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PubMed1997

Anatomic variant of the posterior interventricular coronary artery: implications for coronary angioplasty in acute myocardial infarction.

Acute thrombotic occlusion of an infarct-related artery is frequently found in patients presenting with myocardial infarction. In a patient with acute inferior wall myocardial infarction complicated by continuous chest pain and hemodynamic instability, emergency diagnostic coronary arteriography demonstrated a patent, infarct-related, "pseudo" right coronary artery while, in fact, this vessel was a rare anatomic variant of the posterior interventricular branch with very early origin from the right coronary artery and the true right coronary artery was completely occluded by a thrombotic obstruction. Accurate anatomic-angiographic interpretation of the angiogram was crucial for successful performance of emergency recanalization and revascularization of the true right coronary artery with laser and balloon angioplasty. Once antegrade flow was restored another rare coronary variant was discovered, i.e., a sinoatrial node artery arising from the middle portion of the newly patent right coronary artery.

Adult↗

PubMed1997

[The Creutzfeld-Jakob disease. A sphinx of current neurobiology].

BACKGROUND: Prospective epidemiological studies are being employed to determine the incidence and possible risk factors of Creutzfeldt-Jakob disease (CJD) in five European countries in which bovine spongiform encephalopathy (BSE) occurs at different rates of incidence. PATIENTS AND METHODS: Using a voluntary reporting system throughout the Federal Republic of Germany, suspected cases of CJD were investigated and the incidence calculated. Possible risk factors in patients and control groups were obtained by questionnaire. Serum and cerebrospinal fluid samples served to delineate genetic forms and distinguish the disease from other major dementias. RESULTS: A total of 544 patients with suspected CJD, reported in Germany between 1993 and 1997, were examined. 232 (plus 27 investigated only neuropathologically) were confirmed as definite or probable, an annual incidence per million population of between 0.76 (for 1994) and 0.98 (for 1995), similar to figures from other European countries. In Great Britain, the cases of "new variant" CJD, not yet observed in Germany, were excluded from the calculation of incidence. So far, dementia in the family and handling of horn shavings have been identified as risk factors. A rise in the concentrations of neurone-specific enolase and of S100 protein as well as the demonstration of certain proteins in cerebrospinal fluid (p130/ 131 and 14-3-3, respectively) have been shown as being diagnostically superior to EEG changes. INTERPRETATION: There has so far been no increase in the incidence of CJD within Europe. However, the occurrence of the new variant in Great Britain requires long-term monitoring. The diagnostic criteria used for this can be improved by biochemical methods.

Animals↗

PubMed1975

Temperature sensitive cells in the study of carcinogenic transformation.

Two temperature sensitive variants (ts13 and ts14) of an African green monkey tetraploid kidney cell line (epithelial), carrying temperature sensitive lesions in thymidine metabolism, were transformed by methylnitrosourea (MNU) at the permissive temperature of 33 degrees C, nor was there any transformation in the wild type parental cell line of BSC-1 at these temperatures under similar conditions. A comparative study of the cell cycle and metabolic efficiency in the 3 cell lines was performed in order to get an understanding of the physiology of the "target cells" in culture. Compared with the parental cell line of BSC-1, ts13 and ts14 cells were blocked in the G1 phase of the cell cycle during the time that the cell were in contact with the carcinogen (MNU); the variant cells also had higher mitotic indices at this time. The cells of ts13 which showed 50% more transformation than those of ts14 differed from the latter in having larger numbers of viable cells arrested in mitosis over the G1 period. The results were interpreted to indicate that there were other factors, besides cells arrested being in G1, which contributed to the difference in the frequency of transformation between the variant cell lines which had an otherwise similar physiology. Using gel electrophoresis a new protein was located in the nuclei of the transformed cells of ts13 and ts14 which was absent in the wild type cell line of BSC-1 or in the variants ts13 and ts14 at 39-5 degrees C.

Cell Fusion↗

PubMed2004

Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome.

Heterochromatin is defined classically by condensation throughout the cell cycle, replication in late S phase and gene inactivity. Facultative heterochromatin is of particular interest, because its formation is developmentally regulated as a result of cellular differentiation. The most extensive example of facultative heterochromatin is the mammalian inactive X chromosome (Xi). A variety of histone variants and covalent histone modifications have been implicated in defining the organization of the Xi heterochromatic state, and the features of Xi heterochromatin have been widely interpreted as reflecting a redundant system of gene silencing. However, here we demonstrate that the human Xi is packaged into at least two nonoverlapping heterochromatin types, each characterized by specific Xi features: one defined by the presence of Xi-specific transcript RNA, the histone variant macroH2A, and histone H3 trimethylated at lysine 27 and the other defined by H3 trimethylated at lysine 9, heterochromatin protein 1, and histone H4 trimethylated at lysine 20. Furthermore, regions of the Xi packaged in different heterochromatin types are characterized by different patterns of replication in late S phase. The arrangement of facultative heterochromatin into spatially and temporally distinct domains has implications for both the establishment and maintenance of the Xi and adds a previously unsuspected degree of epigenetic complexity.

Cell Line↗

PubMed1989

The effects of kinetic occlusion and categorization on amodal completion. A comment on Gerbino and Salmaso (1987).

The experimental study of Gerbino and Salmaso (1987) focused on the process of amodal completion, i.e. the process that leads to the impression of a total pattern in the absence of information about all parts of the pattern. One of the questions that they have attempted to answer with respect to this process is whether or not it depends on the categorization of the modal part (i.e. the part about which visual information is present) as a modification of a complete prototype. The major conclusion of their experiments is that amodal completion does not depend upon categorization. Furthermore, they interpret their results as indicating that neither the truncated form of the occluded part nor the unification/segregation of contour segments are phenomenally real. We designed some variants of the tunnel effect to demonstrate (1) that the explicit categorization of some parts of the input can have an influence on amodal completion and (2) that the truncated form of a pattern can be phenomenally real. Our results corroborate these hypotheses and can, therefore, interpreted as refuting two rather central claims of Gerbino and Salmaso (1987). The conclusion of our experiment must be that amodal completion is not as primary as they have supposed but can be influenced by kinetic occlusion and categorization stored in visual memory.

Adult↗

PubMed2003

Characterization of a Gyrodactylus salaris variant: infection biology, morphology and molecular genetics.

A laboratory population of a Danish Gyrodactylus salaris variant founded by 1 single specimen was established and infection studies performed. Rainbow trout as well as Atlantic salmon of 3 different stocks were infected both in cohabitation systems and as single-parasite infections on isolated hosts. Both infection systems revealed that this particular morphotype exhibits low virulence towards Atlantic salmon. Thus, in isolated hosts, the parasites could either not establish or only reproduce to a limited degree on salmon. Rainbow trout, in contrast, proved to be rather susceptible to infection with this G. salaris variant and abundances on this host species always attained significantly higher values in cohabitation systems compared to salmon. Detailed morphological examination confirmed the very high resemblance to G. salaris (sensu stricto), as the range of variation in sclerite characters of the morphotype is almost fully covered by the total range of variation reported for reference G. salaris. Morphological similarities to the closely related congeneric species G. bohemicus were noted. Molecular studies, however, showed that the morphotype most likely represents a G. salaris variant, as it differed only slightly from G. salaris sensu Malmberg, 1957, which is also known to inhabit Danish watercourses. The genomic target region investigated does not allow us to rule out the possibility that it represents a variant form of G. thymalli. Sequences of the ribosomal RNA internal transcribed spacer (ITS) revealed that single individuals contained 2 different ITS sequences, one identical to reference sequence of G. salaris while the other differed at 3 positions. This can be interpreted as an example of a hybrid or, more likely, as intra-individual variation of ITS within single individuals. As one of the nucleotide changes in the variant ITS affects an Hae III restriction site, the current G. salaris variant can be distinguished from G. salaris sensu Malmberg by RFLP diagnosis.

Animals↗

PubMed2000

New variants of a method of MRI scale standardization.

One of the major drawbacks of magnetic resonance imaging (MRI) has been the lack of a standard and quantifiable interpretation of image intensities. Unlike in other modalities, such as X-ray computerized tomography, MR images taken for the same patient on the same scanner at different times may appear different from each other due to a variety of scanner-dependent variations and, therefore, the absolute intensity values do not have a fixed meaning. We have devised a two-step method wherein all images (independent of patients and the specific brand of the MR scanner used) can be transformed in such a way that for the same protocol and body region, in the transformed images similar intensities will have similar tissue meaning. Standardized images can be displayed with fixed windows without the need of per-case adjustment. More importantly, extraction of quantitative information about healthy organs or about abnormalities can be considerably simplified. This paper introduces and compares new variants of this standardizing method that can help to overcome some of the problems with the original method.

Algorithms↗

PubMed2005

Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining.

Microsatellite analysis (MSA) in tumour tissue is useful for pre-selection of hereditary non-polyposis colorectal cancer (HNPCC) patients for mutation screening, but is time-consuming and cost-intensive. Immunohistochemistry (IHC) for expression of MLH1 and MSH2 proteins is simple, fast, and indicates the affected gene. IHC has therefore been proposed as an alternative pre-screening method. However, some authors report a lower sensitivity of IHC compared with MSA. The present study reports IHC results for MSH2 and MLH1 performed in 82 tumours with high microsatellite instability (MSI-H) from 81 carriers of pathogenic mutations in MSH2 or MLH1. One hundred per cent (38/38) of the tumours from MSH2 mutation carriers showed loss of MSH2 staining; in all cases, the affected MSH2 gene was predicted correctly by IHC. Complete loss of MLH1 expression was observed in 66% (29/44) of MLH1 mutation carriers. Weak positive MLH1 staining was observed in 14 (32%) cases and, in one case, normal MLH1 staining was seen. The pathologist was aware of the weak staining pattern as an indicator of an MLH1 mutation; 98% of the MLH1 mutations were predicted correctly. To evaluate whether weak positive MLH1 staining is observed more often with in-frame or missense mutations, IHC data from 23 MSI-H tumours from carriers of unspecified variants were added and mutations were grouped into truncating mutations, large non-truncating deletions, and small non-truncating mutations. Weak MLH1 staining was observed in all three categories and it is postulated that other factors, such as mutation of the second allele, also influence protein expression. In conclusion, IHC can be regarded as a very useful method for selecting HNPCC patients for mutation analysis, as long as it is interpreted by an experienced pathologist. The high specificity of IHC in terms of indicating the affected gene is useful for evaluating unspecified variants. However, the staining pattern does not predict whether the underlying germ-line mutation is truncating or not.

Adaptor Proteins, Signal Transducing↗

PubMed1992

Proton transfer roles of lysine 64 and glutamic acid 64 replacing histidine 64 in the active site of human carbonic anhydrase II.

The CO2 hydration activities of cloned human carbonic anhydrase II (carbonate hydro-lyase, EC 4.2.1.1) and variants with Lys, Glu, Gln or Ala replacing His at sequence position 64 have been measured in a variety of different buffers in the pH range 6-9. The variants with Lys-64, Gln-64 and Ala-64 showed non-Michaelis-Menten behavior under some conditions, apparent substrate inhibition being prominent near pH 9. However, asymptotic Michaelis-Menten parameters could be estimated for the limit of low substrate concentrations. All variants show distinct buffer specificities, and imidazole derivatives, Ches and phosphate buffers yield higher kcat values that Bicine, Taps and Mops buffers under otherwise similar conditions. These results are interpreted in terms of different pathways for a rate-limiting proton transfer. In unmodified enzyme, the very high catalytic activity depends on His-64 functioning as an efficient proton transfer group, but this pathway is not available in the variants with Gln-64 and Ala-64. Imidazoles, Ches and phosphate are thought to participate in a metal center-to-buffer proton transfer pathway, whereas Bicine, Taps, Mops and Mes appear to lack this capacity, so that the rate-limiting proton transfer occurs in a metal center-to-bulk water pathway for these variants. The Lys-64 and Glu-64 variants give significantly higher kcat values in Taps, Mops and Mes buffers than the Ala-64 and Gln-64 variants. The pH dependencies of these kcat values are compatible with the hypothesis that Lys-64 and Glu-64 can function as proton transfer groups. Thus, at pH near 9, Lys-64 appears to be only 5-times less efficient than His-64, while Glu-64 is inefficient. At pH 6, Lys-64 is an inefficient proton transfer group, but Glu-64 is only 2-3-times less efficient than His-64. The data indicate that Lys-64 and Glu-64 have pKa values near 8 and below 6, respectively.

Binding Sites↗

PubMed2004

Genetic association studies in Alzheimer's disease research: challenges and opportunities.

Genetic association studies have identified important risk factors for Alzheimer's disease and other diseases. However, the ease with which these methods can be applied and the shear number of polymorphisms in the human genome has led to a well-characterized multiple comparison problem-given the number of genetic variants being tested, it is likely that many of the positive findings reported in the literature to date will prove to be false positive findings explained simply by random fluctuation in data and type I error. The disparity of findings in initial positive reports versus subsequent negative replication studies observed in the Alzheimer's disease literature underscores this problem. The problem of a high false positive rate can be addressed in part by using statistical correction for multiple comparisons in larger and statistically more powerful samples and in meta-analyses of smaller samples. National initiatives are now being considered to address this problem by encouraging sharing of genetic material. Of equal concern in planning future initiatives are methodological issues that are the domain of the epidemiologist. In fact, it is possible that disparate findings across case-control studies reported to date may be explained in part by problems in the design, analysis and interpretation of these studies. The involvement of epidemiologists may improve the situation in this regard. For example, population stratification bias, control selection bias and prevalent case bias can be minimized by careful study design and by appropriate statistical analysis. Regarding interpretation of case-control studies, a more careful consideration of the strength of evidence for a given genetic variant may help to temper enthusiasm for, or appropriately qualify, positive findings. Epidemiologists have well-developed causal criteria for this purpose. This paper reviews the current state of case-control studies of genetic variants in Alzheimer's disease from the epidemiological perspective. The problem of multiple comparisons and a high false positive rate is reviewed. The potential for bias in case-control studies of Alzheimer's disease is reviewed by way of example. Future initiatives to promote case-control studies of genetic variants in Alzheimer's disease can only benefit from increased awareness the tools of epidemiology.

Alzheimer Disease↗

PubMed1998

The long-term dynamics of tuberculosis and other diseases with long serial intervals: implications of and for changing reproduction numbers.

The net and basic reproduction numbers are among the most widely-applied concepts in infectious disease epidemiology. A net reproduction number (the average number of secondary infectious cases resulting from each case in a given population) of above 1 is conventionally associated with an increase in incidence; the basic reproduction number (defined analogously for a 'totally susceptible' population) provides a standard measure of the 'transmission potential' of an infection. Using a model of the epidemiology of tuberculosis in England and Wales since 1900, we demonstrate that these measures are difficult to apply if disease can follow reinfection, and that they lose their conventional interpretations if important epidemiological parameters, such as the rate of contact between individuals, change over the time interval between successive cases in a chain of transmission (the serial interval). The net reproduction number for tuberculosis in England and Wales appears to have been approximately 1 from 1900 until 1950, despite concurrent declines in morbidity and mortality rates, and it declined rapidly in the second half of this century. The basic reproduction number declined from about 3 in 1900, reached 2 by 1950, and first fell below 1 in about 1960. Reductions in effective contact between individuals over this period, measured in terms of the average number of individuals to whom each case could transmit the infection, meant that the conventional basic reproduction number measure (which does not consider subsequent changes in epidemiological parameters) for a given year failed to reflect the 'actual transmission potential' of the infection. This latter property is better described by a variant of the conventional measure which takes secular trends in contact into account. These results are relevant for the interpretation of trends in any infectious disease for which epidemiological parameters change over time periods comparable to the infectious period, incubation period or serial interval.

Adolescent↗

PubMed1982

The effect of inhibitors of folic acid absorption on the transfer rate constants in the rat everted proximal jejunum: a method for their evaluation from a three-compartment model.

When solute transfer through the intestinal in vitro everted sac preparation is described by a three-compartment system, solute transfer rate constants can be derived for the mucosal and serosal permeability barriers. A catenary variant has been presented as well as a mammillary one where paracellular movement of solute is additionally allowed for. The first order differential rate equations governing the change in solute concentration in all three compartments with respect to time have been solved and the explicit analytical solutions provided. Since these solutions are cumbersome to use in the estimation of the required rate constants, a least squares procedure has been applied directly to the differential form of the rate equations in order to derive the rate constants without recourse to the analytical solutions. Verification of the solutions and of the estimated rate constants was by substitution of the latter into the former to test the goodness of fit for folic acid absorption data. Both variants take into account the simultaneous fluid movement which occurs during absorption experiments and which complicates the interpretation of absorption data. The mammillary model showed that only 10% of folic acid movement could pass directly through the paracellular pathways and that the bulk of folate movement is probably through the epithelial cells. However the catenary model without paracellular movement gave just as good fit to the data and was used subsequently. Experiments investigating the effect of substances implicated in folate malabsorption were analyzed in terms of the catenary model for folic acid absorption, in order to investigate their effects on the transfer rate constants free from the complicating effects on fluid movement. When pronounced inhibition took place, as with methotrexate, the mucosal rate constants were reduced, whereas the serosal rate constants were elevated. Also, the forward (k12) mucosal rate constant correlated significantly with the overall folate transfer in contrast to the other rate constants. These observations are consonant with the concept of a mucosally sited entry step exerting a controlling influence over the transfer rate of folic acid rather than a serosally sited exit process and with the conclusion that this may be the site of action of substances causing folate malabsorption.

Animals↗

PubMed1978

Pancreatic pseudotumors: computed tomography.

Although pancreatic disease is suspected initially by historical or biochemical findings, the nature of the pathologic process in the past was frequently established only through invasive procedures. Inferences can be drawn from routine roentgenologic examinations, but visualization of the pancreas has only recently been achieved. Of the currently available noninvasive imaging procedures, computed tomography, in our opinion, is the screening procedure of choice. Care in the interpretation of pancreatic masses must be exercised since some of the findings can be attributed to anatomic variants, normal adjacent structures, or other neighboring pathologic processes.

Aged↗

PubMed2005

The relationship between the pharmacology of antiepileptic drugs and human gene variation: an overview.

Individual differences in clinical responsiveness to antiepileptic drugs are due to a complex interaction between environmental factors and genetic variation. Considerable interest has arisen in exploiting advances in molecular genetics to improve drug therapy for epilepsy and many other diseases; however, practical application of pharmacogenetics has been difficult to realize. Attempts to define gene variants that are associated with therapeutic (or adverse) effects of antiepileptic drugs rely currently on the prior identification of candidate genes and the subsequent evaluation of the distribution of allelic variants between individuals who have a "good" versus a "poor" clinical response. Many factors can adversely affect interpretation of such data, and careful consideration must be given to the design of genetic association studies involving candidate genes. Candidate genes may be identified in a number of ways; however, for studies of drugs, application of knowledge derived from basic pharmacology can suggest focused and testable hypotheses that are based on the fundamental principles of drug action. Thus, studies of genetic variation as they relate to proteins involved in antiepileptic drug kinetics and dynamics will identify key polymorphisms in endogenous molecules that determine degrees of drug efficacy and toxicity. Delineation of these effects in the coming years will promote enhanced success in the treatment of epilepsy.

Anticonvulsants↗

PubMed1976

A normal level of adenosine deaminase activity in the red cell lysates of carriers and patients with severe combined immunodeficiency disease.

The red cell lysates of two children with severe combined immunodeficiency disease (SCID) exhibited a virtually total absence of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) when standard volumes were assayed. Under these conditions the parents exhibited depressed specific activity except for one mother, whose lysate showed a normal value for activity. Upon storage of the lysate at 4 degrees, a significant amount of activity appeared in one of the SCID children, and the activity of the heterozygous carriers was stimulated. With the use of a sensitive spectrophotometric assay based on conversion of inosine to uric acid, it was shown that the specific enzymatic activity in each of the SCID patients increased progressively as the volume of lysate assayed was lowered. With the smallest amount of lysate this specific activity was in the normal range. Similarly, the specific activity of each of the parents' lysates increased to the level of normal (or, in one case, about twice normal) as smaller volumes were assayed. The activity in the SCID patient was inhibitable by 2-fluoroadenosine and N6-methyladenosine, known competitive inhibitors of human red cell adenosine deaminase. The lysate from the SCID patient was also shown to inhibit adenosine deaminase partially purified from a normal individual. The results are interpreted in terms of a genetically programmed production of an adenosine deaminase inhibitor in at least one variant of the severe combined immunodeficiency disease.

Adenosine Deaminase↗

PubMed2005

Pseudomonas aeruginosa biofilm formation and slime excretion on antibiotic-loaded bone cement.

BACKGROUND: Infection is an infrequent but serious complication of prosthetic joint surgery. These infections will usually not clear until the implant is removed and re-implantation has a high failure rate, especially when Pseudomonas aeruginosa is involved. MATERIAL AND METHODS: We examined Pseudomonas aeruginosa biofilm formation on plain and gentamicin-loaded bone cement with confocal scanning laser microscopy (CSLM). Two different stains were applied in order to visualize and quantify the distribution of bacterial cells and extracellular polymeric substances (slime) from the bone cement surface to the top of the biofilm. Staining with LIVE/DEAD viability stain differentiated between live and dead bacteria within the biofilm, and slime production was evaluated after staining with Calcofluor white. RESULTS: CSLM showed that the biofilm was a nonuniform structure of variable thickness, with differences in local bacterial cell and slime densities. Incorporation of gentamicin in bone cement resulted in a 44% reduction in bacterial viability, while the slime density increased significantly. In addition, conventional plate counting showed the development of small-colony variants on gentamicin-loaded bone cement with a decreased sensitivity for gentamicin (MIC: 8 m/L), as compared with normal-sized colonies taken from plain and gentamicin-loaded bone cement (MIC: 3 m/L). The enhanced slime production on antibiotic-loaded bone cement, together with the formation of small-colony variants, resulted in decreased susceptibility to antibiotics--probably concomitant with the onset of persistent and relapsing infections. INTERPRETATION: In the clinical situation, our findings help to explain the frequent re-implantation failure of joint replacements infected with P. aeruginosa when the procedure has been performed using antibiotic-loaded bone cement.

Anti-Bacterial Agents↗

PubMed1994

The effect of engineering surface loops on the thermal stability of Bacillus subtilis neutral protease.

Using genetic techniques the contribution of surface loops to the thermal stability of Bacillus subtilis neutral protease (NP-sub) was studied. Mutations were designed to make the surface of NP-sub more similar to the surface of more thermostable neutral proteases such as thermolysin (TLN). The mutations included the replacement of an irregular loop by a shorter variant and the introduction of a ten-residue beta-hairpin. In general, these drastic mutations had little effect on the production and activity of NP-sub, indicating the feasibility of major structural rearrangements at the surface of proteins. In the most stable mutant, exhibiting an increase in thermal stability of 1.1 degree C, approximately 10% of the surface of NP-sub was modified. Several NP-sub variants carrying multiple mutations were constructed. Non-additive effects on thermal stability were observed, which were interpreted on the basis of a model for thermal inactivation, that emphasizes the importance of local unfolding processes for thermal stability.

Amino Acid Sequence↗

PubMed1994

An internal dosimetry intercomparison study.

Pacific Northwest Laboratory performed a study to evaluate the consistency of internal dosimetry assessments. A total of eleven laboratories, including DOE sites and NRC licensees, participated in this intercomparison study. Participants were asked to respond to five actual exposure scenarios, previously used in a similar European study. The participating dosimetrists assessed the data of the test scenarios and calculated results in terms of estimated radionuclide intake and the resulting internal doses. To maintain confidentiality, results are given without identifying any site. Except for one scenario, the results showed that the standard deviation of the final results on committed effective dose equivalent for each exposure scenario was about 30-50% of the mean value, giving a consistency slightly greater variant than that of the European study. The discrepancies can be attributed to variations in 1) the interpretation and statistical treatment of the bioassay data; 2) the biokinetic models applied; and 3) the computational tools used. This represents a preliminary study; further intercomparison testing is needed to fully evaluate the problem of dose-assessment inconsistency.

Administration, Inhalation↗