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Comparison of event rates and survival in patients with unexplained syncope without documented ventricular tachyarrhythmias versus patients with documented sustained ventricular tachyarrhythmias both treated with implantable cardioverter-defibrillators.

Patients with unexplained syncope and inducible ventricular tachyarrhythmias during electrophysiologic testing have an increased cardiac mortality rate. We compared event rates and survival of 178 patients with unexplained syncope and no documented ventricular arrhythmias (syncope group) versus 568 patients with documented sustained ventricular tachycardia (VT or fibrillation (VF) (VT/VF group) treated, as part of a lead (Ventritex TVL) investigation, with similar implantable cardioverter-defibrillators (ICDs) capable of extensive data storage. The 2 groups shared similar clinical characteristics. The mean follow-up was 11 months for the syncope group and 14 months for the VT/VF group. The mean time from device implantation to first appropriate therapy was similar in the 2 groups (109 +/- 140 vs 93 +/- 131 days, p = 0.40). Actuarial probability of appropriate ICD therapy was 49% and 55% at 1 and 2 years, respectively, in syncope group and 49% and 58% in VT/VF group (p = 0.57). Recurrent syncope was associated with ventricular tachyarrhythmias in 85% and 92% of the syncope group and VT/VF group, respectively (p = 0.54). At 2 years, actuarial survival was 91% in the syncope group and 93% in VT/VF group (p = 0.85). We conclude that patients treated with ICD with unexplained syncope and induced VT/VF have an equally high incidence of appropriate ICD therapy and low mortality compared with similar patients with documented VT/VF. These findings, plus the high association between recurrent syncope and ventricular arrhythmias, indicate that VT/VF are likely etiologies in selected patients with unexplained syncope and support ICD therapy in such cases.

Aged↗

Effects of nonsteroidal anti-inflammatory drugs on renal function: focus on cyclooxygenase-2-selective inhibition.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can affect renal function in a variety of ways. The most important clinical effects are decreased sodium excretion, decreased potassium excretion, and declines in renal perfusion. Decreased sodium excretion can result in weight gain, peripheral edema, attenuation of the effects of antihypertensive agents, and rarely precipitation of chronic heart failure. Hyperkalemia can occur to a degree sufficient to cause cardiac arrhythmias. Renal function can decline sufficiently enough to cause acute renal failure. Risk factors for all of these effects have been identified, allowing prospective identification of patients at risk with institution of appropriate precautionary measure. All NSAIDs seem to share these adverse effects. Preliminary data from cyclooxygenase-2-selective inhibitors suggest that they also affect renal prostaglandins. Therefore, the same cautions should be exercised with their use as with traditional NSAIDs.

Anti-Inflammatory Agents, Non-Steroidal↗

Treating endometriosis as an autoimmune disease.

OBJECTIVE: To review the literature on the role of autoimmunity in the etiology of endometriosis, compare the similarities in the pathophysiologies between endometriosis and autoimmune diseases, and discuss the use of immunomodulators currently used to treat autoimmune diseases as potential therapies for endometriosis. DESIGN: The literature on endometriosis and other autoimmune diseases was reviewed, and summary data are presented. RESULTS: Endometriosis shares many similarities with autoimmune diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. These similarities include elevated levels of cytokines, decreased cell apoptosis, and T- and B-cell abnormalities. Because the use of immunomodulators and inflammatory modulators has proven to be an effective means of medical management for these autoimmune diseases, similar therapies may prove useful in treating endometriosis. CONCLUSION(S): Although substantial evidence indicates that endometriosis at least shares many similarities with autoimmune diseases, endometriosis is primarily treated by using compounds that induce a hypoestrogenic environment. A review of the literature combined with the shortcomings of current means of medical management for endometriosis support the postulate that treatment of endometriosis with immunomodulators and inflammatory modulators is warranted.

Adjuvants, Immunologic↗

The protein kinase resource and other bioinformation resources.

The Internet, especially the World Wide Web has transformed how today's researchers communicate, share information, and analyze their data. Unfortunately, the vast number of online databases, information resources and analytical tools, some of them masked by unfamiliar titles and Internet addresses, has hindered their universal and effective use by the research community. To overcome these hurdles, subject- and function-specific compendiums are now available which organize information and online tolls in a manner familiar to the biological researcher. The Protein Kinase Resource and the CMS Molecular Biology Resource are two excellent examples of web compendia.

Databases as Topic↗

Allergic rhinitis and asthma: how important is the link?

Dysfunction of the upper and lower airways frequently coexist, and they appear to share key elements of pathogenesis. Data from epidemiologic studies indicate that nasal symptoms are experienced by as many as 78% of patients with asthma and that asthma is experienced by as many as 38% of patients with allergic rhinitis. Studies also have identified a temporal relation between the onset of rhinitis and asthma, with rhinitis frequently preceding the development of asthma. Patients with allergic rhinitis and no clinical evidence of asthma commonly exhibit nonspecific bronchial hyperresponsiveness. The observation that management of allergic rhinitis also relieves symptoms of asthma has heightened interest in the link between these diseases. Intranasal corticosteroids can prevent increases in nonspecific bronchial reactivity and asthma symptoms associated with seasonal pollen exposure. Similarly, among patients with perennial rhinitis, daily asthma symptoms, exercise-induced bronchospasm, and bronchial responsiveness to methacholine are reduced after administration of intranasal corticosteroids. Antihistamines, with or without decongestants, reduce seasonal rhinitis symptoms, asthma symptoms, and objective measurements of pulmonary function among patients with rhinitis and asthma. The mechanisms that connect upper and lower airway dysfunction are under investigation. They include a nasal-bronchial reflex, mouth breathing caused by nasal obstruction, and pulmonary aspiration of nasal contents. Nasal allergen challenge results in increases in lower airway reactivity within 30 minutes, suggesting a neural reflex. Improvements in asthma associated with increased nasal breathing may be the result of superior humidification, warming of inspired air, and decreased inhalation of airborne allergens. Postnasal drainage of inflammatory cells during sleep also may affect lower airway responsiveness. A link between allergic rhinitis and asthma is evident from epidemiologic, pathophysiologic, and clinical studies. Future research, however, is needed to determine whether nasal therapy can alter the natural history of asthma.

Administration, Intranasal↗

An analysis of flexible anterior chamber lenses with special reference to the normalized rate of lens explantation.

A survey of 1204 closed-loop anterior chamber intraocular lenses (AC-IOLs) and 310 open-loop AC-IOLs accessioned between November 1982 and January 1990 was conducted at the Center for Intraocular Lens Research. An analysis of complication rates was done after normalization of data with respect to market share totals. The results establish that an unacceptable complication rate is associated with the closed-loop design when compared with either the tripod or quadripod lens styles. Furthermore, the closed-loop designs, while comprising an estimated 45% of the total number of AC-IOLs estimated to be implanted in the United States (n = 674,000), were responsible for 80% of the AC-IOLs explanted after complications and accessioned at the authors' center. A rethinking of the extreme condemnation of all anterior chamber IOLs that has surfaced in recent years is warranted. This is particularly true with respect to indications for use of sutured posterior chamber (PC) IOLs as well as with regard to possible use of open-loop AC-IOLs in less-industrialized nations.

Anterior Chamber↗

Application of multicolor fluorescence in situ hybridization analysis for detection of cross-contamination and in vitro progression in commonly used murine tumor cell lines.

Murine tumor models are potent tools for cancer studies, most of which make use of a limited number of murine tumor cell lines that are exchanged by many research groups around the world. Although cross-contamination and in vitro karyotypic progression are well-known risks with respect to the identity of tumor cell lines, these parameters are rarely evaluated. Notably, routine karyotyping of murine cell lines is laborious and technically demanding because mouse chromosomes are morphologically similar. We therefore used a 21-color fluorescence in situ hybridization (FISH) approach (COBRA) for screening two groups of frequently used murine tumor cell lines, each of which shares known immunologic determinants. Multicolor analysis revealed that the sharing of immunologic determinants among three murine lymphoma cell lines (EL-4, MBL-2, and RBL-5) is directly related to their common origin. In several of the cell lines, the chromosomal derivatives had rearranged further, suggesting that the cross-contamination events were not recent. In contrast, karyotypic analysis of three murine colon cancer cell lines (C26, CC36, and C51) showed that these constituted independent tumor clones despite the sharing of immunologic determinants. Our data point out that cross-contamination and in vitro evolution of murine tumor cell lines are a common phenomenon, and that multicolor FISH analysis is an efficient tool for verifying the origin and tracking the evolution of murine cell lines.

Adenocarcinoma↗

HLA antigens, alleles and haplotypes among the Yup'ik Alaska natives: report of the ASHI Minority Workshops, Part II.

As part of the American Society for Histocompatibility and Immunogenetics coordinated studies among minority populations, human leukocyte antigen (HLA) alleles were defined for 460 volunteer Yup'ik Eskimos from the Yukon Kuskokwim delta region of southwestern Alaska. The study group included 252 adults with no other first-degree relatives and 48 informative nuclear families. Full Yupik ancestry through both maternal and paternal grandparents was claimed by 81.1% of participants. HLA-A, -B, -Cw, -DRB1, and -DQB1 alleles were determined by SBT, SSOP, reverse SSOP, and/or RSCA according to the protocols of five participating laboratories. Polymorphism was limited with 3-6 alleles comprising > 80% of the alleles observed at each locus. Homozygosity was high, particularly at the HLA-A and -DQB1 loci, with 36.6% and 44% of individuals having a single allele defined at these respective loci. HLA-A, -B, and -DRB1 alleles were in Hardy-Weinberg equilibrium, whereas HLA-Cw and -DQB1 alleles gave significant deviation (p = 0.002; 0.005). Significant linkage disequilibrium (p < or = 0.00001) was observed in all pairwise evaluations. A new Cw*0806 allele was observed in high linkage disequilibrium with B*4801(Delta = 0.099; Delta(rel) = 1.0). Three extended haplotypes were found to have frequencies > 5%, the most prevalent being A*2402; B*4801; DRB1*0401; DQB1*0301 (0.0933). Comparison of available class I data indicate that the Yup'ik share several common alleles with other Native American populations, including: A*2402, *0206, *6801; B*1501, *2705, *3501, *4002, *4801, *5101; and Cw*0202, *0304, *0401. Comparisons of class II data also confirm a close relationship of the Yup'ik to two other Eskimo populations, Siberian and East Greenland Eskimos. DRB1*0401 and *1101, which occur in high frequency among these Eskimo populations, but not in other Native Americans, were also prevalent among the Yup'ik, with respective frequencies of 0.232 and 0.107.

Alaska↗

Mechanisms of repair and remodeling following acute lung injury.

At present, we largely lack the ability to correlate the clinical course of ARDS patients with potential factors involved in the biochemical and cellular basis of lung repair. This requires very large patient databases with measurement of many biochemical parameters. Important mechanistic determinants during the repair phase can be sought by correlation with late outcomes, but a large-scale cooperative effort among multiple centers with sharing of follow-up data and patient specimens is essential. We also lack detailed human histologic material from many phases of ARDS and, particularly, know little of the long-term morphologic impact of ARDS in survivors. Establishment of a national registry that follows ARDS survivors and that would seek their cooperation in advance in obtaining autopsy specimens when they die of other causes would be very valuable. Correlating the pathology with their pulmonary function during recovery would give important insights into the reasons for the different patterns of abnormal pulmonary functions. The factors that determine the success of repair are of critical importance in testing new ARDS treatment strategies. Would accelerating the resolution of alveolar edema alter the course of subsequent fibrosis and inflammation? Does surfactant replacement therapy--a costly proposition in adults with ARDS--lead to better long-term outcomes in survivors? How much should we worry about the use of high levels of oxygen for support of arterial partial pressure of oxygen? Is it better to accept hyperoxia to avoid pressure or volume trauma induced by mechanical ventilation with higher minute ventilations? These major management issues all may affect the success of the late repair and recovery process. Intervention trials need to examine the long-term physiologic and functional outcomes.

Animals↗

The expression pattern of a mouse doublesex-related gene is consistent with a role in gonadal differentiation.

The signal for somatic sex determination in mammals, Caenorhabditis elegans and Drosophila melanogaster is chromosomal, but the overall mechanisms do not appear to be conserved between the phyla. However it has been found quite recently that the C. elegans sex-determining gene Mab-3 contains a domain highly homologous to the Drosophila sex-determining gene doublesex (dsx) and shares a similar role. These data suggest that at least some aspects of the regulation of sex determination might be conserved. In humans, a doublesex-related gene (DMRT1) was identified at less than 30 kb from the critical region for sex reversal on chromosome 9p24 (TD9). In order to get insights into the role of DMRT1 in sex determination/differentiation, we have isolated DMRT1 mouse homologue (Dmrt1) and analysed its expression pattern. The gene is expressed in the genital ridges of both sexes during the sex-determining switch and it shows male/female dimorphism at late stages of sex differentiation.

Amino Acid Sequence↗

Molecular characteristics and physiology of microsporidia.

A survey of the molecular features of microsporidia is presented which attempts to comment on unresolved questions concerning the physiology of these amitochondrial intracellular parasites. Various transports of host-derived molecules can be predicted and trehalose appears as a potential reserve of glucose for energy metabolism. Significant insights into membrane lipids, polyamine metabolism and sporogony-specific proteins have been gained. Some species, such as Encephalitozoon cuniculi, are heterogeneous entities and harbor a small genome. Although showing a variation in genome size of 8.5-fold, microsporidia share reduced rDNA genes. Finally, data on gene organization and a possible evolutionary relationship with fungi are considered.

Animals↗

Common aetiology for diverse language skills in 4 1/2-year-old twins.

Multivariate genetic analysis was used to examine the genetic and environmental aetiology of the interrelationships of diverse linguistic skills. This study used data from a large sample of 4 1/2-year-old twins who were tested on measures assessing articulation, phonology, grammar, vocabulary, and verbal memory. Phenotypic analysis suggested two latent factors: articulation (2 measures) and general language (the remaining 7), and a genetic model incorporating these factors provided a good fit to the data. Almost all genetic and shared environmental influences on the 9 measures acted through the two latent factors. There was also substantial aetiological overlap between the two latent factors, with a genetic correlation of 0.64 and shared environment correlation of 1.00. We conclude that to a large extent, the same genetic and environmental factors underlie the development of individual differences in a wide range of linguistic skills.

Chi-Square Distribution↗

Pythium phragmitis sp. nov., a new species close to P. arrhenomanes as a pathogen of common reed (Phragmites australis).

During a study on the occurrence and pathogenicity of oomycetes in the reed-belt (Phragmites australis) of Lake Constance (Germany), a new Pythium resembling the important cereal pathogen species complex P. arrhenomanes/P. graminicola was consistently isolated from necrotic mature reed leaves and reed rhizosphere samples. The new species proved to be significantly more aggressive towards reed leaves and seedlings in vitro than related species. It is characterised by filamentous, inflated sporangia and plerotic oospores with usually more than one antheridium. ITS and cox II sequence data indicate this new species shares a common ancestor with P. arrhenomanes, but the sequence differences are clearly consistent with a divergence of the two taxa and with P. phragmitis being a distinct species. ITS 1 and 2 of 15 isolates of the taxon consistently differed from P. arrhenomanes by 13 positions. Sequence analyses of the cox II gene confirmed the new species' phylogenetic position. This paper gives a formal description of the taxon as P. phragmitis sp. nov., providing information on morphology, ecology and pathogenicity in comparison to related species. As indicated by the close association to Phragmites australis, the high aggressiveness towards reed leaves and seedlings, and the abundance in the investigated stands, Pythium phragmitis might act as a reed pathogen of considerable importance, in particular under flooding situations.

Cyclooxygenase 2↗

Alpha-macroglobulin from Limulus polyphemus exhibits proteinase inhibitory activity and participates in a hemolytic system.

Significant primary sequence homology between the alpha-macroglobulin family of proteinase inhibitors and the complement components C3, C4, and C5 implies that these proteins arose from a common ancestor. Hemolymph from the ancient invertebrate Limulus polyphemus contains both complement-like and proteinase inhibitory activity. In this report, we present evidence that L. polyphemus alpha-macroglobulin not only possesses proteinase inhibitory activity, but it also participates in the lytic system of the horseshoe crab. The protein is a disulfide-linked dimer of subunits of molecular mass 185 kDa. Upon reaction with proteinase or methylamine, L. polyphemus alpha-macroglobulin underwent a major conformational change and no proteinase-associated multimerization was detected. L. polyphemus alpha-macroglobulin is the only detectable inhibitor of a number of proteinases in L. polyphemus hemolymph. Proteinase inhibition follows the general "trapping" mechanism shared by most alpha-macroglobulins; however, no covalent linking of proteinases to the inhibitor was detected despite the presence of a functional thiolester. Moreover, the inhibitor demonstrated thiolester-mediated binding to sheep erythrocytes, a property also observed with complement components such as C3. Depletion of functional protein by treatment of hemolymph with methylamine destroyed the proteinase inhibitory capacity and the lytic activity of the hemolymph. Both activities were restored by adding purified protein to depleted hemolymph. Studies with purified L. polyphemus alpha-macroglobulin demonstrated that the thiolester incorporates glycerol as well as methylamine, a property shared by human C3. The data support the hypothesis that L. polyphemus alpha-macroglobulin is both a proteinase inhibitor and part of a lytic system, providing a link between the two distinct sides of the alpha-macroglobulin family. Because both properties are contained in one molecule, we propose the name "limac" to describe this Limulus alpha-macroglobulin complement-like protein.

Amino Acid Sequence↗

Inescapable shock-induced potentiation of morphine analgesia in rats: involvement of opioid, GABAergic, and serotonergic mechanisms in the dorsal raphe nucleus.

Exposure of rats to inescapable shock (IS) potentiated the analgesic response to a low dose (1 mg/kg) of morphine 24 hr later. This effect was blocked by naltrexone (10 micrograms), diazepam (5 micrograms), or 8-hydroxy-2-(di-n-propylamine)-tetralin (8-OH-DPAT; 1 microgram) microinjected into the dorsal raphe nucleus (DRN) 15 min before IS. When microinjected into the DRN at the time of tail-flick testing, 8-OH-DPAT also effectively prevented this effect. Further, intra-DRN administration of a beta-carboline mimicked the effects of IS, because rats treated with methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (1 microgram) and simply restrained displayed potentiated morphine analgesia 24 hr later. These data suggest that this phenomenon shares mechanisms in common with other effects of IS at the level of the DRN.

Animals↗

Improving group decisions by better pooling information: a comparative advantage of group decision support systems.

This study compared a group decision support system (GDSS) with face-to-face (FTF) group discussion on characteristics of information exchange and decision quality. Participants given conflicting information tended to share more of their unique data and engaged in more critical argumentation when using the GDSS than when meeting FTF. Conversely, when information was consistent among members, there were no such differences between FTF and GDSS groups. The GDSS groups significantly outperformed the FTF groups in agreeing on the superior hidden profile candidate, especially when there was a lack of prediscussion consensus. Individual-level analyses revealed that members of GDSS groups that did not have a prediscussion consensus tended to experience stronger preference shifts toward the group's consensus decision.

Adult↗

Systematic functional analysis of the Caenorhabditis elegans genome using RNAi.

A principal challenge currently facing biologists is how to connect the complete DNA sequence of an organism to its development and behaviour. Large-scale targeted-deletions have been successful in defining gene functions in the single-celled yeast Saccharomyces cerevisiae, but comparable analyses have yet to be performed in an animal. Here we describe the use of RNA interference to inhibit the function of approximately 86% of the 19,427 predicted genes of C. elegans. We identified mutant phenotypes for 1,722 genes, about two-thirds of which were not previously associated with a phenotype. We find that genes of similar functions are clustered in distinct, multi-megabase regions of individual chromosomes; genes in these regions tend to share transcriptional profiles. Our resulting data set and reusable RNAi library of 16,757 bacterial clones will facilitate systematic analyses of the connections among gene sequence, chromosomal location and gene function in C. elegans.

Animals↗

Tumour necrosis factor 5' promoter single nucleotide polymorphisms influence susceptibility to rheumatoid arthritis (RA) in immunogenetically defined multiplex RA families.

Tumour necrosis factor (TNF) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA) and it has been shown that the TNF-lymphotoxin (TNF-LT) region influences susceptibility to RA. To investigate the role of the TNF-LT locus further, inheritance of TNF 5' promoter alleles was determined in multiplex RA families. Six previously defined TNF promoter single nucleotide polymorphisms (SNPs) (-238, -308, -376, -857, -863, -1031) were observed in these families and in addition, a heretofore undocumented adenine (A) to cytosine (C) substitution at position -572 relative to the transcription start site was defined. TNF 5' promoter SNPs were found to co-segregate with specific TNF microsatellite haplotypes. In particular, the SNP -308A allele was found to be inherited with the TNF a2, b3, c1, d1, e3 (H2) microsatellite haplotype (P < 0.001) which had previously been found to be associated with RA in individuals heterozygous for the HLA-DR 'shared epitope' (SE). When the data were stratified by the presence of the SE with further stratification according to SE DR subtypes and analysed by transmission disequilibrium test (TDT) for which offspring were assumed independent, the -308A and -857T alleles were found to be associated with RA in patients carrying the SE (P = 0.0076 and 0.0063 respectively). The data were further stratified to analyse for association in individuals homozygous or heterozygous for SE alleles. Results showed that the -308A allele was significantly associated with RA susceptibility in individuals heterozygous for the SE (P < 0.001) with the significance only occurring in patients carrying HLA-DR4 (P < 0.001), while the -857T allele was significant in individuals homozygous for the SE (P = 0.0039). Further analysis using the pedigree disequilibrium test (PDT) which conservatively adjusts for all sources of familial correlation except that conferred by linkage disequilibrium still indicated a significant role for the -308A and -857T alleles. These data provide evidence that TNF promoter SNPs may play an independent role in RA susceptibility in specific immunogenetically-defined groups of RA patients.

Arthritis, Rheumatoid↗