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At least 397 records · Page 22Linked to original sources
PubMed2006

Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation.

The role of CD4+ T cells in the control of persistent viral infections beyond the provision of cognate help remains unclear. We used polychromatic flow cytometry to evaluate the production of the cytokines interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2, the chemokine macrophage inflammatory protein (MIP)-1beta, and surface mobilization of the degranulation marker CD107a by CD4+ T cells in response to stimulation with cytomegalovirus (CMV)-specific major histocompatibility complex class II peptide epitopes. Surface expression of CD45RO, CD27, and CD57 on responding cells was used to classify CD4+ T cell maturation. The functional profile of virus-specific CD4+ T cells in chronic CMV infection was unique compared with that observed in other viral infections. Salient features of this profile were: (a) the simultaneous production of MIP-1beta, TNF-alpha, and IFN-gamma in the absence of IL-2; and (b) direct cytolytic activity associated with surface mobilization of CD107a and intracellular expression of perforin and granzymes. This polyfunctional profile was associated with a terminally differentiated phenotype that was not characterized by a distinct clonotypic composition. Thus, mature CMV-specific CD4+ T cells exhibit distinct functional properties reminiscent of antiviral CD8+ T lymphocytes.

Adult↗
PubMed2004

Plasminogen activator inhibitor 1, fibrin, and the vascular response to injury.

Intravascular fibrin deposition is believed to play an important role in the development of intimal hyperplasia, which is a hallmark of several human vascular disorders, including atherosclerosis and restenosis after balloon angioplasty. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor or tissue- and urinary-type plasminogen activator, plays a key role in fibrin homeostasis by controlling plasmin formation. PAI-1 may also modulate vascular pathology via alternative pathways, such as inhibiting activated protein C and altering interactions between vascular smooth muscle cells and the extracellular matrix. The diverse functional profile of PAI-1 likely accounts for the variation observed in its impact on intimal hyperplasia in different disease models. This review examines recent studies addressing the vascular function of PAI-1, and those assessing the role of fibrin as a downstream mediator of PAI-1's effects.

Animals↗
PubMed2006

Molecular targeting of growth factor receptor-bound 2 (Grb2) as an anti-cancer strategy.

Growth factor receptor-bound 2 (Grb2) is a ubiquitously expressed adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. As such, it has been implicated in the oncogenesis of several important human malignancies. In addition to this function, research over the last decade has revealed other fundamental roles for Grb2 in cell motility and angiogenesis--processes that also contribute to tumor growth, invasiveness and metastasis. This functional profile makes Grb2 a high priority target for anti-cancer drug development. Knowledge of Grb2 protein structure, its component Src homology domains and their respective structure-function relationships has facilitated the rapid development of sophisticated drug candidates that can penetrate cells, bind Grb2 with high affinity and potently antagonize Grb2 signaling. These novel compounds offer considerable promise in our growing arsenal of rationally designed anti-cancer therapeutics.

Animals↗
PubMed1990

Effects of prazosin HCl on the urethral pressure profile in patients with benign prostatic hyperplasia.

The effects of prazosin HCl on the urethral pressure profile (UPP) were studied in 14 patients with benign prostatic hyperplasia. Urethral pressure profilometry was performed 1 h after oral administration of 1 or 2 mg prazosin HCl. Functional profile and continence zone lengths were significantly reduced following administration of 1 or 2 mg prazosin HCl, as compared with the pretreatment lengths. The administration of 2 mg prazosin HCl resulted in a significant decrease in prostatic peak pressure, whereas the maximum urethral closure pressure exhibited an insignificant decrease. The results suggest that the effects of prazosin HCl on UPP were dose dependent within the range from 1 to 2 mg.

Aged↗
PubMed1997

Profiles of psychological functioning in the old and oldest old.

Cluster analysis was applied to 12 measures of intellectual, personality, self-related, and social functioning collected in the 1st cross-sectional wave of the Berlin Aging Study (BASE; N = 516). Central questions concerned the number, profile desirability (functional status), and the membership of the subgroups obtained. Of the 9 subgroups extracted, 4 reflected different patterns of desirable functioning (47% of the sample), and 5 reflected less desirable functioning (53%). Relative risk of a less desirable profile was 2.5 times higher for the oldest old (85-103 years) than for people between the ages of 70-84 years and was 1.25 times higher for women compared with men. Relationships with education, health, and mortality suggested underlying systemic differences. Consistent with theoretical propositions about a "4th age" and the incomplete architecture of life span development (P.B. Baltes, 1997) the oldest old appear to have a distinct and less desirable psychological profile.

Activities of Daily Living↗
PubMed1999

Comparative pharmacological and functional analysis of the human dopamine D4.2 and D4.10 receptor variants.

The human dopamine D4 receptor is a D2-like receptor which is a target for most common neuroleptics. Previous investigations have shown that this receptor displays a large polymorphic variation in the third intracellular loop involving a variable number of direct imperfect tandem repeats (VNTR) of 16 amino acids. The shortest and longest repeat variants reported to date contain two and 10 repeat units (D4.2 and D4.10). No major pharmacological differences have been reported for the most common variants of this receptor (D4.2, D4.4 and D4.7), although the D4.7 was reported by us to display a slightly lower potency for dopamine in functional assays. Direct pharmacological and functional comparison of the longest and shortest variants in this study suggest no major discrepancies in pharmacological or functional profile between both receptors. Both receptors display, on average, a 15-fold and 90-fold lower potency for epinephrine and norepinephrine, respectively, compared with dopamine. We observed small increases in functional potency and affinity for dopamine and quinpirole at the D4.10 receptor variant compared with the D4.2 receptor. Our data indicate that there is no direct relationship between the length of the polymorphism and changes in pharmacology or functional activity. These findings are a suitable caution against the arbitrary pooling of D4 receptor VNTR genotypes in genetic studies, based on length.

Amino Acid Sequence↗
PubMed1992

Construction of detubularized ileal neobladder after radical cystoprostatectomy.

In an attempt to improve the patient's quality of life, we performed construction of neobladder using detubularized ileum along with radical cystoprostatectomy in 3 male patients with invasive bladder cancer. The mean followup was 28.3 months (16-45 months). All 3 patients achieved continent urination through the natural urine pathway-urethra with a satisfactory urinary stream during the day, but only 2 of them could also obtain continence in the night. Urodynamic study of the ileal neobladder showed a low pressure (mean 15.3 cm water) and no involuntary pressure spikes in the neobladder. The maximal urethral closure pressure (mean 62.0 cm water) and functional profile length (mean 3.0 cm) were adequate. In addition, the maximal uroflow rate was good (mean 16.7 ml/sec). There was no reflux in any of our patients. The radionuclide renal function study revealed that the renal function was preserved after operation in all 3 patients. Neocystourethroscopy showed no tumor and no stricture at the ileourethral anastomotic site in our 3 patients. There was no complication related to the operation. No disturbances of nutrition or electrolytes were found in any patient. All 3 patients had a satisfactory quality of life after operation though one patient died of widespread metastasis 16 months after operation. In conclusion, construction of detubularized ileal neobladder may be one of the ideal surgical procedures for bladder substitution after radical cystoprostatectomy.

Aged↗
PubMed1994

Th2-like CD8+ T cells showing B cell helper function and reduced cytolytic activity in human immunodeficiency virus type 1 infection.

We analyzed at clonal level the functional profile of circulating or skin-infiltrating T lymphocytes from two individuals infected with the human immunodeficiency virus type 1 (HIV-1), suffering from a Job's-like syndrome (eczematous dermatitis, recurrent skin and sinopulmonary infections, and hypergammaglobulinemia E) and showing virtually no circulating CD4+ T cells. Most of the CD3+ T cell clones generated from both patients were CD4- CD8+ TCR alpha beta +. The others were CD4- CD8- TCR alpha beta + which exhibited reduced mRNA expression for the CD8 molecule or no mRNA expression for either CD4 or CD8 molecules. The great majority of both CD4- CD8+ and CD4- CD8- did not produce interferon (IFN) gamma and exhibited reduced cytolytic activity. Rather, most of them produced large amounts of both interleukin (IL) 4 and IL-5 and provided B cell helper function for IgE synthesis. These data suggest that a switch of cytolytic CD8+ T cells showing a Th1-like cytokine secretion profile to cells that make Th2-type cytokines, exhibit reduced cytolytic potential, and provide B cell helper function can occur in the course of HIV-1 infection. These cells may contribute to the reduced defense against viral infections and intracellular parasites and account for the elevated IgE serum levels, eosinophilia, and the allergic-like clinical manifestations seen in a proportion of HIV-1-infected individuals.

B-Lymphocytes↗
PubMed1987

Urodynamic appraisal of the Marshall-Marchetti test in women with stress urinary incontinence.

To determine the reliability of the Marshall-Marchetti test as a diagnostic and prognostic preoperative screening test for stress urinary incontinence, the changes observed in urethral pressure profiles under resting and stressful situations were recorded and compared following varying degrees of elevation of the urethra and the urethrovesical junction. The characteristic similarity of changes was evident in the functional profile length, urethral closure pressure, and cough pressure profile of the urethra during performance of the Marshall-Marchetti test and intentional urethral occlusion. This study clearly invalidated the Marshall-Marchetti test by objectively demonstrating that the Marshall-Marchetti test restored continence under stress of coughing by occluding the urethra and the urethrovesical junction.

Adult↗
PubMed2004

Large-scale overproduction, functional purification and ligand affinities of the His-tagged human histamine H1 receptor.

This report describes an efficient strategy for amplified functional purification of the human H1 receptor after heterologous expression in Sf9 cells. The cDNA encoding a C-terminally histidine-tagged (10xHis) human histamine H1 receptor was used to generate recombinant baculovirus in a Spodoptera frugiperda-derived cell line (IPLB-Sf9). As judged from its ligand affinity profile, functional receptor could be expressed at high levels (30-40 pmol per 10(6) cells). Rapid proteolysis in the cell culture led to limited fragmentation, without loss of ligand binding, but could be efficiently suppressed by including the protease inhibitor leupeptin during cell culture and all subsequent manipulations. Effective solubilization of functional receptor with optimal recovery and stability required the use of dodecylmaltoside as a detergent in the presence of a high concentration of NaCl and of a suitable inverse agonist. Efficient purification of solubilized receptor could be achieved by affinity chromatography over nickel(II) nitrilotriacetic acid resin. Functional membrane reconstitution of purified H1 receptor was accomplished in mixed soybean lipids (asolectin). The final proteoliposomic H1 receptor preparation has a purity greater than 90% on a protein basis and displays a ligand binding affinity profile very similar to the untagged receptor expressed in COS-7 cells. In conclusion, we are able to produce pharmacologically viable H1 receptor in a stable membrane environment allowing economic large-batch operation. This opens the way to detailed studies of structure-function relationships of this medically and biologically important receptor protein by 3D-crystallography, FT-IR spectroscopy and solid-state NMR spectroscopy.

Animals↗
PubMed2003

A new measure for optical performance.

Because diffraction and aberration affect the performance of the optical system, a new metric is advanced that emphasizes the link between these three aspects. In general, the modulation transfer function is used as a measure for contrast sensitivity reduction, whereas the root mean square error is often used to quantify the optical quality of the system. However, for a given object, wavefront aberrations can alter the output image very differently even though they have the same root mean square error and modulation transfer function profile. A distinction between coherent and incoherent illumination is made, and a new measure, called optical transfer error, is defined to characterize optical performance complementarily to root mean square and modulation transfer function. The optical transfer error measures the optical excellence in terms of the shape of the wavefront as well as the theoretical performance results. Several illustrations are presented to better discuss optical performance.

Contrast Sensitivity↗
PubMed1999

Prevalence and characteristics of patients with severe mental illness and borderline intellectual functioning. Report from the UK700 randomised controlled trial of case management.

BACKGROUND: Low cognitive ability and developmental delays have been implicated in the causation of mental illness. AIMS: To examine the prevalence, socio-demographic characteristics, psychopathology and social functioning profiles of people with low intelligence and recurrent psychotic illness. METHOD: A multi-centre randomised controlled trial of case management provided the opportunity to explore associations between mental illness and borderline intellectual functioning (assessed using the National Adult Reading test). RESULTS: Overall prevalence of borderline intelligence was 18%. Significant positive associations were shown with: being Black Caribbean; having a father who worked in a manual occupation; lower educational achievement; having had special education; longer course of illness. Those with borderline intelligence had greater disability and were more likely to suffer extrapyramidal side-effects and show evidence of negative symptoms. Educational achievement, history of special education and social class were the best socio-demographic predictors of intellectual level. CONCLUSIONS: Many patients who attend generic psychiatric services have considerable intellectual deficits. This may lead to difficulties in other domains of adaptive functioning, and merits further investigation as well as clinical vigilance.

Adolescent↗
PubMed2003

Native and recombinant interleukin-2, two functionally distinct molecules.

Recombinant IL-2 (rIL-2) produced in prokaryotes, is widely used in lieu of native IL-2, which is secreted by T cells, to assess the functional profile of this cytokine. We provide evidence that a naturally occurring species of post-translationally modified IL-2 (moIL-2) exhibits enhanced bioactivity compared to rIL-2, as tested at the biochemical and functional level. We show that moIL-2 has high binding affinity for the IL-2 receptor (IL-2R), induces the immediate expression of the IL-2R alpha chain and rapidly activates downstream signaling molecules. Finally, in contrast to rIL-2, moIL-2 can promote the antigen-independent proliferation of resting lymphocytes. Collectively, our data demonstrate that native moIL-2 is functionally distinct from rIL-2, suggesting the existence of diverse IL-2 variants which may be critical for the shaping of the immune response.

Cell Division↗
PubMed1996

Induction of Th2 cytokines and control of collagen-induced arthritis by nondepleting anti-CD4 Abs.

CD4+ T cells play a key role in the development of cell-mediated autoimmune diseases, and their modulation has been used to prevent autoimmune diseases in animal models. The effect of the nondepleting anti-CD4 mAb (KT6) was investigated in collagen-induced arthritis (CIA) in DBA/1 mice and in adoptive transfer of CIA into SCID mice. KT6 (200 microg/dose/mouse) was administered systematically from the day of collagen type II (CII) immunization and continued by alternate-day injection until day 11. Only 20% of KT6-treated mice developed arthritis compared with 100% of the isotype control treated mice (p < 0.001). KT6 treatment in a similar regimen also abrogated the adoptive transfer of CIA into SCID mice. Serum levels of IgG2a anti-CII Abs in KT6-treated DBA/1 mice were significantly reduced (p < 0.001), while IgG1 anti-CII were not significantly changed (p > 0.05). Lymph node cells of mice treated in vivo with KT6 had a reduced production of IFN-gamma but increased IL-4 upon in vitro challenge with CII. Furthermore, KT6 could also reverse the profile of cytokine release of in vivo primed and pathogenic CII-specific T cells. These results demonstrate that in vivo modulation with nondepleting anti-CD4 Abs prevents CIA, likely by altering the functional profile of Th1 T cells to Th2. Furthermore, we demonstrate that this treatment can not only prevent, but more importantly also control pathogenic T cells by switching their cytokine production from a Th1 to a Th2-like profile. Our results thus provide compelling evidence of how treatment with nondepleting anti-CD4 may control an autoimmune process. They also indicate that this approach not only prevents, but also could control ongoing autoimmune diseases.

Animals↗
PubMed2000

Opioid activity profiles indicate similarities between the nociceptin/orphanin FQ and opioid receptors.

Nociceptin (orphanin FQ) is the recently discovered peptide agonist for the orphan receptor opioid receptor-like 1 (ORL1). Despite the high sequence homology between ORL1 and the opioid receptors, most opioids lack affinity for the nociceptin receptor. The affinity and functional profile of opioids possessing activity at the nociceptin receptor was determined using [3H]nociceptin and nociceptin-stimulated [35S]GTPgammaS binding. The mu-opioid receptor-selective agonist lofentanil potently and competitively displaced [3H]nociceptin at rat brain receptors (IC(50) 62 nM). Lofentanil exhibited full agonism for enhancement of [35S]GTPgammaS binding to human recombinant ORL1 receptors (EC(50) 50 nM). The related piperidines ohmefentanyl and sufentanil and the nonselective opioid receptor agonist etorphine were less potent nociceptin receptor agonists. The kappa(1)+kappa(3)-opioid receptor agonist/mu-opioid receptor antagonist naloxone benzoylhydrazone was a pure antagonist at both rat brain and human ORL1 receptors. The nonselective opioid receptor partial agonist buprenorphine and the nonselective opioid receptor antagonist (-)-quadazocine exhibited pure antagonism at rat brain receptors, but displayed partial agonism at human ORL1 receptors. Thus, opioids displaying full agonism at the nociceptin receptor are also opioid receptor agonists, whereas opioids that are antagonists or partial agonists at the nociceptin receptor show antagonism or partial agonism at opioid receptors. In addition, the stereospecificity required at opioid receptors appears to be retained at the nociceptin receptor, since (+)-quadazocine is inactive at both receptors. These findings illustrate the structural and functional homology of the opioid recognition site on these two receptor classes and suggest that opioids may provide leads for the design of nonpeptide nociceptin receptor agonists and antagonists lacking affinity for the classical opioid receptors.

Animals↗
PubMed2005

In vivo transcriptional profile analysis reveals RNA splicing and chromatin remodeling as prominent processes for adult neurogenesis.

Neural stem cells and neurogenesis persist in the adult mammalian brain subventricular zone (SVZ). Cells born in the rodent SVZ migrate to the olfactory bulb (Ob) where they differentiate into interneurons. To determine the gene expression and functional profile of SVZ neurogenesis, we performed three complementary sets of transcriptional analysis experiments using Affymetrix GeneChips: (1) comparison of adult mouse SVZ and Ob gene expression profiles with those of the striatum, cerebral cortex, and hippocampus; (2) profiling of SVZ stem cells and ependyma isolated by fluorescent-activated cell sorting (FACS); and (3) analysis of gene expression changes during in vivo SVZ regeneration after anti-mitotic treatment. Gene Ontology (GO) analysis of data from these three separate approaches showed that in adult SVZ neurogenesis, RNA splicing and chromatin remodeling are biological processes as statistically significant as cell proliferation, transcription, and neurogenesis. In non-neurogenic brain regions, RNA splicing and chromatin remodeling were not prominent processes. Fourteen mRNA splicing factors including Sf3b1, Sfrs2, Lsm4, and Khdrbs1/Sam68 were detected along with 9 chromatin remodeling genes including Mll, Bmi1, Smarcad1, Baf53a, and Hat1. We validated the transcriptional profile data with Northern blot analysis and in situ hybridization. The data greatly expand the catalogue of cell cycle components, transcription factors, and migration genes for adult SVZ neurogenesis and reveal RNA splicing and chromatin remodeling as prominent biological processes for these germinal cells.

Animals↗
PubMed2001

Structure-function relationships of complement receptor type 1.

Human complement receptor type 1 (CR1) is a large, multifunctional glycoprotein which is a member of the regulators of complement activation family. Like other members of this family, it is composed mainly of tandemly arranged modules, each about 60-70 amino acids long, known as complement control protein repeats (CCPs). Each domain folds independently and contains a hydrophobic core wrapped in beta sheets. These domains mediate interactions with C3/C4-derived fragments. CR1 is the most versatile inhibitor of both classical and alternative pathway C3 and C5 convertases due to its decay-accelerating activity and co-factor activity for C3b/C4b cleavage. Moreover, CR1 plays a major role in immune complex clearance due to its high affinity for C3b and C4b. CR1 is an excellent model to study structure-function relationships because its functions are mediated by two distinct but highly homologous sites, each composed of three CCPs. CR1 derivatives carrying just one active site were used to define critical sequences/amino acids. This was achieved by testing functional profiles of the proteins carrying a mutated active site produced by substituting peptides/amino acids with their counterparts from the other site. These mutated proteins, of which we analyzed over 100, permitted the fine mapping of the functional sites. CR1 on primate erythrocytes varies in size. In most cases it is smaller and has fewer active sites than does human CR1. This variation was used to determine that increased copy number (3,000 to 20,000 versus 300 for human CR1) compensates for a smaller size. Moreover, studies of primate CR1 led to the finding that subtle differences in the critical areas, as compared to human sites, produce active sites with a broader functional repertoire. These alterations ensure that short CR1 forms possess similar biologic activities to the large CR1 forms. There is much interest in producing therapeutic agents to inhibit unwanted complement activation. Based on these structure-function analyses, smaller and more potent complement inhibitors derived from CR1 can be produced.

Amino Acid Sequence↗
PubMed2005

Local overpressure treatment reduces vestibular symptoms in patients with Meniere's disease: a clinical, randomized, multicenter, double-blind, placebo-controlled study.

OBJECTIVES: To evaluate the efficacy of a new device, the Meniett, in the treatment of Meniere's disease. The device delivers pressure pulses to the middle ear through a ventilating tube in the tympanic membrane at a frequency of 6 Hz for 0.6 second. After rising to a pressure level of 1.2 kPa, the pressure oscillates between 0.4 and 1.2 kPa. It is believed that the pressure changes are conveyed to the inner ear, inducing a transport of fluids via the pressure outlets and thus reducing the endolymphatic hydrops. STUDY DESIGN: A clinical, randomized, multicenter, double-blind, placebo-controlled study. A total of 40 patients were included that had active Meniere's disease according to American Academy of Otolaryngology-Head and Neck Surgery criteria, aged between 20 and 65 years, with a history of at least eight attacks during the past year. After insertion of the ventilation tube, the patients should have had attacks of vertigo for 2 months before entering the study. OUTCOME MEASURES: Primary study endpoints were change in frequency of vertigo, change of functionality profile, and change in patient perception of vertigo (visual analogue scale); secondary endpoints were perception of tinnitus, aural pressure, and hearing, as well as an audiologic evaluation of hearing before and after the treatment period. RESULTS: The functionality level improved statistically significantly in the active group compared with the placebo group (p=0.0014), as did the visual analogue scale evaluation of vertigo (p=0.005). There was a trend toward a reduction of the frequency of vertiginous attacks that was not significant (p=0.090). With regard to the secondary endpoints, there was no statistical difference between active and placebo groups. CONCLUSION: Local overpressure treatment is a novel treatment that is noninvasive, nondestructive, and safe. It significantly reduces vestibular symptoms in patients with Meniere's disease. The Meniett was cleared by the Food and Drug Administration in 2000.

Adult↗