Biomedical subjects

David Fletcher

Publications and source records attributed to David Fletcher.

10 recordsLinked to original sources

PubMed2006

Clinical recommendations for the use of recombinant human erythropoietin in patients with hepatitis C virus being treated with ribavirin.

Today, combination antiviral therapy with pegylated interferon-alpha and ribavirin (RBV) allows many patients infected with hepatitis C virus (HCV) to achieve a sustained virological response, which is equivalent to cure. Data also support the clinical benefit of combination antiviral therapy in patients coinfected with HCV and HIV, and in patients who have received a liver transplant. Antiviral therapy with pegylated interferon-alpha and RBV is, however, associated with a high incidence and significant magnitude of anemia. This anemia may have several mechanisms, including bone marrow suppression and hemolysis. In addition, patients coinfected with HIV may have both pre-existing and RBV-associated anemia. Management of anemia in patients with HCV through RBV dose reduction or treatment discontinuation may compromise the effectiveness of treatment, because studies have demonstrated that treatment adherence or maintenance of antiviral therapy dose is an important predictor of sustained virological response. Anemia associated with combination antiviral therapy in patients with HCV is frequently associated with an inadequate or blunted endogenous erythropoietin response. Accumulating evidence now supports the use of recombinant human erythropoietin (rHuEpo) to manage anemia in these patients, with the objective of maintaining the RBV dose, but clinical standards are lacking. The present article reviews the data relevant to the use of rHuEpo in this patient population and proposes a set of clinical practice standards to assist clinicians in selecting patients for rHuEpo and in implementing rHuEpo therapy effectively.

Algorithms↗

PubMed2005

Histological and histochemical observations on salivary microliths in ferret.

The fortuitous observation of salivary microliths in ferret was pursued in the present investigation. Major salivary glands obtained post-mortem from mature ferrets of either sex were examined with the use of histology and light microscopical histochemistry for calcium, protein, amino acids, mucosubstances and hydrolytic enzymes. Microliths were detected in most parotids, but were absent from submandibular and sublingual glands. The microliths were usually seen in lumens, and occasionally in parenchyma and interstices. They were variably stained for calcium, tryptophan, and neutral and acidic mucosubstances, similarly to acinar or ductal secretory granules. Unlike secretory granules, microliths showed autofluorescence, high levels of tyrosine and a low concentration of -SS- groups. Acid phosphatase and beta-glucuronidase reaction surrounded non-luminal microliths. The present data establish ferret as a new model for the investigation of salivary microliths and do not support the notion of microliths being almost absent from the parotid. Probably there is secretory inactivity in ferret parotid and this fosters the formation and accumulation of microliths containing calcium and disintegrated secretory material.

Acid Phosphatase↗

PubMed2005

Relation of exaggerated cytokine responses of CF airway epithelial cells to PAO1 adherence.

In many model systems, cystic fibrosis (CF) phenotype airway epithelial cells in culture respond to P. aeruginosa with greater interleukin (IL)-8 and IL-6 secretion than matched controls. In order to test whether this excess inflammatory response results from the reported increased adherence of P. aeruginosa to the CF cells, we compared the inflammatory response of matched pairs of CF and non CF airway epithelial cell lines to the binding of GFP-PAO1, a strain of pseudomonas labeled with green fluorescent protein. There was no clear relation between GFP-PAO1 binding and cytokine production in response to PAO1. Treatment with exogenous aGM1 resulted in greater GFP-PAO1 binding to the normal phenotype compared to CF phenotype cells, but cytokine production remained greater from the CF cell lines. When cells were treated with neuraminidase, PAO1 adherence was equalized between CF and nonCF phenotype cell lines, but IL-8 production in response to inflammatory stimuli was still greater in CF phenotype cells. The polarized cell lines 16HBEo-Sense (normal phenotype) and Antisense (CF phenotype) cells were used to test the effect of disrupting tight junctions, which allows access of PAO1 to basolateral binding sites in both cell lines. IL-8 production increased from CF, but not normal, cells. These data indicate that increased bacterial binding to CF phenotype cells cannot by itself account for excess cytokine production in CF airway epithelial cells, encourage investigation of alternative hypotheses, and signal caution for therapeutic strategies proposed for CF that include disruption of tight junctions in the face of pseudomonas infection.

Bacterial Adhesion↗

PubMed2005

Organic secretory products, adaptive responses and innervation in the parotid gland of ferret: a histochemical study.

To qualify cellular events of possible pathophysiological significance in the parotid of ferret, tissue obtained post-mortem from mature animals of either sex was examined by light microscopical histochemistry for calcium, protein, amino acids, mucosubstances and hydrolases, and by neurohistology. Calcium was localised in acinar cells replete with granules containing protein, disulphides and usually carboxylated mucosubstances. Acid phosphatase activity was basally concentrated in the acinar cells. The granular luminal region of striated ductal cells showed protein, tryptophan, disulphides, neutral mucosubstances, and E600-sensitive esterase and Naphthol AS-D chloroacetate esterase activities, whereas their basal region showed acid phosphatase activity. Strong periluminal activity of acid phosphatase and E600-resistant esterase characterised the collecting ducts. Cholinesterase activity was associated with an extensive network of nerve fibres embracing parenchyma. Catecholamine fluorescence was not seen. beta-glucuronidase reactive macrophages abounded in the interstices. The results suggest that while the acini in the parotid of ferret secrete polyionic glycoproteins, shielded by calcium, the striated ducts secrete tryptophan-rich products comprising neutral glycoproteins and showing proteolytic activity. Innervation is of the cholinergic type and parenchymal lysosomal activity, possibly related to autophagy of stored secretory products and heterophagy of luminal material, is brisk. Macrophages contribute to maintaining the glandular microenvironment, wherein secretory activity appears to be lethargic.

Acid Phosphatase↗

PubMed2005

Stress in elite sport performers: a comparative study of competitive and organizational stressors.

The purpose of this study was to compare the content and quantity of competitive and organizational stressors in elite athletes. Ten international performers were interviewed about sources of stress. Content analysis of the data involved categorizing the demands associated primarily and directly with competitive performance (#CS = 21) under the post hoc dimension "performance issues", and the demands associated primarily and directly with the sport organization (#OS = 72) under one of the following four post hoc dimensions: "environmental issues", "personal issues", "leadership issues" and "team issues". Frequency analysis revealed that the participants mentioned the competitive stressors (sigma = 95) less than the organizational stressors (sigma = 215). Further analysis within these categories showed that the mean number of participants citing individual competitive stressors (M = 4.52) was greater than the mean number of participants citing individual organizational stressors (M = 2.99). The findings indicate that elite athletes experience and recall more demands associated primarily and directly with the sport organization than with competitive performance. Furthermore, this population appears more likely to mention similar competitive stressors but varied organizational stressors, probably because the former are inherent and endemic to elite sport, whereas the latter are essentially extraneous and widely distributed.

Adult↗

PubMed2004

Glycosylations in demilunar and central acinar cells of the submandibular salivary gland of ferret investigated by lectin histochemistry.

'Resting' submandibular salivary glands obtained post-mortem from mature ferrets of both sexes were examined here. The binding patterns of labelled lectins applied to paraffin sections of tissue slivers fixed in an aldehyde-HgCl2 mixture and the effects of pretreatment procedures on the results were assessed lightmicroscopically. Lectins with affinity for terminal GalNAc residues (DBA, SBA) bound preferentially to demilunar acinar cells which were also strongly reactive with Fuc-directed UEA I. In contrast, lectins with affinity for neuraminic acid (SNA, WGA) bound to central acinar cells where consistent binding of DBA and SNA occurred only after neuraminidase digestion, and variation in the binding of UEA I was seen. The reactivities corresponded with the distribution of secretory granules, but staining in Golgi-like areas occurred in central acinar cells with PNA lectin. The results suggest that glycosylations are more advanced in central than demilunar acinar cells of the ferret submandibular gland. Possibly demilunar and central acinar cells reflect phenotypic changes of a single secretory cell, the 'central' acinar phenotype being influenced by incorporation of neuraminic acid in glycoprotein side chains and by increased Golgi activity.

Animals↗

PubMed2004

Identification and staging of pancreatic tumours using computed tomography, endoscopic ultrasound and mangafodipir trisodium-enhanced magnetic resonance imaging.

Pancreatic malignancy can be staged by a number of different investigations, either alone or in combination. The purpose of the present study was to compare the use of endoscopic ultrasound, CT and mangafodipir trisodium-enhanced MRI for the staging of pancreatic malignancy, particularly with respect to determining resectability prior to surgery. Twenty-seven patients referred for the investigation of a suspected pancreatic malignancy were entered into the trial. All patients had contrast-enhanced CT, gadolinium and mangafodipir trisodium-enhanced MRI, and endoscopic ultrasound (EUS). Images were assessed for nodal staging, tumour staging and resectability for each investigation, and the results compared with findings at surgery. The results for the accuracy of MRI, CT and EUS, in detecting T4 disease versus T3 or lower was 78, 79 and 68%, respectively; nodal involvement was 56, 63 and 69%, respectively; and overall resectability (including the T stage, presence of involved nodes and metastases) was 83, 76 and 63%, respectively. There was no significant difference demonstrated between the three tests. The present study suggests that for patients referred for investigation and staging of pancreatic malignancy, EUS and MRI scanning convey little advantage over contrast-enhanced CT. Furthermore, although mangafodipir trisodium improved the conspicuity of pancreatic tumours, it has little influence on T staging.

Contrast Media↗

PubMed2002

Neurological correction of lysosomal storage in a mucopolysaccharidosis IIIB mouse model by adeno-associated virus-mediated gene delivery.

Mucopolysaccharidosis (MPS) IIIB is characterized by mild somatic features and severe neurological diseases leading to premature death. No definite treatment is available for MPS IIIB patients. We constructed two recombinant adeno-associated virus (rAAV) vectors containing the human alpha-N-acetylglucosaminidase (NaGlu) cDNA driven by either a CMV or a neuron-specific enolase (NSE) promoter. In vitro, these rAAV vectors mediated efficient expression of recombinant NaGlu in human MPS IIIB fibroblasts and mouse MPS IIIB somatic and brain primary cell cultures. The secreted rNaGlu was taken up by both human and mouse MPS IIIB cells in culture and degraded the accumulated glycosaminoglycans (GAG). A direct microinjection (10(7) viral particles, 1 microl/10 minutes per injection) of vectors containing the NSE promoter resulted in long-term (6 months, the duration of the experiments) expression of rNaGlu in multiple brain structures/areas of adult MPS IIIB mice. Consistent with previous studies, the main target cells were neurons. However, while vector typically transduced an area of 400-500 microm surrounding the infusion sites, the correction of GAG storage involved neurons of a much broader area (1.5 mm) in a 6-month duration of experiments. These results provide a basis for the development of a treatment for neurological disease in MPS IIIB patients using AAV vectors.

Acetylglucosaminidase↗

PubMed2002

Lipolytic and esterolytic activities in posterior lingual glands of rat: a histochemical study.

Catalytic activities of lingual lipase were investigated by enzyme histochemistry in post-mortem tongues from male rats. Sections of fresh-frozen or formalin-calcium fixed tissue were incubated with naphthol-AS-nonanoate and alpha-naphthyl acetate substrate mixtures. The effects of pH level, sodium taurocholate activator and E600 inhibitor were also examined. The use of cryostat sections of tissues fixed in formalin-calcium and of nonanoate substrate within the range of pH 4.4-6.4, were optimal for localizing maximum reaction product, captured by Fast Blue BB, in acini and demilunes of the posterior deep and superficial lingual glands respectively. The reaction product corresponded with the distribution of secretory granules and failed to develop when taurocholate was omitted from the incubation medium. Similarly localized E600-resistant reaction product occurred with the acetate substrate and hexazotized New Fuchsin at pH 7.4, in the absence of taurocholate. Lipase and conventional esterase activities appear to be superimposed in posterior lingual glands of rat. The ability of their acini and demilunes to hydrolyse nonanoate substrate at an acidic pH optimum, when activated by sodium taurocholate, seems attributable to lipase destined for secretion into saliva--hence convenient for routine histochemical identification of the enzyme.

Animals↗

PubMedDate not supplied

Equivalence relationships between stage-structured population models.

Matrix population models are widely applied in conservation ecology to help predict future population trends and guide conservation effort. Researchers must decide upon an appropriate level of model complexity, yet there is little theoretical work to guide such decisions. In this paper we present an analysis of a stage-structured model, and prove that the model's structure can be simplified and parameterised in such a way that the long-term growth rate, the stable-stage distribution and the generation time are all invariant to the simplification. We further show that for certain structures of model the simplified models require less effort in data collection. We also discuss features of the models which are not invariant to the simplification and the implications of our results for the selection of an appropriate model. We illustrate the ideas using a population model for short-tailed shearwaters (Puffinus tenuirostris). In this example, model simplification can increase parameter elasticity, indicating that an intermediate level of complexity is likely to be preferred.

Animals↗