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PubMed1990

Free association as a method of self-observation in relation to other methodological principles of psychoanalysis.

The method of free association, especially in its self-observative aspect, may be seen as a useful criterion for differentiating among various clinical approaches to psychoanalysis, not only as they evolved in the course of its history but also as they are being practiced today. It is suggested that it may be of some relevance to view the existing variants of clinical psychoanalysis as being based upon differing emphases on one or another of the basic operational concepts, such as free association, interpretation, and the mental disposition of the analyst.

Free Association↗

PubMedDate not supplied

Analysis of different variants of erythrocyte survival using digital computers.

In the paper a method is presented, enabling parameter estimation of erythrocyte survival patterns, what is an important element in the diagnosis of haemolytic anaemias. The method is based on a computer program, fitting the experimental data to eight variants of theoretical patterns with use of a weighted least squares criterion. A simple statistical test of approximation quality is described and several interpretational examples are given. The program may be easily handled by a physician with small programming experience.

Anemia, Hemolytic↗

PubMed1977

Differences in affinity of variant beta chains for alpha chains: a possible explanation for the variation in the percentages of beta chain variants in heterozygotes.

The alpha and beta chains of the hemoglobins A, S, Leslie and N-Baltimore have been isolated as PMB derivates by CM-cellulose and DEAE-cellulose chromatography. The relative affinities of the betaA, betaS, betaLeslie and betaN-Baltimore chains for alpha chains were measured through quantitation by chromatography of the hemoglobins A and Leslie, A and S, and A and N-Baltimore that were formed when variable amounts of alpha chains were added to a mixture of equal amounts of the appropriate beta chains. The data indicate a greatly decreased affinity of betaLeslie chains for alpha chains; a similar preference of alpha chains for betaA chains was observed for mixtures involving alpha, betaA, and betaS chains, but the affinity of betaS chains for alpha chains was higher than that of betaLeslie chains. The betaN-Baltimore chains assembled with alpha chains at a similar rate as betaA chains. The data as interpreted indicate that the affinity of certain beta chains for alpha chains can be a major post-translational control mechanism which regulates the level of a beta chain variant in heterozygotes.

Chromatography, DEAE-Cellulose↗

PubMed2002

Pathogenicity of missense and splice site mutations in hMSH2 and hMLH1 mismatch repair genes: implications for genetic testing.

BACKGROUND: In hereditary non-polyposis colorectal cancer, over 90% of the identified mutations are in two genes, hMSH2 and hMLH1. A large proportion of the mutations detected in these genes are of the missense type which may be either deleterious mutations or harmless polymorphisms. AIM: To investigate whether nine missense and one splice site mutation of hMLH1 and hMSH2, in 10 kindreds with a familial history of colorectal cancer or young age of onset, could be interpreted as pathogenic. METHODS: Clinical and genetic characteristics were collected: (i) evolutionary conservation of the codon involved; (ii) type of amino acid change; (iii) occurrence of mutation in healthy controls; (iv) cosegregation of mutation with disease phenotype; (v) functional consequences of gene variant; and (vi) microssatellite instability and immunoexpression of hMSH2 and hMLH1 analysis. RESULTS: Seven different missense and one splice site mutation were identified. Only 1/8 was found in the control group, 2/7 occurred in conserved residues, and 5/7 resulted in non-conservative changes. Functional studies were available for only 2/8 mutations. Segregation of the missense variant with disease phenotype was observed in three kindreds. CONCLUSION: In the majority of families included, there was no definitive evidence that the missense or splice site alterations were causally associated with an increased risk of developing colorectal cancer. Until further evidence is available, these mutational events should be regarded and interpreted carefully and genetic diagnosis should not be offered to these kindreds.

Adaptor Proteins, Signal Transducing↗

PubMed1995

Paracortical nodular T-cell lymphoma. Identification of an unusual variant of peripheral T-cell lymphoma.

Peripheral T-cell lymphomas (PTCLs) are regarded as diffuse proliferations. We describe an unusual paracortical nodular growth pattern in four nodal PTCLs that were initially interpreted as atypical lymphoid hyperplasia in three patients and small B-cell lymphoma with plasmacytic differentiation in a fourth. The nodules were vague to easily discernible and produced minimal to partial architectural distortion. Sinuses were often open, and scattered cortical lymphoid follicles with atretic to hyperplastic germinal centers were present. Clusters of tumor cells abutted some follicles in all cases, and in one case they exhibited focal T-zone expansion. Hypervascularity was not prominent, but a few nodules surrounded epithelioid venules, imparting an angiofollicular appearance. The nodules were composed primarily of small lymphocytes with irregular nuclei admixed with scattered large transformed cells, both cell types having clear cytoplasm. Paraffin immunoperoxidase showed that the nodules were composed of T cells. Dendritic cell networks were present only in follicular centers. Southern blot analysis found T-cell receptor gene rearrangements and a germline immunoglobulin gene configuration in all four nodes. These paracortical clear cell nodules of clonal T cells may be a special type of PTCL. Alternatively, they may represent early foci of lymphoma or they may be a subgroup of T-zone lymphoma. Paracortical nodular PTCL must be differentiated from atypical hyperplastic lesions and some B-cell lymphomas.

Aged↗

PubMed2004

Precaval right renal arteries: prevalence and morphologic associations at spiral CT.

PURPOSE: To determine the prevalence and morphologic associations of precaval right renal arteries at spiral computed tomography (CT). MATERIALS AND METHODS: The authors retrospectively reviewed 186 arterial phase contrast material-enhanced spiral CT scans of the abdomen (5.0-mm section thickness in 97 scans, 2.5 mm in 89 scans) obtained during a 2-year period to identify patients with precaval right renal arteries. During routine interpretation of CT scans at daily readout, the authors prospectively identified 39 additional patients with precaval right renal arteries. All cases were evaluated for anatomic variants and associated clinical findings. Fisher exact analysis and chi2 analysis were performed to compare the frequency of anatomic variants between patients with and those without precaval renal arteries. RESULTS: Nine of 186 patients had precaval right renal arteries, for a prevalence of 5%. In the 48 patients with precaval renal arteries, 52 precaval arteries were found, of which 48 were accessory and four were dominant. Fourteen patients had right pelviectasis to the level of the precaval artery, and three of these had a clinical diagnosis of right ureteropelvic junction obstruction. Eighteen (35%) of the 52 precaval renal arteries arose from the anterior aspect of the aorta (within 30 degrees of the midline). The lower pole of the right kidney was rotated anteriorly in two (22%) of nine and 13 (33%) of 39 patients with precaval renal arteries in the retrospective and prospective groups, respectively, compared with four (2%) of 177 patients without precaval arteries (P <.05 and P <.001, respectively). CONCLUSION: On the basis of these results, precaval right renal arteries appear to be more common than previously reported. Anterior rotation of the lower pole of the right kidney should prompt a search for precaval renal arteries.

Adult↗

PubMed2005

Automatic detection of subsystem/pathway variants in genome analysis.

MOTIVATION: Proteins work together in pathways and networks, collectively comprising the cellular machinery. A subsystem (a generalization of pathway concept) is a group of related functional roles (such as enzymes) jointly involved in a specific aspect of the cellular machinery. Subsystems provide a natural framework for comparative genome analysis and functional annotation. A subsystem may be implemented in a number of different functional variants in individual species. In order to reliably project functional assignments across multiple genomes, we have to be able to identify the variants implemented in each genome. The analysis of such variants across diverse species is an interesting problem by itself and may provide new evolutionary insights. However, no computational techniques are presently available for an automated detection and analysis of subsystem variants. RESULTS: Here we formulate the subsystem variant detection problem as finding the minimum number of subgraphs of a subsystem, which is represented as a graph, and solve the optimization problem by integer programming approach. The performance of our method was tested on subsystems encoded in the SEED, a genomic integration platform developed by the Fellowship for Interpretation of Genomes as a component of a large-scale effort on comparative analysis and annotation of multiple diverse genomes. Here we illustrate the results obtained for two expert-encoded subsystems of the biosynthesis of Coenzyme A and FMN/FAD cofactors. Applications of variant detection, to support genomic annotations and to assess divergence of species, are briefly discussed in the context of these universally conserved and essential metabolic subsystems. SUPPLEMENTARY INFORMATION: The details of the variant detection results are available at http://ffas.burnham.org/svar/supp.html.

Animals↗

PubMed2004

SNPs, haplotypes, and model selection in a candidate gene region: the SIMPle analysis for multilocus data.

Modern molecular techniques make discovery of numerous single nucleotide polymorphims (SNPs) in candidate gene regions feasible. Conventional analysis relies on either independent tests with each variant or the use of haplotypes in association analysis. The first technique ignores the dependencies between SNPs. The second, though it may increase power, often introduces uncertainty by estimating haplotypes from population data. Additionally, as the number of loci expands for a haplotype, ambiguity in interpretation increases for determining the underlying genetic components driving a detected association. Here, we present a genotype-level analysis to jointly model the SNPs via a SNP interaction model with phase information (SIMPle) to capture the underlying haplotype structure. This analysis estimates both the risk associated with each variant and the importance of phase between pairwise combinations of SNPs. Thus, rather than selecting between genotype- or haplotype-level approaches, the SIMPle method frames the analysis of multilocus data in a model selection paradigm, the aim to determine which SNPs, phase terms, and linear combinations best describe the relation between genetic variation and a trait of interest. To avoid unstable estimation due to sparse data and to incorporate both the dependencies among terms and the uncertainty in model selection, we propose a Bayes model averaging procedure. This highlights key SNPs and phase terms and yields a set of best representative models. Using simulations, we demonstrate the utility of the SIMPle model to identify crucial SNPs and underlying haplotype structures across a variety of causal models and genetic architectures.

Bayes Theorem↗

PubMed1990

Assignment of proton resonances, identification of secondary structural elements, and analysis of backbone chemical shifts for the C102T variant of yeast iso-1-cytochrome c and horse cytochrome c.

Resonance assignments for the main-chain, side-chain, exchangeable side chain, and heme protons of the C102T variant of Saccharomyces cerevisiae iso-1-cytochrome c in both oxidation states (with the exception of Gly-83) are reported. (We have also independently assigned horse cytochrome c.) Some additional assignments for the horse protein extend those of Wand and co-workers [Wand, A. J., Di Stefano, D. L., Feng, Y., Roder, H., & Englander, S. W. (1989) Biochemistry 28, 186-194; Feng, Y., Roder, H., Englander, S. W., Wand, A. J., & Di Stefano, D. L. (1989) Biochemistry 28, 195-203]. Qualitative interpretation of nuclear Overhauser enhancement data allows the secondary structure of these two proteins to be described relative to crystal structures. Comparison of the chemical shift of the backbone protons of the C102T variant and horse protein reveals significant differences resulting from amino acid substitution at positions 56 and 57 and further substitutions between residue 60 and residue 69. Although the overall folding of yeast iso-1-cytochrome c and horse cytochrome c is very similar, there can be large differences in chemical shift for structurally equivalent residues. Chemical shift differences of amide protons (and to a lesser extent alpha protons) represent minute changes in hydrogen bonding. Therefore, great care must be taken in the use of differences in chemical shift as evidence for structural changes even between highly homologous proteins.

Amino Acid Sequence↗

PubMed2003

Systematic characterization of mutations in yeast acetohydroxyacid synthase. Interpretation of herbicide-resistance data.

Acetohydroxyacid synthase (AHAS, EC 4.1.3.18) catalyses the first step in branched-chain amino acid biosynthesis and is the target for sulfonylurea and imidazolinone herbicides, which act as potent and specific inhibitors. Mutants of the enzyme have been identified that are resistant to particular herbicides. However, the selectivity of these mutants towards various sulfonylureas and imidazolinones has not been determined systematically. Now that the structure of the yeast enzyme is known, both in the absence and presence of a bound herbicide, a detailed understanding of the molecular interactions between the enzyme and its inhibitors becomes possible. Here we construct 10 active mutants of yeast AHAS, purify the enzymes and determine their sensitivity to six sulfonylureas and three imidazolinones. An additional three active mutants were constructed with a view to increasing imidazolinone sensitivity. These three variants were purified and tested for their sensitivity to the imidazolinones only. Substantial differences are observed in the sensitivity of the 13 mutants to the various inhibitors and these differences are interpreted in terms of the structure of the herbicide-binding site on the enzyme.

Acetolactate Synthase↗

PubMed2003

Palaeopathological and variant conditions of the Homo heidelbergensis type specimen (Mauer, Germany).

Although early Homo specimens are now known from a number of African, Asian and European Middle Pleistocene sites, the taxon Homo heidelbergensis was initially introduced for the Mauer jaw recovered in 1907. Fossil hominids from the earlier Middle Pleistocene of Europe are very rare and the Mauer mandible is generally accepted as one of the most ancient, with an age of approximately 700 kyr. A new preparation of the mandible was conducted in 1996 and gave rise to the detailed palaeopathological examination which is presented here. Based on comparative analyses, the extreme breadth of the mandibular ramus and its flat intercondylar incision, in conjunction with the flattening and broadening of the coronoid process tip, results either from an idiosyncratic pattern of the course and insertion of the temporalis muscle on the coronoid process or from the temporalis possessing an accessory head. The incidence of periodontal pocketing, together with a vertical reduction of the alveolar margin to approximately 3.00 mm, and a slight protuberance formed in vicinity of the right M(2)can safely be interpreted as pathognomonic indications of periodontal disease. The short distance between the enamel-dentine junction of the teeth and the horizontal alveolar margins could either be an inherited variant or may result from incipient osteoporosis. In addition, an arthrotic condition with slight osteophytic peripheral exostoses and an arthrolit (i.e. an articular calculus or "joint mouse") on the left condylus articularisand a depression in the medial part of the left mandibular condyle extending into the inferior part of the ramus are present. These features are indicative of a trauma-induced osteochondrosis dissecans. The diagnosis therefore suggests that the observed depression results from a well-healed fracture. This traumatic event illustrates the demanding living conditions endured by humans during the European Middle Pleistocene. The variations and pathological conditions observed in Mauer do not question the mandible's role as type specimen for the taxon Homo heidelbergensis.

Alveolar Process↗

PubMed2004

Conflicting interpretations of the prevalence of mutations associated with drug resistance in antiviral naïve HIV-1 patients with acute and chronic infection.

The routine determination of drug resistance in newly HIV-1 infected individuals records a potential increase in transmissions of drug-resistant variants. Plasma samples from 38 individuals classified as newly infected (seroconversion time <12 months) and twenty four individuals with an established infection (seroconversion time ranging from 3 to 10 years) were analyzed for the presence of mutations by Trugene HIV-1 genotyping assay and Virtual phenotype. Results on the newly infected and the chronically infected individuals showed a limited number of relevant mutations associated with substantial resistance to reverse transcriptase and protease inhibitors. In particular, three patients (4.8%) carried viral major mutations (T69D and M41L) associated with resistance to reverse transcriptase inhibitors, whereas only one showed the presence of M46L, which is correlated with partial resistance to some protease inhibitors. The clinical interpretation based on different approaches to monitor resistance showed that the Virconet interpretation was less grave than Trugene, suggesting that these interpretations need standardization for the currently used sequencing methods and that they may be associated with different outcomes when eventually are used.

Acute Disease↗

PubMed1991

[Papillary process of the caudate lobe--erroneous sonography interpretation as a space-occupying lesion].

The sonographic appearance of the papillary process separated from the caudate lobe of the liver by a fissure is reported. In 2 out of 5 patients, this variant anatomy mimicked a mass lesion. The papillary process is located dorsal to the left lobe of the liver and in front of the portal vein and common hepatic artery. The echogenicity of the papillary process is identical to liver parenchyma. Knowledge of the sonographic appearance and vascular relationship may help to avoid errors in diagnosis.

Aged↗

PubMed2006

Genetic association studies in cancer: good, bad or no longer ugly?

For some time, investigators have appreciated that genetic association studies in cancer are complex because of the multi-stage process of cancer and the daunting challenge of analysing genetic variants in population and family studies. Because of recent technological advances and annotation of common genetic variation in the human genome, it is now possible for investigators to study genetic variation and cancer risk in many different settings. While these studies hold great promise for unravelling multiple genetic risk factors that contribute to the set of complex diseases called cancer, it is also imperative that study design and methods of interpretation be carefully considered. Replication of results in sufficiently large, well-powered studies is critical if genetic variation is to realise the promise of personalised medicine--namely, using genetic data to individualise medical decisions. In this regard, the plausibility of validated genetic variants can only be realised by the study of gene-gene and gene-environment interactions. The genetic association study in cancer has come a long way from the days of restriction fragment length polymorphisms, and now promises to scan an entire genome 'agnostically' in search of genetic markers for a disease or outcome. Moreover, the application and interpretation of these studies should be conducted cautiously.

Genetic Predisposition to Disease↗

PubMed1988

Myoelectric reactions to ultra-low frequency and low-frequency whole body vibration.

5 healthy males were exposed to vertical sinusoidal whole body vibration (WBV) at 5 frequencies (F1 = 0.315 Hz, F2 = 0.63 Hz, F3 = 1.25 Hz, F4 = 2.5 Hz, F5 = 5.0 Hz) and 2 intensities (I1 = 1.2 ms-2 rms, F1-F5; I2 = 2.0 ms-2 rms, F2-F5). Erector spinae EMGs were derived at the levels of the first thoracic (T1) and third lumbar (L3) spinous processes, rectified and synchronously averaged, as were the accelerations of the seat and the head. WBV induced vibration-synchronous EMG activity (T1 and L3) which exceeded the activity without WBV during enhanced gravitation and decreased during lowered gravitation from F1 to F3. At F4 and F5, these phase relations changed drastically, thus suggesting a different trigger mechanism. The extreme average EMG-amplitudes remained nearly constant at F1 to F3 and increased at higher frequencies. Maximum EMG activity was higher at I2 than at I1. WBV from F1 to F3 is supposed to cause tonic muscular activity triggered by the otoliths; at higher frequencies, stretch reflexes probably gain additional importance. The results hint at an increasing sensory conflict with decreasing frequency of WBV and are interpreted within the theoretical framework of different modes of motor control. Relations between transmissibility and muscle activity suggest the usefulness of including time-variant spring-characteristics into biomechanical models.

Adolescent↗

PubMed2004

Bovine spongiform encephalopathy and Creutzfeldt-Jakob disease: facts and uncertainties underlying the causal link between animal and human diseases.

Following an outbreak of bovine spongiform encephalopathy (BSE) in dairy cows in the United Kingdom (UK), 153 definite and probable human cases of new variant Creutzfeldt-Jakob disease (nvCJD) have been reported, almost exclusively in the UK. Although exposure to the BSE agent is the most plausible interpretation for the occurrence of nvCJD, the causal link between the BSE prion and nvCJD is still debated. This review discusses the pros and cons of nvCJD as a separate nosographic entity, the scientific basis for a correlation between BSE and nvCJD, the validity of the current diagnostic criteria for CJD and nvCJD, the contribution of epidemiology to the detection of a causal relation between BSE and nvCJD, and the present and future directions of the epidemiological research on BSE, CJD and nvCJD.

Animals↗

PubMedDate not supplied

Is it appropriate to use core clerkship grades in the selection of residents?

OBJECTIVE: This study challenges the appropriateness of using core clerkship grades for resident selection. The authors hypothesize that substantial variability occurred in the system of grading. DESIGN: In this retrospective cross-sectional study, variability in the grading systems for third-year core clinical clerkships were examined. From the Medical Student Performance Evaluation of applicants from U.S. medical schools for residency training in the authors' department in 2004 and 2005, the authors gathered the following variables: medical school, third-year core clerkship grading systems, and percentage of students in each grade category. Descriptive analyses were conducted and within institution variability across clerkship scores was analyzed using repeated measure analysis of variance (ANOVA) and t-test. SETTING: University teaching hospital. PARTICIPANTS: The survey covered 121 of 122 U.S. medical schools accredited by the AAMC/LCME. RESULTS: Grading systems used included: variations of Honors/Pass/Fail (H,P,F) system in 76 schools, letter grade systems in 22 schools, and other variants (eg, Outstanding, Advanced, and Proficient in 6 schools and Pass/Fail in 4 schools). Thirteen schools (10%) provided either no grading system or no interpretable system. Grading systems included were further defined into 2 scores in 6 schools, 3 in 34 schools, 4 in 38 schools, 5 in 23 schools, and more than 6 in 6 schools. For schools using a grading system containing 3 or more scores, the percentage of students given the highest grade was significantly less in Surgery (28%) compared with Family Medicine (34%) and Psychiatry (35%) (p = 0.001). CONCLUSIONS: Core clerkship grading systems and the percentage to which institutions grade students as having achieved the highest performance level vary greatly among U.S. medical schools. Within institutions, significant variability exists among clerkships in the percentage of the highest grade given, which makes interpersonal comparison based on core clerkship grades difficult and suggests that this method may not be a reliable indicator of performance.

Achievement↗

PubMed2026

3D Proteomics: Structural, Functional, Chemical and Biomarker Discovery Proteomics With LiP-MS.

Protein structural dynamics drive changes in protein function, making the capture of such dynamics essential for interrogating biological systems. Here we review limited proteolysis coupled to mass spectrometry (LiP-MS), a structural and chemical proteomics method that uses changes in susceptibility to protease cleavage to profile proteome-wide protein structural changes within complex biological samples. In the decade since its development, LiP-MS has become a broadly used structural proteomics method, with peptide-level resolution. It has identified drug targets, delineated altered cellular pathways in response to complex perturbations, revealed structural information on otherwise challenging protein targets, and demonstrated the new concept of structural biomarkers of disease. Because LiP-MS simultaneously probes numerous types of molecular events, such as molecular binding, changes in enzyme activity, chemical modifications, allosteric conformational changes, aggregation, and unfolding, it supports a new proteomics workflow which we term 3D proteomics. This workflow enables the detection of specific functional sites within proteins that are altered upon perturbation, thereby guiding the generation of molecular hypotheses. Further, by globally profiling structural in addition to protein abundance changes, LiP-MS has proven able to greatly increase the information content of functional proteomics screens. In sum, LiP-MS has supported the development of a novel conceptual framework for generating, visualizing, and interpreting structural proteomics data with peptide level resolution, thereby comprehensively probing biological systems. Here we survey the applications of LiP-MS, discuss methodological variants developed by us and others, and describe the use of this new type of omics readout for structural, functional, chemical, and biomarker discovery proteomics.

Proteomics↗