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PubMed2003

A defect in hematopoietic stem cell migration explains the nonrandom X-chromosome inactivation in carriers of Wiskott-Aldrich syndrome.

A defect in cell trafficking and chemotaxis plays an important role in the immune deficiency observed in Wiskott-Aldrich syndrome (WAS). In this report, we show that marrow cells from WAS protein (WASP)-deficient mice also have a defect in chemotaxis. Serial transplantation and competitive reconstitution experiments demonstrated that marrow cells, including hematopoietic progenitors and stem cells (HSCs), have decreased homing capacities that were associated with a defect in adhesion to collagen. During development, HSCs migrate from the liver to the marrow and the spleen, prompting us to ask if a defect in HSC homing during development may explain the skewed X-chromosome inactivation in WAS carriers. Preliminary evidence has shown that, in contrast to marrow progenitor cells, fetal liver progenitor cells from heterozygous females had a random X-chromosome inactivation. When fetal liver cells from WASP-carrier females were injected into irradiated recipients, a nonrandom inactivation of the X-chromosome was found at the level of hematopoietic progenitors and HSCs responsible for the short- and long-term hematopoietic reconstitution. Therefore, the mechanism of the skewed X-chromosomal inactivation observed in WAS carriers may be related to a migration defect of WASP-deficient HSCs.

Actins↗

PubMed2002

The molecular genetics of the human I locus and molecular background explain the partial association of the adult i phenotype with congenital cataracts.

The human i and I antigens are characterized as linear and branched repeats of N-acetyllactosamine, respectively. Conversion of the i to the I structure requires I-branching beta-1,6-N-acetylglucosaminyltransferase activity. It has been noted that the null phenotype of I, the adult i phenotype, is associated with congenital cataracts in Asians. Previously, the identification of molecular changes in the IGnT gene, associated with the adult i phenotype, has been reported. In the present study, we demonstrate that the human I locus expresses 3 IGnT forms, designated IGnTA, IGnTB, and IGnTC, which have different exon 1, but identical exons 2 and 3, coding regions. The molecular genetics proposed for the I locus offer a new perspective on the formation and expression of the I antigen in different cells and provide insight into the questions derived from investigation of the adult i phenotype. Molecular genetic analyses of the I loci of the 2 adult i groups, with and without congenital cataracts, were performed, and enzyme function assays and expression patterns for the 3 IGnT transcripts in reticulocytes and lens-epithelium cells were analyzed. The results suggest a molecular genetic mechanism that may explain the partial association of the adult i phenotype with congenital cataracts and indicate that a defect in the I locus may lead directly to the development of congenital cataracts. The results also suggest that the human blood group I gene should be reassigned to the IGnTC form, not the IGnTB form, as described previously.

Adult↗

PubMed2005

A uniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases.

Most primary central nervous system lymphomas (PCNSLs) in immunocompetent patients are diffuse large B-cell lymphomas (DLBCLs), characterized by poor prognosis, compared with systemic forms. A germinal center B-cell-like (GCB) origin of PCNSL was hypothesized on the basis of BCL-6 expression and ongoing mutational activity. Our goal herein was to determine, for 83 PCNSLs, the percentages of GCB and activated B-cell-like (ABC) phenotypes and their prognostic significance. CD10, BCL-6, MUM1, BCL-2, and CD138 antigens were immunohistochemically labeled on paraffin-embedded sections; the first 4 were positive in 2.4%, 55.5%, 92.6%, and 55.5% of the tumors, respectively. None of the 56 tested samples expressed CD138. Among the 82 patients with complete information, 79 (96.3%) were classified as ABC; 42 (51.2%) expressed BCL-6+ MUM1+, suggesting an "activated GCB" origin; 33 (40.2%) were exclusively MUM1+, and the remaining 4 (4.9%) were negative for all markers tested. These findings provide new insights into interpreting the poor PCNSL prognostic, which may, in part, be due to biologic aggressiveness associated with its activated B-cell-like pattern. We postulate assigning PCNSL a histogenetic "time-slot," overlapping late GC and early post-GC, that could explain the predominant ABC phenotype observed.

Adult↗

PubMed2001

Mimicry between neurokinin-1 and fibronectin may explain the transport and stability of increased substance P immunoreactivity in patients with bone marrow fibrosis.

Bone marrow (BM) fibrosis may occur in myeloproliferative diseases, lymphoma, myelodysplastic syndrome, myeloma, and infectious diseases. In this study, the role of substance P (SP), a peptide with pleiotropic functions, was examined. Some of its functions-angiogenesis, fibroblast proliferation, and stimulation of BM progenitors-are amenable to inducing BM fibrosis. Indeed, a significant increase was found in SP-immunoreactivity (SP-IR) in the sera of patients with BM fibrosis (n = 44) compared with the sera of patients with hematologic disorders and no histologic evidence of fibrosis (n = 46) (140 +/-12 vs 18 +/-3; P <.01). Immunoprecipitation of sera SP indicated that this peptide exists in the form of a complex with other molecule(s). It was, therefore, hypothesized that SP might be complexed with NK-1, its natural receptor, or with a molecule homologous to NK-1. To address this, 3 cDNA libraries were screened that were constructed from pooled BM stroma or mononuclear cells with an NK-1 cDNA probe. A partial clone (clone 1) was retrieved that was 97% homologous to the ED-A region of fibronectin (FN). Furthermore, sequence analyses indicated that clone 1 shared significant homology with exon 5 of NK-1. Immunoprecipitation and Western blot analysis indicated co-migration of SP and FN in 27 of 31 patients with BM fibrosis. Computer-assisted molecular modeling suggested that similar secondary structural features between FN and NK-1 and the relative electrostatic charge might explain a complex formed between FN (negative) and SP (positive). This study suggests that SP may be implicated in the pathophysiology of myelofibrosis, though its role would have to be substantiated in future research. (Blood. 2001;97:3025-3031)

Adult↗

PubMed2006

Low degree metabolites explain essential reactions and enhance modularity in biological networks.

BACKGROUND: Recently there has been a lot of interest in identifying modules at the level of genetic and metabolic networks of organisms, as well as in identifying single genes and reactions that are essential for the organism. A goal of computational and systems biology is to go beyond identification towards an explanation of specific modules and essential genes and reactions in terms of specific structural or evolutionary constraints. RESULTS: In the metabolic networks of Escherichia coli, Saccharomyces cerevisiae and Staphylococcus aureus, we identified metabolites with a low degree of connectivity, particularly those that are produced and/or consumed in just a single reaction. Using flux balance analysis (FBA) we also determined reactions essential for growth in these metabolic networks. We find that most reactions identified as essential in these networks turn out to be those involving the production or consumption of low degree metabolites. Applying graph theoretic methods to these metabolic networks, we identified connected clusters of these low degree metabolites. The genes involved in several operons in E. coli are correctly predicted as those of enzymes catalyzing the reactions of these clusters. Furthermore, we find that larger sized clusters are over-represented in the real network and are analogous to a 'network motif. Using FBA for the above mentioned three organisms we independently identified clusters of reactions whose fluxes are perfectly correlated. We find that the composition of the latter 'functional clusters' is also largely explained in terms of clusters of low degree metabolites in each of these organisms. CONCLUSION: Our findings mean that most metabolic reactions that are essential can be tagged by one or more low degree metabolites. Those reactions are essential because they are the only ways of producing or consuming their respective tagged metabolites. Furthermore, reactions whose fluxes are strongly correlated can be thought of as 'glued together' by these low degree metabolites. The methods developed here could be used in predicting essential reactions and metabolic modules in other organisms from the list of metabolic reactions.

Bacteria↗

PubMed2001

A model combining cell physiology and population genetics to explain Escherichia coli laboratory evolution.

BACKGROUND: Laboratory experiments under controlled conditions during thousands of generations are useful tools to assess the processes underlying bacterial evolution. As a result of these experiments, the way in which the traits change in time is obtained. Under these conditions, the bacteria E. coli shows a parallel increase in cell volume and fitness. RESULTS: To explain this pattern it is required to consider organismic and population contributions. For this purpose we incorporate relevant information concerning bacterial structure, composition and transformations in a minimal modular model. In the short time scale, the model reproduces the physiological responses of the traits to changes in nutrient concentration. The decay of unused catabolic functions, found experimentally, is introduced in the model using simple population genetics. The resulting curves representing the evolution of volume and fitness in time are in good agreement with those obtained experimentally. CONCLUSIONS: This study draws attention on physiology when studying evolution. Moreover, minimal modular models appear to be an adequate strategy to unite these barely related disciplines of biology.

Cell Cycle↗

PubMed2002

Birth and death of protein domains: a simple model of evolution explains power law behavior.

BACKGROUND: Power distributions appear in numerous biological, physical and other contexts, which appear to be fundamentally different. In biology, power laws have been claimed to describe the distributions of the connections of enzymes and metabolites in metabolic networks, the number of interactions partners of a given protein, the number of members in paralogous families, and other quantities. In network analysis, power laws imply evolution of the network with preferential attachment, i.e. a greater likelihood of nodes being added to pre-existing hubs. Exploration of different types of evolutionary models in an attempt to determine which of them lead to power law distributions has the potential of revealing non-trivial aspects of genome evolution. RESULTS: A simple model of evolution of the domain composition of proteomes was developed, with the following elementary processes: i) domain birth (duplication with divergence), ii) death (inactivation and/or deletion), and iii) innovation (emergence from non-coding or non-globular sequences or acquisition via horizontal gene transfer). This formalism can be described as a birth, death and innovation model (BDIM). The formulas for equilibrium frequencies of domain families of different size and the total number of families at equilibrium are derived for a general BDIM. All asymptotics of equilibrium frequencies of domain families possible for the given type of models are found and their appearance depending on model parameters is investigated. It is proved that the power law asymptotics appears if, and only if, the model is balanced, i.e. domain duplication and deletion rates are asymptotically equal up to the second order. It is further proved that any power asymptotic with the degree not equal to -1 can appear only if the hypothesis of independence of the duplication/deletion rates on the size of a domain family is rejected. Specific cases of BDIMs, namely simple, linear, polynomial and rational models, are considered in details and the distributions of the equilibrium frequencies of domain families of different size are determined for each case. We apply the BDIM formalism to the analysis of the domain family size distributions in prokaryotic and eukaryotic proteomes and show an excellent fit between these empirical data and a particular form of the model, the second-order balanced linear BDIM. Calculation of the parameters of these models suggests surprisingly high innovation rates, comparable to the total domain birth (duplication) and elimination rates, particularly for prokaryotic genomes. CONCLUSIONS: We show that a straightforward model of genome evolution, which does not explicitly include selection, is sufficient to explain the observed distributions of domain family sizes, in which power laws appear as asymptotic. However, for the model to be compatible with the data, there has to be a precise balance between domain birth, death and innovation rates, and this is likely to be maintained by selection. The developed approach is oriented at a mathematical description of evolution of domain composition of proteomes, but a simple reformulation could be applied to models of other evolving networks with preferential attachment.

Animals↗

PubMed2003

Sexual selection on land snail shell ornamentation: a hypothesis that may explain shell diversity.

BACKGROUND: Many groups of land snails show great interspecific diversity in shell ornamentation, which may include spines on the shell and flanges on the aperture. Such structures have been explained as camouflage or defence, but the possibility that they might be under sexual selection has not previously been explored. PRESENTATION OF THE HYPOTHESIS: The hypothesis that is presented consists of two parts. First, that shell ornamentation is the result of sexual selection. Second, that such sexual selection has caused the divergence in shell shape in different species. TESTING THE HYPOTHESIS: The first part of the hypothesis may be tested by searching for sexual dimorphism in shell ornamentation in gonochoristic snails, by searching for increased variance in shell ornamentation relative to other shell traits, and by mate choice experiments using individuals with experimentally enhanced ornamentation. The second part of the hypothesis may be tested by comparing sister groups and correlating shell diversity with degree of polygamy. IMPLICATIONS OF THE HYPOTHESIS: If the hypothesis were true, it would provide an explanation for the many cases of allopatric evolutionary radiation in snails, where shell diversity cannot be related to any niche differentiation or environmental differences.

Animals↗

PubMed2005

Identification of polymorphisms explaining a linkage signal: application to the GAW14 simulated data.

We applied three approaches for the identification of polymorphisms explaining the linkage evidence to the Genetic Analysis Workshop 14 simulated data: 1) the genotype-IBD sharing test (GIST); 2) an approach suggested by Horikawa and colleagues; and 3) the homozygote sharing test (HST). These tests were compared with a family-based association test. Two linked regions with highest nonparametric linkage scores were selected to apply these methods. In the first region, Horikawa's method identified the most SNPs within the region containing the disease susceptibility locus, while HST performed best in the second region. However, Horikawa's method also had the most type I errors. These methods show potential as additional tools to complement family-based association tests for the identification of disease susceptibility variants.

Chromosomes, Human, Pair 1↗

PubMed2004

Can mutations in ELA2, neutrophil elastase expression or differential cell toxicity explain sulphasalazine-induced agranulocytosis?

BACKGROUND: Drug-induced agranulocytosis, a severe side effect marked by a deficit or absolute lack of granulocytic white blood cells, is a rare side-effect of the anti-inflammatory drug sulphasalazine. Mutations in the human neutrophil elastase gene (ELA2), causing increased intracellular concentration of this serine protease, inhibits neutrophil differentiation in severe congenital neutropenia (SCN). Since the clinical symptoms of agranulocytosis and SCN are similar, we hypothesized that it may origin from a common genetic variation in ELA2 or that sulphasalazine may affect human neutrophil elastase activity and protein expression. METHODS: We screened for genetic differences in ELA2 in DNA from 36 patients who had suffered from sulphasalazine-induced agranulocytosis, and compared them with 72 patients treated with sulphasalazine without blood reactions. We also performed in vitro studies of the blood cell lines HL60 and U937 after sulphasalazine exposure with respect to cell survival index, neutrophil elastase protein expression and activity. RESULTS: None of the mutations in ELA2, which previously have been reported to be associated with SCN, was found in this material. Protein expression of human neutrophil elastase in lymphoma U937 cells was not affected by treatment with concentrations equivalent to therapeutic doses. Cell survival of lymphoma U937 and promyelocytic leukemia HL-60 cells was not affected in this concentration range, but exhibited a decreased proliferative capacity with higher sulphasalazine concentrations. Interestingly the promyelocytic cells were more sensitive to sulphasalazine than the lymphoma cell line. CONCLUSION: Neutrophil elastase expression and ELA2 mutations do, however, not seem to be involved in the etilogy of sulphasalazine-induced agranulocytosis. Why sulphasalazine is more toxic to promyelocytes than to lymphocytes remains to be explained.

Journal Article↗

PubMed2005

Could flies explain the elusive epidemiology of campylobacteriosis?

BACKGROUND: Unlike salmonellosis with well-known routes of transmission, the epidemiology of campylobacteriosis is still largely unclear. Known risk factors such as ingestion of contaminated food and water, direct contact with infected animals and outdoor swimming could at most only explain half the recorded cases. DISCUSSION: We put forward the hypothesis that flies play a more important role in the transmission of the bacteria, than has previously been recognized. Factors supporting this hypothesis are: 1) the low infective dose of Campylobacter; 2) the ability of flies to function as mechanical vectors; 3) a ubiquitous presence of the bacteria in the environment; 4) a seasonality of the disease with summer peaks in temperate regions and a more evenly distribution over the year in the tropics; 5) an age pattern for campylobacteriosis in western travellers to the tropics suggesting other routes of transmission than food or water; and finally 6) very few family clusters. SUMMARY: All the evidence in favour of the fly hypothesis is circumstantial and there may be alternative explanations to each of the findings supporting the hypothesis. However, in the absence of alternative explanations that could give better clues to the evasive epidemiology of Campylobacter infection, we believe it would be unwise to rule out flies as important mechanical vectors also of this disease.

Animals↗

PubMed2004

A study of the average effect of the 3'APOB-VNTR polymorphism on lipidemic parameters could explain why the short alleles (<35 repeats) are rare in centenarians.

BACKGROUND: In studies on the genetics of human aging, we observed an age-related variation of the 3'APOB-VNTR genotypic pool (alleles: Short, S, <35 repeats; Medium, M, 35-39 repeats; Long, L, >39 repeats) with the homozygous SS genotype showing a convex frequency trajectory in a healthy aging population. This genotype was rare in centenarians, thus indicating that the S alleles are unfavorable to longevity, while common in adults, thus indicating a protective role at middle age. This apparent paradox could be due to possible effects exerted by the above polymorphism on lipidemic parameters. Aim of the work was to get insights into these puzzling findings METHODS: We followed a double strategy. Firstly, we analyzed the average effects of S (alphaS), M (alphaM), and L (alphaL) alleles on lipidemic parameters in a sample of healthy people (409 subjects aged 20-102 years) recruited in Calabria (southern Italy). The (alphaS), (alphaM), and (alphaL) values were estimated by relating 3'APOB-VNTR genotypes to lipidemic parameters, after adjustment for age, sex and body mass index (multiple regression). Then, we analyzed the S alleles as susceptibility factors of Cardiovascular Atherosclerotic Disease (CD) in CD patients characterized either by low serum HDL-Cholesterol or by high serum LDL-Cholesterol (CD-H and CD-L patients, 40 and 40 subjects respectively). The Odds Ratios (OR) were computed for carriers of S alleles in CD-H and CD-L patients matched for origin, sex and age with controls extracted from the sample of healthy subjects. RESULTS: By the analysis of the healthy sample group we found that the S alleles lower the average values of serum Total Cholesterol (alphaS = -5.98 mg/dL with [-11.62/-0.74] 95% confidence interval) and LDL-Cholesterol (alphaS = -4.41 mg/dL with [-8.93/-0.20] 95% confidence interval) while the alleles M and L have no significant effect on the lipidemic phenotype. In line with these findings, the analysis of CD patients showed that the S alleles are protective as for CD-L (O.R. = 0.55 with [0.21/0.98] 95% confidence interval) while neutral as for CD-H (O.R. = 0.75 with [0.32/1.60] 95% confidence interval). CONCLUSION: On the whole, the S alleles would be advantageous in adults (by protecting from CD-L) while dangerous in the elderly, probably by lowering serum cholesterol below a critical threshold. This could explain the convex frequency trajectory of SS genotypes previously observed in a healthy aging population.

3' Flanking Region↗

PubMed2005

Explaining inconsistencies between data on condom use and condom sales.

BACKGROUND: Several HIV prevention programs use data on condom sales and survey-based data on condom prevalence to monitor progress. However, such indicators are not always consistent. This paper aims to explain these inconsistencies and to assess whether the number of sex acts and the number of condoms used can be estimated from survey data. This would be useful for program managers, as it would enable estimation of the number of condoms needed for different target groups. METHODS: We use data from six Demographic and Health Surveys to estimate the total annual number of sex acts and number of condoms used. Estimates of the number of sex acts are based on self-reported coital frequency, the proportion reporting intercourse the previous day, and survival methods. Estimates of the number of condoms used are based on self-reported frequency of use, the proportion reporting condom use the previous day and in last intercourse. The estimated number of condoms used is then compared with reported data on condom sales and distribution. RESULTS: Analysis of data on the annual number of condoms sold and distributed to the trade reveals very erratic patterns, which reflect stock-ups at various levels in the distribution chain. Consequently, condom sales data are a very poor indicator of the level of condom use. Estimates of both the number of sexual acts and the number of condoms used vary enormously based on the estimation method used. For several surveys, the highest estimate of the annual number of condoms used is tenfold that of the lowest estimate. CONCLUSIONS: Condom sales to the trade are a poor indicator of levels of condom use, and are therefore insufficient to monitor HIV prevention programs. While survey data on condom prevalence allow more detailed monitoring, converting such data to an estimated number of sex acts and condoms used is not straightforward. The estimation methods yield widely different results, and it is impossible to determine which method is most accurate. Until the reliability of these various estimation methods can be established, estimating the annual number of condoms used from survey data will not be feasible. Collecting survey data on the number of sex acts and the number of condoms used in a fixed time period may enable the calculation of more reliable estimates of the number of sex acts and condoms used.

Adolescent↗

PubMed2004

Relationship between CRP and hypofibrinolysis: Is this a possible mechanism to explain the association between CRP and outcome in critically ill patients?

BACKGROUND-: Endothelial cell dysfunction may be implicated in the development of multiple organ failure (MOF) by a number of mechanisms. Among these, altered fibrinolysis promotes fibrin deposition, which may create microvascular alterations during inflammation. Elevated concentrations of C-reactive protein (CRP), especially when these persist over time, are correlated with an increased risk of MOF and death. CRP may inhibit fibrinolysis by inducing plasminogen activator inhibitor-1 (PAI-1) release from human aortic endothelial cells. Moreover, the administration of recombinant CRP in volunteers may increase circulating PAI-1 levels.In this study, we tested the hypothesis that CRP is associated with hypofibrinolysis in intensive care patients with and without sepsis. METHODS-: We studied the association of inflammation and abnormal fibrinolysis in intensive care unit (ICU) patients with (n = 11) and without (n = 21) sepsis. The inflammatory response was assessed by serum concentration of C-reactive protein (CRP), a marker of the acute phase reaction, which increase rapidly in the inflammatory response, and the plasma fibrinolytic capacity was evaluated by the Euglobulin Clot Lysis Time (ECLT), determined by a new semi-automatic method. RESULTS-: ECLT was significantly higher in septic than non-septic patients (1104 +/- 439 vs 665 +/- 275 min; p = 0.002) and was significantly correlated with CRP concentration (R2 = 0.45; p < 0.001). In a multivariate analysis, CRP was the strongest predictor of ECLT (R2 = 0.51, F = 25.6, p < 0.001). In addition, the overall ICU length of stay was significantly correlated with CRP (R2 = 0.264, p = 0.003) and ECLT (R2 = 0.259, p = 0.003). CONCLUSION-: In critically ill patients a significant correlation thus exists between plasma fibrinolytic capacity and serum CRP levels. Our data were obtained in the first 24 hours of ICU admission or of sepsis, thus, the relation between CRP and hypofibrinolysis appeared very quickly. This finding is compatible with a link between inflammation and abnormal fibrinolysis, and may explain the negative prognostic value of CRP in critically ill patients.

Journal Article↗

PubMed2006

Minor shift in background substitutional patterns in the Drosophila saltans and willistoni lineages is insufficient to explain GC content of coding sequences.

BACKGROUND: Several lines of evidence suggest that codon usage in the Drosophila saltans and D. willistoni lineages has shifted towards a less frequent use of GC-ending codons. Introns in these lineages show a parallel shift toward a lower GC content. These patterns have been alternatively ascribed to either a shift in mutational patterns or changes in the definition of preferred and unpreferred codons in these lineages. RESULTS AND DISCUSSION: To gain additional insight into this question, we quantified background substitutional patterns in the saltans/willistoni group using inactive copies of a novel, Q-like retrotransposable element. We demonstrate that the pattern of background substitutions in the saltans/willistoni lineage has shifted to a significant degree, primarily due to changes in mutational biases. These differences predict a lower equilibrium GC content in the genomes of the saltans/willistoni species compared with that in the D. melanogaster species group. The magnitude of the difference can readily account for changes in intronic GC content, but it appears insufficient to explain changes in codon usage within the saltans/willistoni lineage. CONCLUSION: We suggest that the observed changes in codon usage in the saltans/willistoni clade reflects either lineage-specific changes in the definitions of preferred and unpreferred codons, or a weaker selective pressure on codon bias in this lineage.

Animals↗

PubMed2006

Explaining variation in GP referral rates for x-rays for back pain.

BACKGROUND: Despite the availability of clinical guidelines for the management of low back pain (LBP), there continues to be wide variation in general practitioners' (GPs') referral rates for lumbar spine x-ray (LSX). This study aims to explain variation in GPs' referral rates for LSX from their accounts of the management of patients with low back pain. METHODS: Qualitative, semi-structured interviews with 29 GPs with high and low referral rates for LSX in North East England. Thematic analysis used constant comparative techniques. RESULTS: Common and divergent themes were identified among high- and low-users of LSX. Themes that were similar in both groups included an awareness of current guidelines for the use of LSX for patients with LBP and the pressure from patients and institutional factors to order a LSX. Differentiating themes for the high-user group included: a belief that LSX provides reassurance to patients that can outweigh risks, pessimism about the management options for LBP, and a belief that denying LSX would adversely affect doctor-patient relationships. Two specific differentiating themes are considered in more depth: GPs' awareness of their use of lumbar spine radiology relative to others, and the perceived risks associated with LSX radiation. CONCLUSION: Several key factors differentiate the accounts of GPs who have high and low rates of referral for LSX, even though they are aware of clinical guideline recommendations. Intervention studies that aim to increase adherence to guideline recommendations on the use of LSX by changing the ordering behaviour of practitioners in primary care should focus on these factors.

Journal Article↗

PubMed2005

Brain atrophy and lesion load as explaining parameters for cognitive impairment in multiple sclerosis.

Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system, with lesions widespread through the brain and spinal cord. An important manifestation is cognitive impairment, which, though difficult to measure, may have a major social impact. To better understand the relationship between structural tissue damage and cognitive impairment, we examined the extent and spatial distribution of brain lesions, as measured by magnetic resonance imaging (MRI), in relation to abnormal cognitive performance as measured by the Brief Repeatable Battery (BRB) in 82 MS patients. Possible confounders, like fatigue, pain and depression were also assessed. Brain MR image analysis included hyperintense T2 and hypointense T1 lesion load in the whole brain and the four lobes separately, as well as whole brain volume measurements. Cognitive impairment (defined as more than two abnormal tests) was found in 67% of the patients. Moderately strong correlations were found between the subtests of the BRB and the lesion loads in the brain regions hypothesized to be associated with that cognitive test, although these correlations were in general not much stronger than those between the subtests and the overall lesion load (due to strong interrelationships). The Spatial Recall Test correlated best with parietal lesion load; the Symbol Digit Modalities Test, the Paced Auditory Serial Addition Task (PASAT) and the Word List Generation best with frontal, parietal and temporal lesion load; while the Verbal List Generation Test Index correlated only with atrophy. Atrophy and lesion load were the main factors determining the test scores, explaining 10-25% of the variance in the test results, and were more important than fatigue, pain and depression; only depression had a minor, but significant, additional effect on the PASAT. In conclusion, cognitive impairment in MS is moderately dependent on amount (and distribution) of structural brain damage, especially in the more physically impaired patients group.

Adult↗

PubMed1987

Explaining and understanding in psychopathology.

Psychoanalytical methodology has been described as causal explanation or hermeneutic understanding. This methodological dichotomy has been introduced into psychopathology by Karl Jaspers. Contemporary authors' contributions in the area are discussed. Although these authors accept a role for both methods, they agree with Jaspers that psychoanalysis should be subjected to the logical limitations of hermeneutic analysis. A logical framework for the interaction of explaining with understanding is presented and discussed in relation to psychiatric research.

Humans↗