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Biomedical subjects

R Parker

Publications and source records attributed to R Parker.

At least 19 recordsLinked to original sources

Molecular modeling studies of the binding characteristics of phosphates to sevelamer hydrochloride--assessing a novel technique to reduce phosphates contamination.

Recent advances in the use of polymeric materials for the remediation of phosphate from aqueous systems, including biological environments, have prompted the use of computational techniques to determine which methods are feasible to model such complex systems and to model the mechanism of binding action. In particular, Sevelamer Hydrochloride (Renagel) is used as our model polymer. A relatively simple system is constructed with a dimer of Sevelamer Hydrochloride and four phosphate ions used for capture. This work reports on molecular dynamics and Monte Carlo simulations used to determine average structure, and points of intermolecular interaction, and calculate changes in volume after the successful capture of phosphate in our model. Our resulting volume changes are of the order of 20-25%, in comparison to experimental swelling measurements on similar systems, which have an average swelling of 50-60% in aqueous media.

Models, Molecular↗

Intratumoral oxygenation of invasive squamous cell carcimoma of the vulva is not correlated with regional lymph node metastasis.

INTRODUCTION: Tumour hypoxia has been found to be associated with tumour aggressiveness. Our primary aim was to explore the relationship between pretreatment tumour oxygenation in primary vulvar carcinoma and nodal status. Our secondary objective was to assess if there was a relationship between the clinical and biological variables. METHODS: 20 women with ISCC of the vulva were assessed with pretreatment primary tumour oxygenation with an Eppendorf pO2 probe. Patients underwent standard surgical management. Pathological assessment of the primary and nodal tissues was then performed. Primary tumour specimens were also stained for microvessel density and carbonic anhydrase IX. The relationship between smoking, preoperative Hgb, tumour CAIX expression, MVD, and Eppendorf pO2 measurements vs nodal metastasis and between these clinical and biological variables was assessed. RESULTS: Seven patients had positive lymph nodes, 13 had negative nodes. While neither current smoking status, tumour size, tumour oxygen measurements, MVD and CAIX expression correlated with metastatic nodal disease, a low preoperative Hgb correlated with pathological nodal status (p < 0.027). CONCLUSIONS: Although this analysis failed to demonstrate a strong correlation between various measures of tumour oxygenation with nodal metastasis, it may be due to the small number of patients. Only preoperative anaemia is correlated with nodal metastasis in early ISCC of the vulva.

Aged↗

Fracture of the radial donor site after composite free flap harvest: a ten-year review.

The options for donor sites as a source of tissue for free vascularised osteocutaneous flaps are numerous, however, the radial forearm still has an important role. This series reports the largest published record of radial donor site fracture following the harvesting of osteocutaneous radial forearm free flaps used for reconstruction after ablative surgery for malignant disease. The relevant literature is reviewed. A retrospective review of cases treated using these flaps from 1991-2000 (inclusive) is carried out. Factors involved in the aetiology of fractures are discussed. Thirteen fractures are identified from seventy one osteocutaneous flaps (18%). A statistically significant majority of fractures occur in females. Limiting the percentage of radius diameter harvested is important and beveling of the osteotomy cuts may be advantageous in minimising weakening. Prophylactic plating of the donor site, particularly in the female patient, should be actively considered. The earlier the fracture occurs in the post-operative period, the more likely the need for operative intervention.

Aged↗

Modelling potential impacts of bottom trawl fisheries on soft sediment biogeochemistry in the North Sea.

Bottom trawling causes physical disturbance to sediments particularly in shelf areas. The disturbance due to trawling is most significant in deeper areas with softer sediments where levels of natural disturbance due to wave and tidal action are low. In heavily fished areas, trawls may impact the same area of seabed more than four times per year. A single pass of a beam trawl, the heaviest gear routinely used in shelf sea fisheries, can kill 5-65% of the resident fauna and mix the top few cm of sediment. We expect that sediment community function, carbon mineralisation and biogeochemical fluxes will be strongly affected by trawling activity because the physical effects of trawling are equivalent to those of an extreme bioturbator, and yet, unlike bioturbating macrofauna, trawling does not directly contribute to community metabolism. We used an existing box-model of a generalised soft sediment system to examine the effects of trawling disturbance on carbon mineralisation and chemical concentrations. We contrasted the effects of a natural scenario, where bioturbation is a function of macrobenthos biomass, with an anthropogenic impact scenario where physical disturbance results from trawling rather than the action of bioturbating macrofauna. Simulation results suggest that the effects of low levels of trawling disturbance will be similar to those of natural bioturbators but that high levels of trawling disturbance prevent the modelled system from reaching equilibrium due to large carbon fluxes between oxic and anoxic carbon compartments. The presence of macrobenthos in the natural disturbance scenario allowed sediment chemical storage and fluxes to reach equilibrium. This is because the macrobenthos are important carbon consumers in the system whose presence reduces the magnitude of available carbon fluxes. In soft sediment systems, where the level physical disturbance due to waves and tides is low, model results suggest that intensive trawling disturbance could cause large fluctuations in benthic chemical fluxes and storage.

Journal Article↗

Quality control of mRNA 3'-end processing is linked to the nuclear exosome.

An emerging theme in messenger RNA metabolism is the coupling of nuclear pre-mRNA processing events, which contributes to mRNA quality control. Most eukaryotic mRNAs acquire a poly(A) tail during 3'-end processing within the nucleus, and this is coupled to efficient export of mRNAs to the cytoplasm. In the yeast Saccharomyces cerevisiae, a common consequence of defective nuclear export of mRNA is the hyperadenylation of nascent transcripts, which are sequestered at or near their sites of transcription. This implies that polyadenylation and nuclear export are coupled in a step that involves the release of mRNA from transcription site foci. Here we demonstrate that transcripts which fail to acquire a poly(A) tail are also retained at or near transcription sites. Surprisingly, this retention mechanism requires the protein Rrp6p and the nuclear exosome, a large complex of exonucleolytic enzymes. In exosome mutants, hypo- as well as hyperadenylated mRNAs are released and translated. These observations suggest that the exosome contributes to a checkpoint that monitors proper 3'-end formation of mRNA.

Cell Nucleus↗

Serum PSA evaluations during salvage radiotherapy for post-prostatectomy biochemical failures as prognosticators for treatment outcomes.

INTRODUCTION: Serum prostate specific antigen (PSA) levels have proved to be sensitive markers for the diagnosis of prostate cancer. In addition, PSA levels are useful for detecting and monitoring prostate cancer progression after radiotherapy. Serum PSA evaluations during radiotherapy, however, have not been well documented. In this study, we investigate the prognostic value of PSA evaluations during salvage radiotherapy for prostatectomy failures. METHODS: Forty-one patients with biochemical failures after prostatectomy treated with salvage radiotherapy consented to have their serum PSA levels evaluated at 30 Gy and 45 Gy of irradiation. All 41 patients had negative metastatic workup and pathologically uninvolved pelvic lymph nodes at the time of referral for salvage radiotherapy. Radiation therapy was delivered with 10--25 MV photons, with doses of 59.4--66.6 Gy. No patients received hormonal ablation therapy before irradiation. RESULTS: The mean follow-up for all patients was 30.9 months. At last follow-up, 28/41 patients (68.3%) were free from biochemical failure, with 20 of 41 patients (48.8%) expressing undetectable PSA levels. Serum PSA evaluations at 30 Gy did not significantly predict for either biochemical (p = 0.0917) or clinical (p = 0.106) disease-free outcome. However, serum PSA evaluations at 45 Gy significantly predicted for both biochemical (p = 0.0043) and clinical (p = 0.0244) disease-free outcomes, with PSA elevations at 45 Gy significantly associated with poor outcomes. On univariate analysis of prognosticators for biochemical failures, the following were significant: an elevation in serum PSA levels at 45 Gy, detectable serum PSA immediately after prostatectomy, Gleason score 7--10, and serum PSA level >1 ng/ml before salvage radiotherapy. CONCLUSION: Evaluation of serum PSA level at 45 Gy of salvage radiotherapy for biochemical relapses after prostatectomy may serve as a significant prognosticator for both biochemical and clinical disease-free outcomes.

Adenocarcinoma↗

Experience with oseltamivir in the control of a nursing home influenza B outbreak.

Oseltamivir prophylaxis was very effective in protecting nursing home residents from ILI and in halting this outbreak of influenza B. A portion of the total ILI cases may have been due to influenza A, as this strain was isolated in one resident. The 10% attack rate in this facility, controlled with oseltamivir, compares favourably with another influenza B outbreak in a similar facility in the same region, over the same time frame (ILI onset 27 December to 17 January). Oseltamivir prophylaxis was not used to manage this second outbreak of laboratory-confirmed influenza B. Of the 236 residents, 45 developed ILI for an overall attack rate of 19%, nearly double the rate in the oseltamivir-controlled setting (10%). While oseltamivir was effective in controlling influenza B in this outbreak, further experience and evaluation is required before it can be routinely recommended for prophylaxis of influenza in nursing home outbreaks. Although earlier attempts by others using oseltamivir in the control of influenza A outbreaks have also met with success, it is not yet licensed for this purpose. Compared to amantadine, oseltamivir has a relatively high cost for the control of influenza A outbreaks and this may continue to limit its wider acceptance. The cost-effectiveness of oseltamivir in the control of influenza B outbreaks needs to be specifically addressed given the typically milder nature of influenza B strains. However, such a distinction is not clinically reliable and elderly residents of long-term care facilities remain vulnerable to serious complications associated with influenza infection in general. An alternate agent for influenza chemoprophylaxis that is effective against both influenza A and B, is easily administered and has few side effects, could greatly enhance current prevention and control measures and warrants serious assessment. The spread of this outbreak from the geographically separate ward to other areas of the facility in which residents had not received prophylaxis, underscores the likely role of staff as a vehicle for transmission during facility outbreaks. While accurate staff ILI rates could not be determined, their immunization rates were low, and many staff were ill during the outbreak. Isolation of residents with ILI and prophylaxis of non-ill residents on the initial outbreak wards was insufficient to prevent the spread of the outbreak, although it was subsequently halted once prophylaxis was extended to all residents. In view of the uncertainty over this medication's widespread use, in the absence of licensure or previous studies demonstrating its effectiveness in the prophylaxis and control of influenza B outbreaks, initiation of oseltamivir prophylaxis was staggered by ward. In a declared influenza A outbreak, the protocol in a long term care facility is to initiate amantadine prophylaxis on all residents, rather than ward-by-ward. While anti-viral prophylaxis may be an effective secondary control measure in the management of influenza outbreaks, optimal primary prevention would be more effective. This would require increased vaccine coverage of residents and particularly of staff, who play an important role in the importation and transmission of influenza within these facilities.

Acetamides↗

The transcription factor associated Ccr4 and Caf1 proteins are components of the major cytoplasmic mRNA deadenylase in Saccharomyces cerevisiae.

The major pathways of mRNA turnover in eukaryotes initiate with shortening of the poly(A) tail. We demonstrate by several criteria that CCR4 and CAF1 encode critical components of the major cytoplasmic deadenylase in yeast. First, both Ccr4p and Caf1p are required for normal mRNA deadenylation in vivo. Second, both proteins localize to the cytoplasm. Third, purification of Caf1p copurifies with a Ccr4p-dependent poly(A)-specific exonuclease activity. We also provide evidence that the Pan2p/Pan3p nuclease complex encodes the predominant alternative deadenylase. These results, and previous work on Pan2p/Pan3p, define the mRNA deadenylases in yeast. The strong conservation of Ccr4p, Caf1p, Pan2p, and Pan3p indicates that they will function as deadenylases in other eukaryotes. Interestingly, because Ccr4p and Caf1p interact with transcription factors, these results suggest an unexpected link between mRNA synthesis and turnover.

Blotting, Northern↗

Spontaneous regression of stage IV clear cell carcinoma of the endometrium in a patient with essential thrombocytosis.

OBJECTIVE: The aim of this study was to document a case of advanced stage clear cell carcinoma of the endometrium which underwent spontaneous regression (SR) and comment on the possible contribution of the patient's thrombocytosis. CASE REPORT: A 73-year-old woman with essential thrombocytosis presented with vaginal bleeding. Imaging demonstrated a complex uterine mass, a 4-cm infrarenal mass, and a 5-cm subumbilical mass. Biopsy of the subumbilical mass revealed adenocarcinoma, and endometrial curettage revealed extensively necrotic clear cell endometrial carcinoma. At hysterectomy 5 weeks later, the infrarenal and subumbilical masses were not identified. The endometrial tumor was almost completely necrotic. She received no adjuvant therapy and remains disease-free 6 years later. Interestingly, her platelet-lowering agent (hydroxyurea) was discontinued shortly before, and her platelet count was significantly elevated at the time of her presentation with endometrial carcinoma. CONCLUSION: This report documents a rare case of SR of advanced endometrial carcinoma, and we speculate that increased circulating platelets were a major contributing factor.

Adenocarcinoma, Clear Cell↗

Targeting an mRNA for decapping: displacement of translation factors and association of the Lsm1p-7p complex on deadenylated yeast mRNAs.

The major pathway of eukaryotic mRNA decay involves deadenylation-dependent decapping followed by 5' to 3' exonucleolytic degradation. By examining interactions among mRNA decay factors, the mRNA, and key translation factors, we have identified a critical transition in mRNP organization that leads to decapping and degradation of yeast mRNAs. This transition occurs after deadenylation and includes loss of Pab1p, eIF4E, and eIF4G from the mRNA and association of the decapping activator complex, Lsm1p-7p, which enhances the coimmunoprecipitation of a decapping enzyme complex (Dcp1p and Dcp2p) with the mRNA. These results define an important rearrangement in mRNP organization and suggest that deadenylation promotes mRNA decapping by both the loss of Pab1p and the recruitment of the Lsm1p-7p complex.

DNA-Binding Proteins↗

Defects in the mRNA export factors Rat7p, Gle1p, Mex67p, and Rat8p cause hyperadenylation during 3'-end formation of nascent transcripts.

The biosynthesis and function of eukaryotic mRNAs requires a series of events including nuclear polyadenylation, transport to the cytoplasm, translation, and ultimately mRNA degradation. To identify the interrelationships between these events, we examined the synthesis and fate of mRNAs in several strains defective in mRNA export. Strains carrying lesions in RAT7, GLE1, MEX67, and RAT8, produce nascent transcripts carrying poly(A) tails roughly 30 residues longer than the nascent poly(A) tails observed in wild type. In the rat7-1, rat8-2, and mex67-5 strains, the hyperadenylated transcripts undergo a novel form of deadenylation to chase into a population with normal poly(A) tail lengths, which cofractionate with polysomes, undergo nonsense-mediated decay, and are degraded by the normal cytoplasmic decay machinery. This suggests a relationship between the mechanism of processing to a normal poly(A) tail length and the ability of these transcripts to proceed in their metabolism. These observations provide further support for the view that mRNA 3'-end formation and mRNA export are mechanistically coupled events.

Active Transport, Cell Nucleus↗

Computational modeling of eukaryotic mRNA turnover.

The process of eukaryotic gene expression involves a diverse number of steps including transcription, RNA processing, transport, translation, and mRNA turnover. A critical step in understanding this process will be the development of mathematical models that quantitatively describe and predict the behavior of this complex system. We have simulated eukaryotic mRNA turnover in a linear multicomponent model based on the known mRNA decay pathways in yeast. Using rate constants based on experimental data for the yeast unstable MFA2 and stable PGK1 transcripts, the computational modeling reproduces experimental observations after minor adjustments. Subsequent analysis and a series of in silico experiments led to several conclusions. First, we demonstrate that mRNA half-life as commonly measured underestimates the average life span of an mRNA. Second, due to the properties of the pathways, the measurement of a half-life can predominantly measure different steps in the decay network. A corollary of this fact is that different mRNAs will be affected differentially by changes in specific rate constants. Third, the way to obtain the largest change of levels of mRNA for the smallest changes in rate is by changing the rate of deadenylation, where a large amount of regulation of mRNA decay occurs. Fourth, the 3'-to-5' degradation of mRNA shows mRNA-specific rates of degradation that are dependent on the 5' structure of the mRNA. These programs can be run over the Web, are adaptable to other eukaryotes, and provide outputs as graphs and virtual northern gels, which can be directly compared to experimental data. Therefore, this model constitutes a useful tool for the quantitative analysis of the process and control of mRNA degradation in eukaryotic cells.

Biological Transport↗

The DEAD box helicase, Dhh1p, functions in mRNA decapping and interacts with both the decapping and deadenylase complexes.

A major pathway of mRNA turnover in eukaryotic cells initiates with deadenylation, leading to mRNA decapping and subsequent 5' to 3' exonuclease digestion. We show that a highly conserved member of the DEAD box family of helicases, Dhh1p, stimulates mRNA decapping in yeast. In dhh1delta mutants, mRNAs accumulate as deadenylated, capped species. Dhh1p's effects on decapping only occur on normal messages as nonsense-mediated decay still occurs in dhh1delta mutants. The role of Dhh1p in decapping appears to be direct, as Dhh1p physically interacts with several proteins involved in mRNA decapping including the decapping enzyme Dcp1p, as well as Lsm1p and Pat1p/Mrt1p, which function to enhance the decapping rate. Additional observations suggest Dhh1p functions to coordinate distinct steps in mRNA function and decay. Dhh1p also associates with Pop2p, a subunit of the mRNA deadenylase. In addition, genetic phenotypes suggest that Dhh1p also has a second biological function. Interestingly, Dhh1p homologs in others species function in maternal mRNA storage. This provides a novel link between the mechanisms of decapping and maternal mRNA translational repression.

Amino Acid Sequence↗

Maillard reaction kinetics in model preservation systems in the vicinity of the glass transition: experiment and theory.

Rates of reactant consumption for the Maillard reaction between lysine and glucose were measured for a noncrystallizing trehalose-sucrose-water matrix in the glass transition region. At temperatures above the glass transition temperature (T(g)), the consumption rates showed Arrhenius temperature dependence with activation energies of 135 and 140 kJ mol(-1) for lysine and glucose, respectively. Finite reaction rates were observed for glassy samples that were faster than that of one of the nonglassy samples. A comparison of experimental results with predicted diffusion-controlled reaction rate constants indicated that the reaction was reaction-controlled at temperatures above T(g) and approached the diffusion-influenced regime in the glassy state. The needs for further research on reactant diffusivity, the theory of the orientation dependence of reactivity, and a detailed understanding of the reaction mechanism and kinetics were identified.

Chemical Phenomena↗