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Candidate genes and single nucleotide polymorphisms (SNPs) in the study of human disease.

The genomic revolution has generated an extraordinary resource, the catalog of variation within the human genome, for investigating biological, evolutionary and medical questions. Together with new, more efficient platforms for high-throughput genotyping, it is possible to begin to dissect genetic contributions to complex trait diseases, specifically examining common variants, such as the single nucleotide polymorphism (SNP). At the same time, these tools will make it possible to identify determinants of disease with the expectation of eventually, tailoring therapies based upon specific profiles. However, a number of methodological, practical and ethical issues must be addressed before the analysis of genetic variation becomes a standard of clinical medicine. The currents of variation in human biology are reviewed here, with a specific emphasis on future challenges and directions.

Base Sequence↗

Serial Analysis of Gene Expression: Applications in Malaria Parasite, Yeast, Plant, and Animal Studies.

The serial analysis of gene expression (SAGE) method is based on the isolation of unique sequence tags from individual transcripts and concatenation of tags serially into long DNA molecules. SAGE is an innovative technique that offers the potential of cataloging both the identity and relative frequencies of mRNA transcripts in a given RNA preparation. It can quantify low-abundance transcripts and reliably detect relatively small differences in transcript abundance between cell populations. SAGE data can be used to complement studies in cases where other gene expression methods may be more convenient or efficient. SAGE can be used in a wide variety of applications to identify disease-related genes, to analyze the effect of drugs on tissues, and to provide insights into the disease pathways. The most important application of SAGE is the identification of differentially expressed genes. In this review, we describe various applications of this powerful technology in malarial parasite, yeast, plant, and animal systems.

Journal Article↗

Temporal expression of cell cycle-related proteins during spermatogenesis: establishing a timeline for onset of the meiotic divisions.

During spermatogenesis, the complex events of the first meiotic prophase and division phase bring about dramatic changes in nuclear organization. One factor frustrating mechanistic dissection of these events is lack of knowledge about precisely what events occur, in what order they occur, and how they may be interrelated by temporal sequence; in other words, a precise timeline is lacking. This temporal ordering problem can be tackled by following expression and localization in mouse spermatocytes of proteins critical to events of the meiotic cell division process. These include ones that are primarily chromosomal and related to pairing and recombination, as well as kinases and substrates that mediate the cell cycle transition. Distinct and protein-specific patterns occur with respect to expression and localization throughout meiotic prophase and division and dramatic relocalization of proteins occurs as spermatocytes enter the meiotic division phase. This information provides a foundation for a meiotic timeline that can be augmented to provide, eventually, a complete catalog of meiotic events and their temporal sequence. Such a framework can clarify mechanisms of normal meiosis as well as mutant phenotypes and aberrations of the meiotic process that lead to aneuploidy.

Animals↗

Report of the committee on structural chromosome changes in neoplasia.

An enormous amount of data on neoplasia-associated chromosome aberrations has accumulated over the past two years. More than 4,000 tumors with a chromosome anomaly identified by banding have been published since HGM9, and the total number of cases contained in the registry on which the Catalog of Chromosome Aberrations in Cancer (Mitelman, 1988) is based is now well above 12,000. The information presently available is, however, still in many respects incomplete. First, the data is heavily biased in favor of hematologic disorders. Solid tumors comprise only 20% of the total data base, which is totally disproportionate to the relative contribution of these disorders to human cancer morbidity and mortality. For example, malignant epithelial tumors (carcinomas), which cause almost 80% of all cancer deaths in man, comprise only 7% of the total. Second, our knowledge about early stage tumors is very limited. For example, the great majority of the solid tumors that have been studied cytogenetically have been metastatic lesions or effusions (advanced tumors usually have a large number of complex structural and numerical chromosome aberrations). Obviously, many more such neoplasms will have to be studied before the primary (pathogenetically essential) changes can be distinguished from the confusing variety of secondary abnormalities that may dominate the karyotype. It should be noted that secondary changes may also be nonrandom, and may be important for tumor progression. Therefore, no attempt has been made in this report to distinguish between primary and secondary changes. All nonrandomly occurring abnormalities that met the criteria for inclusion are listed in Table 1 irrespective of their presumed pathogenetic significance. Results of molecular genetic studies (e.g. the demonstration of loss of heterozygosity or gene amplification) were not considered, although they may be included in the HGM10.5 report. A total of 149 nonrandom chromosome changes were identified (Table 1) in 43 different types of neoplastic disorders, including hematologic diseases and malignant lymphomas, as well as tumors of epithelial, mesenchymal, neurogenic, germ cell, and melanocytic origin. The aberrations comprise a variety of structural chromosome rearrangements (translocations, inversions, insertions, deletions, duplications and isochromosomes), and all chromosomes, except the Y chromosome are involved. The great majority (121 of the 149 identified aberrations) represent well-defined, specific structural changes. More than half of them are consistently associated with a particular morphologic disease characteristic. Twenty-eight of the aberrations, although nonrandom, are not characterized as well. Most are deletions or translocations that only affect a certain chromosome region, often spanning several bands.(ABSTRACT TRUNCATED AT 400 WORDS)

Chromosome Aberrations↗

Cytogenetic nomenclature of deer mice, Peromyscus (Rodentia): revision and review of the standardized karyotype. Report of the Committee for the Standardization of Chromosomes of Peromyscus.

A revision of the standardized karyotype of deer mice (Peromyscus) is presented. This revision addresses short-comings of the original standardization, contains a substantial increase in the number of G-band markers and provides a nomenclature for the G-bands of each autosome and the X chromosome. Using the revised standardized karyotype, we specify the particular G-bands or patterns that identify each chromosome and catalog the more problematic chromosome identifications and likely misidentifications. For each chromosome, we present an overview of previously reported variation in euchromatic arrangement and heterochromatic constitution. We then review previous applications of the standardized karyotype and summarize the predominant findings from cytogenetic and cytosystematic studies of Peromyscus and related taxa.

Animals↗

The behavioral repertoire of the black-and-white ruffed lemur, Varecia variegata variegata (Primates: Lemuridae).

A stable social group of 7 semifree-ranging black-and-white ruffed lemurs (Varecia variegata variegata) was studied for 4 months to catalog the behavioral repertoire of this species. Observations focussed on particular aspects of behavior were conducted before and after this 4-month period to supplement information gathered. Behavior in 11 major categories is detailed: postures, terrestrial locomotion, arboreal locomotion, feeding behavior, vocalizations, scent-marking, affinitive social behavior, agonistic social behavior, play behavior, sexual behavior, and parental behavior. Ruffed lemurs frequently used body positions and locomotor patterns unusual among lemurids, including bipedal hanging and long-descent leaps. These behaviors reinforce dental evidence that Varecia are among the most frugivorous of the Malagasy lemurs. Low intragroup cohesion, infrequent social interaction, and antiphonal use of several long-distance vocalizations suggest that ruffed lemurs naturally exhibit fission-fusion sociality. Social structure based on interindividual familiarity probably extends across foraging parties for several of the diurnally active lemurs; however, thus far only Varecia seems likely to exhibit fission-fusion sociality analogous to that seen in spider monkeys and chimpanzees.

Animals↗

The monosomy 7 clone in interphase and metaphase cell population: a combined chromosome and primed in situ labeling study.

Loss of a chromosome 7 is associated with a poor prognosis in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Some studies have shown higher frequencies of monosomy 7 (-7) in dividing than nondividing myeloid cells, which might indicate that -7 confers a proliferative advantage on the host cell. As other groups have not been able to confirm this, we compared the -7 frequencies in bone marrow metaphases as studied with conventional cytogenetics and in interphase cells using primed in situ (PRINS) labeling. We found significantly higher -7 frequencies in metaphase than in interphase cells irrespective of diagnosis and presence or absence of additional chromosome aberrations. Further, we found a significant correlation between the -7 percentages in resting and dividing cells. Finally, as our material showed a clear male preponderance, Mitelman's Catalog of Chromosome Aberrations in Cancer was searched for -7. Of 815 cases with AML or MDS, 491 (60.3%) were found to be men. To our knowledge, this is the first observation of a clear deviation from the 1:1 sex ratio in -7 patients.

Acute Disease↗

[Dangers due to smoking and passive smoking].

Smoking has become the most important single cause of illness and death. Since the rate of cure for the most frequent types of organ cancers is still very poor with little chance of improvement in the foreseeable future, it has become necessary to put more emphasis on cancer prevention. The same holds true for the dangers of passive smoking, which have now been confirmed by all the representative scientific bodies at home and abroad. Legal protection of nonsmokers in the workplace is long overdue. The irresponsible inactivity on the part of our government with regard to smoking and passive smoking has been sharply denounced, since it has become obvious that neither health education and information nor appeals to the public can bring about a change in the situation, but only the implementation of a whole catalog of measures, including adequate legislation.

Humans↗

Material representations: from the genetic code to the evolution of cellular automata.

We present a new definition of the concept of representation for cognitive science that is based on a study of the origin of structures that are used to store memory in evolving systems. This study consists of novel computer experiments in the evolution of cellular automata to perform nontrivial tasks as well as evidence from biology concerning genetic memory. Our key observation is that representations require inert structures to encode information used to construct appropriate dynamic configurations for the evolving system. We propose criteria to decide if a given structure is a representation by unpacking the idea of inert structures that can be used as memory for arbitrary dynamic configurations. Using a genetic algorithm, we evolved cellular automata rules that can perform nontrivial tasks related to the density task (or majority classification problem) commonly used in the literature. We present the particle catalogs of the new rules following the computational mechanics framework. We discuss if the evolved cellular automata particles may be seen as representations according to our criteria. We show that while they capture some of the essential characteristics of representations, they lack an essential one. Our goal is to show that artificial life can be used to shed new light on the computation-versus-dynamics debate in cognitive science, and indeed function as a constructive bridge between the two camps. Our definitions of representation and cellular automata experiments are proposed as a complementary approach, with both dynamics and informational modes of explanation.

Artificial Intelligence↗

A distributed computing tool for generating neural simulation databases.

After developing a model neuron or network, it is important to systematically explore its behavior across a wide range of parameter values or experimental conditions, or both. However, compiling a very large set of simulation runs is challenging because it typically requires both access to and expertise with high-performance computing facilities. To lower the barrier for large-scale model analysis, we have developed NeuronPM, a client/server application that creates a "screen-saver" cluster for running simulations in NEURON (Hines & Carnevale, 1997). NeuronPM provides a user-friendly way to use existing computing resources to catalog the performance of a neural simulation across a wide range of parameter values and experimental conditions. The NeuronPM client is a Windows-based screen saver, and the NeuronPM server can be hosted on any Apache/PHP/MySQL server. During idle time, the client retrieves model files and work assignments from the server, invokes NEURON to run the simulation, and returns results to the server. Administrative panels make it simple to upload model files, define the parameters and conditions to vary, and then monitor client status and work progress. NeuronPM is open-source freeware and is available for download at http://neuronpm.homeip.net . It is a useful entry-level tool for systematically analyzing complex neuron and network simulations.

Animals↗

Potential roles for diatomists in nanotechnology.

Diatoms produce diverse three-dimensional structures that, due to their exponential rate of growth, may be of use in the manufacture of components for nanotechnology as an alternative to present linear lithographic techniques. Vapor replacement of the silicon permits the conversion of diatom silica valves and other structures to metal/ceramics, with no loss of structure. The literature on diatom nanotechnology is reviewed, along with suggestions on how diatomists might enhance this emerging technology. There is a need for a systematics based catalog of parts (via genomics technologies), improved diatom culture techniques, better understanding of the mechanisms of diatom morphogenesis and motility, and genetic manipulation, mutagenesis, and selection, as via the chemostat-like compustat. Given the self-motility of raphid diatoms, they could form the basis for industrially useful nanobots.

Biomimetics↗

The idiot savant: a review of the syndrome.

Since it was first described a century ago, the phenomenon of the idiot savant--the juxtaposition of severe mental handicap and prodigious mental ability--has remained unexplained. The author defines the condition, reviews and summarizes the world literature on this topic since the early reports, describes more recent cases, and catalogs and categorizes idiot savant abilities. Theories to explain the condition are reviewed, newer research findings are highlighted, and the far-reaching implications of the idiot savant syndrome for understanding normal brain function, particularly memory, are outlined.

Adult↗

Principles of supportive psychotherapy.

I have attempted to survey and outline the conceptual differences between expressive and supportive forms of psychotherapy based on the construct of a spectrum with these forms of treatment at each end. As one moves toward the middle of the spectrum, the situation becomes more difficult to define and, to a certain extent, elements of each may be present in the other form of treatment. However, the more that the therapist can consistently maintain an understanding of the differences between these forms of therapy, and the more consistently he or she can apply them in terms of the tactics and the technical interventions used, the more likely is it that the goals of the treatment process will be achieved. If there is too much overlap or if too much confusion exists between the different strategic approaches (and the appropriate tactics involved), the therapist may inadvertently reinforce disturbed and regressive behavior; or the therapist may inadvertently keep the patient from benefiting optimally from the kind of treatment that has been undertaken. There is no way to catalog or describe all of the different available types of intervention, but it is possible to generalize and conceptually predict what the effects are likely to be given the nature of the treatment process being undertaken. The vast majority of psychiatric patients will probably make use primarily of supportive elements in the treatment experience and only a relatively small proportion of the total population will be optimally helped by an expressive treatment undertaking. It therefore becomes necessary to use creative and consistently organized ways of being supportive and to base the choice of tactics on the psychodynamic understanding of the strategy and technique of the therapeutic process.

Catharsis↗

The psychiatrist's role as medical director: task distributions and job satisfaction.

OBJECTIVES: Previous surveys of the alumni of Columbia University's fellowship in public psychiatry suggest that a large number of alumni fill positions as program medical directors. In contrast with agency medical directors, program medical directors work within team structures and maintain a high degree of clinical involvement. The fellowship faculty surveyed the alumni to catalog the tasks performed by program medical directors, agency medical directors, and staff psychiatrists and to determine the extent to which these tasks contribute to job satisfaction. METHODS: A survey form was developed using a list of tasks derived from the American Psychiatric Association's guidelines for psychiatrists working in organized mental health care delivery systems and from a recent article that surveyed job descriptions of psychiatrists in community mental health centers. The survey form was distributed to all current fellows and alumni in active practice (N = 89). RESULTS AND CONCLUSIONS: Seventy-two forms were returned, for a response rate of 81 percent. Respondents who were medical directors performed a greater variety of tasks and reported higher job satisfaction than those who were staff psychiatrists. Higher job satisfaction was related to a greater variety of tasks performed, especially tasks involving clinical collaboration. Most of the respondents were program medical directors rather than agency medical directors. The position of program medical director constitutes a relatively small and attainable step above that of staff psychiatrist. Agencies would do well to consider creating positions of program medical directors for their staff psychiatrists whenever feasible, and psychiatrists committed to public-sector careers should negotiate to have such positions.

Adult↗

The otolaryngologist as a role model.

Throughout our daily interactions with medical students and residents, each of us, whether we like it or not, functions as a role model. Since role modeling is primarily a passive function - teaching by example - we may not be acutely aware of this role and its importance. In what respect is the concept of the role model important to otolaryngology-head and neck surgery? In addition to the function of specific training - teaching the trade - most of the literature on role modeling cites 2 major areas of significance: 1) influencing medical students' career choices and 2) facilitating socialization into the world of medicine with the establishment of an appropriate professional identity. This brief article reviews some of the current literature, catalogs those attributes that have been identified as those of excellent role models, and offers some thoughts as to what our specialty might consider in response to the challenges to medical education in the changing health care environment.

Career Choice↗

Nationwide survey of postsecondary education services for students with learning disabilities.

Postsecondary services for students with learning disabilities vary a great deal from campus to campus, and published guides to postsecondary education services are often inaccurate and incomplete. A nationwide survey was conducted to investigate student service provisions in 2-year colleges and 4-year colleges and universities. The purpose of the study was to identify and catalog postsecondary education service goals and options for students with learning disabilities, and to determine differences between the goals service providers have for these students and services actually provided. The findings and their implications for service providers at both high school and college levels are discussed.

Data Collection↗

A compilation of partial sequences of randomly selected cDNA clones from the rat incisor.

The formation of tooth organs is regulated by a series of developmental programs. We have initiated a genome project with the ultimate goal of identifying novel genes important for tooth development. As an initial approach, we constructed a unidirectional cDNA library from the non-calcified portion of incisors of 3- to 4-week-old rats, sequenced cDNA clones, and classified their sequences by homology search through the GenBank data base and the PIR protein data base. Here, we report partial DNA sequences obtained by automated DNA sequencing on 400 cDNA clones randomly selected from the library. Of the sequences determined, 51% represented sequences of new genes that were not related to any previously reported gene. Twenty-six percent of the clones strongly matched genes and proteins in the data bases, including amelogenin, alpha 1(I) and alpha 2(I) collagen chains, osteonectin, and decorin. Nine percent of clones revealed partial sequence homology to known genes such as transcription factors and cell surface receptors. A significant number of the previously identified genes were expressed redundantly and were found to encode extracellular matrix proteins. Identification and cataloging of cDNA clones in these tissues are the first step toward identification of markers expressed in a tissue- or stage-specific manner, as well as the genetic linkage study of tooth anomalies. Further characterization of the clones described in this paper should lead to the discovery of novel genes important for tooth development.

Amelogenesis↗

Age-related neoplasia in a lifetime study of ad libitum-fed and food-restricted B6C3F1 mice.

Longevity, body weight, and age-specific neoplasia were determined in 1,064 B6C3F1 mice as part of a coordinated study of food restriction (FR). Restricted animals were offered 60% of the diet consumed by the ad libitum (AL) group. Longevity data were derived from a set of 56 animals of each sex from each diet group, which were examined whenever dead or moribund. For cross-sectional data, a parallel set of 210 animals were sacrificed in groups of 12-15 at 6-mo intervals. Lifetime body weight was reduced in the FR mice approximately proportional to restriction (i.e., 40%). Food restriction increased the age at 50% survival (median) by 36% in both sexes and increased the maximal lifespan (mean age of oldest 10%) by 21.5% in males and by 32.5% in females. In 56 males of the longevity groups, there were 89 neoplasms in the AL subgroup versus 53 in FR; 56 AL females had 100, versus 58 in 55 FR females. Increase in lifespan of the restricted animals was achieved primarily by decrease in incidence and delay of onset of fatal tumors, of which lymphoma was the most prominent. This report catalogs all of the neoplasms (1,103) observed in longevity and cross-sectional groups, by diet, sex, and age. These data add to the existing knowledge base needed for future studies of dietary restriction and aging as well to evaluate nutrition of animals used in bioassays.

Aging↗