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State of the art: refinement of multiple sequence alignments.

BACKGROUND: Accurate multiple sequence alignments of proteins are very important in computational biology today. Despite the numerous efforts made in this field, all alignment strategies have certain shortcomings resulting in alignments that are not always correct. Refinement of existing alignment can prove to be an intelligent choice considering the increasing importance of high quality alignments in large scale high-throughput analysis. RESULTS: We provide an extensive comparison of the performance of the alignment refinement algorithms. The accuracy and efficiency of the refinement programs are compared using the 3D structure-based alignments in the BAliBASE benchmark database as well as manually curated high quality alignments from Conserved Domain Database (CDD). CONCLUSION: Comparison of performance for refined alignments revealed that despite the absence of dramatic improvements, our refinement method, REFINER, which uses conserved regions as constraints performs better in improving the alignments generated by different alignment algorithms. In most cases REFINER produces a higher-scoring, modestly improved alignment that does not deteriorate the well-conserved regions of the original alignment.

Algorithms↗

Assuring access to state-of-the-art care for U.S. minority populations: the first 2 years of the Minority-Based Community Clinical Oncology Program.

BACKGROUND: The Minority-Based Community Clinical Oncology Program (MBCCOP) was initiated in September 1990 to expand the National Cancer Institute's (NCI's) clinical trials network to minority populations. Institutions, organizations, and/or physician groups that had more than 50% of new cancer patients from minority groups were eligible to participate. There has been no previous evaluation of the MBCCOP. PURPOSE: This study was designed to describe the early implementation of the MBCCOP and identify the challenges that have emerged in developing a network aimed at increasing the participation of minority populations in clinical trials. METHODS: Data were taken from primary and secondary sources, including site visits and patient log data, that described performance of 12 MBCCOP centers initially funded in September 1990. Accrual was measured by the number of credits earned per MBCCOP for patients enrolled in research protocols for cancer treatment or for prevention and control, which includes activities such as early detection, pain control, and rehabilitation. These accrual credits, assigned by the NCI, were based on the complexity of the protocol and the amount of resources expected to be required for accrual of patients by the MBCCOP. RESULTS: Data for the first 2 years of the MBCCOP showed that 344 patients were accrued to trials of treatment protocols from June 1, 1990, to May 31, 1991, and this number increased to 470 during the second accrual year, June 1, 1991, to May 31, 1992. Similarly, accrual of patients to cancer prevention and control studies increased from 256 in 1990-1991 to 423 in 1991-1992. More than 70% of the MBCCOP patients entered in studies were from minority populations. The proportion of eligible MBCCOP patients entered into treatment protocols was identical with that experienced by the initial Community Clinical Oncology Program (CCOP). Results also demonstrated that MBCCOP centers operate in an environment characterized by socio-economic decline and limited resources, both having substantial effects on the implementation of clinical trials among minorities. While minority patients are willing to participate in clinical trials, there are profound barriers involving language, logistics, and the appropriateness of available protocols. Participating physicians, nurses, and support personnel report a high level of agreement with program goals and have developed unique approaches to meeting the challenges faced in the implementation of this program. CONCLUSIONS: The MBCCOPs have demonstrated their ability to participate in clinical trials. Evaluation reveals, however, that they are emerging organizations influenced by factors endemic to the community they serve and their own structure. The MBCCOPs are confronting substantial challenges, yet they provide an important link to the overall NCI clinical trials network.

Aged↗

The development of expressive elaboration in fictional narratives.

PURPOSE: This study analyzed the development of expressive elaboration in fictional narratives for school-age children. METHOD: The analysis was derived from high-point analysis, but it was tailored to capture the artful aspects of fictional storytelling. Narratives were elicited with a short picture sequence of a likely life event from 293 children whose ages ranged from 5 to 12 years. RESULTS: Results showed a significant age effect for expressive elaboration with narrative length controlled. For three age clusters (5-6 years, 7-9 years, and 10-12 years), the 13 types of expressive elaboration showed diverse patterns of acquisition in terms of presence, frequency, and developmental change. Appendages (introducer, abstract, theme, coda, ender) were lowest in both presence and frequency, and increased in presence with age. Orientations (names, relations, personality) were more common and increased in presence with age. Evaluations (modifiers, expressions, repetition, internal states, dialogue) were most frequent and showed age changes in both presence and frequency. CLINICAL IMPLICATIONS: This study provides an additional window on narrative competence. The analysis and results can guide narrative assessment and intervention.

Age Factors↗

[Aphasia and artistic creation].

An artist active drawing and waterpainting, most prominent in sculpture, suffered an apopleptic insult at 66 years of age. Right hemiparesis and severe motor aphasia remained but this with rare unexpected and sometimes rather complicated productions in spoken, and also in written language in spite of modest progress in writing exercise. His behaviour witnessed of the memory of remote and complicated stored material. Some months after the insult he resumed his artistic activity using his left hand and continued it principally in the same manner as before his illness. His drawing and water-painting displayed some uncertainty of lines and sometimes coarseness of the stain spots. His pieces of sculpture regained the quality of his earlier works, as proven already by the first statue he made after the insult. While it is generally accepted that the motor aphasia does not essentially affect the artistic production, even of high quality, in painting, this is the first instance which proves that the same holds true for sculpture. In this case the mechanisms inciting the finest innervation on the side of the cortical center of the left hand, can work with promptness. In motor aphasia the mechanisms indispensable for the correct realisation of the function are affected without a final extinction of the function itself. Motor asphasia is an instrumental disorder not necessarily accompanied by disturbances of the intelligence.

Adult↗

Quality-of-life measures in chronic diseases of childhood.

SCOPE OF THE REPORT: This report is concerned with the evaluation of measures broadly designed to measure quality of life (QoL) in children and adolescents, either by self-report or proxy raters. Four research questions were identified: (1) To what extent are adult measures used in the evaluation of healthcare interventions in children? (2) How appropriate are adult measures for use with children? (3) To what extent do child self-reports correspond with assessments made by parents and carers? (4) How feasible and reliable are proxy measures of QoL in different disease contexts? OBJECTIVES: (1) To review the state of the art with regard to measurement of QoL for children. (2) To make recommendations regarding the value of currently available measures for different purposes. (3) To identify further research needs. METHOD: Electronic databases were searched for the period 1980-July 1999 for articles relating to measures of QoL, health status or well-being in children (under 18 years) with chronic disease. Handsearching of relevant journals and cross-referencing with reference lists in identified articles was also carried out. Key workers in the field were contacted for additional information, and the Internet was searched for relevant websites. RESULTS: Forty-three measures were identified (19 generic and 24 disease-specific). Sixteen measures allowed for completion by children and parent/caregiver; seven only allowed for completion by a proxy, and the remainder (n = 17) allowed only for child completion. The measures were described as QoL (n = 30), health status, (n = 2), perception of illness (n = 1), life satisfaction (n = 1) and quality of well-being (n = 1). RESULTS - TO WHAT EXTENT ARE ADULT MEASURES USED IN THE EVALUATION OF HEALTHCARE INTERVENTIONS IN CHILDREN?: Three studies were identified where adult measures were used with very few changes made for children. In 11 studies involving nine separate measures of QoL, adult measures were used as a model for work with children. RESULTS - HOW APPROPRIATE ARE ADULT MEASURES FOR USE WITH CHILDREN?: Adult measures may fail to tap the specific aspects of QoL that are important to the child. Measures based on adult work impose considerable response burden for children, in terms of length, reading skills and response scale. Wording and format of adult measures may need to be modified to account for children's cognitive and language skills. More basic research is needed to determine the level of response burden that children of different ages can manage. Assessments of difficulty (e.g. reading age) need to be routinely included with information about new measures. RESULTS - TO WHAT EXTENT DO CHILD SELF-REPORTS CORRESPOND WITH ASSESSMENTS MADE BY PARENTS AND CARERS?: Fourteen studies were identified in which concor-dance between child and parent was investigated, often as part of the development of a new measure. There was some evidence for greater concordance between child and parent for physical functioning compared with social and emotional domains, but greater heterogeneity in the latter measures may contribute to inconsistent results. There was no simple relationship between concordance and moderating variables such as age, gender and illness, but this conclusion was addressed only very rarely. RESULTS - HOW FEASIBLE AND RELIABLE ARE PROXY MEASURES OF QOL IN DIFFERENT DISEASE CONTEXTS?: Only five papers fulfilled the review criteria. Evaluation is difficult because authors fail to justify their choice of measures, and do not report critical information such as completion rates or missing data. Use of existing measures can potentially eliminate the time and expense required to develop a comprehensive measure of QoL, but a full battery of standardised tests may be expensive in terms of time for administration and scoring. In addition, battery measures tend to be lengthy and therefore demanding for sick patients. They are not recommended for work with children. RECOMMENDATIONS FOR RESEARCH - MINIMUM CRITERIA FOR NEW MEASURES: A set of procedures needs to be established for the development of new measures. These need to draw on the experience gained in development of child and adult measures to date. Basic research to enhance understanding of how children interpret questions in QoL measures is recommended. We need to understand the differences in meaning of items between children and adults, and between children of different ages. Some attempt to develop measures for children of 6 years or more have been reported, and these should be further developed. (ABSTRACT TRUNCATED)

Adolescent↗

Preventing school failure: the physician as child advocate.

Attending school heralds the end of the relative protection and nurture of home life. During the school day, a child experiences successes and failures that portend future feelings of self-worth and self-esteem. Usually children experiencing difficulty at school are identified by teachers, however, children are overlooked. When they are and subsequently experience chronic failure and frustration, long-term morbidity may ensue. Ideally, methods to identify potential learning problems should be available. Unfortunately, the state of the art does not allow accurate identification of problems before they occur. After any number of screening tests, we can accurately predict school successes, but predicting failure is elusive. Early school failure, however, like many maladies, can be diagnosed, particularly if a physician has a high index of suspicion and looks for signs and symptoms of ongoing failure and frustration. Family history, neonatal course, presence of minor congenital anomalies and soft neurological signs, attention problems and lack of age-appropriate processing skills in the preschool period should place a child at risk. Close observation should designate those children who fail to mobilize associated strengths that maintain development. Early intervention will reduce morbidity associated with academic difficulty. Longitudinally, reduction of chronic failure may be the most crucial intervention. The unfortunate cycle of developmental dysfunction leading to school failure and lowered self esteem with subsequent social pathology and delinquency is well known. To the extent that physicians are able to ensure appropriate school services for children experiencing failure, this cycle can be short circuited, adding significantly to the physician's traditional armamentarium.

Adolescent↗

A comparative study of cells in inflammation, EAE and MS using biomedical literature data mining.

Biomedical literature and database annotations, available in electronic forms, contain a vast amount of knowledge resulting from global research. Users, attempting to utilize the current state-of-the-art research results are frequently overwhelmed by the volume of such information, making it difficult and time-consuming to locate the relevant knowledge. Literature mining, data mining, and domain specific knowledge integration techniques can be effectively used to provide a user-centric view of the information in a real-world biological problem setting. Bioinformatics tools that are based on real-world problems can provide varying levels of information content, bridging the gap between biomedical and bioinformatics research. We have developed a user-centric bioinformatics research tool, called BioMap, that can provide a customized, adaptive view of the information and knowledge space. BioMap was validated by using inflammatory diseases as a problem domain to identify and elucidate the associations among cells and cellular components involved in multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE). The BioMap system was able to demonstrate the associations between cells directly excavated from biomedical literature for inflammation, EAE and MS. These association graphs followed the scale-free network behavior (average gamma = 2.1) that are commonly found in biological networks.

Animals↗

Children's perceptions of the nursing profession in Poland.

The drawing, as a kind of artistic language, used by the child-artist to express his or her thoughts and opinions concerning their environment is an immensely interesting form of cognition for the viewers of such artistic creations. The aim of the study was the analysis of the presentation of the image of the nursing profession created by children and the application of these experiences in vocational education of nurses. The objects of the analysis, were 182 artistic creations of children living in eastern Poland. The detailed analysis of the works was carried out by three independent competent judges who grouped the works according to the accepted indicators of evaluation. The young artists created the image of the nurse that presents a detailed range of professional duties, the quality of the child-nurse relationship and the prognostic vision of the new activities that will be put into practice in the future. The rich content of the drawings was complemented by the high artistic value of the composition. The study material collected should be used not only by nurses participating in care of children, but also in vocational education of nurses for more complete preparation of candidates to perform their future profession.

Adolescent↗

A combined approach to data mining of textual and structured data to identify cancer-related targets.

BACKGROUND: We present an effective, rapid, systematic data mining approach for identifying genes or proteins related to a particular interest. A selected combination of programs exploring PubMed abstracts, universal gene/protein databases (UniProt, InterPro, NCBI Entrez), and state-of-the-art pathway knowledge bases (LSGraph and Ingenuity Pathway Analysis) was assembled to distinguish enzymes with hydrolytic activities that are expressed in the extracellular space of cancer cells. Proteins were identified with respect to six types of cancer occurring in the prostate, breast, lung, colon, ovary, and pancreas. RESULTS: The data mining method identified previously undetected targets. Our combined strategy applied to each cancer type identified a minimum of 375 proteins expressed within the extracellular space and/or attached to the plasma membrane. The method led to the recognition of human cancer-related hydrolases (on average, approximately 35 per cancer type), among which were prostatic acid phosphatase, prostate-specific antigen, and sulfatase 1. CONCLUSION: The combined data mining of several databases overcame many of the limitations of querying a single database and enabled the facile identification of gene products. In the case of cancer-related targets, it produced a list of putative extracellular, hydrolytic enzymes that merit additional study as candidates for cancer radioimaging and radiotherapy. The proposed data mining strategy is of a general nature and can be applied to other biological databases for understanding biological functions and diseases.

Biomarkers, Tumor↗

The depiction of seizures in film.

PURPOSE: The purpose was to describe the depiction of epilepsy in English language film. METHODS: The list of films, developed by consulting several databases, film scholars, and neurologists, includes every film suggested by any source. By using the saturation techniques of grounded theory, names of films were sought until no new names were received. All films were reviewed by an experienced board-certified neurologist. RESULTS: Seizures were depicted in 20 films. Generally, seizures are used in film to develop narrative or enrich character. They serve four functions: (a) a principal character has epilepsy; thus the condition is critical to character and narrative; (b) a seizure is used to drive the narrative; (c) a seizure is used to enrich a minor role; and (d) a seizure is feigned to distract attention from another activity. CONCLUSIONS: Conclusions can be drawn in four areas: character, accuracy of depiction, roles and responses of onlookers, and the place of epilepsy in the films: (a) Epilepsy is one dimension linked with other aspects of an individual to enrich character; (b) Seizures are depicted fairly accurately, but their frequent representation as uncontrollable and violent is exaggerated and out of date; (c) In the films, the onlookers' responses range from fear to taking correct measures; and (d) The presence of epilepsy is never arbitrary, but the function varies. Overall, the view of epilepsy conveyed in film continues to be distorted, sensationalized, and presented in the most frightening ways.

Epilepsy↗

Drugs held and sold by pharmacists of the Jewish community of medieval (11-14th centuries) Cairo according to lists of materia medica found at the Taylor-Schechter Genizah collection, Cambridge.

The importance of the Genizah for the research of the medieval Mediterranean communities, supplying information on almost every aspect of life, is well known among historian. Less known is that pharmacy was the most popular of all branches of the healing art in the medieval Jewish community of Cairo, according to the Genizah manuscripts. Sources for study of medieval practical drugs are extremely rare since most records naturally vanish over the years, and only some medical books, which contained theoretical pharmacology, have survived to the present day. Drugs lists enable us to understand medieval practical pharmacy and to reconstruct their inventories. This study reports on 71 original drugs lists that were found in the Genizah; they are different from merchants' letters dealing with commerce in drugs and give no instructions for the use or preparation of formulas as usually found in prescriptions. Twenty-six lists are written in Judeo-Arabic and 45 in Arabic, none of the lists is written in Hebrew. The longest list contains 63 identified substances. These lists were apparently used by pharmacists for professional and business purposes as inventories of drugs, records, orders, or even receipts. Two hundred and six different drugs are mentioned in the drugs lists of which 167 are of plant origin, 16 are of animal origin, and the remaining 23 are inorganic. The lists point directly to the place they occupied on the shelves of the pharmacies that could be found in the lanes and alleys of the Jewish quarter of Cairo. The most frequently mentioned substance were myrobalan (27), pepper and saffron (21), lentisk (15), almond, basil, rose, rosemary (14), cattle products, camphor and spikenard (13).

Animals↗

In vitro fertilization-conceived offspring exhibit altered Long Interspersed Nuclear Elements-1 retrotransposition dynamics associated with long-term disease risks.

BACKGROUND: In vitro fertilization has transformed reproductive medicine, yet offspring conceived through in vitro fertilization display elevated risks for diverse long-term health conditions, with underlying mechanisms unclear. Long Interspersed Nuclear Elements-1, a mobile genetic element responsive to environmental stress, represents a potential mediator. OBJECTIVE: This study aimed to test the hypothesis that in vitro fertilization procedures may act as an embryonic stressor that alters Long Interspersed Nuclear Elements-1 dynamics, potentially contributing to genomic instability associated with long-term disease susceptibility. STUDY DESIGN: Umbilical cord blood or peripheral blood from 33 in vitro fertilization and 42 naturally conceived neonates were collected for whole-genome sequencing. Total Long Interspersed Nuclear Elements-1 proportion in individual genome was counted with Bowtie2 software. De novo Long Interspersed Nuclear Elements-1 insertion and Long Interspersed Nuclear Elements-1 deletion were detected with Mobile Element Locator Tool. Three parent-matched in vitro fertilization-naturally conceived sibling pairs were included to control for genetic background. Disease association analysis was performed for genes within 500 kb of differential Long Interspersed Nuclear Elements-1 sites in The Database for Annotation, Visualization and Integrated Discovery (DAVID). Statistical analysis was performed using the R language. RESULTS: In vitro fertilization offspring demonstrate elevated global Long Interspersed Nuclear Elements-1 content compared to naturally conceived controls (P=.04). This finding was corroborated in 3 sibling pairs from identical genetic backgrounds, where in vitro fertilization-conceived children consistently exhibited higher Long Interspersed Nuclear Elements-1 levels than their naturally conceived siblings. Eleven genomic loci with differential Long Interspersed Nuclear Elements-1 insertion frequencies and 14 loci with differential Long Interspersed Nuclear Elements-1 deletion frequencies between in vitro fertilization offspring and naturally conceived controls were identified. Notably, these differential Long Interspersed Nuclear Elements-1 sites demonstrated significant enrichment near genes implicated in metabolic, cardiovascular, neuropsychiatric, and neoplastic diseases, conditions associated with in vitro fertilization conception. CONCLUSION: These findings provide preliminary evidence that in vitro fertilization conception is associated with increased Long Interspersed Nuclear Elements-1 content and altered genomic distribution of Long Interspersed Nuclear Elements-1 elements. The proximity of these differential Long Interspersed Nuclear Elements-1 sites to disease-associated genes suggests a plausible genomic mechanism linking in vitro fertilization-associated embryonic stress to elevated disease risk. This work provides valuable molecular insights that may inform the ongoing discussion about assisted reproductive technology safety and suggests that continued attention to genomic integrity in in vitro fertilization-conceived individuals would be beneficial.

Humans↗

An empirical analysis of training protocols for probabilistic gene finders.

BACKGROUND: Generalized hidden Markov models (GHMMs) appear to be approaching acceptance as a de facto standard for state-of-the-art ab initio gene finding, as evidenced by the recent proliferation of GHMM implementations. While prevailing methods for modeling and parsing genes using GHMMs have been described in the literature, little attention has been paid as of yet to their proper training. The few hints available in the literature together with anecdotal observations suggest that most practitioners perform maximum likelihood parameter estimation only at the local submodel level, and then attend to the optimization of global parameter structure using some form of ad hoc manual tuning of individual parameters. RESULTS: We decided to investigate the utility of applying a more systematic optimization approach to the tuning of global parameter structure by implementing a global discriminative training procedure for our GHMM-based gene finder. Our results show that significant improvement in prediction accuracy can be achieved by this method. CONCLUSIONS: We conclude that training of GHMM-based gene finders is best performed using some form of discriminative training rather than simple maximum likelihood estimation at the submodel level, and that generalized gradient ascent methods are suitable for this task. We also conclude that partitioning of training data for the twin purposes of maximum likelihood initialization and gradient ascent optimization appears to be unnecessary, but that strict segregation of test data must be enforced during final gene finder evaluation to avoid artificially inflated accuracy measurements.

Algorithms↗

["I am but mad north-north-west"--Hamlet's portrayed delusion].

Whereas science refers to the real world existing independently and conditioned by cause and effect, the world of literature is fictitious, created by the artist in our imagination by means of language, an artefact conditioned by aesthetic laws, a world sui generis. Accordingly, Hamlet is no person, but a literary figure, doing, saying, thinking and feeling only what the poet dictated him word for word. The essential difference between the two worlds is often overlooked. That "blind spot" has a long-standing tradition in European intellectual history and goes back i.a. to the German "Hamlet experience" in the eighteenth, the "Hamlet fever" and the felt spiritual kinship (Seelenverwandtschaft) in the nineteenth century. Teleological literary criticism, centering around Hamlet's "character" and isolating his psychologically evaluated monologues (e.g. Bradley), refrained from Hamlet's fictionality and role-play and led to blurring beyond recognition the boundaries between real person and literary figure (e.g. Freud, Jones) and assisted in reducing a dramatic role to a medical case history. Speaking of Hamlet, one has to start from Shakespeare's text, our subject matter. A dramatic play being a plot turned into dialogue, the poet's vocabulary used (but indirectly also the vocabulary not used) is particularly informative. When referring to Hamlet's "antic disposition", Shakespeare uses a wide range of over 20 different terms, the most frequented being mad/madness (44 times). Evidence of primary importance are the five occasions after the apparition of his father's ghost, when Hamlet speaks of hist "madness" as an assumed role. In Act I "madness occurs first as a mere possibility when Hamlet informs his friends, he might "put an antic disposition on"; in Act II vis-a-vis Rosencrantz and Guildenstern ("I am but mad north-north-west") it is his deliberate action under certain conditions; in Act III it occurs thrice, first in his declaration of intent ("They are coming to the play, I must be idle" (i.e. "mad"), next in answering the king ("I fare of the chamaeleon's dish"), and once again in a particularly explicit distinction for his mother ("I am essentially not in madness, but mad in craft"). The evidence of all other instances of mad/madness represented here corroborates these findings: madness as an adopted role and not as a character trait. - It should also be noted that Shakespeare's main source (Belleforests adaptation of the Amleth-story from Saxo Grammaticus) already knew of the motive of stimulated madness as a cover for revenge. Hamlet assumes the role of a "madman" in order to have full scope for action, first, to test by help of the "play in the play" the truth of his father's apparition as a ghost demanding revenge as well as the actual guilt of Claudius and, when that is established, for preparing and executing his revenge. By acting himself, Hamlet becomes guilty and (Shakespeare having chosen the dramatic genre of tragedy) pays for his success with his life. Considering the constant border-crossings between the spheres of real persons and fictive literary figures in psychological approaches to Hamlet, we stressed the essential difference of a literary work of art from real life. At the same time, the inherent limitations of that difference must be shown as well. Although the world of belles lettres is fictive and non-existent in reality, it does not play in a vacuum. It is fed, in many ways, by the poet's experience of his own days as well as by the work's position within the realm of literary tradition (genre, sources, etc.). It is perhaps easy, to insist on the self-contained nature of literature, making literary criticism an arcane activity of a few elected professionals. The price to pay would be, as Laurence Lerner points out, that great literature will no longer tell us anything about life, and the poet's subtle insights, his wisdom, his understanding of the soul and of the world cease to enrich the general read

Delusions↗