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W Martin

Publications and source records attributed to W Martin.

At least 19 recordsLinked to original sources
PubMed2007

Differential effects of nitric oxide synthase inhibitors on endothelium-dependent and nitrergic nerve-mediated vasodilatation in the bovine ciliary artery.

BACKGROUND AND PURPOSE: We have previously demonstrated that L-NMMA (NG-monomethyl-L-arginine) selectively inhibits vasodilatation produced by endothelium-derived nitric oxide but not nitrergic nerves in the bovine penile artery. The present study investigated whether L-NMMA had a similar selective action in the bovine ciliary artery. We also investigated whether two recently introduced inhibitors of neuronal nitric oxide synthase (nNOS), AAAN (N-(4S)-4-amino-5-[aminoethyl]aminopentyl-N'-nitroguanidine) and L-NPA (NG-propyl-L-arginine), produced selective blockade of vasodilatation induced by nitrergic nerves but not endothelium-derived nitric oxide. EXPERIMENTAL APPROACH: Rings of bovine ciliary artery were suspended in a wire myograph for tension recording. Neurogenic (nitrergic) vasodilatation was elicited by electrical field stimulation, and endothelium-dependent, nitric oxide-mediated dilatation was evoked using bradykinin. KEY RESULTS: L-NMMA inhibited vasodilatation induced by endothelium-derived nitric oxide but not the nitrergic nerves. In fact, L-NMMA, acted like L-arginine in protecting nitrergic vasodilatation against inhibition by L-NAME (NG-nitro-L-arginine methyl ester). AAAN had no effect on vasodilatation induced by either nitrergic nerves or endothelium-derived nitric oxide, but L-NPA inhibited both with equal potency. CONCLUSIONS AND IMPLICATIONS: In the bovine ciliary artery, L-NMMA acts as a selective inhibitor of the vasodilatation induced via endothelial NOS, without affecting that operating via nNOS. Furthermore, the putative nNOS inhibitors, AAAN and L-NPA failed to produce the expected selective inhibition of nitrergic vasodilatation in this artery.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2006

Independent wheat B and G genome origins in outcrossing Aegilops progenitor haplotypes.

The origin of modern wheats involved alloploidization among related genomes. To determine if Aegilops speltoides was the donor of the B and G genomes in AABB and AAGG tetraploids, we used a 3-tiered approach. Using 70 amplified fragment length polymorphism (AFLP) loci, we sampled molecular diversity among 480 wheat lines from their natural habitats encompassing all S genome Aegilops, the putative progenitors of wheat B and G genomes. Fifty-nine Aegilops representatives for S genome diversity were compared at 375 AFLP loci with diploid, tetraploid, and 11 nulli-tetrasomic Triticum aestivum wheat lines. B genome-specific markers allowed pinning the origin of the B genome to S chromosomes of A. speltoides, while excluding other lineages. The outbreeding nature of A. speltoides influences its molecular diversity and bears upon inferences of B and G genome origins. Haplotypes at nuclear and chloroplast loci ACC1, G6PDH, GPT, PGK1, Q, VRN1, and ndhF for approximately 70 Aegilops and Triticum lines (0.73 Mb sequenced) reveal both B and G genomes of polyploid wheats as unique samples of A. speltoides haplotype diversity. These have been sequestered by the AABB Triticum dicoccoides and AAGG Triticum araraticum lineages during their independent origins.

Crosses, Genetic↗
PubMed2006

Downscatter correction and choice of collimator in 123I imaging.

(123)I imaging is increasingly used in nuclear medicine but downscatter from high (>300 keV) energy emissions degrades the image and introduces variation in sensitivity with depth when imaging with a low energy collimator. A dual windowing technique using a matched window immediately above the principle window to correct for the effects of downscatter is described. The technique is shown to correct for the variation in sensitivity with depth and to reduce outlying scatter. Quantitative imaging of (123)I using a low energy collimator should always employ downscatter correction.

Humans↗
PubMed2006

A phase I/II multicentric trial of gemcitabine and epirubicin in patients with advanced pancreatic carcinoma.

Potential synergistic interaction between gemcitabine (GEM) and epirubicin (EPI) in pancreatic cancer have been described previously. The maximum-tolerated dose in this trial was GEM 1000 mg m(-2) and EPI 45 mg m(-2). Median time to progression was 5.1 months and median survival time 7.4 months. This combination appears well tolerated and shows promising clinical activity.

Adult↗
PubMed2006

Confirmation of immunogenic consensus sequence HIV-1 T-cell epitopes in Bamako, Mali and Providence, Rhode Island.

The design of epitope-driven vaccines for HIV has been significantly hampered by concerns about conservation of vaccine epitopes across clades of HIV. In previous work, we have described a computer-driven method for a cross-clade HIV vaccine comprised of overlapping, highly conserved helper T-cell epitopes or "immunogenic consensus sequence epitopes" (ICS epitopes). Here, we evaluated and compared the immunogenicity of 20 ICS HIV epitopes in ELISpot assays performed using peripheral blood monocytes (PBMC) from HIV-infected donors in Providence, Rhode Island, USA and in Bamako, Mali, West Africa. Each core 9-mer HIV sequence contained in a given consensus peptide was conserved in at least 105 to as many as 2,250 individual HIV-1 strains. Nineteen of the 20 ICS epitopes (95%) were confirmed in ELISpot assays using PBMC obtained from 13 healthy, HIV-1 infected subjects in Providence, and thirteen of the epitopes (65%) were confirmed in ELISpot assays using PBMC derived from 42 discarded blood units obtained at the Central Blood Bank in Bamako. Twelve of the epitopes were confirmed in ELISpot assays performed both in Providence and Bamako. These data confirm the utility of bioinformatics tools to select and design novel vaccines containing "immunogenic consensus sequence" T-cell epitopes for a globally relevant vaccine against HIV; a similar approach may also be useful for any pathogen that exhibits high variability (influenza, HCV, or variola for example). An HIV vaccine containing these immunogenic consensus sequences is currently under development.

Amino Acid Sequence↗
PubMed2006

Surgical trainees benefit from good consultant working practices: an audit on the effect on training of a new consultant rota.

PURPOSE: To retrospectively assess operative supervision for orthopaedic trainees over an 18 week period when trauma and orthopaedic consultants changed their on call working practice from one week on call to a four day/three day block, during a fortnight period. OUTCOME: The rota changes had important implications on workload and consultant availability to supervise juniors during operation with a positive effect upon training such that trauma surgery supervision rates increased significantly (p<0.001) after the introduction of these new working arrangements. Working life for consultants and ultimately patient care were also felt to improve and consultants' working hours were closer to the European working hours directives.

Consultants↗
PubMed2005

Selective and sensitive determination of amisulpride in human plasma by liquid chromatography-tandem mass spectrometry with positive electrospray ionisation and multiple reaction monitoring.

The development of a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with positive electrospray ionisation (ESI(+)) and multiple reaction monitoring (MRM) for the selective and sensitive bioanalytical determination of amisulpride, a substituted benzamide derivative, in human plasma is described. Plasma was cleaned up using a liquid-liquid extraction (diisopropylether:dichloromethane=1:1 (v/v)) procedure. The chemically related drug sulpiride was used as internal standard (ISTD) and a primary calibration function was established in the concentration range of 0.50-500.52 ng/ml for amisulpride in plasma by triple analysis of the corresponding calibration standards. A linear relationship between concentration and signal intensity (given as peak area ratio analyte/ISTD) was obtained (linear regression: r=0.9999). A lower limit of quantification (LLQ) of 0.50 ng/ml was used during measurement of study plasma samples. Satisfying results of within-day precision (CV=0.79 to 1.98%) and accuracy (mean relative deviation: -1.68 to 3.58%) and between-day precision (CV=1.34 to 4.62%) and accuracy (mean relative deviation: -1.73 to -3.77%) as well as of recovery (amisulpride: 81.74 to 84.83%; sulpiride: 58.65%) and selectivity investigations confirmed the high reliability of this established LC-MS/MS method. Sufficient stability of amisulpride in plasma was achieved during freeze-thaw-cycles, for storage periods of 24h at room temperature and 20 days at <-20 degrees C as well as in extracts (storage conditions: <-20 degrees C, 6 days and 7 degrees C, 6 days) with mean relative deviations between - 2.83 and 2.91%. An example of a pharmacokinetic profile determined after administration of an amisulpride 200mg dose in a pilot study is given in this paper. A peak plasma concentration (C(max)) of 522.58 ng/ml was achieved after 3.55 h (t(max)). Corresponding values of areas under the plasma concentration-time curve (AUC) of 3405.35 ngh/ml (AUC(0-infinity)) and 3306.54 ngh/ml (AUC(0-tlast)) were obtained. The terminal plasma elimination half-life (t(1/2)) was 10.36 h.

Amisulpride↗
PubMed2005

[Acute myocardial infarction due to spontaneous coronary artery dissection].

BACKGROUND: Spontaneous coronary dissection is a rare cause of acute myocardial infarction (AMI). Its aetiology and treatment have not yet been well defined. In this report, we review the clinical presentation, the aetiology, the risk factors and the treatment of 6 cases of AMI due to spontaneous coronary dissection. METHODOLOGY AND RESULTS: We have reviewed 1100 cases of AMI having undergone coronary angiography in our institution during the period December 1999 to January 2004. Six cases (0.5%; 5 men, mean age: 38 years) in which spontaneous coronary dissection had been retained as final aetiology were further analyzed. Four patients had no cardiovascular risk factors but, interestingly, in all 6 patients we found a clear triggering factor of the acute event: extreme physical stress (5), or psychological stress (1). Thrombolysis had been performed in 5 patients, and the coronary angiography carried out thereafter showed a dissection of the left anterior descending coronary (2 cases), of the right coronary artery (3 cases) or of the left circumflex artery (1 case). All patients had a preserved coronary flow (TIMI 3). On the basis of the angiographical findings, medical treatment (4 patients), coronary artery by-pass grafting (1 patient), or percutaneous angioplasty with stenting (1 patient) were performed. The only major cardiac adverse event observed in the early follow up was a sudden acute thrombosis of the coronary stent. CONCLUSION: In young patients without cardiovascular risk factors and presenting with AMI subsequent to a physical or emotional stress, spontaneous coronary artery dissection should imperatively be taken into consideration as a possible diagnosis. Since intravenous thrombolysis may worsen the dissection, we recommend primary emergency coronarography as a diagnostic and (sometimes) therapeutic treatment option.

Adult↗
PubMed2005

De-immunization of therapeutic proteins by T-cell epitope modification.

Many therapeutic proteins in clinical use have been shown to elicit antibody responses which in some cases have been linked to adverse events. Conventional animal models, although convenient, have rarely been predictive of immunogenicity in humans. New methods for predicting the potential immunogenicity of therapeutic proteins are needed. This treatise proposes a new approach which pairs in silico T-cell epitope analysis with in vitro studies. T-cell epitope mapping algorithms such as EpiMatrix can be used to evaluate a candidate therapeutic protein for T-helper epitopes, followed by confirmation of the T-helper epitopes using in vitro methods such as MHC binding assays and T-cell assays. Once these are identified, substitution of key amino acids in the T-cell epitopes may attenuate the immunogenicity of the protein, since modification of the amino acids in anchor position(s) can abrogate binding to human class II MHC molecules and presentation of the peptides, in the context of MHC, to T-helper cells. Following substitution of the key amino acids, immunogenicity of the modified protein can be evaluated in vitro. In parallel, the potential effect of the modifications on the structure of the protein can be evaluated using in silico modeling methods. This multi-step process has been termed DeFT for de-immunization of functional therapeutics. In this article we review the rationale for the approach, provide several retrospective examples that prove the approach in principle, and describe potential applications to therapeutic protein design. The demand for pre-clinical means of evaluating therapeutic proteins is expected to increase with the number of therapeutic proteins and monoclonal antibodies entering the pre-clinical pipeline. Examples provided offer some preliminary proof that the de-immunization approach may improve clinical outcomes.

Animals↗
PubMed2004

Analyzing Mycobacterium tuberculosis proteomes for candidate vaccine epitopes.

Secreted antigens of Mycobacterium tuberculosis (Mtb) induce strong T cell responses and interferon-gamma (IFN-gamma) secretion, both of which are integral in the defense against Mtb. We used web-based tools (SignaIP and Prosite) to identify putative secreted proteins from Mtb genomes CDC 1551 and H37Rv. We then used EpiMatrix, a proprietary pattern-matching algorithm, to do a preliminary analysis of these proteins for regions that contained a high number of class II MHC binding motif matches. The use of bioinformatics tools reduced the number of potential epitopes to be screened to 5% of the 1.3 million overlapping peptides. Peripheral blood mononuclear cells (PBMC) were obtained from healthy, asymptomatic tuberculin skin test-positive donors. Of the 17 highest-ranking peptide candidates that could be synthesized for this preliminary in vitro evaluation, 15 (88%) stimulated IFN-gamma response, and eight (47%) stimulated lymphocyte proliferation in vitro. IFN-gamma ELISpot assays were therefore a more sensitive test for T cell response to these peptides than were proliferation assays. One highly promiscuous epitope (MT2281-26-J, WRRRPLSSALLSFGLLLGGLPL) induced IFN-gamma secretion in PBMC from 11 of 25 Mtb immune subjects (44%). Overall, 15 epitopes, and MT2281-26-J in particular, are candidates for inclusion in a multi-epitope TB vaccine. These findings support the systematic application of bioinformatics tools to whole genomes when used in combination with in vitro methods for screening and confirming epitopes.

Amino Acid Sequence↗
PubMed2004

Combining entacapone with levodopa/DDCI improves clinical status and quality of life in Parkinson's Disease (PD) patients experiencing wearing-off, regardless of the dosing frequency: results of a large multicentre open-label study.

The efficacy of entacapone and its impact on patient quality of life (QOL) was investigated in an open-label study of 899 patients with idiopathic Parkinson's Disease (PD) experiencing wearing-off fluctuations. Patients were divided into 3 groups (3, 4 or 5 doses daily) based on their current levodopa dosage frequency. Patients received 200 mg entacapone with each levodopa/dopa-decarboxylase inhibitor (DDCI) dose, while continuing their same levodopa/DDCI dosage regimen for 4 weeks. Primary efficacy measure was the Investigators' Clinical Global Impression of Change (CGIC). Patient QoL was assessed using the validated 8-item Parkinson's Disease Questionnaire (PDQ-8). Investigators' CGIC revealed that 76.5% of entacapone treated patients experienced an improvement in global status after 4 weeks. Treatment with entacapone was also associated with improvement in patient QoL, with a mean reduction (improvement) in PDQ-8 score of 1.8 from baseline. This study confirms and extends the results of earlier studies demonstrating that, independent of dosing frequency, completing levodopa/DDCI therapy with entacapone provides clinically relevant improvements in global status and QoL in PD patients experiencing wearing-off on their current levodopa dosing frequency.

Aged↗
PubMed2004

[Severe postoperative inflammation following implantation of a Stratasis sling].

The tension-free pubourethral sling procedure using a small intestinal submucosa sling (e.g., Stratasis, Cook Urological, Spencer/IN, USA) is of interest to the reconstructive urologist because of its reported regenerative capabilities and lack of immunogenicity. We report a severe postoperative inflammatory complication 4 weeks after the procedure. Severe inflammation with abscess formation led to reconstructive surgery to deal with the secondary complications.

Adult↗
PubMed2004

Bioequivalence study of generic amlodipine in healthy Thai male volunteers.

SUBJECTS, MATERIAL AND METHODS: To determine the bioequivalence of 10 mg generic amlodipine in healthy male volunteers, the reference and the test formulations were administered as a single oral dose after overnight fasting in a crossover study separated by 2-week washout interval. After dosing, serial blood samples were collected for a period of 144 h. Plasma amlodipine concentrations were determined by LC-MS/MS and the pharmacokinetic parameters were analyzed by non-compartmental analysis. RESULTS: The mean elimination half-life (t1/2) for the test (40 h) and the reference (44 h) were within the values previously reported. The rate of absorption reflected by tmax had a difference of -0.33 h, with a 90% CI of (-1.52)-0.85 (acceptable range +/- 1.3). Although the tmax of the test (5 h) was faster than the reference (6 h), the mean (90% CI) of the AUC(0-infinity) and Cmax ratios Test/Reference were 0.91 (0.87-0.97) and 1.01 (0.93-1.09), respectively. These values were within the range of 0.80-1.25, thus, the study demonstrated the bioequivalence of the 2 formulations.

Adult↗
PubMed2003

Modelling the immunogenicity of therapeutic proteins using T cell epitope mapping.

A new approach to designing therapeutic proteins is emerging, due to an improved understanding of T cell modulation of the immune response and new methods for modelling T cell epitopes using bioinformatics. In silico T cell epitope-mapping using the bioinformatics, when combined with other ex silico means of evaluating MHC-peptide and T cell interaction such as tetramers and HLA transgenic mice, enables the evaluation of dysfunctional immune responses to therapeutic proteins. This approach may even permit researchers to develop means of modulating anticipated adverse effects. The pocket profile method for developing T cell epitope prediction tools is reviewed here, and a comparison between the pocket profile method and the extended anchor method for epitopes restricted by the class II allele HLA DR B*0101 is described.

Animals↗
PubMed2002

Practice parameter: initiation of treatment for Parkinson's disease: an evidence-based review [RETIRED]: report of the Quality Standards Subcommittee of the American Academy of Neurology.

In 1993, the last AAN Practice Parameter on medical treatment of Parkinson's disease (PD) concluded that levodopa was the most effective drug for management of this disorder. Since then, a number of new compounds including non-ergot dopamine agonists (DA) and sustained-release levodopa have been released and studied. Thus, the issue of treatment in de novo PD patients warrants reexamination. Specific questions include: 1) does selegiline offer neuroprotection; 2) what is the best agent with which to initiate symptomatic treatment in de novo PD; and 3) is there a benefit of sustained release levodopa over immediate-release levodopa? Using evidence-based principles, a literature review using MEDLINE, EMBASE, and the Cochrane Library was performed to identify all human trials in de novo PD between 1966 and 1999. Only articles that fulfilled class I or class II evidence were included. Based on this review, the authors conclude: 1) Selegiline has very mild symptomatic benefit (level A, class II evidence) with no evidence for neuroprotective benefit (level U, class II evidence). 2) For PD patients requiring initiation of symptomatic therapy, either levodopa or a DA can be used (level A, class I and class II evidence). Levodopa provides superior motor benefit but is associated with a higher risk of dyskinesia. 3) No evidence was found that initiating treatment with sustained-release levodopa provides an advantage over immediate-release levodopa (level B, class II evidence).

Humans↗