Biomedical subjects

J J Doyle

Publications and source records attributed to J J Doyle.

At least 19 recordsLinked to original sources

PubMed2006

Comparative outcome of hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia following cyclophosphamide and total body irradiation or VP16 and total body irradiation conditioning regimens.

To compare the outcome of hematopoietic stem cell transplantation (HSCT) in pediatric acute lymphoblastic leukemia (ALL) conditioned with two different regimens: (1) single dose of VP16 (60 mg/kg over 4 h) and total body irradiation (TBI; 1200 cGy, in six fractions) or (2) Cyclophosphamide 50 mg/kg over 1 h daily for 4 days followed by the same dose of TBI. One hundred and seven children with ALL received fully matched HSCT from 1990 to 2003 in the Hospital for Sick Children, Toronto. All received cyclosporin A and a short course of methotrexate for graft-versus-host disease (GVHD) prophylaxis. The VP16 group, there were 36 matched related donor transplants (MRD) and 26 matched unrelated donor transplants (MUD), and in the cyclophosphamide group there were 23 MRD and 22 MUD transplants. Neutrophil engraftment occurred at a median of 18 and 17 days for the VP16/TBI and the CY/TBI groups, respectively. The 3 year event-free survival and overall survival were 47 +/- 7 and 55 +/- 7% for those receiving VP16/TBI, and 51 +/- 8 and 53 +/- 8% for the CY/TBI group. There were no significant differences in the prevalence of acute or chronic GVHD and transplant-related mortality between the two groups. Both VP16/FTBI and CY/FTBI regimen are equally effective regimens.

Adolescent↗

PubMed2005

Placing paleopolyploidy in relation to taxon divergence: a phylogenetic analysis in legumes using 39 gene families.

Young polyploid events are easily diagnosed by various methods, but older polyploid events become increasingly difficult to identify as chromosomal rearrangements, tandem gene or partial chromosome duplications, changes in substitution rates among duplicated genes, pseudogenization or locus loss, and interlocus interactions complicate the means of inferring past genetic events. Genomic data have provided valuable information about the polyploid history of numerous species, but on their own fail to show whether related species, each with a polyploid past, share a particular polyploid event. A phylogenetic approach provides a powerful method to determine this but many processes may mislead investigators. These processes can affect individual gene trees, but most likely will not affect all genes, and almost certainly will not affect all genes in the same way. Thus, a multigene approach, which combines the large-scale aspect of genomics with the resolution of phylogenetics, has the power to overcome these difficulties and allow us to infer genomic events further into the past than would otherwise be possible. Previous work using synonymous distances among gene pairs within species has shown evidence for large-scale duplications in the legumes Glycine max and Medicago truncatula. We present a case study using 39 gene families, each with three or four members in G. max and the putative orthologues in M. truncatula, rooted using Arabidopsis thaliana. We tested whether the gene duplications in these legumes occurred separately in each lineage after their divergence (Hypothesis 1), or whether they share a round of gene duplications (Hypothesis 2). Many more gene family topologies supported Hypothesis 2 over Hypothesis 1 (11 and 2, respectively), even after synonymous distance analysis revealed that some topologies were providing misleading results. Only ca. 33% of genes examined support either hypothesis, which strongly suggests that single gene family approaches may be insufficient when studying ancient events with nuclear DNA. Our results suggest that G. max and M. truncatula, along with approximately 7000 other legume species from the same clade, share an ancient round of gene duplications, either due to polyploidy or to some other process.

Computational Biology↗

PubMed2005

Direct costs of glaucoma and severity of the disease: a multinational long term study of resource utilisation in Europe.

BACKGROUND: Resource utilisation and direct costs associated with glaucoma progression in Europe are unknown. As population progressively ages, the economic impact of the disease will increase. METHODS: From a total of 1655 consecutive cases, the records of 194 patients were selected and stratified by disease severity. Record selection was based on diagnoses of primary open angle glaucoma, glaucoma suspect, ocular hypertension, or normal tension glaucoma; 5 years minimum follow up were required. Glaucoma severity was assessed using a six stage glaucoma staging system based on static threshold visual field parameters. Resource utilisation data were abstracted from the charts and unit costs were applied to estimate direct costs to the payer. Resource utilisation and estimated direct cost of treatment, per person year, were calculated. RESULTS: A statistically significant increasing linear trend (p = 0.018) in direct cost as disease severity worsened was demonstrated. The direct cost of treatment increased by an estimated 86 for each incremental step ranging from 455 euro per person year for stage 0 to 969 euro per person year for stage 4 disease. Medication costs ranged from 42% to 56% of total direct cost for all stages of disease. CONCLUSIONS: These results demonstrate for the first time in Europe that resource utilisation and direct medical costs of glaucoma management increase with worsening disease severity. Based on these findings, managing glaucoma and effectively delaying disease progression would be expected to significantly reduce the economic burden of this disease. These data are relevant to general practitioners and healthcare administrators who have a direct influence on the distribution of resources.

Adult↗

PubMed2004

Health-related quality of life (HRQL) scores reported from parents and their children with chronic illness differed depending on utility elicitation method.

OBJECTIVE: To describe the relationship between health-related quality of life (HRQL) as measured by utility when elicited from parents and their children with chronic illness. STUDY DESIGN AND SETTING: We enrolled families of children admitted for cancer chemotherapy and those attending outpatient rheumatology, hemophilia and bone marrow transplantation clinics. Children in grade 6 or higher were included. The child's HRQL was rated by parent and child using the Standard Gamble (SG), Visual Analogue Scale (VAS), Time Trade-Off (TTO), and Health Utilities Index Mark 2/3 (HUI2 and HUI3). RESULTS: 22 families were included. The mean parent SG was 0.92 +/- 0.09, which was similar to the mean SG elicited from their children of 0.92 +/- 0.10. The parent and child SG were moderately concordant (ICC=0.64, 95% CI=0.30, 0.83; P=.0005). In contrast, TTO scores were not concordant (ICC=0.14, 95% CI=-0.29, 0.53; P=.3), with parents (mean TTO=0.77 +/- 0.31) rating HRQL worse than children (mean TTO=0.92 +/- 0.11; P=.04). Similarly, the mean parent HUI2 of 0.82 +/- 0.22 was lower than the child HUI2 of 0.95 +/- 0.07; P=.02 and HUI2 were not concordant (ICC=0.11, 95% CI=-0.35, 0.53; P=.3) between parents and children. CONCLUSION: Parents and children rate HRQL similarly according to SG, but parents rate HRQL significantly worse using TTO and HUI2.

Adolescent↗

PubMed2003

Construct validation of the Health Utilities Index and the Child Health Questionnaire in children undergoing cancer chemotherapy.

The objective of this study was to evaluate the construct validity of two questionnaire-based measures of health-related quality of life (HRQL) in children undergoing cancer chemotherapy: the Health Utilities Index (HUI) and the Child Health Questionnaire (CHQ). Subjects were children hospitalised for chemotherapy. To examine construct validity: (1). a priori expected relations between CHQ concepts and HUI attributes were examined; (2). HUI and CHQ summary scores were compared to visual analogue scale (VAS) scores. Ease of completion was rated using a 5-point categorical scale and completion time was recorded. A total of 36 subjects were included. The maximum score was seen in 15 (47%) of HUI3 assessments. As predicted, CHQ body pain was moderately correlated with HUI3 pain (r=0.51), CHQ physical functioning was moderately correlated with HUI2 mobility (r=0.58) and CHQ mental health was moderately correlated with HUI2 emotion (r=0.53). Only the CHQ psychosocial subscale (and not HUI) was correlated with VAS (r=0.44). The CHQ and the HUI were both easy to use. The HUI questionnaires required less time to complete (mean=3.1, s.d.=1 min) compared with CHQ (mean=13.1, s.d.=3.4 min, P<0.0001). In conclusion, HUI and CHQ demonstrated construct validity in children undergoing cancer chemotherapy. The Health Utilities Index is subject to a ceiling effect whereas CHQ requires more time to complete.

Adolescent↗

PubMed2003

Validity of a modified standard gamble elicited from parents of a hospital-based cohort of children.

OBJECTIVES: To examine the validity of a modified standard gamble (Mod SG) (nondeath baseline) by comparing these scores to SG (death baseline), time trade off (TTO), visual analog scale (VAS), Health Utilities Index (HUI), and Child Health Questionnaire (CHQ). METHODS: Respondents were parents of in-patients with cancer receiving chemotherapy and parents of children without cancer attending outpatient clinics. Construct validity was determined by comparing a priori hypotheses to actual correlations between measures. Discriminant validity was examined by anticipating that in-patients with cancer would have lower HRQL than outpatients. RESULTS: 85 families were included. Both Mod SG and SG were moderately correlated with TTO (r=0.50 and r=0.49; P<.01 for both). Both Mod SG and SG were moderately correlated with TTO (r=0.47 and r=0.05, P<0.002 for both). CONCLUSION: The Mod SG did not perform better than SG. Two nonoverlapping groups of HRQL measures were demonstrated.

Adolescent↗

PubMed2003

Low-intensity hematopoietic stem-cell transplantation across human leucocyte antigen barriers in dyskeratosis congenita.

Since the results of conventional hematopoietic stem-cell transplantation (HSCT) for patients with dyskeratosis congenita (DC) are poor owing to the high incidence of transplant-related complications, we explored the use of a low-intensity HSCT regimen. We report two children with DC with severe cytopenia, who underwent successful HSCT from a matched unrelated donor after conditioning with fludarabine, cyclophosphamide, and antithymocyte globulin. Graft-versus-host-disease (GVHD) prophylaxis consisted of corticosteroids and cyclosporin A. The regimen was well tolerated, no significant transplant-related complications were observed, and engraftment was rapid and complete. At 15 and 16 months after HSCT, the children were fully engrafted, in excellent clinical condition, full-donor chimerism, and no signs of GVHD. We conclude that a low-intensity regimen is sufficient to induce durable engraftment using matched unrelated donor HSCT in DC patients, with minimal 1-year transplant-related toxicity. Longer follow-up will determine whether this regimen also reduces long-term toxicity.

Adrenal Cortex Hormones↗

PubMed2003

Life-threatening pulmonary hemorrhages post bone marrow transplantation in Hurler syndrome. Report of three cases and review of the literature.

Hurler syndrome (MPS-IH) is an autosomal recessive mucopolysaccharide storage disorder caused by deficiency of lysosomal alpha-L-iduronidase (IDU) enzyme activity. This results in accumulation of heparan sulfate and dermatan sulfate substances. Untreated children develop progressive developmental deterioration and multisystem morbidity with a median survival of 5 years. Allogeneic bone marrow transplantation (BMT) is the only long-lasting treatment that ameliorates or halts the aggressive course of the disease. Pulmonary hemorrhage (PH) is an unusual complication of BMT and has not been previously reported in MPS-IH post-BMT. We report three children with MPS-IH with life-threatening PH around the time of engraftment. All needed intensive-care support and one child developed recurrent PH that required prolonged ventilation.

Bone Marrow Transplantation↗

PubMed2003

Underlying chronic granulomatous disease in a patient with bronchocentric granulomatosis.

We present a case of bronchocentric granulomatosis in a woman with no history of asthma who was colonised with Aspergillusfumigatus. A family history of chronic granulomatous disease prompted further testing that demonstrated severely depressed neutrophil oxidant production and gp91(phox) deficiency compatible with the X linked carrier state of chronic granulomatous disease. Only one report of the association of these two rare diseases has previously appeared in the literature. We postulate that an ineffective immune response led to the prolonged colonisation of Afumigatus resulting in a hypersensitivity reaction that was manifest clinically as bronchocentric granulomatosis.

Adult↗

PubMed2002

Single-centre experience with allogeneic bone marrow transplantation for acute lymphoblastic leukaemia in childhood: similar survival after matched-related and matched-unrelated donor transplants.

Seventy percent of children with acute lymphoblastic leukaemia (ALL) who may benefit from bone marrow transplant (BMT) lack a human leucocyte antigen (HLA)-matched related donor (MRD). For these children, BMT from a matched unrelated donor (MUD) represents a therapeutic option. We reviewed the course of 62 children with ALL who received fully matched marrow allografts at our institution between 1990 and 1998: 36 with MRDs and 26 with MUDs. Clinical characteristics were similar in the two groups. The interval from attainment of pre-BMT complete remission to transplant was significantly longer in the MUD group. Conditioning (etoposide/total body irradiation) and graft-versus-host disease (GVHD) prophylaxis regimens were the same for all patients, and all received T cell-replete bone marrow. There was no significant difference in probability of engraftment, or time to engraftment, in the two groups. MUD BMT recipients had a significantly greater incidence of grade II-IV acute GVHD (58% versus 24% in the MRD group; P = 0.02), and demonstrated a trend towards more chronic GVHD (39% versus 15%; P = 0.06). Three years post BMT, the probabilities of transplant-related mortality were 33 +/- 11% and 20 +/- 8% in MUD and MRD groups respectively (P = 0.38); the probabilities of relapse were 28 +/- 12% and 41 +/- 9% respectively (P = 0.19). Lansky or Karnofsky performance scores in event-free survivors were 90-100 in 87% of the MUD group and 83% of the MRD group. With a median follow up of 38 months (range, 3-97), 3-year event-free survival was 49 +/- 11% and 47 +/- 9% in the MUD and MRD BMT groups respectively (P = 0.71). These results suggest that MUD BMT is a valuable therapy for children with ALL in whom BMT is indicated, and underscore the importance of efforts aimed at expediting unrelated donor searches for patients lacking a MRD.

Adolescent↗

PubMed2002

A cost-effectiveness evaluation of amlodipine usage in patients with coronary artery disease in Sweden.

The objective of this analysis was to calculate the cost-effectiveness of amlodipine therapy in patients with coronary artery disease in Sweden. It is hypothesised that treatment with amlodipine will have an impact on overall cardiovascular disease treatment costs, resulting in a positive cost-effectiveness profile. A Markov cohort simulation model was constructed to simulate event-related and procedure-related health economic outcomes of coronary artery disease populations on amlodipine versus those on placebo. Patient level data from the Prospective Evaluation of the Vascular Effects of Norvasc Trial was used to populate the model. The total number of adverse cardiovascular clinical outcomes experienced over a three-year period was lower for patient on amlodipine than for those on placebo. The rate of hospitalisation per patient due to angina, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, congestive heart failure, and myocardial infarction in the placebo cohort was 64.7%, while the rate in the amlodipine cohort was 46.9%. The cost per patient was Swedish kroner (SEK)26,600 for amlodipine patients and SEK27,400 for placebo patients. The use of amlodipine resulted in improved clinical outcomes as well as a slight savings in cost over a three-year period.

Amlodipine↗

PubMed2001

Phylogenetic utility of the nuclear gene malate synthase in the palm family (Arecaceae).

There is currently a shortage of DNA regions known to be useful for phylogenetic research in palms (Arecaceae). We report the development and use of primers for amplifying and sequencing regions of the nuclear gene malate synthase. In palms the gene appears to be single-copy, with exon regions that are phylogenetically informative within the family. We constructed a phylogeny of 45 palms and five outgroup taxa using 428 bp of malate synthase exon regions. We found that some major clades within the family were recovered, but there was a lack of resolution among the genera in subfamilies Arecoideae, Ceroxyloideae, Coryphoideae, and Phytelephantoideae. In a second analysis, malate synthase exon regions totaling 1002 bp were sequenced for 16 palms and two outgroup taxa. There was increased bootstrap support for some groups and for the placement of the monotypic genus Nypa as sister to the rest of the family. A comparison with data sets from noncoding regions of the chloroplast genome indicates that malate synthase sequences are more variable and potentially contain more phylogenetic information. We found no evidence of multiple copies of the malate synthase gene in palm genomes.

Cell Nucleus↗

PubMed2001

Initial bone marrow aspiration in childhood idiopathic thrombocytopenia: decision analysis.

PURPOSE: Bone marrow aspiration (BMA) is routinely performed before starting steroid therapy in children with idiopathic thrombocytopenia, primarily to rule out leukemia. METHODS: A decision tree for the initial management of a child older than age 6 months, presenting with idiopathic thrombocytopenia, without blasts on the peripheral smear was constructed. The three strategies are: 1) initial BMA in all patients; 2) initial BMA only in patients at high risk; and 3) empiric therapy for all patients without initial BMA. High-risk criteria include any of: platelet count >50 x 10(9)/L; hemoglobin <100 g/L (age younger than 12 months) or <110 g/L (age older than 12 months): white blood cell count <5 x 10(9)/L (younger than 6 years) or <4 x 10(9)/L (older than 6 years); or absolute neutrophil count <1.5 x 10(9)/L (younger than 6 years) or <2 x 10(9)/L (older than 6 years). The results are expressed as quality-adjusted life years (QALYs), a measure that estimates the overall life expectancy in years for patients receiving a particular treatment strategy, corrected for the patient's quality of life. RESULTS: The base case results are: 1) BMA all = 69.649 QALYs; 2) high-risk BMA = 69.652 QALYs; and 3) empiric therapy = 69.644 QALYs. These results indicate a three-way toss-up because there is less than a 4-day quality-adjusted difference (0.01) between strategies. CONCLUSION: This study indicates that the initial BMA does not significantly change the overall QALYs of a child presenting with thrombocytopenia and, consequently, is not mandatory in every patient before starting steroids.

Adolescent↗

PubMed2001

Phylogeny of the Celastraceae inferred from phytochrome B gene sequence and morphology.

Phylogenetic relationships within Celastraceae were inferred using a simultaneous analysis of 61 morphological characters and 1123 base pairs of phytochrome B exon 1 from the nuclear genome. No gaps were inferred, and the gene tree topology suggests that the primers were specific to a single locus that did not duplicate among the lineages sampled. This region of phytochrome B was most useful for examining relationships among closely related genera. Fifty-one species from 38 genera of Celastraceae were sampled. The Celastraceae sensu lato (including Hippocrateaceae) were resolved as a monophyletic group. Loesener's subfamilies and tribes of Celastraceae were not supported. The Hippocrateaceae were resolved as a monophyletic group nested within a paraphyletic Celastraceae sensu stricto. Goupia was resolved as more closely related to Euphorbiaceae, Corynocarpaceae, and Linaceae than to Celastraceae. Plagiopteron (Flacourtiaceae) was resolved as the sister group of Hippocrateoideae. Brexia (Brexiaceae) was resolved as closely related to Elaeodendron and Pleurostylia. Canotia was resolved as the sister group of Acanthothamnus within Celastraceae. Perrottetia and Mortonia were resolved as the sister group of the rest of the Celastraceae. Siphonodon was resolved as a derived member of Celastraceae. Maytenus was resolved as three disparate groups, suggesting that this large genus needs to be recircumscribed.

Journal Article↗

PubMed2001

Economic and quality-of-life impact of rheumatoid arthritis.

Although RA is a disabling disease with increased mortality and an unknown cure, early treatment with DMARD therapy improves patient outcomes. The economic and humanistic effects of this disease are substantial, with patients becoming increasingly disabled from RA. It is extremely encouraging to the rheumatology community that leflunomide provides significant and sustained improvements in clinical signs and symptoms, and offers practicing physicians an additional option in the treatment of RA. It improves and maintains physical function and HRQoL. Leflunomide's effects were consistent across three studies over two years of treatment. It has been demonstrated to improve physical function as measured by the HAQ DI, and HRQoL as indicated by the SF-36 data, two instruments held up as the gold standard for the assessment of patient outcomes in RA clinical trials.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

Prevalence of pulmonary disorders in patients with newly diagnosed rheumatoid arthritis.

Our objective was to determine the prevalence of airway hyperreactivity (AHR) in patients with newly diagnosed rheumatoid arthritis (RA) who had received no disease-modifying antirheumatic drugs (DMARDs) and to characterise the spectrum of lung diseases identifiable in these patients at the time of presentation. Eighteen consecutive patients with newly diagnosed RA referred to our medical centre's rheumatology clinic over 2 years underwent pulmonary evaluation with arterial blood gas analysis, chest radiographs, spirometry before and after bronchodilator medication, and body plethysmography. They returned on subsequent days in random order for methacholine inhalation challenge (MIC) and eucapnic voluntary hyperventilation (EVH) as bronchoprovocation techniques. One patient had severe obstructive disease at presentation and therefore did not undergo bronchoprovocation. We found a wide variety of pulmonary abnormalities, including two patients with hypoxia (12%), two with obstruction (12%), three with restriction (18%) and four with AHR (23%). The data also suggest a strong association between pulmonary diseases in RA and cigarette smoking. Although no single characteristic lung disease such as AHR was identified in patients presenting with RA, the association between lung disease and cigarette smoking is striking and underscores the need to emphasise smoking cessation in this patient population.

Adult↗

PubMed2000

Amyotrophic lateral sclerosis with multiple sclerosis: a clinical and pathological report.

We report a 62-year-old woman with a past history of painful central visual loss who developed progressive quadriparesis and bulbar palsy. Neurological examination revealed widespread upper and lower motor neuron signs in the bulbar region and extremities. Electromyography demonstrated widespread active and chronic motor axon loss. Magnetic resonance neuroimaging studies revealed enhancing callosal and periventricular white matter lesions and cervical and thoracic cord hyperintensities. Cerebrospinal fluid analysis was consistent with multiple sclerosis. The patient died of respiratory failure two years after presentation, and autopsy revealed multifocal demyelination involving the corpus callosum, cerebellum and spinal cord as well as pathologic findings typical of amyotrophic lateral sclerosis. A review of the literature confirms the exceedingly unusual combination of amyotrophic lateral sclerosis with multiple sclerosis.

Autopsy↗

PubMed2000

"Low-risk" prediction rule for pediatric oncology patients presenting with fever and neutropenia.

PURPOSE: To prospectively derive and validate a clinical prediction rule to allow a more tailored approach to the management of pediatric oncology outpatients presenting with fever and neutropenia. PATIENTS AND METHODS: The clinical prediction rule was derived over a 1-year period and then validated over the following 8 months in a new set of fever and neutropenia episodes. Patients were excluded if they presented with comorbidity or an abnormal chest x-ray (CXR). RESULTS: Significant bacterial infection (SBI; defined as any blood or urine culture positive for bacteria, interstitial or lobar consolidation on CXR, or unexpected death from infection) was documented in 43 of the 227 episodes. Multivariate analysis found four significant factors: bone marrow disease, general appearance unwell on initial examination, monocyte count less than 0.1 x 10(9)/L, and peak oral or oral equivalent temperature greater than 39 degrees C. Only the monocyte count contributed to determining a low-risk group, excluding SBI with 84% sensitivity (95% confidence interval [CI], 61% to 100%), 42% specificity (95% CI, 38% to 46%), and a negative predictive value of 92% (95% CI, 76% to 100%). If the monocyte count was >/= 0.1 x 10(9)/L at the time of presentation (low risk), the incidences of SBI and bacteremia were 8% and 5%, respectively, versus 25% and 17% in the high-risk group. When validated in a new population of 136 episodes of fever and neutropenia, the incidences of SBI and bacteremia in the low-risk group were 12% and 5%, respectively, and 25% and 19% in the high-risk group. CONCLUSION: Pediatric oncology outpatients with fever and neutropenia who present with an initial monocyte count of >/= 0.1 x 10(9)/L and do not have comorbidity or an abnormal CXR at the time of presentation are at lower risk for SBI and can be considered for less aggressive initial therapy.

Adolescent↗