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At least 595 records · Page 33Linked to original sources
PubMed2006

PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion.

Hepatitis C virus (HCV)-specific CD8 cell exhaustion may represent a mechanism of HCV persistence. The inhibitory receptor PD-1 has been reported to be up-regulated in exhausted CD8 cells. Therefore, we studied PD-1 expression longitudinally during acute HCV infection. Most HCV-specific CD8 cells expressed PD-1 at the time of acute illness, irrespective of the final outcome. PD-1 expression declined with the acquisition of a memory phenotype and recovery of an efficient CD8 cell function in resolving HCV infections, whereas high levels were maintained when HCV persisted and HCV-specific CD8 cells remained dysfunctional. Blocking PD-1/PDL-1 interaction with an anti-PDL-1 antibody improved the capacity of expansion of virus-specific CD8 cells.

Antigens, CD↗
PubMed2006

Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression.

The majority of people infected with hepatitis C virus (HCV) fail to generate or maintain a T-cell response effective for viral clearance. Evidence from murine chronic viral infections shows that expression of the coinhibitory molecule PD-1 predicts CD8+ antiviral T-cell exhaustion and may contribute to inadequate pathogen control. To investigate whether human CD8+ T cells express PD-1 and demonstrate a dysfunctional phenotype during chronic HCV infection, peripheral and intrahepatic HCV-specific CD8+ T cells were examined. We found that in chronic HCV infection, peripheral HCV-specific T cells express high levels of PD-1 and that blockade of the PD-1/PD-L1 interaction led to an enhanced proliferative capacity. Importantly, intrahepatic HCV-specific T cells, in contrast to those in the periphery, express not only high levels of PD-1 but also decreased interleukin-7 receptor alpha (CD127), an exhausted phenotype that was HCV antigen specific and compartmentalized to the liver, the site of viral replication.

Adult↗
PubMed2002

Identification of a novel mitogen-activated protein kinase kinase activation domain recognized by the inhibitor PD 184352.

Utilizing a genetic screen in the yeast Saccharomyces cerevisiae, we identified a novel autoactivation region in mammalian MEK1 that is involved in binding the specific MEK inhibitor, PD 184352. The genetic screen is possible due to the homology between components of the yeast pheromone response pathway and the eukaryotic Raf-MEK-ERK signaling cascade. Using the FUS1::HIS3 reporter as a functional readout for activation of a reconstituted Raf-MEK-ERK signaling cascade, randomly mutagenized MEK variants that were insensitive to PD 184352 were obtained. Seven single-base-change mutations were identified, five of which mapped to kinase subdomains III and IV of MEK. Of the seven variants, only one, a leucine-to-proline substitution at amino acid 115 (Leu115Pro), was completely insensitive to PD 184352 in vitro (50% inhibitory concentration >10 micro M). However, all seven mutants displayed strikingly high basal activity compared to wild-type MEK. Overexpression of the MEK variants in HEK293T cells resulted in an increase in mitogen-activated protein (MAP) kinase phosphorylation, a finding consistent with the elevated basal activity of these constructs. Further, treatment with PD 184352 failed to inhibit Leu115Pro-stimulated MAP kinase activation in HEK293T cells, whereas all other variants had some reduction in phospho-MAP kinase levels. By using cyclic AMP-dependent protein kinase (1CDK) as a template, an MEK homology model was generated, with five of the seven identified residues clustered together, forming a potential hydrophobic binding pocket for PD 184352. Additionally, the model allowed identification of other potential residues that would interact with the inhibitor. Directed mutation of these residues supported this region's involvement with inhibitor binding.

Amino Acid Sequence↗
PubMed1980

Effects of organic solutes on transmural PD and Na transport in freshwater prawn intestine.

Addition of 1 mM L-alanine or 0.5 mM D-glucose to the mucosal surface of freshwater prawn (Macrobrachium rosenbergii) intestine rapidly increased transmural potential difference (PD) (serosa became more positive). Luminal perfusion with 1 mM D-alanine did not affect the spontaneous PD. Addition of 10 mM serosal L-alanine induced a slow elevation in PD with the same polarity as shown with luminal alanine. The alanine-evoked PD was a hyperbolic function of luminal alanine concentration and was reduced to zero with 0.5 mM serosal ouabain. Luminal 1 mM L-alanine stimulated JNanet from mucosa to serosa from 1.29 +/- 0.45 to 2.83 +/- 0.66 mu mol . cm-2 . h-1. Extensive metabolic breakdown of L-alanine and D-glucose occurred during intestinal transit resulting in a small, but significant, net flux of unaltered sugar from lumen to blood (103.9 +/- 23.1 nmol . cm-2 . h-1) and an absence of net amino acid flow. While 1 mM alanine influx into the epithelium was largely Na dependent, quantitatively insigificant amounts of Na were cotransported into the cell with amino acid (approx 52 nmol . cm-2 . h-1) to account for increased JNanet observed in the presence of this organic solute. Electrogenic effects of luminal nutrients result from their catabolism to fuels for the basolateral Na pump, Increased Na-pump activity stimulates Na entry into the cell by allosteric apical carrier proteins and enhances transmural PD by accelerating net movement of cation across the tissue.

Alanine↗
PubMed1977

G-6-PD activity of the red cells in chronic renal failure.

The G-6-PD activity of erythrocytes was studied in 75 patients with chronic renal failure and 74 normal subjects. The mean value of G-6-PD was higher in the chronic renal failure group and the difference was highly significant. During haemodialysis the G-6-PD activity did not return to normal but was further elevated, though the increase was not statistically significant. A highly significant negative correlation was found between red cell G-6-PD and haematocrit. After separation of the red cells according to age by centrifugation, G-6-PD was highest in the top (young cells) and lowest in the bottom (old) cells, both in normals and uraemic patients. The enzyme activity was higher at all levels in the uraemic subjects, significantly in the top and middle layers. Although our findings may be due to an increased proportion of young erythrocytes in uraemia there are objections to this explanation; the alternative possibility of a life-long metabolic abnormality in uraemic red cells deserves careful consideration.

Adolescent↗
PubMed1986

An electrochemical and multispectroscopic study of corrosion of Ag-Pd-Cu-Au alloys.

Corrosion of a multi-phase Ag-Pd-Cu-Au-based commercial dental casting alloy and a Cu-Pd-rich and Ag-rich single-phase alloy was studied by open-circuit potential measurements, atomic absorption spectrometry, and electron spectroscopy. The alloys were immersed in an artificial saliva solution for 24 hr while the open-circuit potentials of the alloys were measured. The potentials were found to stabilize at certain levels after a steep rise during the first hours of the experiment. Cu was found to dissolve considerably from the Cu-Pd-rich alloy, with simultaneous enrichment of Pd in the surface layer of the alloy. Ag dissolved slightly from the Ag-rich alloy, but both Cu and Ag were found to dissolve from the multi-phase alloy. Neither Pd nor Au dissolved from any of the alloys studied.

Chemical Phenomena↗
PubMed2004

Characterization of the potent combined endothelin(A/B)-antagonist PD 142893 on cerebral vessels.

A disturbed balance between endothelin (ET)-1 and nitric oxide (NO) seems to play a key role in the development of delayed cerebral vasospasm following subarachnoidal hemorrhage. Therefore, the effect of PD 142893 one of the first potent ET(A)- and ET(B)-receptor antagonists was characterized on the contraction and relaxation induced by ET-1 and bigET-1 on rat basilar artery (BA). Concentration-effect curves (CECs) were constructed by cumulative application of ET-1 or big ET-1 on BA ring segments with (E+) and without (E-) functionally intact endothelium. The effect of PD 142893 was determined by the modified pK(b) value and the shift between the CECs. PD 142893 inhibited the contraction by ET-1 and bigET-1. The pK(b)-values were for ET-1: 5.17 (E+) and 5.15 (E-) and for big ET-1: 5.34 (E+) and 5.57 (E-), respectively. A significant relaxation of pre-contracted segments by ET-1 or big ET-1 was neither observed in the presence nor in the absence of the receptor antagonist. The present data suggest a competitive inhibition of the ET(A)-receptor mediated contraction of cerebral arteries by PD 142893. The ET(B)-dependent relaxation of the cerebrovasculature is inhibited by PD 142893 at least in a comparable amount of contraction.

Animals↗
PubMed2005

The PD-(D/E)XK superfamily revisited: identification of new members among proteins involved in DNA metabolism and functional predictions for domains of (hitherto) unknown function.

BACKGROUND: The PD-(D/E)XK nuclease superfamily, initially identified in type II restriction endonucleases and later in many enzymes involved in DNA recombination and repair, is one of the most challenging targets for protein sequence analysis and structure prediction. Typically, the sequence similarity between these proteins is so low, that most of the relationships between known members of the PD-(D/E)XK superfamily were identified only after the corresponding structures were determined experimentally. Thus, it is tempting to speculate that among the uncharacterized protein families, there are potential nucleases that remain to be discovered, but their identification requires more sensitive tools than traditional PSI-BLAST searches. RESULTS: The low degree of amino acid conservation hampers the possibility of identification of new members of the PD-(D/E)XK superfamily based solely on sequence comparisons to known members. Therefore, we used a recently developed method HHsearch for sensitive detection of remote similarities between protein families represented as profile Hidden Markov Models enhanced by secondary structure. We carried out a comparison of known families of PD-(D/E)XK nucleases to the database comprising the COG and PFAM profiles corresponding to both functionally characterized as well as uncharacterized protein families to detect significant similarities. The initial candidates for new nucleases were subsequently verified by sequence-structure threading, comparative modeling, and identification of potential active site residues. CONCLUSION: In this article, we report identification of the PD-(D/E)XK nuclease domain in numerous proteins implicated in interactions with DNA but with unknown structure and mechanism of action (such as putative recombinase RmuC, DNA competence factor CoiA, a DNA-binding protein SfsA, a large human protein predicted to be a DNA repair enzyme, predicted archaeal transcription regulators, and the head completion protein of phage T4) and in proteins for which no function was assigned to date (such as YhcG, various phage proteins, novel candidates for restriction enzymes). Our results contributes to the reduction of "white spaces" on the sequence-structure-function map of the protein universe and will help to jump-start the experimental characterization of new nucleases, of which many may be of importance for the complete understanding of mechanisms that govern the evolution and stability of the genome.

Amino Acid Motifs↗
PubMed2004

A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients.

The association between polymorphisms in the programmed death (PD-1) gene and susceptibility to systemic lupus erythematosus (SLE) was determined using genomic DNA, isolated from a population-based cohort of 95 SLE patients and 155 healthy controls. Polymorphisms in the complete PD-1 gene except the large intron 1 were detected by sequencing. Furthermore, the patients were stratified according to the presence or absence of lupus nephropathy. The influence of the detected single nuclear polymorphisms (SNPs) on this specific clinical disease parameter was determined. In total, we identified 12 single nucleotide polymorphisms, of which six were novel and eight were considered to be rare (the frequency of the minor allele of these was less than 1% in our study populations). We found a significant association of an intronic 6867C/G SNP in the PD-1 gene with the presence of lupus nephropathy. As the 6867C/G SNP is located in a putative binding site for the transcriptional repressor ZEB, the associated allele of this SNP potentially alters the transcriptional regulation of PD-1. This report, for the first time, indicates that a 6867C/G SNP of the PD-1 gene is associated with lupus nephropathy in Caucasian SLE patients.

Adolescent↗
PubMed2004

Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in PD: a randomized trial.

OBJECTIVE: To compare the efficacy of unilateral pallidotomy and bilateral subthalamic nucleus (STN) stimulation in patients with advanced Parkinson disease (PD) in a randomized, observer-blind, multicenter trial. METHODS: Thirty-four patients with advanced PD were randomly assigned to have unilateral pallidotomy or bilateral STN stimulation. The primary outcome was the change from baseline to 6 months in the motor part of the Unified PD Rating Scale (motor UPDRS) in the off phase. Secondary outcomes were parkinsonian symptoms in the on phase (motor UPDRS), dyskinesias (Clinical Dyskinesia Rating Scale and dyskinesias UPDRS), functional status (activities of daily living UPDRS and Schwab and England scale), PD Quality of Life questionnaire, changes in drug treatment, and adverse effects. RESULTS: The off phase motor UPDRS score improved from 46.5 to 37 points in the group of pallidotomy patients and from 51.5 to 26.5 in the STN stimulation patients (p = 0.002). Of the secondary outcome measures, on phase motor UPDRS and dyskinesias UPDRS improved significantly in favor of the STN stimulation patients. Reduction of antiparkinsonian drugs was greater after STN stimulation than after pallidotomy. One patient in each group had a major adverse effect. CONCLUSIONS: Bilateral STN stimulation is more effective than unilateral pallidotomy in reducing parkinsonian symptoms in patients with advanced PD.

Aged↗
PubMed2000

Objective changes in motor function during placebo treatment in PD.

OBJECTIVE: To examine the frequency, temporal development, and stability of objectively derived motor changes during placebo treatment in PD and to define the clinical domains and demographic groups most affected. BACKGROUND: Placebo effects are documented in neurology, but the timing and specific disabilities most susceptible to changes during placebo treatment in PD have not been examined. METHODS: The authors examined the placebo-treated group from a randomized, multicenter, placebo-controlled clinical trial of monotherapy ropinerole in PD patients without motor fluctuations. In 105 patients, they evaluated placebo-associated effects on the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS), dividing the motor examination into four categories: tremor, bradykinesia, rigidity, and gait/balance/midline functions. The motor UPDRS and its subscales were compared over time (at baseline and at 4, 12, and 24 weeks) using Wilcoxon's signed rank test. They applied a rigorous definition of placebo-associated improvement as an improvement over baseline score in motor UPDRS of at least 50% or a change in at least two motor items at any one visit by > or =2 points. RESULTS: During the 6-month study, 16% of subjects improved on placebo treatment. The prevalence of response was steady (8 to 9%) at any one visit without a predominance of an early effect. No patient showed a placebo-associated improvement on all visits. All domains of parkinsonian disability were subject to placebo-associated improvement, with a trend toward more response in bradykinesia and rigidity than in tremor or gait/balance/midline function. Gender, age, disease duration, and baseline disability score did not influence the likelihood of improvement in association with placebo treatment. CONCLUSION: Based on a rigorous definition of placebo-associated improvement, prominent improvements in objective measures of PD disability occur during clinical trials. Because placebo-associated improvements occur throughout a 6-month trial, placebo-controlled studies in PD should be at least 6 months to capture early as well as late improvements.

Aged↗
PubMed2000

Motor impairment in PD: relationship to incident dementia and age.

OBJECTIVE: To analyze the relationship of specific motor impairment in idiopathic PD to incident dementia. BACKGROUND: The total Unified PD Rating Scale (UPDRS) motor score at baseline has been associated with an increased risk of developing dementia in PD. METHODS: A cohort of 214 nondemented community-dwelling patients with PD was followed annually with neurologic and neuropsychological evaluations. The association of baseline motor impairment with incident dementia was analyzed using Cox proportional hazards models. Facial expression, tremor, rigidity, and bradykinesia were analyzed as part of subscore A (indicative of dopaminergic deficiency); speech and axial impairment were analyzed as part of subscore B (indicative of predominantly nondopaminergic deficiency). The correlation between the six motor domains and age was also analyzed. RESULTS: Of 173 patients followed for at least 1 year, 50 became demented according to the Diagnostic and Statistical Manual of Mental Disorders, revised 3rd edition (DSM III-R) criteria (mean follow-up, 3.6 +/- 2. 2 years). When both subscores A and B were entered into the Cox model, subscore B was associated with incident dementia (relative risk = 1.19; 95% CI, 1.09 to 1.30; p = 0.0001), in addition to gender, age, and education, whereas subscore A was not (relative risk = 1.03; 95% CI, 0.99 to 1.07; p = 0.19). Of the six motor domains, speech and bradykinesia were associated with incident dementia (p < 0.05), and axial impairment approached significance (p = 0.06). Only axial impairment was correlated with age (correlation coefficient = 0.32; p < 0.001). CONCLUSION: The findings suggest that motor impairment mediated predominantly by nondopaminergic systems is associated with incident dementia in PD. Axial impairment may be the result of a combined effect of the disease and the aging process.

Age Factors↗
PubMed2000

Olanzapine and clozapine: comparative effects on motor function in hallucinating PD patients.

OBJECTIVE: To compare olanzapine and clozapine for safety and efficacy measures of psychosis and motor function in patients with PD and chronic hallucinations. BACKGROUND: Hallucinations occur in approximately one third of patients with PD treated chronically with dopaminergic drugs. Although clozapine is known to be an effective antipsychotic agent that does not significantly exacerbate parkinsonism, its use requires frequent blood count assessment. Olanzapine is another novel antipsychotic that is not associated with blood dyscrasia, and if equally effective could become the preferred drug for treating hallucinations in subjects with PD. METHODS: A randomized, double-blind, parallel comparison of olanzapine and clozapine in patients with PD with chronic hallucinations was conducted. The primary outcome measure was the Scale for the Assessment of Positive Symptoms (SAPS) for psychotic symptoms. The Unified Parkinson's Disease Rating Scale (UPDRS) motor subscale was used as a secondary outcome measure and as a safety monitoring tool. RESULTS: After 15 patients had completed the study, safety stopping rules were invoked because of exacerbated parkinsonism in olanzapine-treated subjects. UPDRS motor impairment scores from baseline to study end significantly increased with olanzapine treatment, and change scores between the olanzapine and clozapine groups significantly differed. The primary clinical domains responsible for the motor decline were gait and bradykinesia. Even with a smaller patient number than originally anticipated, clozapine significantly improved hallucinations and overall behavioral assessment, whereas olanzapine had no effect. CONCLUSIONS: At the doses studied, olanzapine aggravates parkinsonism in comparison with clozapine and should not be regularly used in the management of hallucinations in patients with PD.

Aged↗
PubMedDate not supplied

[Genetico-epidemiological and molecular investigation of G-6-PD deficiency in a Brazilian community].

This paper reports on a study of the G-6-PD deficiency in Bragança Paulista, São Paulo State, Brazil. A total of 4,621 male blood donors were investigated over a 36-month period. Of these, 80 had the G-6-PD deficiency. Molecular analysis was performed on 70 unrelated G-6-PD deficients through DNA amplification followed by digestion with restriction enzymes and single strand conformation polymorphism analysis (SSCP). In 98.6%, the G-6-PD A- (202 G<--A) mutation was observed through digestion of exon 4 with Nla III. The presence of an uncommon mutation in exon 9 was also observed through SSCP. No case of the Mediterranean variant was observed. These results indicate that the A- (202G<--A) variant, almost exclusive, was introduced into the community not only by individuals of African origin, but also by European immigrants, mainly Italian, Spanish, and Portuguese. The Italian contribution in terms of the G-6-PD Mediterranean variant was smaller than its contribution to beta thalassemia, probably due to the Northern Italian origin of these immigrants.

Brazil↗
PubMed2000

TGF-alpha as well as VEGF, PD-ECGF and bFGF contribute to angiogenesis of esophageal squamous cell carcinoma.

It has been demonstrated that vascular endothelial growth factor (VEGF) is associated with tumor progression as an angiogenic factor in esophageal squamous cell carcinoma (SCC)s. However, the role of other angiogenic factors such as transforming growth factor-alpha (TGF-alpha), platelet-derived endothelial cell growth factor (PD-ECGF), and basic fibroblast growth factor (bFGF) are still unknown in esophageal SCCs. In this study, we detected the expression of VEGF, TGF-alpha, PD-ECGF and bFGF in tissue specimens from 96 patients with SCC of the esophagus by immunohistochemical staining. To evaluate angiogenesis, endothelial cells were stained immunohistochemically and microvessel density (MVD) was counted in 24 cases. The positive rates for VEGF, TGF-alpha, PD-ECGF and bFGF were 65% (62/96), 67% (64/96), 66% (63/96), and 49% (47/96), respectively. Only TGF-alpha expression had a strong correlation with the average MVD (p=0.0059). However, the MVD increased as the number of positive factors for these 4 factors increased (p=0.0023). The expression of all of these factors significantly correlated to the depth of tumor invasion, and lymph node metastasis. Finally, survival analysis of the patients revealed that VEGF, TGF-alpha, and PD-ECGF were significant prognostic factors. However, multivariate analysis revealed that these factors were not prognostic. Thus, we suggest that TGF-alpha as well as VEGF, PD-ECGF and bFGF may be associated with angiogenesis, and the progression and metastasis of esophageal squamous cell carcinoma.

Adult↗
PubMed2003

Evaluation of the amalgamation reaction of experimental Ag-Sn-Cu alloys containing Pd using a mercury plating technique.

A mercury plating technique was used to determine the phases forming on experimental Ag-Sn-Cu alloy powders (with and without Pd) exposed to electrolytically deposited mercury. Four series of alloy powders were made: a) 1.5% Pd with 10-14% Cu (CU series); b) 1.0% Pd with 10-14% Cu (1PD series); c) 1.5% Pd with different ratios of Ag3Sn (gamma) to Ag4Sn (beta) with 12% Cu (AGSN series); and d) 9-13% Cu with no Pd (NOPD series). Each powder was pressed on a freshly prepared amalgam specimen made from the same powder and metallographically polished until cross sections appeared; mercury was electroplated on the alloy particles. Alloy powders, amalgams and electroplated specimens were examined using XRD and SEM/EDS. XRD confirmed the presence of gamma2 in amalgams made from alloys with Cu < 13% or with Ag3Sn/Ag4Sn > 0.8. Specimens with moderately plated Hg showed gamma1 (Ag2Hg3) polyhedra and eta' Cu6Sn5, but not gamma2. This method effectively identifies alloys prone to forming gamma2.

Copper↗
PubMed2001

[Trust and cooperation: an experimental study of PD with choice of dependence].

This study examined the relationship between cooperation and trust in interpersonal trust formation. Previous studies of trust and cooperation using prisoner's dilemma (PD) games failed, methodologically as well as conceptually, to distinguish the former from the latter. In response to the criticism on the use of iterated PD games, and for the purpose of investigating dynamic relationship between trust and cooperation, an improvement in research methodology was recently proposed: namely, PD with choice of dependence (PD/D; Kakiuchi & Yamagishi, 1997; Yamagishi & Kakiuchi, 2000). We conducted an experiment to compare formation of trust relations in PD and PD/D. Result indicated a higher level of cooperation in PD/D than in PD. Further analysis of strategies used to build trustful relationship, where two partners trusted each other and reciprocated the other's trusting behavior, revealed that participants in PD/D adopted "cautious and unconditional cooperation strategy" rather than TFT strategy.

Adult↗
PubMed1999

Clinical implication of expression of platelet-derived endothelial cell growth factor (PD-ECGF) in metastatic lesions of uterine cervical cancers.

The platelet-derived endothelial cell growth factor (PD-ECGF) level was significantly (P < 0.05) increased in 8 of 40 metastatic lymph node lesions of uterine cervical cancers. The prognosis of the eight patients with high PD-ECGF (>10,000 pg/mg protein) in metastatic lymph node lesions was extremely poor. On the other hand, the 24-month survival rate of the 32 patients with low PD-ECGF (<10,000 pg/mg protein) in metastatic lymph node lesions was 75%. This indicates that PD-ECGF may contribute to the advancement of metastatic lesions, and that the PD-ECGF level in metastatic lesions may be a prognostic indicator.

Adult↗