades can trigger different developmental pathways in identical cells. For example, PC12 cells differentiate after treatment with NGF, but proliferate after stimulation with EGF. However, their receptors seem to utilize the same signal transducing components. Thus, intracellular signalling specificity remains an enigma. Here, we apply a network model, in which each protein species participating in signal transduction is represented by an element. The elements are connected to each other according to the signalling pathways resembling parallel distributed processes. A general property of these systems is applied to the problem of signal specificity: slight differences in the input may result in completely different outputs, which negates the necessity of specific proteins to each pathway. This line of thinking might explain the specificity of hormones, although they use the same signal transduction network.

Animals↗

Loss of intraventricular fluid melatonin can explain the neuropathology of Alzheimer's disease.

Loss of intraventricular fluid melatonin explains why Alzheimer's disease neuropathology has a laminar, regional and neural-system-specific pattern, which includes the entorhinal cortex, CA1 of the hippocampus, the dorsal raphe nucleus and the locus ceruleus. High metabolic activity may be part of the neuronal vulnerability. Without elevated levels of ventricular fluid melatonin, the hydroxyl radical damages the mitochondria of the most active neurons, causing apoptosis, with resultant failure of the memory system. General brain atrophy follows in the absence of new memory formation.

Alzheimer Disease↗