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Biomedical subjects

D Swan

Publications and source records attributed to D Swan.

At least 19 recordsLinked to original sources
PubMed2002

Outcome of necrosectomy in acute pancreatitis: the case for continued vigilance.

BACKGROUND: Surgery for pancreatic necrosis complicating acute severe pancreatitis carries a high risk of mortality and may be influenced by a range of variables including patterns of referral, case selection and quality of care. METHODS: An observational study of a consecutive series of 54 patients undergoing pancreatic necrosectomy in a specialist Hepatobiliary unit over an 8-year study period. Principal outcomes were organ dysfunction and physiological derangement in relation to surgery, microbial colonization of necrosis and relation to outcome, re-operation rates, requirement for peri-operative nutritional support, trends in mortality and survival analysis. RESULTS: Necrosectomy was associated with statistically significant deterioration in immediate postoperative organ dysfunction scores (ANOVA P < 0.01). Infected necrosis was present in 36 (68%). Fungal colonization of necrosis was present in 5 (9%). Mortality in this subgroup was 80% (4 deaths). There was no association between bacterial colonization of necrosis and death in this study (P = 0.77; Fisher exact test; relative risk 0.9,95% confidence interval 0.54-1.54). Twenty patients (37%) required further surgical intervention with an average of 1.5 surgical procedures per patient. Twenty-three patients (43%) died. Patient survival to discharge was best predicted by admission APACHE-II score with relative risk of death increasing 14% for each unit increase in APACHE-II score at admission. CONCLUSIONS: The results of the present study illustrate that there is no place for complacency in the surgical management of patients with severe acute pancreatitis. A clinical governance approach would promote pre-defined protocols between admitting hospitals and tertiary referral centres. Future research should target new interventions in patients with high admission APACHE-II scores in whom prognosis is particularly poor and explore the role of infection of necrotic tissue.

APACHE↗
PubMed2001

Transient transfection of Theileria annulata.

We have developed a method to transiently transfect infective, uninucleate, Theileria annulata sporozoites. Transfection vectors have been constructed using a number of T. annulata 5' gene flanking sequences linked to the enhanced green fluorescence protein (eGFP) reporter gene. Sporozoites were transfected with these constructs using the lipid transfection agent SuperFect, then allowed to infect purified bovine mononuclear cells (PBMs). Green fluorescence was observed in developing trophozoites, 36-40 h post infection, using constructs containing the upstream regions of the T. annulata Hsp70, T. annulata merozite surface antigen 1 (TamS1) and T. annulata macroschizont-specific AT hook-containing protein2 (TashAT2) genes. A construct with the 5' TamS1 upstream sequence in reverse orientation gave no detectable fluorescence indicating fluorescence was derived by expression from the T. annulata promoter. A cytomegalovirus (CMV) promoter construct showed no activity in this stage of the parasite. However, when this construct was introduced directly into schizont-infected cells by electroporation, fluorescence was observed in the bovine cells but not the schizont. We describe the significance of these results in relation to novel control strategies and the fundamental biology of Theileria parasites.

5' Untranslated Regions↗
PubMed2001

Induction of the mammalian node requires Arkadia function in the extraembryonic lineages.

The early mammalian embryo is patterned by signals emanating from extraembryonic and embryonic signalling centres, most notably the anterior visceral endoderm (AVE) and the node, respectively. The AVE is responsible for anterior development, whereas further axis specification depends on the node, the equivalent of Spemann's organizer. Formation of the node, at the anterior primitive streak, depends on expression of the transcription factor HNF3beta (ref. 4). However, both the source and the nature of the signals responsible for inducing the node have been unknown. Here we describe a recessive lethal mutation, arkadia, generated using gene-trap mutagenesis. Mutant embryos establish an AVE but fail to maintain anterior embryonic structures and lack a node. The mutation has disrupted the Arkadia gene, which encodes a putative intracellular protein containing a RING domain. Arkadia is essential for HNF3beta expression in the anterior primitive streak. Analysis with chimaeras, however, shows that Arkadia functions within extraembryonic tissues, revealing that these are required to induce the node. Furthermore, our experiments show that Arkadia interacts genetically with the transforming growth factor (TGF)beta-like factor Nodal, implying that Nodal mediates the function of Arkadia in node induction.

Amino Acid Sequence↗
PubMed2001

A decrease in remodeling accounts for the accumulation of arachidonic acid in murine mast cells undergoing apoptosis.

The goal of this study was to examine arachidonic acid (AA) metabolism by murine bone marrow-derived mast cells (BMMC) during apoptosis induced by cytokine depletion. BMMC deprived of cytokines for 12-48 h displayed apoptotic characteristics. During apoptosis, levels of AA, but not other unsaturated fatty acids, correlated with the percentage of apoptotic cells. A decrease in both cytosolic phospholipase A(2) expression and activity indicated that cytosolic phospholipase A(2) did not account for AA mobilization during apoptosis. Free AA accumulation is also unlikely to be due to decreases in 5-lipoxygenase and/or cyclooxygenase activities, since BMMC undergoing apoptosis produced similar amounts of leukotriene B(4) and significantly greater amounts of PGD(2) than control cells. Arachidonoyl-CoA synthetase and CoA-dependent transferase activities responsible for incorporating AA into phospholipids were not altered during apoptosis. However, there was an increase in arachidonate in phosphatidylcholine (PC) and neutral lipids concomitant with a 40.7 +/- 8.1% decrease in arachidonate content in phosphatidylethanolamine (PE), suggesting a diminished capacity of mast cells to remodel arachidonate from PC to PE pools. Further evidence of a decrease in AA remodeling was shown by a significant decrease in microsomal CoA-independent transacylase activity. Levels of lyso-PC and lyso-PE were not altered in cells undergoing apoptosis, suggesting that the accumulation of lysophospholipids did not account for the decrease in CoA-independent transacylase activity or the induction of apoptosis. Together, these data suggest that the mole quantities of free AA closely correlated with apoptosis and that the accumulation of AA in BMMC during apoptosis was mediated by a decreased capacity of these cells to remodel AA from PC to PE.

Animals↗
PubMed2001

Treatment of canine leproid granuloma syndrome: preliminary findings in seven dogs.

OBJECTIVE: To determine effective treatment strategies for patients with refractory canine leproid granuloma syndrome. DESIGN: Multi-institutional retrospective/prospective case series using client-owned dogs. PROCEDURE: Seven dogs (four Boxers, one Dobermann, one Bullmastiff and one Bullmastiff cross-bred; ages 3 to 11 years) with leproid granulomas were treated successfully using a variety of treatment regimens. These cases were recruited because: lesions were either widely distributed over the dog; progressive, despite routine therapy, or were associated with particularly disfiguring lesions. The treatment regimen evolved during the course of the clinical study. RESULTS: Combination therapy using rifampicin (5 to 15 mg/kg p.o., every 24 h) and clarithromycin (8 to 24 mg/kg p.o. daily; dose divided every 8 or every 12 h) was used most frequently and proved to be effective and free from side effects. Total daily doses of clarithromycin in excess of 14 mg/kg were considered optimal and long treatment courses, in the order of 1 to 3 months, were used. Combination therapy using rifampicin (25 mg/kg; that is, higher than the recommended dose) and clofazimine was effective in one case, but resulted in hepatotoxicity. A topical formulation of clofazimine in petroleum jelly was used as an adjunct to oral rifampicin and doxycycline in another patient treated successfully. CONCLUSION: Based on our evolving clinical experience, a combination of rifampicin (10 to 15 mg/kg p.o., every 24 h) and clarithromycin (15 to 25 mg/kg p.o. total daily dose; given divided every 8 to 12 h) is currently recommended for treating severe or refractory cases of canine leproid granuloma syndrome. Treatment should be continued (typically for 4 to 8 weeks) until lesions are substantially reduced in size and ideally until lesions have resolved completely. A topical formulation, containing clofazimine in petroleum jelly may be used as an adjunct to systemic drug therapy. Further work is required to determine the most cost effective treatment regimen for this condition.

Animals↗
PubMed2000

Correlates of simulated hill climb cycling performance.

The aim of this study was to assess the relationship between several commonly used aerobic and anaerobic cycle ergometer tests and performance during a treadmill cycling hill climb. Eight competitive cyclists (age 27+/-7 years; body mass 73.2+/-5.2 kg; height 177+/-6 cm; mean +/- s) completed six tests in random order: a lactate minimum test; a Wingate anaerobic power test; and two 6-km climbs at 6% and two 1-km climbs at 12% gradient performed on a motorized treadmill. The mean times and power outputs for the 6-km and 1-km climbs were 16:30+/-1:08 min: s and 330+/-17.8 W, and 4:19+/-0:27 min: s and 411+/-24.4 W, respectively. The best individual predictor of 6-km and 1-km performance times was the time for the corresponding climb at the other distance (r = 0.97). The next strongest predictor of both hill climb performances was the average power produced during the Wingate test divided by body mass. Stepwise regression analysis showed that the two variables contributing most to the prediction equation for both climbs were the Wingate average power per unit of body mass and maximal aerobic power divided by total mass (rider + bike), which together accounted for 92 and 96% of the variability in the 6-km and 1-km climbs. In conclusion, among competitive cyclists, the Wingate average power per unit of body mass was the best single predictor of simulated cycling hill climb performance at the distance and gradient used.

Adaptation, Physiological↗
PubMed2000

Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: A North Central Cancer Treatment Group Trial.

PURPOSE: Hot flashes represent a significant clinical problem for some breast cancer survivors. Safe, effective treatment is needed for this prominent clinical problem. Although it has been shown that estrogen or progesterone replacement therapy can alleviate this problem, there are continued safety concerns regarding the use of hormonal therapies in these women. Based on anecdotal information, we hypothesized that soy-derived phytoestrogens, weak estrogen-like substances in the soybean that demonstrate estrogen agonist and/or antagonist effects when they bind to estrogen receptors, could alleviate hot flashes. This current trial was designed to investigate this hypothesis. PATIENTS AND METHODS: This double-blind clinical trial involved breast cancer survivors with substantial hot flashes. After randomization, patients underwent a 1-week baseline period with no therapy. This was followed by 4 weeks of either soy tablets or placebo. The patients then crossed over to the opposite arm in a double-blind manner for the last 4 weeks. Patients completed a daily questionnaire documenting hot flash frequency, intensity, and perceived side effects. RESULTS: Of the 177 women who were randomized and started the study substance, 155 (88%) provided useable data over the first 5 weeks; 149 provided usable data over the entire 9 weeks. There was no suggestion that the soy product was more effective in reducing hot flashes than the placebo. At study completion, patients preferred the soy product 33% of the time, the placebo 37% of the time, and neither substance 31% of the time. No toxicity was observed. CONCLUSION: The soy product did not alleviate hot flashes in breast cancer survivors.

Adolescent↗
PubMed2000

An upstream element of the TamS1 gene is a site of DNA-protein interactions during differentiation to the merozoite in Theileria annulata.

Apicomplexan parasites are major pathogens of humans and domesticated animals. A fundamental aspect of apicomplexan biology, which may provide novel molecular targets for parasite control, is the regulation of stage differentiation. Studies carried out on Theileria annulata, a bovine apicomplexan parasite, have provided evidence that a stochastic process controls differentiation from the macroschizont to the merozoite stage. It was postulated that this process involves the presence of regulators of merozoite gene expression in the preceding stage of the life cycle, and that during differentiation a quantitative increase of these factors occurs. This study was carried out to test these postulations. Nuclear run-on analysis showed that TamS1 expression is controlled, at least in part, at the transcriptional level. The transcription start site showed homology with the consensus eukaryotic initiator motif, and study of the 5' upstream region by the electrophoretic mobility-shift assay demonstrated that a 23 bp motif specifically bound factors from parasite-enriched nuclear extracts. Three complexes were shown to bind to a 9 bp core binding site (5'-TTTGTAGGG-3'). Two of these complexes were present in macroschizont extracts but were found at elevated levels during differentiation. Both complexes contain a polypeptide of the same molecular mass and may be related via the formation of homodimer or heterodimer complexes. The third complex appears to be distinct and was detected at time points associated with the transition to high level merozoite gene expression.

Adult↗
PubMed1999

Phase III controlled evaluation of glutamine for decreasing stomatitis in patients receiving fluorouracil (5-FU)-based chemotherapy.

Mucositis is a prominent dose-limiting toxicity associated with 5-FU-based chemotherapy. On the basis of preliminary data suggesting that the amino acid glutamine could alleviate this problem, the authors developed this trial. Patients scheduled to receive their first 5-FU-based chemotherapy regimen were selected for study. Following stratification, patients were randomized, in a double-blind manner, to receive oral glutamine or a placebo preparation in a prophylactic manner. Patients in both groups were given oral cryotherapy before chemotherapy and were evaluated for mucositis by standard physicians' evaluation and by a self-report instrument. Sixty-six patients were randomized to receive glutamine and 68 to receive the placebo preparation. There were no significant differences or substantial trends in the mucositis scores between the two study arms as measured by either the physicians or the patients. It was concluded that the dose and schedule of glutamine used in this clinical trial does not alleviate 5-FU-induced mucositis.

Administration, Oral↗
PubMed1998

Directing differentiation in Theileria annulata: old methods and new possibilities for control of apicomplexan parasites.

Apicomplexan parasites are major pathogens of humans and domesticated animals. The ability of these organisms to evade the host immune response and the emergence of drug-resistant parasites indicates a need for the identification of novel control strategies. Ideally, selected targets should be shared by a range of apicomplexans and fundamental to parasite biology. One process of apicomplexan biology which may provide this type of target is the molecular regulation of stage differentiation. This paper has reviewed studies carried out on differentiation of Theileria annulata and has highlighted general similarities with other apicomplexan differentiation steps. Similarities include asynchrony of differentiation, the loss (attenuation) of differentiation potential and an association between reduced proliferation and differentiation. In addition, novel data are presented assessing a possible role for a signal transduction mechanism or a direct involvement of classical heat-shock polypeptides in regulating differentiation of T. annulata in vitro. These studies, and previously published data, have led to the postulation that progression to the next stage of the life-cycle can be predetermined and involves the attainment of a quantitative threshold by regulators of gene expression. A modification of this model takes into account that for certain in-vitro systems, or differentiation steps in vivo, the process has to be initiated by alteration of the extracellular environment. Work which has shown that the time taken to achieve differentiation can be increased or decreased is also outlined. The ability to change the timing of differentiation suggests that the associated regulatory mechanism could be manipulated directly to significantly influence the outcome of an apicomplexan infection. The observation that a number of existing drugs and control strategies may exert their protective effect by altering differentiation potential supports this possibility.

Animals↗
PubMed1997

Picture naming deficits in developmental dyslexia: the phonological representations hypothesis.

The picture and word naming performance of developmental dyslexics was compared to the picture and word naming performance of non-dyslexic ("garden variety") poor readers, reading age, and chronological age-matched controls. The stimulus list used for both tasks was systematically manipulated for word length and word frequency. In order to examine picture naming errors in more depth, an object name recognition test assessed each subject's vocabulary knowledge of those names which they were unable to spontaneously label in the picture naming task. Findings indicated that the dyslexic and the garden variety poor readers exhibited a picture naming deficit relative to both chronological and reading age-matched controls. Findings also indicated that both groups of impaired readers obtained superior scores in the word naming task than in the picture naming task, while both groups of controls showed no difference in performance across tasks. The dyslexics' picture naming errors, but not those of the garden variety poor readers, were particularly marked on polysyllabic and/or low frequency words, indicating a possible phonological basis to the picture naming deficit of the dyslexic children. These children also recognized significantly more unnamed target words than all comparison groups, suggesting a particular difficulty in retrieving the phonological codes of known picture names rather than a vocabulary deficit. Results are discussed in terms of dyslexics' difficulty in encoding full segmental phonological representations of names in long-term memory and/or in processing these representations in order to generate required names on demand.

Adolescent↗
PubMed1997

Phonological awareness deficits in developmental dyslexia and the phonological representations hypothesis.

The claim that the well-documented difficulties shown by dyslexic children in phonological awareness tasks may arise from deficits in the accuracy and the segmental organization of the phonological representations of words in their mental lexicons is receiving increasing interest from researchers. In this experiment, two versions of the phonological representations hypothesis were investigated by using a picture naming task and a battery of phonological measures at three linguistic levels (syllable, onset-rime, phoneme). The picture naming task was used to identify words for which dyslexic and control children had accurate vs inaccurate phonological representations, and performance in the phonological awareness tasks was then compared for the words which had precise vs imprecise representations. Findings indicated that frequency effects in the phonological awareness tasks at all levels disappeared for dyslexic and control children once representational quality was taken into account, and that the availability of sublexical units for analysis appeared to differ according to (1) the accuracy and retrieval of the phonological representation and (2) the linguistic level tapped by the phonological awareness task.

Awareness↗
PubMed1996

A review and economic evaluation of bronchodilator delivery methods in hospitalized patients.

BACKGROUND: Bronchodilator delivery by metered dose inhaler (MDI) to treat airflow obstruction is considered to be less expensive and as effective as nebulized therapy. OBJECTIVES: To document the utilization of bronchodilator delivery methods in a tertiary care Canadian university teaching hospital and to perform an economic evaluation. METHODS: A prospective 6-week audit of 4 preselected hospital wards (respiratory, thoracic surgery, general surgery, and a general internal medicine clinical teaching unit) and a cost-minimization economic evaluation were performed. Bronchodilator (salbutamol and ipratropium bromide) doses, frequency, and delivery methods, either MDI or wet nebulizer (WN), were recorded for 95 patients treated with aerosolized bronchodilators. Direct costs for medications and hourly wages including benefits and equipment were obtained. Time and motion studies identified time allocated to MDI and WN delivery. We used sensitivity analyses to test assumptions that could significantly affect treatment costs, especially assumptions about medications, labor, and spacer devices. Costs are expressed in Canadian dollars (Can$1 = US$0.75). RESULTS: Sixty-seven patients (70.5%) were treated with WN, 6 (6.3%) with MDI, and 22 (23.2%) with both WN and MDI. Self-administration of salbutamol by MDI was the least expensive: $1.27 for 200-microgram doses and $1.73 for 400-microgram doses compared with $2.62 for a 2.5-mg dose delivered by WN. The difference in cost between equivalent treatments (400-microgram MDI vs 2.5-mg WN) is only $0.89. Sensitivity analyses showed that MDI was the least expensive therapy when self-administration was possible and for all levels of supervision if more than 4 minutes was needed to administer a WN treatment. CONCLUSIONS: Bronchodilator delivery by WN is commonly prescribed for hospitalized patients despite evidence for equivalency of effect using MDI and in the absence of substitution protocols. Previous studies have estimated a far greater cost differential based on unrealistic labor estimates. We found that supervision of patients using MDIs minimized the differential cost between WN and MDI therapy and that cost savings are maximal in patients who can self-administer MDI therapy. Methodologically sound economic evaluations can better identify true cost savings and variables that need further study.

Adolescent↗
PubMed1993

Sequence comparison of putative regulatory DNA of the 5' flanking region of the myeloperoxidase gene in normal and leukemic bone marrow cells.

Myeloperoxidase (MPO) is an enzyme which is exclusively expressed in immature myeloid cells with downregulation of gene expression occurring during granulocytic maturation. Levels of MPO RNA, protein, and enzyme activity differ, usually in a concordant fashion, among the various classes of acute leukemia and among different cases within a particular class. One portion of the gene thought to be involved in regulation of MPO expression is the proximal 5' flanking region. To determine if mutations in this putatively regulatory region of the MPO gene might be responsible for some of the differences in level of MPO expression among different cases or classes of acute leukemia, we compared the nucleotide sequence of this part of the gene from 16 patients with acute leukemia, with DNA from normal human bone marrow cells and selected other neoplasms and cell lines. The sequence of this regulatory region was found to be identical in cases of acute myeloid leukemia (AML) with tha of normal DNA except for a dA to dG transition in the Alu region, 463 bases upstream from the transcription start site. This base substitution was seen in almost all cases of AML studied, regardless of the level of MPO which they expressed. It was absent from normal human DNA obtained from various tissues, and cases of acute and chronic lymphocytic leukemia, carcinoma of lung, and most cell lines examined. The base substitution was also absent in a remission blood sample from one of the cases which showed the dA to dG transition in leukemic marrow, suggesting that the base substitution is a mutation rather than a polymorphism. Our results suggest that mutations in promoter or enhancer DNA are not an important cause of the differences in level of MPO gene expression seen among different cases or different classes of AML. However, the base substitution we have detected could potentially serve as a useful marker for detection of residual disease in patients with AML following treatment.

Base Sequence↗
PubMed1993

Mutations in the p53 gene in human astrocytomas: detection by single-strand conformation polymorphism analysis and direct DNA sequencing.

The p53 gene was examined in a series of formalin-fixed paraffin-embedded astrocytic neoplasms of various types by polymerase chain reaction (PCR), single-strand conformation polymorphism analysis (SSCP), and direct sequencing of amplified DNA. PCR primers were designed to amplify three DNA fragments encompassing exons 5, 7, and 8 with splice sites, including all four mutational "hot spots" within this gene. SSCP was performed in a polyacrylamide gel containing 10% glycerol. Two mutations were found among the 20 high and intermediate grade adult astrocytomas studied by this sensitive screening technique and confirmed by sequencing of the PCR product. (1) An anaplastic astrocytoma disclosed a T-A transversion in Codon 246 giving rise to a methionine to lysine amino acid substitution. (2) A giant cell glioblastoma disclosed a G to A transition in Codon 285 resulting in a glutamic acid to lysine substitution. Both mutations were associated with loss of the normal allele. Twenty-three DNA fragments that disclosed no mutation by SSCP analysis were confirmed to be negative by direct sequencing of amplified DNA. No mutations were detected in a series of eight juvenile cerebellar astrocytomas, a biologically distinct form of low-grade astrocytoma. Mutations of the p53 gene may play an important pathogenetic role in a subset of human astrocytomas.

Adult↗