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PubMed1999

Combination and multivariate analysis of PSA-based parameters for prostate cancer prediction.

The aim of this study was to evaluate the ability of prostate-specific antigen (PSA)-based parameters including PSA density (PSAD), PSAD of the transition zone (PSA-TZ), percent free PSA, PSA velocity, and their combination to enhance the specificity of PSA for prostate cancer detection in men with serum PSA levels between 4 and 10 ng/mL. We evaluated prospectively 559 consecutive men referred for early detection of prostate cancer who had serum PSA levels between 4 and 10 ng/mL. All men underwent prostatic ultrasonography and sextant biopsy with two additional TZ biopsies. In all cases, if first biopsies were negative an additional set of biopsies was obtained within 6 weeks. The ability of PSAD, PSA-TZ, PSA velocity, percent free PSA, and their combination to improve the detection of prostate cancer was evaluated by univariate and multivariate analysis as well as receiver operating characteristic (ROC) curves. In this prospective study of 559 patients, 217 had prostate cancer and 342 had histologically confirmed benign prostatic hyperplasia. Multivariate analysis and ROC curves showed that PSA-TZ and percent free PSA (f/t PSA) were the most powerful and highly significant predictors of prostate cancer. Areas under the ROC curve (AUC) for PSA-TZ and percent free PSA were 0.827 and 0.778, respectively (p = .01). Combination of f/t PSA with PSA-TZ (AUC = 88.1%) significantly increased AUC as compared to each of the other parameters alone as well as their combination (p = .02). The next best combinations were PSA-TZ + PSAD, PSA-TZ + PSA, and f/t PSA + PSA. PSA-TZ followed by f/t PSA and PSAD were the most powerful predictors of prostate cancer in referred patients with a serum PSA between 4 and 10 ng/mL. f/t PSA + PSA-TZ was the most effective combination. When volume-independent PSA parameters were taken into consideration, f/t PSA + PSA clearly outperformed the other options.

Aged↗
PubMedDate not supplied

Immunomodulating efficacy of combined administration of galactoside-specific lectin standardized mistletoe extract and sodium selenite in BALB/c-mice.

The immunomodulating abilities of commercially available mistletoe extract standardized for the galactoside-specific lectin (mistletoe lectin-1, ML-1) and sodium selenite (Se) were evaluated in BALB/c-mice and compared to non-treated control animals. Following the optimal schedule of administration (ML-1: 1ng/kg BW; days 1, 2, 3, 5 and Se: 3,5 micrograms/kg BW for 7 subsequent days before evaluation) yielded enhanced counts (thymocytes; peritoneal macrophages, MO; peripheral blood leukocytes; lymphocytes, PBL; monocytes, PBM) and activities (CD-25 positive PBL, MAC-3 positive PBM) of desired immune cells reaching statistical significance for most parameters. However, combined administration of ML-1 and Se proved to be superior to monotherapy since immune cell counts (thymocytes, leukocytes, PBL, PBM) and activities (CD-25 positive PBL) exceeded values obtained after monotherapy. These data are in favour of therapeutical strategies in complementary oncology and suggest that the combination of defined immunomodulating substances might positively enhance the efficacy.

Animals↗
PubMed2004

Detecting dementia with the Hopkins Verbal Learning Test and the Mini-Mental State Examination.

The Hopkins Verbal Learning Test (HVLT) and the Mini-Mental State Examination (MMSE) were administered to 323 non-demented elderly and 70 individuals who meet DSM-IV criteria for dementia in order to compare the validity of these two measures for detecting mild dementia and for the two most common dementia subtypes, Alzheimer's disease (AD) and vascular dementia (VaD). The study was conducted in an elderly, ethnically diverse community-dwelling population. Sensitivity, specificity, positive and negative predictive values were calculated over a range of clinically relevant cut scores for each test. We analyzed the influence of age, education, reading ability and sex on test performance using logistic regression models. When sensitivity is held constant at 0.69, the specificity for the HVLT total recall was 0.89 and the MMSE 0.82 for all dementias (P=.10). Age, sex and education did not significantly influence test performance for either test in this sample. Results were similar for AD and VaD. However, while adding a measure of reading ability to the regression models did not affect the overall dementia model, it resulted in improved specificities when combined with the MMSE for AD and combined with the HVLT for VaD. Additional tests such as reading ability can improve discrimination of dementia subtypes. The modest sensitivity of either the HVLT or the MMSE alone suggests that further neuropsychological evaluation is required to confirm dementia diagnosis.

Aged↗
PubMed1989

Fluorescence microscopy in three dimensions.

The combination of the specificity provided by fluorescence microscopy and the ability to quantitatively analyze specimens in three dimensions allows the fundamental organization of cells to be probed as never before. Key features in this emergent technology have been the development of a wide variety of fluorescent dyes or fluorescently labeled probes to provide the requisite specificity. High-quality, cooled charge-coupled devices have recently become available. Functioning as nearly ideal imagers or "electronic film," they are more sensitive than photomultipliers and provide extraordinarily accurate direct digital readout from the microscope. Not only is this precision crucial for accurate quantitative imaging such as that required for the ratioing necessary to determine intracellular ion concentrations, but it also opens the way for sophisticated image processing. It is important to realize that image processing isn't simply a means to improve image aesthetics, but can directly provide new, biologically important information. The impact of modern video microscopy techniques (Allen, 1985; Inoué, 1986) attests to the fact that many biologically relevant phenomena take place at the limits of conventional microscopy. Image processing can be used to substantially enhance the resolution and contrast obtainable in two dimensions, enabling the invisible to be seen and quantitated. Cells are intrinsically three-dimensional. This can simply be a nuisance because of limited depth of focus of the microscope or it could be a fundamental aspect of the problem being studied. In either case, image processing techniques can be used to rapidly provide the desired representation of the data. In this chapter we have discussed the nature of image formation in three dimensions and dealt with several means to remove contaminating out-of-focus information. The most straightforward of these methods uses only information from adjacent focal planes to correct the central one. This approach can be readily applied to virtually any problem and with most commonly available image processing hardware to provide a substantially deblurred image in almost real time. In addition to covering more sophisticated algorithms where the utmost in three-dimensional imaging is required, we have developed a method for extremely rapidly and accurately producing an in-focus, high-resolution "synthetic projection" image from a thick specimen. This is equivalent to that produced by a microscope having the impossible combination of a high-NA objective lens and an infinite depth of focus. A variation on this method allows efficient calculation of stereo pairs.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2003

Intradiabodies, bispecific, tetravalent antibodies for the simultaneous functional knockout of two cell surface receptors.

The specific and high affinity binding properties of intracellular antibodies (intrabodies), combined with their ability to be stably expressed in defined organelles, provides powerful tools with a wide range of applications in the field of functional genomics and gene therapy. Intrabodies have been used to specifically target intracellular proteins, manipulate biological processes, and contribute to the understanding of their functions as well as for the generation of phenotypic knockouts in vivo by surface depletion of extracellular or transmembrane proteins. In order to study the biological consequences of knocking down two receptor-tyrosine kinases, we developed a novel intrabody-based strategy. Here we describe the design, engineering, and characterization of a bispecific, tetravalent endoplasmic reticulum (ER)-targeted intradiabody for simultaneous surface depletion of two endothelial transmembrane receptors, Tie-2 and vascular endothelial growth factor receptor 2 (VEGF-R2). Comparison of the ER-targeted intradiabody with the corresponding conventional ER-targeted single-chain antibody fragment (scFv) intrabodies demonstrated that the intradiabody is significantly more efficient with respect to efficiency and duration of surface depletion of Tie-2 and VEGF-R2. In vitro endothelial cell tube formation assays suggest that the bispecific intradiabody exhibits strong antiangiogenic activity, whereas the effect of the monospecific scFv intrabodies was weaker. These findings suggest that simultaneous interference with the VEGF and the Tie-2 receptor pathways results in at least additive antiangiogenic effects, which may have implications for future drug developments. In conclusion, we have identified a highly effective ER-targeted intrabody format for the simultaneous functional knockout of two cell surface receptors.

Animals↗
PubMed2003

The lysophospholipid receptor G2A activates a specific combination of G proteins and promotes apoptosis.

G2A, a G protein-coupled receptor for which lysophosphatidylcholine (LPC) is a high affinity ligand, belongs to a newly defined lysophospholipid receptor subfamily. Expression of G2A is transcriptionally up-regulated by stress-inducing and cell-damaging agents, and ectopic expression of G2A leads to growth inhibition. However, the G proteins that functionally couple to G2A have not been elucidated in detail. We report here that G2A ligand independently stimulates the accumulation of both inositol phosphates and cAMP. LPC does not further enhance inositol phosphate accumulation but dose-dependently augments intracellular cAMP concentration. Expression of G alpha(q) and G alpha(13) with G2A potentiates G2A-mediated activation of a NF-kappa B-luciferase reporter. These results demonstrate that G2A differentially couples to multiple G proteins including G alpha(s), G alpha(q), and G alpha(13), depending on whether it is bound to ligand. G2A-transfected HeLa cells display apoptotic signs including membrane blebbing, nuclear condensation, and reduction of mitochondrial membrane potential. Furthermore, G2A-induced apoptosis can be rescued by the caspase inhibitors, z-vad-fmk and CrmA. Although apoptosis occurs without LPC stimulation, LPC further enhances G2A-mediated apoptosis and correlates with its ability to induce cAMP elevation in both HeLa cells and primary lymphocytes. Rescue from G2A-induced apoptosis was achieved by co-expression of a G alpha(12/13)-specific inhibitor, p115RGS (regulator of G protein signaling), in combination with 2',5'-dideoxyadenosine treatment. These results demonstrate the ability of G2A to activate a specific combination of G proteins, and that G2A/LPC-induced apoptosis involves both G alpha(13)- and G alpha(s)-mediated pathways.

Amino Acid Chloromethyl Ketones↗
PubMed2001

Recurrent neural network-based approach for early recognition of Alzheimer's disease in EEG.

OBJECTIVE: We explored the ability of specifically designed and trained recurrent neural networks (RNNs), combined with wavelet preprocessing, to discriminate between the electroencephalograms (EEGs) of patients with mild Alzheimer's disease (AD) and their age-matched control subjects. METHODS: Twomin recordings of resting eyes-closed continuous EEGs (as well as their wavelet-filtered subbands) obtained from parieto-occipital channels of 10 early AD patients and 10 healthy controls were input into RNNs for training and testing purposes. The RNNs were chosen because they can implement extremely non-linear decision boundaries and possess memory of the state, which is crucial for the considered task. RESULTS: The best training/testing results were achieved using a 3-layer RNN on left parietal channel level 4 high-pass wavelet subbands. When trained on 3 AD and 3 control recordings, the resulting RNN tested well on all remaining controls and 5 out of 7 AD patients. This represented a significantly better than chance performance of about 80% sensitivity at 100% specificity. CONCLUSION: The suggested combined wavelet/RNN approach may be useful in analyzing long-term continuous EEGs for early recognition of AD. This approach should be extended on larger patient populations before its clinical diagnostic value can be established. Further lines of investigation might also require that EEGs be recorded from patients engaged in certain mental (cognitive) activities.

Aged↗
PubMed2006

Direct transfer of membrane proteins from bacteria to planar bilayers for rapid screening by single-channel recording.

Although the examination of membrane proteins in planar bilayers is a powerful methodology for evaluating their pharmacology and physiological roles, introducing membrane proteins into bilayers is often a difficult process. Here, we use a mechanical probe to transfer membrane proteins directly from Escherichia coli expression colonies to artificial lipid bilayers. In this way, single-channel electrical recordings can be made from both of the major classes of membrane proteins, alpha-helix bundles and beta barrels, which are represented respectively by a K(+) channel and a bacterial pore-forming toxin. Further, we examined the bicomponent toxin leukocidin (Luk), which is composed of LukF and LukS subunits. We mixed separate LukF- and LukS-expressing colonies and transferred the mixture to a planar bilayer, which generated functional Luk pores. By this means, we rapidly screened binary combinations of mutant Luk subunits for a specific function: the ability to bind a molecular adaptor. We suggest that direct transfer from cells to bilayers will be useful in several aspects of membrane proteomics and in the construction of sensor arrays.

Bacterial Proteins↗
PubMed2006

B-cell targeted therapies in rheumatoid arthritis and systemic lupus erythematosus.

B cells appear to have a central role in the immunopathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE); both autoantibody production and B-cell anomalies are characteristic of these diseases. With the recent availability of biologic agents that can deplete B cells or block their function in vivo, it has become possible to target B cells therapeutically. Evidence strongly suggests that novel B-cell targeting agents are effective. In addition, the mechanistic specificity of B-cell targeted approaches, combined with the ability to test them in large randomized controlled trials, will provide an unprecedented opportunity to study the precise roles of B cells in the immunopathogenesis of RA and SLE. The largest volume of information is available for rituximab, a chimeric monoclonal antibody that depletes B cells by binding to the CD20 cell-surface antigen. Information from multiple investigator-sponsored trials and from off-label use suggests efficacy of this antibody in RA, SLE, and other autoimmune syndromes. Randomized controlled trials have also provided solid evidence for the efficacy of rituximab in RA and are ongoing in SLE. Other therapeutic agents supported by controlled data include cytotoxic T-lymphocyte-associated protein 4 immunoglobulin and antibodies against the interleukin-6 receptor and the B-cell survival molecule BLyS. Additional agents and targets are in earlier stages of development. The concerns about infectious complications have so far not proven to be justified. We can reasonably expect important advances in the understanding and treatment of RA and SLE in the next 5-10 years, as B-cell targeting methods become more widespread and sophisticated.

Animals↗
PubMed1979

Hapten-specific T-cell responses to 4-hydroxy-3-nitrophenyl acetyl. I. Genetic control of delayed-type hypersensitivity by VH and I-A-region genes.

Hapten-specific delayed-type hypersensitivity (DTH) was induced in several strains of mice. (4-hydroxy-3-nitrophenyl)acetyl-bovine gamma globulin (NP-BGG)-primed mice which did not bear the Ig1b heavy-chain linkage group made a NP-specific DTH response when challenged with NP bovine serum albumin (BSA) and failed to respond to challenge with (4-hydroxy-5-iodo-3-nitrophenyl)acetyl-bovine serum albumin (NIP-BSA). Strains of NP-BGG-primed mice bearing the Ig1b allotype, including SJL, responded to challenges of either NP-BSA or NIP-BSA. F1 hybrids between a cross-reactive strain, C57BL/6, and two other noncross-reactive strains were cross-reactive. Genetic mapping of the NIP-cross-reactive DTH response localized the trait to the VH-region of the Ig1b heavy-chain linkage group. The fine-specificity pattern of the T-cell anti-NP response, and the genetic mapping of this trait, were analogous to the reported fine specificity and mapping data of the humoral heteroclitic anti-NP response. Adoptive transfer studies on the ability to transfer NP-specific DTH between various strain combinations showed that the T-cell donors and the recipient must have homology for at least the I-A subregion. Whenever NP-specific reactivity was transferred from a strain which cross-reactively responded to NIP, the recipient also responded to both NP and NIP. The implications of the control of NP-primed DTH-reactive populations of T cells by two distinct genetic regions, VH and H-2, were discussed.

Animals↗
PubMed2001

Distortion-product otoacoustic emissions and glycerol testing in endolymphatic hydrops.

OBJECTIVES/HYPOTHESIS: Aural fullness is a frequent symptom of endolymphatic hydrops. Its evaluation may provide valuable information on the initial stage of development of endolymphatic hydrops. STUDY DESIGN: The present investigation was specifically designed to ascertain the ability of the glycerol test, combined with pure tone audiometry and distortion product otoacoustic emissions (DPOAEs) testing, to diagnose endolymphatic hydrops early and to identify patients who may evolve toward Meniere's disease. For these purposes, patients who complained about aural fullness as their only audiologic symptom were selected. METHODS: This investigation consisted of 19 consecutive patients with unilateral or bilateral aural fullness who received no treatment. Each patient underwent glycerol testing measured with conventional pure tone audiometry and with both DPOAEs. For the traditional pure-tone glycerol test, a hearing improvement of at least 10 dB, at the lower two or three frequencies (125, 250, and 500 Hz), was judged as a positive result. For the DPOAE glycerol test, a smaller positive difference (5 dB) for at least three frequencies was interpreted as an ameliorative fluctuation. RESULTS: The outcomes of the glycerol tests (24 ears examined) showed variable patterns. Seven ears showed no significant changes of either the pure-tone audiogram or DPOAE. In seven other ears, the comparison of the traditional glycerol test and the DPOAE glycerol test indicated an improvement in both measures. Another seven ears showed negative glycerol tests, whereas DPOAE responses gradually recovered reaching levels significantly higher than those recorded before glycerol administration. The three remaining ears showed contrasting results. CONCLUSIONS: Patients with aural fullness in the absence of other associated symptoms may potentially be in the initial stages of Meniere's disease. This notion is confirmed by the present findings showing a high rate (58%) of positive glycerol tests in the selected patients. The importance of DPOAE testing is supported by their ability to detect minimal dysfunction, possibly representing endolymphatic hydrops that goes undetected by routine pure-tone audiometry.

Adult↗
PubMed2001

Genitourinary tuberculosis.

The worldwide prevalence of tuberculosis is still high and has remained almost unchanged over the past century as a result of increasing incidence in countries of the Third World. Twenty per cent of patients with tuberculosis will develop an extrapulmonary manifestation over time, the most common site being the genitourinary tract. The patient's history can lead to the sometimes difficult diagnosis. Radiological imaging helps in depicting genitourinary tuberculosis. However, the diagnosis of genitourinary tuberculosis is made on the basis of culture studies and is supported by polymerase chain reaction. The latter has impressive sensitivity and specificity, but lacks the ability to determine biological activity. The combination of three or four anti-tuberculosis drugs over a course of 6 to 9 months remains the treatment of choice. Drug resistance is increasing and necessitates tight therapy control. Tuberculosis of the male seminal duct may be an important cause of male infertility as a result of multiple epididymidal scarring. In these cases testicular sperm extraction is the method of choice for sperm retrieval. The outcome of sperm retrieval followed by intracytoplasmatic sperm injection is not affected.

Humans↗
PubMed2004

Early diagnosis of endolymphatic hydrops with distortion. Product otoacoustic emissions.

The present investigation was specifically designed to evaluate the ability of the glycerol test combined with pure-tone audiometry, distortion-product otoacoustic emissions (DPOAEs) to diagnose endolymphatic hydrops early and to identify patients who may evolve toward Meniere's disease. This investigation consisted of 43 consecutive patients with daily episodes of tinnitus with duration exceeding few hours or with continuous tinnitus who received no treatment. These were the unique symptoms reported by the patients. Each patient underwent glycerol testing measured with conventional pure tone audiometry and with distortion product otoacoustic emissions (DPOAEs). For the traditional pure-tone glycerol test a hearing improvement of at least 10 dB, at the lower two or three frequencies (125,250 and 500 Hz) was judged as positive result. For the DPOAEs glycerol testing, a smaller positive difference (5 dB) for at least three frequencies was interpreted as a significant fluctuation. Twenty four patients showed negative glycerol test both with pure tone audiometry and DPOAEs. In 7 cases the improvement was concurrently observed. In 9 patients post-glycerol changes appeared only in the DPOAEs outcomes. Finally the remaining three patients had two different patterns. Two had different ameliorations of the DPOAEs and pure-audiometry on the left and right sides respectively, and in the last one only post-glycerol, audiograms recovered. The present study re-confirms the potentiality of DPOAEs associated with glycerol test in diagnosing endolymphatic hydrops precociously. The possibility of these patients degenerating into Meniere's disease should not be underestimated.

Adult↗
PubMed2006

Salmonella typhimurium coordinately regulates FliC location and reduces dendritic cell activation and antigen presentation to CD4+ T cells.

During infection, Salmonella transitions from an extracellular-phase (STEX, growth outside host cells) to an intracellular-phase (STIN, growth inside host cells): changes in gene expression mediate survival in the phagosome and modifies LPS and outer membrane protein expression, including altered production of FliC, an Ag recognized by immune CD4+ T cells. Previously, we demonstrated that systemic STIN bacteria repress FliC below the activation threshold of FliC-specific T cells. In this study, we tested the hypothesis that changes in FliC compartmentalization and bacterial responses triggered during the transition from STEX to STIN combine to reduce the ability of APCs to present FliC to CD4+ T cells. Approximately 50% of the Salmonella-specific CD4+ T cells from Salmonella-immune mice were FliC specific and produced IFN-gamma, demonstrating the potent immunogenicity of FliC. FliC expressed by STEX bacteria was efficiently presented by splenic APCs to FliC-specific CD4+ T cells in vitro. However, STIN bacteria, except when lysed, expressed FliC within a protected intracellular compartment and evaded stimulation of FliC-specific T cells. The combination of STIN-mediated responses that reduced FliC bioavailability were overcome by dendritic cells (DCs), which presented intracellular FliC within heat-killed bacteria; however, this ability was abrogated by live bacterial infection. Furthermore, STIN bacteria, unlike STEX, limited DC activation as measured by increased MHC class II, CD86, TNF-alpha, and IL-12 expression. These data indicate that STIN bacteria restrict FliC bioavailability by Ag compartmentalization, and together with STIN bacterial responses, limit DC maturation and cytokine production. Together, these mechanisms may restrain DC-mediated activation of FliC-specific CD4+ T cells.

Animals↗
PubMed2002

Activity of a new class of isonicotinoylhydrazones used alone and in combination with isoniazid, rifampicin, ethambutol, para-aminosalicylic acid and clofazimine against Mycobacterium tuberculosis.

The activities of six derivatives of a new class of isonicotinoylhydrazones were investigated in vitro against Mycobacterium tuberculosis H37Rv ATCC 27294, isoniazid-resistant M. tuberculosis ATCC 35822, rifampicin-resistant ATCC 35838, pyrazinamide-resistant ATCC 35828, streptomycin-resistant ATCC 35820 and 16 clinical isolates of M. tuberculosis. Several compounds showed interesting antimycobacterial activity against both ATCC strains and clinical isolates, but were less active against isoniazid-resistant M. tuberculosis. Combinations of five isonicotinoylhydrazone derivatives and rifampicin, ethambutol, para-aminosalicylic acid, isoniazid and clofazimine were also investigated against M. tuberculosis H37Rv ATCC 27294 and against ATCC drug-resistant strains. Addition of sub-MICs of some isonicotinoylhydrazone derivatives resulted in a four- to 16-fold reduction in MICs of ethambutol, para-aminosalicylic acid and rifampicin with fractional inhibitory concentrations (FICs) ranging between 0.17 and 0.37, suggesting a synergic interaction against M. tuberculosis H37Rv. Increased activity was also observed with other combinations (FICs 0.53-0.75), including isoniazid, and a synergic interaction between one of the isonicotinoylhydrazone derivatives and isoniazid (FIC 0.26) was shown against isoniazid-resistant M. tuberculosis ATCC 35822, whereas no effects were observed on combining the isonicotinoylhydrazones with clofazimine. The ability of isonicotinoylhydrazones to inhibit specifically the growth of M. tuberculosis, the high selectivity index and their ability to enhance the activity of standard antituberculous drugs in vitro indicate that they may serve as promising lead compounds for future drug development for the treatment of M. tuberculosis infections.

Aminosalicylic Acid↗
PubMed1995

Genesis of Sindbis virus by in vivo recombination of nonreplicative RNA precursors.

Genetically engineered RNA transcripts coding for various Sindbis virus (SIN) genes were used to study structure and sequence requirements of RNA recombination in BHK cells. Three different groups of RNA transcripts were made: (i) RNAs which retain the ability to replicate and which carry sequences coding for either viral polymerase or viral structural proteins; (ii) RNAs which lack the complete 3' end of the SIN genome and thus are incapable of replicating; and (iii) RNAs which lack the complete 5' end of the SIN genome and also are incapable of replicating. BHK cells were transfected with specific combinations of these precursor RNAs, and virus production and RNA synthetic abilities of the released virus were determined. We demonstrate in vivo generation of infectious SIN by fusion of (i) replicative RNAs to nonreplicative RNAs and (ii) two nonreplicative RNA precursors. Both homologous and nonhomologous types of recombinations were observed. In the homologous type of recombination, a 694-nucleotide overlap at the crossover region of the first pair of precursors resulted in the addition of an A residue converting the UAG stop codon of nonstructural protein P4 to a UAA stop codon. In the nonhomologous type of recombination, the crossover sites contained deletion of up to 76 nucleotides from one of the precursors and complete preservation of junction sequence from the other precursor. This is also the first report that a cytoplasmic RNA virus can be generated from biologically nonreplicative RNA precursors. These results have implications for initiation of viral RNA synthesis and recombination between RNA viral genomes in general. We favor template switching as a mechanism for the fusion events described here and suggest inclusion of polymerase scanning of diverse nonreplicative RNAs as an inherent feature of the copy choice model of RNA recombination. Very importantly, the facile nature of RNA recombination occurring between nonreplicative RNA precursors should speed up the production and analysis of targeted mutants of SIN and possibly other RNA viruses.

Animals↗
PubMed1990

Myelin basic protein, MHC restriction molecules and T cell repertoire.

Our laboratory has developed a broad base of information in rats and mice describing the properties of encephalitogenic T cells. Using the T cell line selection technique to identify dominant T cell specificities, we were the first to identify new encephalitogenic epitopes and MHC restriction molecules in the Lewis rat and the SJL mouse. Furthermore, using the soft agar technique, we have isolated encephalitogenic Lewis rat T cell clones specific for defined synthetic epitopes of BP. With our colleagues, we have identified and sequenced the V region genes, and deduced the amino acid sequence of proteins which these clones use preferentially in their T cell receptor. Furthermore, we have successfully induced protection against EAE by the lymphocyte vaccination approach, using attenuated encephalitogenic T cells as the vaccine. Using this information, we have made significant progress in characterizing and understanding human T lymphocyte responses to BP. Recent results indicate that MBP reactivity is more frequent in MS patients than in controls, suggesting a greater degree of sensitization, and a potential involvement of BP as a target antigen. Since human BP responses also appear to be directed at immunodominant epitopes (as we have observed in rodents), it is probable that human T cells will also use preferential combinations of T cell receptor V genes. The ability to induce specific regulation or removal of autoreactive T cells will allow for the first time an assessment of cause and effect in human diseases. Immunoregulation directed at the TCR polypeptides may allow selective suppression of encephalitogenic clones, and may have direct application in human diseases such as MS, or in other autoimmune situations where preferential TCR V gene usage can be identified.

Amino Acid Sequence↗
PubMedDate not supplied

Discrimination between normal and glaucomatous eyes with scanning laser polarimetry and optic disc topography: a preliminary report.

PURPOSE: To test the ability of structural parameters (as measured by scanning laser polarimetry (SLP) software 1.0.12 and confocal scanning laser ophthalmoscopy (CSLO) to discriminate between normal and glaucomatous eyes. METHODS: A total of 112 patients with primary open-angle glaucoma and 88 normal individuals were enrolled in the study. All individuals underwent a thorough ophthalmic evaluation, a 24-2 full threshold Humphrey visual field, SLP with the GDx, and CSLO with the TOPSS. Patients with marked cataract or low vision were excluded from the study. Cut-off points were selected and receiver operator characteristic (ROC) curves were created for each individual CSLO and SLP parameter. Finally, multivariate dicriminant formulas were developed in order to achieve a better sensitivity (Se)/specificity (Sp) ratio for the diagnosis of glaucoma, initially separately for each device, and then combining parameters from CSLO and SLP. RESULTS: The mean deviation for the glaucoma group was -10.63 +/- 7.58 dB. Multivariate discriminant formulas resulted in better sensitivity/specificity ratios than any individual parameter, either for CSLO (Se: 90%; Sp: 81%; accuracy: 86%) or SLP (Se: 87%; Sp: 86%; accuracy: 86%). The multivariate formula combining parameters from both devices resulted in an improvement in the ability to diagnose glaucoma. An area under the ROC curve of 0.97 was obtained, with a sensitivity of 93%, a specificity of 91%, and an accuracy of 92%. CONCLUSIONS: The combination of structural parameters derived from CSLO and SLP in a multivariate discriminant formula may enhance the ability to diagnose glaucoma. Further studies investigating a random population are needed in order to test the validity of this formula.

Discriminant Analysis↗