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Linkage of a marker in intron D of the estrogen synthase locus to rheumatoid arthritis.

OBJECTIVE: To test for the presence of linkage of the estrogen synthase (CYP19) locus to rheumatoid arthritis (RA) in affected sibling pair (ASP) families. METHODS: Two data sets of RA ASPs (225 ASPs and 107 ASPs) were genotyped for a polymorphic tetranucleotide marker at the CYP19 locus using fluorescence-based semiautomated genotyping technology. Evidence of linkage was assessed by estimating allele sharing (identical by descent) in affected sibling pairs. The effect of this locus was also examined in patient subgroups stratified by sex and by age at disease onset. RESULTS: An increase in allele sharing at the CYP19 locus was observed in the first data set of 225 ASPs (logarithm of odds [LOD] 0.8; P = 0.04). There was also an increase in allele sharing in a second data set, but this did not reach statistical significance (LOD 0.34; P = 0.1). The highest increase in allele sharing was seen in patients with an age at disease onset that was >50 years (LOD 1.1; P = 0.02). CONCLUSION: An increase in allele sharing at the CYP19 locus has been demonstrated in 2 large samples of RA ASPs. The evidence for linkage was strongest in patients with an age at onset that was >50 years, which suggests that this locus may be a susceptibility locus for developing RA later in life. These data provide preliminary evidence that CYP19 may have a role in RA susceptibility.

Aromatase↗

[Biomedical information networks: the experience of the United States National Library of Medicine].

A rapid and intensive flow of biomedical information is perceived increasingly as a requirement for the advancement of research, professional training, and the delivery of health services to an ever-growing human population. This article examines the concept of a network of information and cooperative services among medical libraries and national, regional and international data banks to maximize the sharing and use of the available resources. The background and record of the National Library of Medicine of the United States, which established the MEDLARS System, are described as a model for guidance. Since the end of the 19th century, when J. S. Billings, the foresighted first director of the Library, devised the first system for the indexing of medical literature, new techniques have been introduced step by step to facilitate the dissemination of biomedical information: mechanization and automatization of the placement of requests and data retrieval, telecommunications and satellite links to the fifteen data banks currently accessible to the user by direct communication through MEDLINE. For such a network to operate successfully, there must be a shift from the idea of regional or national benefit to the plane of global cooperation, through which a higher degree of self-sufficiency can be achieved. Also, relations between the various levels of the system must be based on a collaboration in which each entity pursues its own function subject to the character and multifarious scope of the common purposes. The success of BIREME in Latin America is cited as an incentive to developing countries to participate in the use and distribution of vital information through activities based on individual priorities without forgetting that what is important is not ideals and abstractions, but the human being with his needs, problems and real situation.

History, 19th Century↗

Clinical use and misuse of automated semen analysis.

During the past six years, there has been an explosion of technology which allows automated machine-vision for sperm analysis. CASA clearly provides an opportunity for objective, systematic assessment of sperm motion. But there are many caveats in using this type of equipment. CASA requires a disciplined and standardized approach to semen collection, specimen preparation, machine settings, calibration and avoidance of sampling bias. Potential sources of error can be minimized. Unfortunately, the rapid commercialization of this technology preceded detailed statistical analysis of such data to allow equally rapid comparisons of data between different CASA machines and among different laboratories. Thus, it is now imperative that we standardize use of this technology and obtain more detailed biological insights into sperm motion parameters in semen and after capacitation before we empirically employ CASA for studies of fertility prediction. In the basic science arena, CASA technology will likely evolve to provide new algorithms for accurate sperm motion analysis and give us an opportunity to address the biophysics of sperm movement. In the clinical arena, CASA instruments provide the opportunity to share and compare sperm motion data among laboratories by virtue of its objectivity, assuming standardized conditions of utilization. Identification of men with specific sperm motion disorders is certain, but the biological relevance of motility dysfunction to actual fertilization remains uncertain and surely the subject for further study.

Automation↗

The effect of varying albumin concentration and hydrostatic pressure on hydraulic conductivity and albumin permeability of cultured endothelial monolayers.

An in vitro model of the endothelial transport barrier was developed using bovine aortic endothelial cell monolayers cultured on a porous polycarbonate substrate. Hydraulic conductivity (Lp) was measured by a bubble tracking technique at varying pressure differentials and albumin concentrations. The effective albumin permeability (Pc) was determined by measuring the flux of fluorescent-labeled albumin across monolayers at varying hydrostatic pressures. Lp determined at pressure differentials between 5.0 and 10 cm H2O demonstrated a strong dependence on albumin concentration, decreasing approximately 10-fold from 21.3 x 10(-7) +/- 3.18 x 10(-7) cm/sec/cm H2O (mean +/- SEM) at 0.0 g/dl to 2.35 x 10(-7) +/- 0.20 x 10(-7) cm/sec/cm H2O at 1.0 g/dl albumin. Increasing the albumin concentration from 1.0 to 4.0 g/dl reduced Lp by an additional 16% to 1.97 x 10(-7) +/- 0.17 x 10(-7) cm/sec/cm H2O. Furthermore, Lp was moderately dependent on the pressure differential, increasing by about a factor of two with a doubling of the pressure differential. The effective permeability (Pc) was also dependent on the pressure differential. At an albumin concentration of 4.0 g/dl, Pc increased from 1.37 x 10(-6) +/- 0.26 x 10(-6) cm/sec at 0.0 cm H2O to 5.06 x 10(-6) +/- 1.92 x 10(-6) cm/sec at 10 cm H2O. Analysis of Pc and Jv data, however, demonstrates that water and albumin do not share a common pathway in crossing the endothelial monolayer. These data suggest the existence of a large pore pathway for albumin. Thus, the in vitro system has many of the transport characteristics of intact vessels in vivo and should be useful for physiological studies of the endothelial transport barrier.

Albumins↗

Forensic drug intelligence: an important tool in law enforcement.

Organised criminality is a great concern for national/international security. The demonstration of complex crimes is increasingly dependant on knowledge distributed within law-enforcement agencies and scientific disciplines. This separation of knowledge creates difficulties in reconstructing and prosecuting such crimes. Basic interdisciplinary research in drug intelligence combined with crime analysis, forensic intelligence, and traditional law enforcement investigation is leading to important advances in crime investigation support. Laboratory results constitute one highly dependable source of information that is both reliable and testable. Their operational use can support investigation and even provide undetected connections or organisation of structure. The foremost difficulties encountered by drug analysts are not principally of a chemical or analytical nature, but methodologies to extract parameters or features that are deemed to be crucial for handling and contextualising drug profiling data. An organised memory has been developed in order to provide accurate, timely, useful and meaningful information for linking spatially and temporally distinct events on a national and international level (including cross-border phenomena). Literature has already pointed out that forensic case data are amenable for use in an intelligence perspective if data and knowledge of specialised actors are appropriately organised, shared and processed. As a particular form of forensic case data, the authors' research focuses on parameters obtained through the systematic physical and chemical profiling of samples of illicit drugs. The procedure is used to infer and characterise links between samples that originate from the same and different seizures. The discussion will not, however, focus on how samples are actually analysed and compared as substantial literature on this topic already exists. Rather, attention is primarily drawn to an active and close collaboration between magistrates, forensic scientists, law enforcement investigators and crime analysts from different institutions with the aim of generating, using and validating relevant profiling case data as integral part of investigative and crime analysis processes. Original advances are highlighted through experiences from criminal investigations of offences related to the unlawful importation, exportation, supply and possession of illicit drugs.

Journal Article↗

Anterior cervical graft and plate load sharing.

Anterior discectomy and fusion with an interbody bone graft and anterior plate is a common procedure in cervical spine surgical management. However, the graft may be shielded from some mechanical loading by the plate. Mechanical testing was performed on six cadaveric calf spines that were subjected to a simulated anterior cervical discectomy and fusion with an interbody bone graft alone and with an anterior plate to determine the amount of load sharing between the graft and plate. The load-displacement data were used to compute the amount of load sharing between the graft and the plate as a continuous function of the applied axial compression load. Although the percent load transmitted through the graft decreased (53 to 41%) as the axial load increased (45 to 90 N), the magnitude of load transmitted through the graft increased (24 to 37 N), with corresponding intervertebral strains <6%. In a single-level procedure, an anterior cervical plate serves as a load-sharing device rather than a load-shielding device, enabling graft consolidation as observed in clinical studies.

Animals↗

Science fiction becomes reality with M technologies.

Sophisticated data management--the ability to share information across geographical and technical boundaries via heterogeneous networks with seamless interoperability--was the stuff of science fiction just a few years ago. It is now a reality with M. Thomas Salander, vice chair of the M Technology Association and chairman of the MUMPS Development Committee, sets the scene and shows the way.

Computer Communication Networks↗

Recent advances in the management of biotherapy-related side effects: fatigue.

Limited information about fatigue patterns in patients with cancer exists in the biotherapy literature. When fatigue is mentioned, it is usually to state whether or not it was a dose-limiting side effect. No further data are provided on how fatigue was measured; which patterns were noted and when; and which relationships were found between fatigue and demographic characteristics, type of biologic response modifier, route of administration, or cumulative dose. Thus, there is little available in the biotherapy literature to guide nursing practice in managing this side effect. Theory that guides practice, however, often emanates from the personal experiences of the patients and from the clinical observations and intuitive hunches of the nurses and physicians participating in clinical trials. These individuals have been most generous in sharing their insights and unpublished data with the authors. This paper presents a comprehensive view of current knowledge on fatigue to guide present nursing practice with patients receiving biotherapy and to provide direction for future nursing and clinical trial research.

Fatigue↗

IMIRS: a high-resolution 3D reconstruction package integrated with a relational image database.

Recent advances in electron cryomicroscopy instrumentation and single particle reconstruction have created opportunities for high-throughput and high-resolution three-dimensional (3D) structure determination of macromolecular complexes. However, it has become impractical and inefficient to rely on conventional text file data management and command-line programs to organize and process the increasing numbers of image data required in high-resolution studies. Here, we present a distributed relational database for managing complex datasets and its integration into our high-resolution software package IMIRS (Image Management and Icosahedral Reconstruction System). IMIRS consists of a complete set of modular programs for icosahedral reconstruction organized under a graphical user interface and provides options for user-friendly, step-by-step data processing as well as automatic reconstruction. We show that the integration of data management with processing in IMIRS automates the tedious tasks of data management, enables data coherence, and facilitates information sharing in a distributed computer and user environment without significantly increasing the time of program execution. We demonstrate the applicability of IMIRS in icosahedral reconstruction toward high resolution by using it to obtain an 8-A 3D structure of an intermediate-sized dsRNA virus.

Animals↗

Segregation analysis of prostate cancer in 1,719 white, African-American and Asian-American families in the United States and Canada.

UNLABELLED: Some data suggest that brothers of prostate cancer patients have higher disease risk than their fathers, supporting an X-linked or recessive mode of inheritance. However, higher observed frequencies in brothers than fathers may merely reflect the strong temporal changes in US incidence rates. OBJECTIVES: (a) to evaluate the fit of X-linked, recessive, and dominant modes of inheritance to prostate cancer incidence, specific for calendar year, age, and race, in population-based samples of US and Canadian families; and (b) to evaluate a simple multifactorial model for familial aggregation of prostate cancer due to shared low-penetrance variants of many genes or shared lifestyle factors. METHODS: The data consist of reported prostate cancer incidence in first-degree relatives of 1,719 white, African-American, and Asian-American men with and without prostate cancer at ages <70 years. Model parameters were estimated by maximizing a pseudo-likelihood function of the data, and goodness of model fit was assessed by evaluating discrepancies between observed and expected numbers of pairs of relatives with prostate cancer. RESULTS: After adjusting for temporal trends in prostate cancer incidence rates we found that the X-linked model fit poorly. underpredicting the observed number of affected father-son pairs. This also was true of the recessive model, although the evidence for poor fit did not achieve statistical significance. In contrast, the dominant model provided adequate fit to the data. In this model the race-specific penetrance estimates for carriers of deleterious genotypes were similar among African-Americans and whites, but lower among Asian-Americans: risk by age 80 years for carriers born in 1900 was estimated as 75.3% for African-Americans and whites, and 44.4% for Asian-Americans. None of the Mendelian models fit the data better than did the simple multifactorial model. CONCLUSIONS: The good fit of the multifactorial model suggests that multiple genes, each having low penetrance, may be responsible for most inherited prostate cancer susceptibility, and that the contribution of rare highly penetrant mutations is small.

Adult↗

Why do neuroprotective drugs work in animals but not humans?

Many neuroprotective agents that seemed promising in animal studies of ischemic brain injury prove to have no effect when tested in clinical trials, suggesting that fundamental elements of translational research require better definition. A number of modifications have led to improvements in preclinical and human studies since the earliest controlled trials failed to confirm hypotheses suggested by animal data. Continued re-evaluation and sharing of information derived from the laboratory bench or the patient's bedside should eventually lead to effective neuroprotection in acute stroke. Experimental data should be carefully studied to improve the quality of agents coming to clinical trials and to design trial phasing that effectively determines drug safety and efficacy. This article will examine preclinical modeling and its translation to prospective studies of acute stroke therapy and will focus on some potential solutions directed at clinical trial design.

Animals↗

Sexuality after hysterectomy.

OBJECTIVE: To review the literature regarding sexuality after hysterectomy and identify areas for future research. DATA SOURCES: Articles published between 1970 and 2000 on sexuality and hysterectomy were located using MEDLINE, CINAHL, Psychlit, and Sociofile databases. STUDY SELECTION: English language research dealing with the topic was reviewed. DATA EXTRACTION: Study findings were categorized and include studies of the effect of hysterectomy on sexuality, women's perspectives on hysterectomy, and information sharing with women prior to surgery. DATA SYNTHESIS: A number of studies have explored sexuality after hysterectomy. Many of these studies have methodologic flaws, including vague measures of sexual satisfaction and potential for recall bias. A major source of bias is that the first measure of sexual satisfaction/functioning was performed in the immediate preoperative period when symptoms are more likely to affect sexual functioning. CONCLUSIONS: There are a number of gaps in the knowledge base pertaining to this topic. Future research in this area is needed to provide direction for nurses in the clinical area. Topics for future research include what women and their partners want to know about sexuality following hysterectomy and the most efficient methods to provide them with this information. In addition, sexuality in premorbid women needs to be more fully described.

Adult↗

Recent radiation of endemic Caribbean Drosophila of the dunni subgroup inferred from multilocus DNA sequence variation.

Studies of island endemism provide a unique opportunity to elucidate fundamental mechanisms of speciation. Here we examine intra- and interspecific DNA sequence variation at four unlinked genetic loci among populations of the Drosophila dunni subgroup to provide a detailed genealogical portrait of the process of speciation among these island endemic species. Our data indicate two major rounds of diversification that have shaped the D. dunni subgroup. The first occurred 1.6-2.6 million years ago and separated three major lineages, one in Puerto Rico and the Virgin Islands, a second in the northern Lesser Antilles and Barbados, and a third in St. Vincent and Grenada. A second round of diversification occurred in the last 96,000 years in the northern Lesser Antilles and Barbados. The four distinct species that resulted from this recent round of diversification maintain relatively high amounts of genetic variation, similar to that of a closely related mainland species, and share extensive ancestral polymorphism. These data suggest a minimal role for population bottlenecks linked to founder events in the history of the D. dunni subgroup. Further, the recent divergence of these island populations highlights the extremely rapid development of reproductive isolation and distinct patterns of abdominal pigmentation that has occurred in these species.

Animals↗

Anti-striated muscle antibody activity produced by Trypanosoma cruzi.

We have previously shown that Trypanosoma cruzi shares antigenic determinants with preparations of the calcium-sequestering adenosine triphosphatase of sarcoplasmic reticulum. The cross-reacting antigen (SRA) is also apparently present on the sarcolemma of cardiac myofibers. Using highly specific reference antisera to either the small membranes of T. cruzi or to a tryptic fragment of striated muscle SRA, it was shown that SRA is present in the striated muscle of animals representative of the evolutionary scale ranging from nonhuman primate to fish. The small membranes of nine different T. cruzi strains isolated from widely divergent areas of the American continents also reacted with the reference antisera. This indicates that SRA is present in these T. cruzi strains and may be prevalent among all T. cruzi strains. The shared T. cruzi-striated muscle antigen, SRA, may be a heteroantigen present in all T. cruzi strains and in the striated muscle of all classes of animals. Immunization of rabbits (three of five) or chickens (five pairs of five pairs) with striated muscle membrane preparations of different classes of animals, particularly those of nonhuman primate, chicken, and turtle, gave rise to IgG anti-allogeneic striated muscle antibody activity. Immunization of rabbits (four of nine) and chickens (five pairs of six pairs) with the small membranes of different T. cruzi strains also produced IgG anti-allogeneic striated muscle. These data indicate that T. cruzi shares cross-immunogenicity with striated muscle SRA. Since SRA is apparently present on the sarcolemma of cardiac myofibers, it may be implicated in the immunopathogenesis of Chagas' disease.

Animals↗

Conservation and antigenic cross-reactivity of the transferrin-binding proteins of Haemophilus influenzae, Actinobacillus pleuropneumoniae and Neisseria meningitidis.

Haemophilus influenzae acquires iron from the iron-transporting glycoprotein transferrin via a receptor-mediated process. This involves two outer-membrane transferrin-binding proteins (Tbps) termed Tbp1 and Tbp2 which show considerable preference for the human form of transferrin. Since the Tbps are attracting considerable attention as potential vaccine components, we used transferrin affinity chromatography to examine their conservation amongst 28 H. influenzae type b strains belonging to different outer-membrane-protein subtypes as well as six non-typable strains. Whole cells of all type b and non-typable strains examined bound human transferrin; whilst most strains possessed a Tbp1 of approximately 105 kDa, the molecular mass of Tbp2 varied from 79 to 94 kDa. Antisera raised against affinity-purified native H. influenzae Tbp1/Tbp2 receptor complex cross-reacted on Western blots with the respective Tbps of all the Haemophilus strains examined. When used to probe Neisseria meningitidis Tbps, sera from each of four mice immunized with the Haemophilus Tbp1/2 complex recognized the 68 kDa Tbp2 of N. meningitidis strain B16B6 but not the 78 kDa Tbp2 of N. meningitidis strain 70942. Serum from one mouse also reacted weakly with Tbp1 of strain B16B6. Apart from a weak reaction with the Tbp2 of a serotype 5 strain, this mouse antiserum failed to recognize the Tbps of the porcine pathogen A. pleuropneumoniae. However, a monospecific polyclonal antiserum raised against the denatured Tbp2 of Neisseria meningitidis B16B6 recognized the Tbps of all Haemophilus and Actinobacillus strains examined. Since H. influenzae forms part of the natural flora of the upper respiratory tract, human sera were screened for the presence of antibodies to the Tbps. Sera from healthy adults contained antibodies which recognized both Tbp1 and Tbp2 from H. influenzae but not N. meningitidis. Convalescent sera from meningococcal meningitis patients contained antibodies which, on Western blots, recognized the Tbps2s of both pathogens. These data demonstrate the existence of shared epitopes on the Tbps of H. influenzae, N. meningitidis and A. pleuropneumoniae despite their transferrin species specificity.

Actinobacillus pleuropneumoniae↗

DQCAR microsatellite polymorphism and susceptibility to rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease associated with HLA-DR genes that share a five amino acid sequence motif, QKRAA or QRRAA, from position 70 to 74 in the third hypervariable region of the DRbeta1 molecule. Since the associations between DRB1 genes and susceptibility to RA are incomplete, in this study we examined the CA repeat polymorphic marker DQCAR, located between DQA1 and DQB1 genes, alleles in 98 adult patients with seropositive RA and 100 normal healthy controls. The prevalence of the DQCAR 117 allele was significantly higher in RA patients as compared to normal controls. On the other hand, the frequency of DQCAR 99 was lower in patients than in normal subjects. Analysis of the data suggested that DRB1 genes sharing the QKRAA/QRRAA epitope have the primary association with disease susceptibility and DQCAR alleles do not provide an additional risk for the development of RA.

Adult↗

Assessing progress in systematics with continuous jackknife function analysis.

Systematists expect their hypotheses to be asymptotically precise. As the number of phylogenetically informative characters for a set of taxa increases, the relationships implied should stabilize on some topology. If true, this increasing stability should clearly manifest itself if an index of congruence is plotted against the accumulating number of characters. Continuous jackknife function (CJF) analysis is a new graphical method that portrays the extent to which available data converge on a specified phylogenetic hypothesis, the reference tree. The method removes characters with increasing probability, analyzes the rarefied data matrices phylogenetically, and scores the clades shared between each of the resulting trees and the reference tree. As more characters are removed, the number of shared clades must decrease, but the rate of decrease will depend on how decisively the data support the reference tree. Curves for stable phylogenies are clearly asymptotic with nearly 100% congruence for a substantial part of the curve. Less stable phylogenies lose congruent nodes quickly as characters are excluded, resulting in a more linear or even a sigmoidal relationship. Curves can be interpreted as predictors of whether the addition of new data of the same type is likely to alter the hypothesis under test. Continuous jackknife function analysis makes statistical assumptions about the collection of character data. To the extent that CJF curves are sensitive to violations of unbiased character collection, they will be misleading as predictors. Convergence of data on a reference tree does not guarantee historical accuracy, but it does predict that the accumulation of further data under the sampling model will not lead to rapid changes in the hypothesis.

Algorithms↗

Bioinformatics in neurosurgery.

WITH THE COMPLETION of the Human Genome Project, the amount of molecular biological sequence data available in public databases has reached staggering proportions. Data continue to accumulate at an exponential rate in the postgenomic era. Compilation, storage, searching, sharing, studying, and transmitting of all these data present formidable challenges. To keep pace with this extant database, the science of bioinformatics (sometimes called computational biology) has evolved. Bioinformatics is the combination of biology and computers and usually involves the storage or analysis of molecular biological sequence data at either the deoxyribonucleic acid, ribonucleic acid, or protein (amino acid) level. Most bioinformatics tools are freely available on the Internet for use by investigators around the globe. The collective wisdom from bioinformatics databases worldwide will continue to spawn advances in the neurological sciences for generations to come. Neurosurgeons must be aware of the power and potential applications of bioinformatics for the analysis of neurosurgical diseases.

Animals↗