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Biomedical subjects

S Jones

Publications and source records attributed to S Jones.

At least 145 records · Page 8Linked to original sources
PubMed2001

Interleukin-6 levels decrease in effluent from patients dialyzed with bicarbonate/lactate-based peritoneal dialysis solutions.

OBJECTIVE: Conventional lactate-buffered peritoneal dialysis (PD) solutions have several bioincompatible characteristics, including acidic pH, lactate buffer, and the presence of glucose degradation products (GDPs). These characteristics, along with inflammation, are believed to contribute to membrane dysfunction in peritoneal dialysis patients. A new PD solution containing a bicarbonate/lactate buffer system with physiologic pH and low GDPs has shown improved biocompatibility in both in vitro and ex vivo studies. In the present study, the concentrations of cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and vascular endothelial growth factor (VEGF), were measured in timed overnight effluents from PD patients continuously dialyzed with either lactate-based control solution (C) or bicarbonate/lactate-based solution (B/L) for 6 months. METHODS: Effluents from 92 continuous ambulatory peritoneal dialysis (CAPD) patients were collected when the patients were entered into the study (baseline, all patients on C for more than 3 months), and at 3 and 6 months following randomization to C (n = 31) or to B/L (n = 61). Effluent samples were filtered, stored frozen, and then assayed for IL-6, TNFalpha, and VEGF by ELISA. RESULTS: A significant decrease in effluent IL-6 was seen at 3 months and at 6 months in the B/L-treated patients. Levels of VEGF were significantly reduced at 3 months. No changes in the levels of IL-6 or VEGF were seen in the C-treated patients, and no changes in TNFalpha were seen in either group over time. CONCLUSIONS: Treatment with B/L is associated with decreased IL-6 synthesis and decreased VEGF secretion. The data suggest that the use of B/L solution is associated with reduced intraperitoneal inflammation and potential for angiogenesis. The use of B/L solution may, over time, help to restore peritoneal homeostasis and therefore preserve the function of the membrane in peritoneal dialysis.

Adult↗
PubMed2000

Primary care groups. Time to shape up.

PCGs and PCTs have to find the sort of structure that best fits their purpose. Unlike traditional organisations, they do not have a line of accountability through a hierarchy. While developing, they should concentrate on decentralization. Flexibility should be safeguarded.

Efficiency, Organizational↗
PubMed2000

Amphetamine blocks long-term synaptic depression in the ventral tegmental area.

The mesolimbic dopamine system is essential for reward-seeking behavior, and drugs of abuse are thought to usurp the normal functioning of this pathway. A growing body of evidence suggests that glutamatergic synapses on dopamine neurons in the ventral tegmental area (VTA) are modified during exposure to addictive drugs, producing sensitization, a progressive augmentation in the rewarding properties of psychostimulant drugs with repeated exposure. We have tested the hypothesis that psychostimulant exposure interferes with the synaptic plasticity of glutamatergic inputs to the VTA. We find that excitatory synapses onto VTA dopamine neurons exhibit long-term depression (LTD) in response to low-frequency stimulation and modest depolarization. LTD in the VTA is NMDA receptor-independent but is dependent on intracellular Ca(2+) and can be induced by driving Ca(2+) into the dopamine neuron. Brief exposure to amphetamine entirely blocks LTD at glutamatergic synapses in the VTA, by releasing endogenous dopamine that acts at D2 dopamine receptors. The block of LTD is selective, because amphetamine has no effect on hippocampal LTD. The LTD we have discovered in the VTA is likely to be an important component of excitatory control of the reward pathway; amphetamine will inhibit LTD, removing this normal brake on the glutamatergic drive to dopamine neurons. This effect of amphetamine represents an important mechanism by which normal function of the brain reward system may be impaired during substance abuse.

Amphetamine↗
PubMed2000

Utility of cardiopulmonary exercise in the assessment of clinical determinants of functional capacity in hypertrophic cardiomyopathy.

The utility of metabolic gas exchange measurements in evaluating the severity and determinants of exercise limitation was studied during upright symptom-limited cardiopulmonary exercise in 135 consecutive patients with hypertrophic cardiomyopathy (HC) and 50 healthy age- and gender-matched volunteers. Peak oxygen consumption (VO(2)) was less than predicted (age, gender, and size) in 99% patients. Peak VO(2) was significantly associated with New York Heart Association functional class; however, there was considerable overlap of peak VO(2) between classes I and III (70 +/- 15%, 56 +/- 15%, 35 +/- 11%, respectively). Patients with abnormal blood pressure responses and patients with chronotropic incompetence during exercise had lower percent-predicted peak VO(2) than patients with normal blood pressure and heart rate responses during exercise (p = 0.0001 and p <0.001, respectively). Percent-predicted peak VO(2) was similar in patients with and without resting left ventricular outflow obstruction. Of those patients with resting gradients, however, there was a strong inverse correlation between the magnitude of the gradient and peak VO(2) (r = 0.5; p <0.001). In conclusion, peak VO(2) is significantly related to New York Heart Association functional class in this group of patients with HC, but peak VO(2) is a superior measure of cardiovascular performance in individual patients. Our peak VO(2) data indicate that mechanical obstruction has an adverse pathophysiologic effect on functional capacity and provide the rationale to support treatments aimed at gradient reduction. Low peak VO(2) characteristics including those with normal or near-normal left ventricular wall thickness suggests that measurement of peak VO(2) may aid in the differential diagnosis between HC and athlete's heart.

Adult↗
PubMed2000

Partially unfolded species populated during equilibrium denaturation of the beta-sheet protein Y74W apo-pseudoazurin.

Apo-pseudoazurin is a single domain cupredoxin. We have engineered a mutant in which a unique tryptophan replaces the tyrosine residue found in the tyrosine corner of this Greek key protein, a region that has been proposed to have an important role in folding. Equilibrium denaturation of Y74W apo-pseudoazurin demonstrated multistate unfolding in urea (pH 7.0, 0.5 M Na(2)SO(4) at 15 degrees C), in which one or more partially folded species are populated in 4. 3 M urea. Using a variety of biophysical techniques, we show that these species, on average, have lost a substantial portion of the native secondary structure, lack fixed tertiary packing involving tryptophan and tyrosine residues, are less compact than the native state as determined by fluorescence lifetimes and time-resolved anisotropy, but retain significant residual structure involving the trytophan residue. Peptides ranging in length from 11 to 30 residues encompassing this region, however, did not contain detectable nonrandom structure, suggesting that long-range interactions are important for stabilizing the equilibrium partially unfolded species in the intact protein. On the basis of these results, we suggest that the equilibrium denaturation of Y74W apo-pseudoazurin generates one or more partially unfolded species that are globally collapsed and retain elements of the native structure involving the newly introduced tryptophan residue. We speculate on the role of such intermediates in the generation of the complex Greek key fold.

Amino Acid Sequence↗
PubMed2000

PDGF initiates two distinct phases of protein kinase C activity that make unequal contributions to the G0 to S transition.

BACKGROUND: Platelet-derived growth factor (PDGF) promotes cell-cycle progression by engaging signaling enzymes such as phospholipase Cgamma (PLCgamma). When activated, PLCgamma cleaves phosphatidylinositol-4,5-bisphosphate to produce inositol-1,4, 5-trisphosphate (IP(3)) and diacylglycerol (DAG). IP(3) stimulates the release of calcium from intracellular stores, which together with DAG activate some protein kinase C (PKC) family members. In this study we focused on putative downstream effectors of PLCgamma - PKC family members. We investigated whether, and when, DAG-responsive PKCs contribute to PDGF-dependent DNA synthesis. RESULTS: In HepG2 cells expressing wild-type PDGF beta receptors (betaPDGFRs), PDGF activated at least one PKC family member (PKCepsilon) at two distinct times - within 10 minutes after PDGF stimulation, and then for a longer duration between 5 and 9 hours. Blocking the early burst of PKC activity had no effect on PDGF-dependent DNA synthesis. In contrast, the DNA-synthesis response was reduced by 60-80% when the second phase of PKC activity was blocked. Similarly, DAG rescued PDGF-dependent DNA synthesis in the cells expressing a mitogenically incompetent mutant betaPDGFR, but only when DAG was added at times corresponding to the late phase of PKC activity. Our studies also indicate that the late phase of PKCepsilon activity can be induced by either phosphoinositide 3-kinase-dependent or DAG-dependent pathways in PDGF-stimulated HepG2 cells. CONCLUSIONS: We conclude that PDGF activates PKCs at two distinct times and that these two intervals of PKC activity make unequal contributions to the mitogenic response. The late phase of PKC activity is required for PDGF-dependent DNA synthesis, whereas the early phase of activity is dispensable.

Blotting, Western↗
PubMed2000

Complete numerical solution of electron-hydrogen model collision problem above the ionization threshold

Benchmark results are presented for electrons colliding with hydrogen atoms in the S-wave (Temkin-Poet) model collision problem, which neglects angular momentum. Complete results (elastic, inelastic, and ionization), accurate to 1%, are obtained by numerically integrating Schrodinger's equation subject to correct asymptotic boundary conditions. This marks the first time direct matching to asymptotic boundary conditions has been shown to yield convergent ionization amplitudes for a Coulomb three-body problem. Results are presented for impact energies of 54.4 and 40.8 eV, where comparison with other theories is available.

Journal Article↗
PubMed2000

Transcriptional autoregulation of the bone related CBFA1/RUNX2 gene.

The runt related transcription factor CBFA1 (AML3/PEBP2alphaA/RUNX2) regulates expression of several bone- and cartilage-related genes and is required for bone formation in vivo. The gene regulatory mechanisms that control activation and repression of CBFA1 gene transcription during osteoblast differentiation and skeletal development are essential for proper execution of the osteogenic program. We have therefore defined functional contributions of 5' regulatory sequences conserved in rat, mouse and human CBFA1 genes to transcription. Deletion analysis reveals that 0.6 kB of the bone-related rat or mouse CBFA1 promoter (P1, MASNS protein isoform) is sufficient to confer transcriptional activation, and that there are multiple promoter domains which positively and negatively regulate transcription. Progressive deletion of promoter segments between nt -351 and -92 causes a striking 30- to 100-fold combined decrease in promoter activity. Additionally, 5' UTR sequences repress reporter gene transcription 2- to 3-fold. Our data demonstrate that CBFA1 is a principal DNA binding protein interacting with the 5' region of the CBFA1 gene in osseous cells, that there are at least three CBFA1 recognition motifs in the rat CBFA1 promoter, and that there are three tandemly repeated CBFA1 sites within the 5' UTR. We find that forced expression of CBFA1 protein downregulates CBFA1 promoter activity and that a single CBFA1 site is sufficient for transcriptional autosuppression. Thus, our data indicate that the CBFA1 gene is autoregulated in part by negative feedback on its own promoter to stringently control CBFA1 gene expression and function during bone formation.

5' Untranslated Regions↗
PubMed2000

Functions of cathepsin K in bone resorption. Lessons from cathepsin K deficient mice.

Cathepsin K is a cysteine proteinase expressed predominantly in osteoclasts. Cathepsin K cleaves key bone matrix proteins and is believed to play an important role in degrading the organic phase of bone during bone resorption. Pycnodysostosis, an autosomal recessive osteosclerosing skeletal disorder has recently been shown to result from mutations in the cathepsin K gene. Cathepsin K deficient mice generated by targeted disruption of this proteinase phenocopy many aspects of pycnodysostosis. They display an osteopetrotic phenotype with excessive trabeculation of the bone-marrow space accompanied by an altered ultrastructural appearance of the cathepsin K deficient osteoclasts. These cells also demonstrate an impaired resorptive activity in vitro. In contrast to other forms of osteopetrosis, which are due to disrupted osteoclastogenesis, cathepsin K deficiency is associated with an inhibition of osteoclast activity. Taken together the phenotype of cathepsin K knockout mice underlines the importance of this proteinase in bone remodelling.

Animals↗
PubMed2000

In vivo exposure to bicarbonate/lactate- and bicarbonate-buffered peritoneal dialysis fluids improves ex vivo peritoneal macrophage function.

The impact on peritoneal macrophage (PMO) function of acidic lactate-buffered (Lac-PDF [PD4]; 40 mmol/L of lactate; pH 5.2) and neutral-pH, bicarbonate-buffered (TB; 38 mmol/L of bicarbonate; pH 7. 3) and bicarbonate/lactate-buffered (TBL; 25 mmol/L of bicarbonate/15 mmol/L of lactate; pH 7.3) peritoneal dialysis fluids (PDFs) was compared during a study of continuous therapy with PD4, TB, or TBL. During a run-in phase of 6 weeks when all patients (n = 15) were treated with their regular dialysis regimen with Lac-PDF, median PMO tumor necrosis factor alpha (TNFalpha) release values were 203.6, 89.9, and 115.5 pg TNFalpha/10(6) PMO in the patients subsequently randomized to the PD4, TB, and TBL treatment groups, respectively. Median stimulated TNFalpha values (serum-treated zymosan [STZ], 10 microgram/mL) were 1,894.6, 567.3, and 554.5 pg TNFalpha/10(6) PMO in the same groups, respectively. During the trial phase of 12 weeks, when the three groups of patients (n = 5 per group) were randomized to continuous treatment with PD4, TB, or TBL, median constitutive TNFalpha release values were 204.7, 131.4, and 155.4 pg TNFalpha/10(6) PMO, respectively. Stimulated TNFalpha values (STZ, 10 microgram/mL) were 1,911, 1,832, and 1,378 pg TNFalpha/10(6) PMO in the same groups, respectively. Repeated-measures analysis of variance comparing the run-in phase with the trial phase showed that PMO TNFalpha release was significantly elevated in patients treated with both TB (P = 0.040) and TBL (P = 0.014) but not in patients treated with Lac-PDF (P = 0. 795). These data suggest that patients continuously exposed to bicarbonate- and bicarbonate/lactate-buffered PDFs might have better preserved PMO function and thus improved host defense status.

Adult↗
PubMed2000

A prototype system for testing force platform dynamic performance.

Previous work on in-situ calibration of force platforms has focused primarily on behaviour under static loading conditions. The prototype described in this paper is a dynamic system, designed to approximate the loading profile generated during human gait. The design, construction and performance of an oscillating lead pendulum assembly is described; including three-dimensional visual performance assessment and rigorous multi-component force analysis. No significant difference was found between measured data and a theoretical profile for vertical force and angular displacement. A significant difference was found for the horizontal force component. The authors believe that further development of this prototype model will allow accurate routine dynamic calibration.

Biophysical Phenomena↗
PubMed2000

Solidarity, society and the welfare state in the United Kingdom.

Political argument and institutions in the United Kingdom have frequently been represented as the products of a blend of nationalistic conservatism, liberal individualism and socialism, in which consensus has been prized over ideology. This situation changed, as the standard story has it, with the rise of Thatcherism in the late 1970s, and again with the arrival of Tony Blair's "New Labour" pragmatism in the late 1990s. Solidarity as an element of political discourse makes its appearance in the UK late in the day. It has been most strongly linked to the Third Way debate, as framed most influentially in the work of Prof. Anthony Giddens. In this paper we review the history and pre-history of the debate on solidarity in the UK, focussing mostly on its implications for welfare state reform. In particular we discuss the proposals for the long-term care of the Elderly issued by the Royal Commission on long-term care in 1999. In this context we critically examine the idea that solidarity is a new concept in British political culture, and that it is a concept which has real political "bite" in the project of welfare reform. We examine this through a consideration of Gidden's attempted synthesis of political argument and social theory.

Aged↗
PubMed2000

Talking facilitates cognitive-emotional processes of adaptation to an acute stressor.

The authors examined the influence of talking and the social context of talking on cognitive-emotional processes of adjustment to stressors. Two hundred fifty-six undergraduates viewed a stressful stimulus and were then assigned to a no-talk control condition or 1 of 3 talk conditions: talk alone, talk to a validating confederate, or talk to an invalidating confederate. Two days later, they were reexposed to the stressor. Compared with individuals in the no-talk condition, those in the talk alone and validate conditions had a lower level of intrusive thoughts in the 2-day interim, and they had lower perceived stress when reexposed to the stressor. The effects of talking and validation on perceived stress appeared to be mediated by lowered intrusions. The benefits of talking were diluted when disclosures were invalidated. These findings suggest that talking about acute stressors can facilitate adjustment to stressors through cognitive resolution.

Adaptation, Psychological↗