2024-03-29T08:25:20Z
http://ir.lib.uwo.ca/do/oai/
oai:ir.lib.uwo.ca:biochempub-1003
2009-05-06T03:23:11Z
publication:med
publication:biochempub
publication:pmid
publication:biochem
publication:faculties
publication:medpub
Abetalipoproteinemia: Two Case Reports and Literature Review
Zamel, Rola
Khan, Razi
Pollex, Rebecca L.
Hegele, Robert A.
Abetalipoproteinemia (ABL, OMIM 200100) is a rare, autosomal recessive disorder, characterized by fat malabsorption, acanthocytosis and hypocholesterolemia in infancy. Later in life, deficiency of fat-soluble vitamins is associated with development of atypical retinitis pigmentosa, coagulopathy, posterior column neuropathy and myopathy. ABL results from mutations in the gene encoding the large subunit of microsomal triglyceride transfer protein (MTP; OMIM 157147). To date at least 33 MTP mutations have been identified in 43 ABL patients. We describe the clinical progress of two patients, both currently in the fifth decade of life, who were diagnosed with ABL as children and were treated with high oral doses of fat soluble vitamins, including vitamin E over the last three decades. Treatment appears to have been associated with arrest of the neuropathy and other complications in both patients. Because pharmacologic inhibition of MTP is being developed as a novel approach to reduce plasma cholesterol for prevention of cardiovascular disease, defining the long-term clinical features of patients with a natural deficiency in MTP might provide some insight into the possible effects of such treatments. We review the range of clinical, biochemical and molecular perturbations in ABL.
2008-07-08T07:00:00Z
article
https://ir.lib.uwo.ca/biochempub/4
http://www.ojrd.com/content/3/1/19
Biochemistry Publications
Scholarship@Western
Abetalipoproteinemia
Biochemistry
Medical Biochemistry
oai:ir.lib.uwo.ca:medpub-1000
2009-11-23T06:59:17Z
publication:med
publication:faculties
publication:medpub
Optimizing Care in Osteoporosis: The Canadian Quality Circle Project
Ioannidis, George
Thabane, Lehana
Gafni, Amiram
Hodsman, Anthony
Kvern, Brent
Johnstone, Dan
Plumley, Nathalie
Salach, Lena
Jiwa, Famida
Adachi, Jonathan D.
Papaioannou, Alexandra
Background: While the Osteoporosis Canada 2002 Canadian guidelines provided evidence based strategies in preventing, diagnosing, and managing this condition, publication and distribution of guidelines have not, in and of themselves, been shown to alter physicians clinical approaches. We hypothesize that primary care physicians enrolled in the Quality Circle project would change their patient management of osteoporosis in terms of awareness of osteoporosis risk factors and bone mineral density testing in accordance with the guidelines.
Methods: The project consisted of five Quality Circle phases that included: 1) Training & Baseline Data Collection, 2) First Educational Intervention & First Follow-Up Data Collection 3) First Strategy Implementation Session, 4) Final Educational Intervention & Final Follow-up Data Collection, and 5) Final Strategy Implementation Session. A total of 340 circle members formed 34 quality circles and participated in the study. The generalized estimating equations approach was used to model physician awareness of risk factors for osteoporosis and appropriate utilization of bone mineral density testing pre and post educational intervention (first year of the study). Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated.
Results: After the 1st year of the study, physicians' certainty of their patients' risk factor status increased. Certainty varied from an OR of 1.4 (95% CI: 1.1, 1.8) for prior vertebral fracture status to 6.3 (95% CI: 2.3, 17.9) for prior hip fracture status. Furthermore, bone mineral density testing increased in high risk as compared with low risk patients (OR: 1.4; 95% CI: 1.2, 1.7).
Conclusion: Quality Circle methodology was successful in increasing both physicians' awareness of osteoporosis risk factors and appropriate bone mineral density testing in accordance with the 2002 Canadian guidelines.
2008-10-01T07:00:00Z
article
https://ir.lib.uwo.ca/medpub/1
info:doi/10.1186/1471-2474-9-130
http://www.biomedcentral.com/1471-2474/9/130
Department of Medicine Publications
Scholarship@Western
Osteoporosis
Quality Circle project
Osteoporosis risk factor
Bone mineral density testing
Medical Sciences
Musculoskeletal, Neural, and Ocular Physiology
oai:ir.lib.uwo.ca:medpub-1001
2009-05-06T03:32:00Z
publication:rwkex
publication:med
publication:biophysics
publication:robartspub
publication:rwkex_researcharticles
publication:biophysicspub
publication:medimagingpub
publication:robarts
publication:medimaging
publication:institutes
publication:faculties
publication:medpub
Abnormal Myocardial Perfusion in Hypertrophic Cardiomyopathy: Preliminary Findings of a Cardiovascular MRI Study
White, James A.
Armstrong, Sarah
Al-Admawi, Mohammed
Rambihar, Sherryn
Wisenberg, Gerald
Verschuur, Ivonna
MacDonald, Anna
Harper-Little, Cyndi
So, Aaron
Lee, Ting-Yim
Prato, Frank
Thompson, Terry
Background: Reduced myocardial perfusion has been speculated as a potential mechanism for the development and/or propagation of myocardial fibrosis in hypertrophic cardiomyopathy (HCM). This study aims to evaluate the prevalence, distribution and extent of stress-induced perfusion abnormalities and their relationship to underlying fibrosis in patients with HCM using magnetic resonance imaging.
Methods: 15 patients with echocardiographically diagnosed HCM have been enrolled. Cine imaging, first-pass stress perfusion imaging using vasodilator stress (Dipyridamole), and delayed gadolinium enhancement imaging were performed. Stress hypoperfusion and delayed enhancement images were assessed both quantitatively and visually using a 16-segment model. Conversion of segmental visual scoring to % of LV by volume was achieved for both hypoperfusion (HP) and late enhancement (LE) using a standardized scoring system. For quantitative assessment prospectively defined cut-offs for LE and HP were used.
Results: Maximal wall thickness ranged from 13 to 22 mm (mean 17 ± 2.6 mm). Non-ischemic pattern LE was present in 70% of patients. Perfusion abnormalities were identified on stress perfusion images in 80% of patients using visual analysis and 87% of patients using quantitative analysis. Perfusion abnormalities were predominantly subendocardial, and were regionally associated with segments containing LE (p < 0.01). Mean percent HP and mean percent LE were 17 ± 8.4% and 10 ± 9.3%, respectively by visual estimation and 20.0 ± 12.1% and 14.0 ± 7.4%, respectively by quantitative assessment. Figure 1.
Conclusion: These preliminary results suggest that patients with HCM have a high prevalence of stress-induced myocardial hypoperfusion as represented by reduced first-pass gadolinium enhancement during vasodilator stress. This hypoperfusion appears to extend beyond regions of established LE suggesting a potential contribution of ischemia in the development and/or propagation of myocardial fibrosis in patients with HCM.
2009-01-28T08:00:00Z
article
https://ir.lib.uwo.ca/medpub/2
http://jcmr-online.com/content/11/S1/P55
Department of Medicine Publications
Scholarship@Western
Myocardial perfusion
Myocardial fibrosis
Hypertrophic cardiomyopathy
Cardiology
Other Medical Sciences
oai:ir.lib.uwo.ca:medpub-1002
2009-05-06T03:31:14Z
publication:rwkex
publication:med
publication:biophysics
publication:rwkex_researcharticles
publication:biophysicspub
publication:medimagingpub
publication:medimaging
publication:faculties
publication:medpub
Is Hemorrhage in Acute Reperfused Myocardial Infarction a New Marker for the Severity of Tissue Injury?
Kumar, Andreas
Green, Jordin D.
Sykes, Jane M.
Mitchell, Andrea
Wisenberg, Gerald
Friedrich, Matthias G.
Introduction: Reperfusion injury in myocardial infarction leads to microvascular obstruction, which can occur with or without gross reperfusion hemorrhage. The incidence and implications of reperfusion hemorrhage are not well investigated. A recently described in vivo imaging approach using T2*-weighted cardiovascular magnetic resonance can help investigate the pathophysiology of reperfusion hemorrhage in vivo.
Hypothesis: We hypothesized that hemorrhage reflects a severer from of reperfusion injury and therefore occurs with larger infarct size and worse LV function as compared to reperfusion injury without hemorrhage.
Methods: In 14 female mongrel dogs, myocardial infarction was induced by ligation of the left anterior descending coronary artery for 2–4 hours, followed by reperfusion. On day 3 ± 1, a cardiovascular magnetic resonance study was performed in vivo to (1) assess presence of microvascular obstruction, defining reperfusion injury (2) assess presence of reperfusion hemorrhage (3) quantify left ventricular end-diastolic volume, ejection fraction and cardiac output and (4) quantify infarct size with late enhancement. An independent-samples t-test was performed to compare these parameters in dogs with and without hemorrhage in reperfusion injury.
Results: From 14 dogs, 9 had microvascular obstruction, and 4/9 had reperfusion hemorrhage in addition to microvascular obstruction.
Dogs with hemorrhagic infarcts had significantly larger infarct size (26.1 ± 6.6 g vs. 5.5 ± 3.9 g, p < 0.05), lower LV ejection fraction (28 ± 7% vs. 53 ± 12%, p < 0.05), and lower cardiac output (1.9 ± 0.2 l/min vs. 2.8 ± 0.5 l/min, p < 0.05). There were no differences in LV end-diastolic volume and LV mass.
Discussion and conclusion: In this dog model of ischemia/reperfusion injury, gross hemorrhage was associated with significantly larger infarct size and worse LV functional parameters. This supports the hypothesis that hemorrhage may occur with advanced, severe ischemic tissue injury only.
2009-01-28T08:00:00Z
article
https://ir.lib.uwo.ca/medpub/3
http://jcmr-online.com/content/11/S1/P65
Department of Medicine Publications
Scholarship@Western
Microvascular obstruction
Reperfusion hemorrhage
In vivo imaging
Cardiology
Other Medical Specialties
oai:ir.lib.uwo.ca:robartspub-1000
2018-02-16T17:05:01Z
publication:physics
publication:anatomy
publication:robartspub
publication:biophysicspub
publication:pmid
publication:faculties
publication:physicspub
publication:electricalpub
publication:medpub
publication:anatomypub
publication:med
publication:biophysics
publication:biochempub
publication:electrical
publication:robarts
publication:biochem
publication:institutes
Clinical Field-strength MRI of Amyloid Plaques Induced by Low-level Cholesterol Feeding in Rabbits
Ronald, John A.
Chen, Yuanxin
Bernas, Lisa
Kitzler, Hagen H.
Rogers, Kem A.
Hegele, Robert A.
Rutt, Brian K.
Two significant barriers have limited the development of effective treatment of Alzheimer’s disease. First, for many cases the aetiology is unknown and likely multi-factorial. Among these factors, hypercholesterolemia is a known risk predictor and has been linked to the formation of b-amyloid plaques, a pathological hallmark this disease. Second, standardized diagnostic tools are unable to definitively diagnose this disease prior to death; hence new diagnostic tools are urgently needed. Magnetic resonance imaging (MRI) using high field-strength scanners has shown promise for direct visualization of b-amyloid plaques, allowing in vivo longitudinal tracking of disease progression in mouse models. Here, we present a new rabbit model for studying the relationship between cholesterol and Alzheimer’s disease development and new tools for direct visualization of b-amyloid plaques using clinical field-strength MRI. New Zealand white rabbits were fed either a low-level (0.125–0.25% w/w) cholesterol diet (n = 5) or normal chow (n = 4) for 27 months. High-resolution (66x66x100 mm3; scan time = 96 min) ex vivo MRI of brains was performed using a 3-Tesla (T) MR scanner interfaced with customized gradient and radiofrequency coils. b-Amyloid-42 immunostaining and Prussian blue iron staining were performed on brain sections and MR and histological images were manually registered. MRI revealed distinct signal voids throughout the brains of cholesterol-fed rabbits, whereas minimal voids were seen in control rabbit brains. These voids corresponded directly to small clusters of extracellular b-amyloid-positive plaques, which were consistently identified as iron-loaded (the presumed source of MR contrast). Plaques were typically located in the hippocampus, parahippocampal gyrus, striatum, hypothalamus and thalamus. Quantitative analysis of the number of histologically positive b-amyloid plaques (P50.0001) and MR-positive signal voids (P50.05) found in cholesterol-fed and control rabbit brains corroborated our qualitative observations. In conclusion, long-term, low-level cholesterol feeding was sufficient to promote the formation of extracellular b-amyloid plaque formation in rabbits, supporting the integral role of cholesterol in the aetiology of Alzheimer’s disease. We also present the first evidence that MRI is capable of detecting iron-associated b-amyloid plaques in a rabbit model of Alzheimer’s disease and have advanced the sensitivity of MRI for plaque detection to a new level, allowing clinical field-strength scanners to be employed. We believe extension of these technologies to an in vivo setting in rabbits is feasible and that our results support future work exploring the role of MRI as a leading imaging tool for this debilitating and life-threatening disease.
2009-05-01T07:00:00Z
article
application/pdf
https://ir.lib.uwo.ca/robartspub/1
https://ir.lib.uwo.ca/context/robartspub/article/1000/viewcontent/awp031.pdf
Robarts Imaging Publications
Scholarship@Western
Alzheimer’s disease
Cholesterol
Rabbit model
Magnetic resonance imaging
b-amyloid plaques
Other Medical Sciences
Other Medical Specialties
oai:ir.lib.uwo.ca:biologypub-1003
2009-05-12T22:10:29Z
publication:mnipub
publication:pmid
publication:faculties
publication:medpub
publication:biologypub
publication:med
publication:mni
publication:biology
A Novel Expression Platform for the Production of Diabetes-associated Autoantigen Human Glutamic Acid Decarboxylase (hGAD65)
Wang, Xiaofeng
Brandsma, Martin
Tremblay, Reynald
Maxwell, Denis
Jevnikar, Anthony M.
Huner, Norm
Ma, Shengwu
Background: Human glutamic acid decarboxylase 65 (hGAD65) is a key autoantigen in type 1 diabetes, having much potential as an important marker for the prediction and diagnosis of type 1 diabetes, and for the development of novel antigen-specific therapies for the treatment of type 1 diabetes. However, recombinant production of hGAD65 using conventional bacterial or mammalian cell culture-based expression systems or nuclear transformed plants is limited by low yield and low efficiency. Chloroplast transformation of the unicellular eukaryotic alga Chlamydomonas reinhardtii may offer a potential solution.
Results: A DNA cassette encoding full-length hGAD65, under the control of the C. reinhardtii chloroplast rbcL promoter and 5'- and 3'-UTRs, was constructed and introduced into the chloroplast genome of C. reinhardtii by particle bombardment. Integration of hGAD65 DNA into the algal chloroplast genome was confirmed by PCR. Transcriptional expression of hGAD65 was demonstrated by RT-PCR. Immunoblotting verified the expression and accumulation of the recombinant protein. The antigenicity of algal-derived hGAD65 was demonstrated with its immunoreactivity to diabetic sera by ELISA and by its ability to induce proliferation of spleen cells from NOD mice. Recombinant hGAD65 accumulated in transgenic algae, accounts for approximately 0.25–0.3% of its total soluble protein.
Conclusion: Our results demonstrate the potential value of C. reinhardtii chloroplasts as a novel platform for rapid mass production of immunologically active hGAD65. This demonstration opens the future possibility for using algal chloroplasts as novel bioreactors for the production of many other biologically active mammalian therapeutic proteins.
2008-11-17T08:00:00Z
article
https://ir.lib.uwo.ca/biologypub/4
http://www.biomedcentral.com/1472-6750/8/87
Biology Publications
Scholarship@Western
Human glutamic acid decarboxylase 65
hGAD65
Type 1 diabetes
Chlamydomonas reinhardtii
Biotechnology
Medical Immunology
Nephrology
oai:ir.lib.uwo.ca:vascularpub-1001
2009-07-29T21:16:48Z
publication:vascularpub
publication:robartspub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:biochempub
publication:robarts
publication:biochem
publication:institutes
Quantitative and Qualitative Differences in Subcutaneous Adipose Tissue Stores across Lipodystrophy Types Shown by Magnetic Resonance Imaging
Al-Attar, Salam A.
Pollex, Rebecca L.
Robinson, John F.
Miskie, Brooke A.
Walcarius, Rhonda
Harper Little, Cynthia
Rutt, Brian K.
Hegele, Robert A.
Background: Lipodystrophies are characterized by redistributed subcutaneous fat stores. We previously quantified subcutaneous fat by magnetic resonance imaging (MRI) in the legs of two patients with familial partial lipodystrophy subtypes 2 and 3 (FPLD2 and FPLD3, respectively). We now extend the MRI analysis across the whole body of patients with different forms of lipodystrophy.
Methods: We studied five subcutaneous fat stores (supraclavicular, abdominal, gluteal, thigh and calf) and the abdominal visceral fat stores in 10, 2, 1, 1 and 2 female subjects with, respectively, FPLD2, FPLD3, HIV-related partial lipodystrophy (HIVPL), acquired partial lipodystrophy (APL), congenital generalized lipodystrophy (CGL) and in six normal control subjects.
Results: Compared with normal controls, FPLD2 subjects had significantly increased supraclavicular fat, with decreased abdominal, gluteal, thigh and calf subcutaneous fat. FPLD3 subjects had increased supraclavicular and abdominal subcutaneous fat, with less severe reductions in gluteal, thigh and calf fat compared to FPLD2 subjects. The repartitioning of fat in the HIVPL subject closely resembled that of FPLD3 subjects. APL and CGL subjects had reduced upper body, gluteal and thigh subcutaneous fat; the APL subject had increased, while CGL subjects had decreased subcutaneous calf fat. Visceral fat was markedly increased in FPLD2 and APL subjects.
Conclusion: Semi-automated MRI-based adipose tissue quantification indicates differences between various lipodystrophy types in these studied clinical cases and is a potentially useful tool for extended quantitative phenomic analysis of genetic metabolic disorders. Further studies with a larger sample size are essential for confirming these preliminary findings.
2007-03-12T07:00:00Z
article
https://ir.lib.uwo.ca/vascularpub/2
http://www.biomedcentral.com/1471-2342/7/3
Robarts Vascular Research Publications
Scholarship@Western
Adipose Tissue
Adult
Female
Humans
Image Interpretation
Computer-Assisted
Lipodystrophy
Magnetic Resonance Imaging
Male
Middle Aged
Reproducibility of Results
Sensitivity and Specificity
Image Interpretation, Computer-Assisted
Bioimaging and Biomedical Optics
Medical Genetics
Medical Microbiology
oai:ir.lib.uwo.ca:vascularpub-1002
2009-07-29T21:20:10Z
publication:vascularpub
publication:robartspub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:biochempub
publication:robarts
publication:biochem
publication:institutes
Semi-automated Segmentation and Quantification of Adipose Tissue in Calf and Thigh by MRI: A Preliminary Study in Patients with Monogenic Metabolic Syndrome
Al-Attar, Salam A.
Pollex, Rebecca L.
Robinson, John F.
Miskie, Brooke A.
Walcarius, Rhonda
Rutt, Brian K.
Hegele, Robert A.
Background: With the growing prevalence of obesity and metabolic syndrome, reliable quantitative imaging methods for adipose tissue are required. Monogenic forms of the metabolic syndrome include Dunnigan-variety familial partial lipodystrophy subtypes 2 and 3 (FPLD2 and FPLD3), which are characterized by the loss of subcutaneous fat in the extremities. Through magnetic resonance imaging (MRI) of FPLD patients, we have developed a method of quantifying the core FPLD anthropometric phenotype, namely adipose tissue in the mid-calf and mid-thigh regions.
Methods: Four female subjects, including an FPLD2 subject (LMNA R482Q), an FPLD3 subject (PPARG F388L), and two control subjects were selected for MRI and analysis. MRI scans of subjects were performed on a 1.5T GE MR Medical system, with 17 transaxial slices comprising a 51 mm section obtained in both the mid-calf and mid-thigh regions. Using ImageJ 1.34 n software, analysis of raw MR images involved the creation of a connectedness map of the subcutaneous adipose tissue contours within the lower limb segment from a user-defined seed point. Quantification of the adipose tissue was then obtained after thresholding the connected map and counting the voxels (volumetric pixels) present within the specified region.
Results: MR images revealed significant differences in the amounts of subcutaneous adipose tissue in lower limb segments of FPLD3 and FPLD2 subjects: respectively, mid-calf, 15.5% and 0%, and mid-thigh, 25.0% and 13.3%. In comparison, old and young healthy controls had values, respectively, of mid-calf, 32.5% and 26.2%, and mid-thigh, 52.2% and 36.1%. The FPLD2 patient had significantly reduced subcutaneous adipose tissue compared to FPLD3 patient.
Conclusion: Thus, semi-automated quantification of adipose tissue of the lower extremity can detect differences between individuals of various lipodystrophy genotypes and represents a potentially useful tool for extended quantitative phenotypic analysis of other genetic metabolic disorders.
2006-08-31T07:00:00Z
article
https://ir.lib.uwo.ca/vascularpub/3
http://www.biomedcentral.com/1471-2342/6/11
Robarts Vascular Research Publications
Scholarship@Western
Bioimaging and Biomedical Optics
Medical Microbiology
oai:ir.lib.uwo.ca:nursingpub-1050
2009-08-25T22:58:43Z
publication:fammedpub
publication:fammed
publication:physpharmpub
publication:paed
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:physpharm
publication:nursing
publication:nursingpub
publication:paedpub
Rural Women and Pharmacologic Therapy: Needs and Issues in Rural Canada
Leipert, Beverly
Matsui, Doreen
Wagner, Jessica
Rieder, Michael J.
Introduction: The needs and issues of rural women regarding pharmacologic information and therapy are rarely explored. We sought to explore the needs and issues of rural women in Canada regarding drug-related information and prescription and nonprescription pharmaceuticals.
Methods: We used the qualitative methodology of interpretive description. In-depth semistructured face-to-face interviews were conducted with 20 women aged 17–88 years who lived in rural southwestern Ontario.
Results: Although rural women accessed prescription medications, complementary and alternative medicine (CAM) was highly favoured, and alcohol and illicit drugs such as marijuana, crystal meth and cocaine were prevalent in rural communities. Factors that affected rural women's decisions about which medications to use included access to health care practitioners, costs of medications, experiences of family members and friends with prescribed and alternative medications, attitudes and approaches of health care providers and health store employees, and the women's own expectations and desires. Factors that affected the use of illicit drugs included availability, boredom, peer pressure and cultural norms. Rural factors that influenced access to drug information and use included presence or lack of confidential care, distance to resources, and presence, accessibility and acceptability of rural resources.
Conclusion: Rural women use a variety of drug therapies and sources of information, and experience unique socioeconomic and environmental issues that affect access to appropriate drug-related information and therapies. Further research is needed to clarify and articulate pharmacologic needs, issues and solutions for women in diverse rural settings.
2008-01-01T08:00:00Z
article
https://ir.lib.uwo.ca/nursingpub/46
http://www.cma.ca/index.cfm/ci_id/87426/la_id/1.htm
Nursing Publications
Scholarship@Western
Rural woman
pharmacologic therapy
Canada
Nursing
oai:ir.lib.uwo.ca:medpub-1006
2009-07-31T20:13:35Z
publication:pmid
publication:faculties
publication:medpub
publication:med
Glucagon-like Peptide 1 Improved Glycemic Control in Type 1 Diabetes
Behme, Margaret T.
Dupré, John
McDonald, Thomas J.
Background: Glucagon-like peptide-1 (GLP-1) and its agonists are under assessment in treatment of type 2 diabetes, by virtue of their antidiabetic actions, which include stimulation of insulin secretion, inhibition of glucagon release, and delay of gastric emptying. We examined the potential of GLP-1 to improve glycemic control in type 1 diabetes with no endogenous insulin secretion.
Methods: Dose-finding studies were carried out to establish mid range doses for delay of gastric emptying indicated by postponement of pancreatic polypeptide responses after meals. The selected dose of 0.63 micrograms/kg GLP-1 was administered before breakfast and lunch in 8-hour studies in hospital to establish the efficacy and safety of GLP-1. In outside-hospital studies, GLP-1 or vehicle was self-administered double-blind before meals with usual insulin for five consecutive days by five males and three females with well-controlled C-peptide-negative type 1 diabetes. Capillary blood glucose values were self-monitored before meals, at 30 and 60 min after breakfast and supper, and at bedtime. Breakfast tests with GLP-1 were conducted on the day before and on the day after 5-day studies. Paired t-tests and ANOVA were used for statistical analysis.
Results: In 8-hour studies time-averaged incremental (delta) areas under the curves(AUC) for plasma glucose through 8 hours were decreased by GLP-1 compared to vehicle (3.2 PlusMinus; 0.9, mean PlusMinus; se, vs 5.4 PlusMinus; 0.8 mmol/l, p <.05), and for pancreatic polypeptide, an indicator of gastric emptying, through 30 min after meals (4.0 PlusMinus; 3.1 vs 37 PlusMinus; 9.6 pmol/l, p <.05) with no adverse effects. Incremental glucagon levels through 60 min after meals were depressed by GLP-1 compared to vehicle (-3.7 PlusMinus; 2.5 vs 3.1 PlusMinus; 1.9 ng/l, p <.04). In 5-day studies, AUC for capillary blood glucose levels were lower with GLP-1 than with vehicle (-0.64 PlusMinus; 0.33 vs 0.34 PlusMinus; 0.26 mmol/l, p <.05). No assisted episode of hypoglycaemia or change in insulin dosage occurred. Breakfast tests on the days immediately before and after 5-day trials showed no change in the effects of GLP-1.
Conclusion: We have demonstrated that subcutaneous GLP-1 can improve glucose control in type 1 diabetes without adverse effects when self-administered before meals with usual insulin during established intensive insulin treatment programs.
2003-04-10T07:00:00Z
article
https://ir.lib.uwo.ca/medpub/4
http://www.biomedcentral.com/1472-6823/3/3
Department of Medicine Publications
Scholarship@Western
Type 1 diabetes
Peptide
Glycemic Control
Endocrinology, Diabetes, and Metabolism
Medical Sciences
Nephrology
oai:ir.lib.uwo.ca:medpub-1007
2019-04-22T18:12:59Z
publication:pmid
publication:faculties
publication:medpub
publication:med
Filtering out the Noise: Evaluating the Impact of Noise and Sound Reduction Strategies on Sleep Quality for ICU Patients
Bosma, Karen J.
Ranieri, V. Marco
The review article by Xie and colleagues examines the impact of noise and noise reduction strategies on sleep quality for critically ill patients. Evaluating the impact of noise on sleep quality is challenging, as it must be measured relative to other factors that may be more or less disruptive to patients' sleep. Such factors may be difficult for patients, observers, and polysomnogram interpreters to identify, due to our limited understanding of the causes of sleep disruption in the critically ill, as well as the challenges in recording and quantifying sleep stages and sleep fragmentation in the intensive care unit. Furthermore, most research in this field has focused on noise level, whereas acousticians typically evaluate additional parameters such as noise spectrum and reverberation time. The authors highlight the disparate results and limitations of existing studies, including the lack of attention to other acoustic parameters besides sound level, and the combined effects of different sleep disturbing factors.
2009-05-29T07:00:00Z
article
application/pdf
https://ir.lib.uwo.ca/medpub/5
info:doi/10.1186/cc7798
https://ir.lib.uwo.ca/context/medpub/article/1007/viewcontent/Bosma_2009_BMC.pdf
Department of Medicine Publications
Scholarship@Western
noise
sleep quality
patient
Medical Sciences
oai:ir.lib.uwo.ca:vascularpub-1004
2009-08-04T23:09:44Z
publication:vascularpub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:biochempub
publication:robarts
publication:biochem
publication:institutes
NPC1L1 Haplotype is Associated with Inter-individual Variation in Plasma Low-density Lipoprotein Response to Ezetimibe
Hegele, Robert A.
Guy, Justin
Ban, Matthew R.
Wang, Jian
Background: NPC1L1 encodes a putative intestinal sterol transporter which is the likely target for ezetimibe, a new type of lipid-lowering medication. We previously reported rare non-synonymous mutations in NPC1L1 in an individual who had no plasma lipoprotein response to ezetimibe. We next hypothesized that common variants in NPC1L1 would underlie less extreme inter-individual variations in the plasma LDL cholesterol response to ezetimibe.
Results: In 101 dyslipidemic subjects, we found that NPC1L1 haplotype was significantly associated with inter-individual variation in the response of plasma LDL cholesterol to treatment with ezetimibe for 12 weeks. Specifically, about one subject in eight lacked the common NPC1L1 haplotype 1735C-25342A-27677T and these subjects had a significantly greater reduction in plasma LDL cholesterol with ezetimibe than subjects with at least one copy of this haplotype (-35.9+4.0 versus -23.6+1.6 percent reduction, P = 0.0054). This was paralleled by a similar non-significant trend of between-haplotype difference in reduction of total cholesterol.
Conclusion: These preliminary pharmacogenetic results suggest that NPC1L1 variation is associated with inter-individual variation in response to ezetimibe treatment.
2005-08-12T07:00:00Z
article
https://ir.lib.uwo.ca/vascularpub/5
http://www.lipidworld.com/content/4/1/16
Robarts Vascular Research Publications
Scholarship@Western
Adult
Aged
Azetidines
Cholesterol
LDL
Female
Gene Frequency
Genetic Variation
Haplotypes
Humans
Hypercholesterolemia
Male
Membrane Proteins
Middle Aged
Polymorphism
Single Nucleotide
Proteins
Cholesterol, LDL
Polymorphism, Single Nucleotide
Endocrinology, Diabetes, and Metabolism
Medical Microbiology
oai:ir.lib.uwo.ca:vascularpub-1005
2009-08-04T23:19:17Z
publication:vascularpub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:biochempub
publication:robarts
publication:biochem
publication:institutes
Peroxisomal Proliferator Activated Receptor-γ Deficiency in a Canadian Kindred with Familial Partial Lipodystrophy Type 3 (FPLD3)
Francis, Gordon A.
Li, Gang
Casey, Robin
Wang, Jian
Cao, Henian
Leff, Todd
Hegele, Robert A.
Background: Familial partial lipodystrophy (Dunnigan) type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367) results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-γ. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition.
Methods: We present a Canadian FPLD3 kindred with an affected mother who had loss of fat on arms and legs, but no increase in facial, neck, suprascapular or abdominal fat. She had profound insulin resistance, diabetes, severe hypertriglyceridemia and relapsing pancreatitis, while her pre-pubescent daughter had normal fat distribution but elevated plasma triglycerides and C-peptide and depressed high-density lipoprotein cholesterol.
Results: The mother and daughter were each heterozygous for PPARG nonsense mutation Y355X, whose protein product in vitro was transcriptionally inactive with no dominant-negative activity against the wild-type receptor. In addition the mutant protein appeared to be markedly unstable.
Conclusion: Taken together with previous studies of human PPARG mutations, these findings suggest that PPAR-γ deficiency due either to haploinsufficiency or to substantial activity loss due to dominant negative interference of the normal allele product's function can each contribute to the FPLD3 phenotype.
2006-01-14T08:00:00Z
article
https://ir.lib.uwo.ca/vascularpub/6
http://www.biomedcentral.com/1471-2350/7/3
Robarts Vascular Research Publications
Scholarship@Western
Canada
Cloning
Molecular
Codon
Nonsense
DNA Mutational Analysis
Diabetes Mellitus
Lipoatrophic
Family Health
Female
Heterozygote
Humans
Middle Aged
PPAR gamma
Pedigree
Transcription
Genetic
Cloning, Molecular
Codon, Nonsense
Diabetes Mellitus, Lipoatrophic
Transcription, Genetic
Medical Genetics
oai:ir.lib.uwo.ca:vascularpub-1006
2009-08-13T00:19:27Z
publication:vascularpub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:biochempub
publication:robarts
publication:biochem
publication:institutes
Alstrom Syndrome (OMIM 203800): A Case Report and Literature Review
Joy, Tisha
Cao, Henian
Black, Graeme
Malik, Rayaz
Charlton-Menys, Valentine
Hegele, Robert A.
Durrington, Paul N.
Background: Alstrom syndrome (AS) is a rare autosomal recessive disease characterized by multiorgan dysfunction. The key features are childhood obesity, blindness due to congenital retinal dystrophy, and sensorineural hearing loss. Associated endocrinologic features include hyperinsulinemia, early-onset type 2 diabetes, and hypertriglyceridemia. Thus, AS shares several features with the common metabolic syndrome, namely obesity, hyperinsulinemia, and hypertriglyceridemia. Mutations in the ALMS1 gene have been found to be causative for AS with a total of 79 disease-causing mutations having been described.
Case Presentation: We describe the case of a 27-year old female from an English (Caucasian) kindred. She had been initially referred for hypertriglyceridemia, but demonstrated other features suggestive of AS, including blindness, obesity, type 2 diabetes, renal dysfunction, and hypertension. DNA analysis revealed that she is a compound heterozygote with two novel mutations in the ALMS1 gene - H3882Y and V424I. Examination of her family revealed that her phenotypically unaffected mother and younger sister also had heterozygous mutations in the ALMS1 gene. In addition to presenting these novel molecular findings for AS, we review the clinical and genetic features of AS in the context of our case.
Conclusion: Two novel mutations in the ALMS1 gene causative for AS have been reported here, thereby increasing the number of reported mutations to 81 and providing a wider basis for mutational screening among affected individuals.
2007-12-21T08:00:00Z
article
https://ir.lib.uwo.ca/vascularpub/7
http://www.OJRD.com/content/2/1/49
Robarts Vascular Research Publications
Scholarship@Western
Adult
Blindness
Databases
Genetic
Diabetes Mellitus
Type 2
Female
Heterozygote
Humans
Hyperlipoproteinemia Type IV
Hypertension
Mutation
Obesity
Pedigree
Polymorphism
Single Nucleotide
Proteins
Sequence Analysis
DNA
Syndrome
Databases, Genetic
Diabetes Mellitus, Type 2
Polymorphism, Single Nucleotide
Sequence Analysis, DNA
Medical Genetics
oai:ir.lib.uwo.ca:vascularpub-1007
2011-01-20T22:52:02Z
publication:vascularpub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:biochempub
publication:robarts
publication:biochem
publication:institutes
Heterozygous CAV1 Frameshift Mutations (MIM 601047) in Patients with Atypical Partial Lipodystrophy and Hypertriglyceridemia
Cao, Henian
Alston, Lindsay
Ruschman, Jennifer
Hegele, Robert A.
Background: Mice with a deleted Cav1 gene encoding caveolin-1 develop adipocyte abnormalities and insulin resistance. From genomic DNA of patients with atypical lipodystrophy and hypertriglyceridemia who had no mutations in any known lipodystrophy gene, we used DNA sequence analysis to screen the coding regions of human CAV1 (MIM 601047).
Results: We found a heterozygous frameshift mutation in CAV1, designated I134fsdelA-X137, in a female patient who had atypical partial lipodystrophy, with subcutaneous fat loss affecting the upper part of her body and face, but sparing her legs, gluteal region and visceral fat stores. She had severe type 5 hyperlipoproteinemia, with recurrent pancreatitis. In addition, she had some atypical features, including congenital cataracts and neurological findings. Her father was also heterozygous for this mutation, and had a similar pattern of fat redistribution, hypertriglyceridemia and congenital cataracts, with milder neurological involvement. An unrelated patient had a different heterozygous frameshift mutation in the CAV1 gene, designated -88delC. He also had a partial lipodystrophy phenotype, with subcutaneous fat loss affecting the arms, legs and gluteal region, but sparing his face, neck and visceral fat stores. He also had severe type 5 hyperlipoproteinemia, with recurrent pancreatitis; however he had no clinically apparent neurological manifestations. The mutations were absent from the genomes of 1063 healthy individuals.
Conclusion: Thus, very rare CAV1 frameshift mutations appear to be associated with atypical lipodystrophy and hypertriglyceridemia.
2008-01-31T08:00:00Z
article
https://ir.lib.uwo.ca/vascularpub/8
info:doi/10.1186/1476-511X-7-3
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2276215/
Robarts Vascular Research Publications
Scholarship@Western
Adult
Base Sequence
Caveolin 1
DNA Mutational Analysis
Demography
Female
Frameshift Mutation
Heterozygote
Humans
Hypertriglyceridemia
Lipodystrophy
Male
Middle Aged
Molecular Sequence Data
Medical Genetics
oai:ir.lib.uwo.ca:physpharmpub-1018
2009-08-18T23:43:22Z
publication:physpharmpub
publication:obsgyn
publication:obsgynpub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:physpharm
Mouse Preimplantation Embryo Responses to Culture Medium Osmolarity Include Increased Expression of CCM2 and p38 MAPK Activation
Fong, Barry
Watson, Patricia H.
Watson, Andrew J.
Background: Mechanisms that confer an ability to respond positively to environmental osmolarity are fundamental to ensuring embryo survival during the preimplantation period. Activation of p38 mitogen-activated protein kinase (MAPK) occurs following exposure to hyperosmotic treatment. Recently, a novel scaffolding protein called Osmosensing Scaffold for MEKK3 (OSM) was linked to p38 MAPK activation in response to sorbitol-induced hypertonicity. The human ortholog of OSM is cerebral cavernous malformation 2 (CCM2). The present study was conducted to investigate whether CCM2 is expressed during mouse preimplantation development and to determine whether this scaffolding protein is associated with p38 MAPK activation following exposure of preimplantation embryos to hyperosmotic environments.
Results: Our results indicate that Ccm2 along with upstream p38 MAPK pathway constituents (Map3k3, Map2k3, Map2k6, and Map2k4) are expressed throughout mouse preimplantation development. CCM2, MAP3K3 and the phosphorylated forms of MAP2K3/MAP2K6 and MAP2K4 were also detected throughout preimplantation development. Embryo culture in hyperosmotic media increased p38 MAPK activity in conjunction with elevated CCM2 levels.
Conclusion: These results define the expression of upstream activators of p38 MAPK during preimplantation development and indicate that embryo responses to hyperosmotic environments include elevation of CCM2 and activation of p38 MAPK.
2007-01-10T08:00:00Z
article
https://ir.lib.uwo.ca/physpharmpub/19
http://www.biomedcentral.com/1471-213X/7/2
Physiology and Pharmacology Publications
Scholarship@Western
Animals
Blastocyst
Cells
Cultured
Culture Media
Enzyme Activation
Female
Fluorescent Antibody Technique
Indirect
Gene Expression
Mice
Microfilament Proteins
Microscopy
Confocal
Osmolar Concentration
Phosphorylation
Pregnancy
Reverse Transcriptase Polymerase Chain Reaction
p38 Mitogen-Activated Protein Kinases
Cells, Cultured
Fluorescent Antibody Technique, Indirect
Microscopy, Confocal
Medical Physiology
Obstetrics and Gynecology
oai:ir.lib.uwo.ca:nursingpub-1124
2009-09-07T00:02:45Z
publication:fammedpub
publication:fammed
publication:physpharmpub
publication:paed
publication:faculties
publication:medpub
publication:med
publication:physpharm
publication:nursing
publication:nursingpub
publication:paedpub
Women and Pharmacologic Therapy in Rural and Remote Canada
Leipert, Beverly D.
Matsui, Doreen
Rieder, Michael J.
2006-10-01T07:00:00Z
article
https://ir.lib.uwo.ca/nursingpub/65
http://www.cma.ca/index.cfm/ci_id/50136/la_id/1.htm
Nursing Publications
Scholarship@Western
Adolescent
Aged
Community Pharmacy Services
Complementary Therapies
Female
Health Services Accessibility
Humans
Medical Errors
Patient Education as Topic
Physician's Practice Patterns
Pregnancy
Pregnancy in Adolescence
Rural Health Services
Women's Health
Nursing
oai:ir.lib.uwo.ca:epidempub-1006
2009-09-10T00:17:47Z
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:epidem
publication:epidempub
Prevention of Catheter Lumen Occlusion with rT-PA versus Heparin (Pre-CLOT): Study Protocol of a Randomized Trial [ISRCTN35253449]
Hemmelgarn, Brenda R.
Moist, Louise
Pilkey, Rachel M.
Lok, Charmaine
Dorval, Marc
Tam, Paul Y. W.
Berall, Murray J.
LeBlanc, Martine
Toffelmire, Edwin B.
Manns, Braden J.
Scott-Douglas, Nairne
Background: Many patients with end-stage renal disease use a central venous catheter for hemodialysis access. A large majority of these catheters malfunction within one year of insertion, with up to two-thirds due to thrombosis. The optimal solution for locking the catheter between hemodialysis sessions, to decrease the risk of thrombosis and catheter malfunction, is unknown. The Prevention of Catheter Lumen Occlusion with rt-PA versus Heparin (PreCLOT) study will determine if use of weekly rt-PA, compared to regular heparin, as a catheter locking solution, will decrease the risk of catheter malfunction.
Methods/Design: The study population will consist of patients requiring chronic hemodialysis thrice weekly who are dialyzed with a newly inserted permanent dual-lumen central venous catheter. Patients randomized to the treatment arm will receive rt-PA 1 mg per lumen once per week, with heparin 5,000 units per ml as a catheter locking solution for the remaining two sessions. Patients randomized to the control arm will receive heparin 5,000 units per ml as a catheter locking solution after each dialysis session. The study treatment period will be six months, with 340 patients to be recruited from 14 sites across Canada. The primary outcome will be catheter malfunction, based on mean blood flow parameters while on hemodialysis, with a secondary outcome of catheter-related bacteremia. A cost-effectiveness analysis will be undertaken to assess the cost of maintaining a catheter using rt-PA as a locking solution, compared to the use of heparin.
Discussion: Results from this study will determine if use of weekly rt-PA, compared to heparin, will decrease catheter malfunction, as well as assess the cost-effectiveness of these locking solutions.
2006-04-11T07:00:00Z
article
https://ir.lib.uwo.ca/epidempub/7
http://www.biomedcentral.com/1471-2369/7/8
Epidemiology and Biostatistics Publications
Scholarship@Western
Bacteremia
Blood Coagulation
Catheterization
Cost-Benefit Analysis
Data Collection
Disease-Free Survival
Double-Blind Method
Drug Costs
Equipment Failure
Heparin
Humans
Life Tables
Patient Selection
Recombinant Proteins
Renal Dialysis
Research Design
Sample Size
Solutions
Survival Analysis
Thrombosis
Tissue Plasminogen Activator
Treatment Outcome
Biostatistics
Epidemiology
Nephrology
oai:ir.lib.uwo.ca:medpub-1010
2009-09-16T00:26:46Z
publication:pmid
publication:faculties
publication:medpub
publication:med
Using the Net Benefit Regression Framework to Construct Cost-effectiveness Acceptability Curves: An Example Using Data from a Trial of External Loop Recorders versus Holter Monitoring for Ambulatory Monitoring of "Community Acquired" Syncope
Hoch, Jeffrey S.
Rockx, Marie Antoinette
Krahn, Andrew D.
Background: Cost-effectiveness acceptability curves (CEACs) describe the probability that a new treatment or intervention is cost-effective. The net benefit regression framework (NBRF) allows cost-effectiveness analysis to be done in a simple regression framework. The objective of the paper is to illustrate how net benefit regression can be used to construct a CEAC.
Methods: One hundred patients referred for ambulatory monitoring with syncope or presyncope were randomized to a one-month external loop recorder (n = 49) or 48-hour Holter monitor (n = 51). The primary endpoint was symptom-rhythm correlation during monitoring. Direct costs were calculated based on the 2003 Ontario Health Insurance Plan (OHIP) fee schedule combined with hospital case costing of labour, materials, service and overhead costs for diagnostic testing and related equipment.
Results: In the loop recorder group, 63.27% of patients (31/49) had symptom recurrence and successful activation, compared to 23.53% in the Holter group (12/51). The cost in US dollars for loop recording was 648.50 dollars and 212.92 dollars for Holter monitoring. The incremental cost-effectiveness ratio (ICER) of the loop recorder was 1,096 dollars per extra successful diagnosis. The probability that the loop recorder was cost-effective compared to the Holter monitor was estimated using net benefit regression and plotted on a CEAC. In a sensitivity analysis, bootstrapping was used to examine the effect of distributional assumptions.
Conclusion: The NBRF is straightforward to use and interpret. The resulting uncertainty surrounding the regression coefficient relates to the CEAC. When the link from the regression's p-value to the probability of cost-effectiveness is tentative, bootstrapping may be used.
2006-06-06T07:00:00Z
article
https://ir.lib.uwo.ca/medpub/6
http://www.biomedcentral.com/1472-6963/6/68
Department of Medicine Publications
Scholarship@Western
Bayes Theorem
Cost-Benefit Analysis
Electrocardiography
Ambulatory
Fee Schedules
Hospital Costs
Humans
National Health Programs
Ontario
Prospective Studies
Recurrence
Regression Analysis
Syncope
Tape Recording
Electrocardiography, Ambulatory
Medicine and Health Sciences
oai:ir.lib.uwo.ca:mnipub-1002
2009-09-11T00:23:04Z
publication:mnipub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:mni
The Relationship between Predicted Peptide-MHC Class II Affinity and T-cell Activation in a HLA-DRbeta1*0401 Transgenic Mouse Model
Hill, Jonathan A.
Wang, Dequn
Jevnikar, Anthony M.
Cairns, Ewa
Bell, David A.
The HLA-DRB1*0401 MHC class II molecule (DR4) is genetically associated with rheumatoid arthritis. It has been proposed that this MHC class II molecule participates in disease pathogenesis by presenting arthritogenic endogenous or exogenous peptides to CD4+ T cells, leading to their activation and resulting in an inflammatory response within the synovium. In order to better understand DR4 restricted T cell activation, we analyzed the candidate arthritogenic antigens type II collagen, human aggrecan, and the hepatitis B surface antigen for T-cell epitopes using a predictive model for determining peptide-DR4 affinity. We also applied this model to determine whether cross-reactive T-cell epitopes can be predicted based on known MHC-peptide-TCR interactions. Using the HLA-DR4-IE transgenic mouse, we showed that both T-cell proliferation and Th1 cytokine production (IFN-gamma) correlate with the predicted affinity of a peptide for DR4. In addition, we provide evidence that TCR recognition of a peptide-DR4 complex is highly specific in that similar antigenic peptide sequences, containing identical amino acids at TCR contact positions, do not activate the same population of T cells.
2002-11-04T08:00:00Z
article
https://ir.lib.uwo.ca/mnipub/2
http://arthritis-research.com/content/5/1/R40
Microbiology & Immunology Publications
Scholarship@Western
Aggrecans
Animals
Antigens
Arthritis
Rheumatoid
Autoantigens
Cell Line
Cells
Cultured
Collagen Type II
Cytokines
Epitopes
T-Lymphocyte
Extracellular Matrix Proteins
HLA-DR Antigens
Hepatitis B Surface Antigens
Lectins
C-Type
Lymphocyte Activation
Mice
Mice
Transgenic
Models
Molecular
Molecular Mimicry
Peptides
Proteoglycans
T-Lymphocytes
Arthritis, Rheumatoid
Cells, Cultured
Epitopes, T-Lymphocyte
Lectins, C-Type
Mice, Transgenic
Models, Molecular
Immunology and Infectious Disease
Microbiology
oai:ir.lib.uwo.ca:medpub-1011
2009-09-19T03:17:32Z
publication:biophysicspub
publication:physpharmpub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:physpharm
publication:biophysics
publication:apmaths
publication:apmathspub
Erythropoietin Improves Skeletal Muscle Microcirculation and Tissue Bioenergetics in a Mouse Sepsis Model
Kao, Raymond
Xenocostas, Anargyros
Rui, Tao
Yu, Pei
Huang, Weixiong
Rose, James
Martin, Claudio M.
Introduction: The relationship between oxygen delivery and consumption in sepsis is impaired, suggesting a microcirculatory perfusion defect. Recombinant human erythropoietin (rHuEPO) regulates erythropoiesis and also exerts complex actions promoting the maintenance of homeostasis of the organism under stress. The objective of this study was to test the hypothesis that rHuEPO could improve skeletal muscle capillary perfusion and tissue oxygenation in sepsis.
Methods: Septic mice in three experiments received rHu-EPO 400 U/kg subcutaneously 18 hours after cecal ligation and perforation (CLP). The first experiment measured the acute effects of rHuEPO on hemodynamics, blood counts, and arterial lactate level. The next two sets of experiments used intravital microscopy to observe capillary perfusion and nicotinamide adenine dinucleotide (NADH) fluorescence post-CLP after treatment with rHuEPO every 10 minutes for 40 minutes and at 6 hours. Perfused capillary density during a three-minute observation period and NADH fluorescence were measured.
Results: rHuEPO did not have any effects on blood pressure, lactate level, or blood cell numbers. CLP mice demonstrated a 22% decrease in perfused capillary density compared to the sham group (28.5 versus 36.6 capillaries per millimeter; p < 0.001). Treatment of CLP mice with rHuEPO resulted in an immediate and significant increase in perfused capillaries in the CLP group at all time points compared to baseline from 28.5 to 33.6 capillaries per millimeter at 40 minutes; p < 0.001. A significant increase in baseline NADH, suggesting tissue hypoxia, was noted in the CLP mice compared to the sham group (48.3 versus 43.9 fluorescence units [FU]; p = 0.03) and improved with rHuEPO from 48.3 to 44.4 FU at 40 minutes (p = 0.02). Six hours after treatment with rHuEPO, CLP mice demonstrated a higher mean perfused capillary density (39.4 versus 31.7 capillaries per millimeter; p < 0.001) and a lower mean NADH fluorescence as compared to CLP+normal saline mice (49.4 versus 52.7 FU; p = 0.03).
Conclusion: rHuEPO produced an immediate increase in capillary perfusion and decrease in NADH fluorescence in skeletal muscle. Thus, it appears that rHuEPO improves tissue bioenergetics, which is sustained for at least six hours in this murine sepsis model.
2007-05-18T07:00:00Z
article
https://ir.lib.uwo.ca/medpub/7
http://ccforum.com/content/11/3/R58
Department of Medicine Publications
Scholarship@Western
Animals
Disease Models
Animal
Energy Metabolism
Erythropoietin
Mice
Mice
Inbred C57BL
Microcirculation
Muscle
Skeletal
Sepsis
Treatment Outcome
Disease Models, Animal
Mice, Inbred C57BL
Muscle, Skeletal
Medical Sciences
Musculoskeletal, Neural, and Ocular Physiology
oai:ir.lib.uwo.ca:medpub-1012
2010-08-31T00:19:25Z
publication:vascularpub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:biochempub
publication:robarts
publication:biochem
publication:institutes
Gene-gene and Gene-environment Interactions: New Insights into the Prevention, Detection and Management of Coronary Artery Disease
Lanktree, Matthew B.
Hegele, Robert A.
Despite the recent success of genome-wide association studies (GWASs) in identifying loci consistently associated with coronary artery disease (CAD), a large proportion of the genetic components of CAD and its metabolic risk factors, including plasma lipids, type 2 diabetes and body mass index, remain unattributed. Gene-gene and gene-environment interactions might produce a meaningful improvement in quantification of the genetic determinants of CAD. Testing for gene-gene and gene-environment interactions is thus a new frontier for large-scale GWASs of CAD. There are several anecdotal examples of monogenic susceptibility to CAD in which the phenotype was worsened by an adverse environment. In addition, small-scale candidate gene association studies with functional hypotheses have identified gene-environment interactions. For future evaluation of gene-gene and gene-environment interactions to achieve the same success as the single gene associations reported in recent GWASs, it will be important to pre-specify agreed standards of study design and statistical power, environmental exposure measurement, phenomic characterization and analytical strategies. Here we discuss these issues, particularly in relation to the investigation and potential clinical utility of gene-gene and gene-environment interactions in CAD.
2009-02-26T08:00:00Z
article
https://ir.lib.uwo.ca/medpub/8
info:doi/10.1186/gm28
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664961/
Department of Medicine Publications
Scholarship@Western
Coronary artery disease
Gene-gene interaction
Gene-environment interaction
Cardiology
Medical Genetics
oai:ir.lib.uwo.ca:vascularpub-1008
2009-09-23T22:29:49Z
publication:vascularpub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:biochempub
publication:robarts
publication:biochem
publication:institutes
Genetic Determinants of Statin Intolerance
Oh, Jisun
Ban, Matthew R.
Miskie, Brooke A.
Pollex, Rebecca L.
Hegele, Robert A.
Background: Statin-related skeletal muscle disorders range from benign myalgias--such as non-specific muscle aches or joint pains without elevated serum creatinine kinase (CK) concentration--to true myositis with >10-fold elevation of serum CK, to rhabdomyolysis and myoglobinuria. The genetic basis of statin-related muscle disorders is largely unknown. Because mutations in the COQ2 gene are associated with severe inherited myopathy, we hypothesized that common, mild genetic variation in COQ2 would be associated with inter-individual variation in statin intolerance. We studied 133 subjects who developed myopathy on statin monotherapy and 158 matched controls who tolerated statins without incident or complaint.
Results: COQ2 genotypes, based on two single nucleotide polymorphisms (SNP1 and SNP2) and a 2-SNP haplotype, all showed significant associations with statin intolerance. Specifically, the odds ratios (with 95% confidence intervals) for increased risk of statin intolerance among homozygotes for the rare alleles were 2.42 (0.99 to 5.89), 2.33 (1.13 to 4.81) and 2.58 (1.26 to 5.28) for SNP1 and SNP2 genotypes, and the 2-SNP haplotype, respectively.
Conclusion: These preliminary pharmacogenetic results, if confirmed, are consistent with the idea that statin intolerance which is manifested primarily through muscle symptoms is associated with genomic variation in COQ2 and thus perhaps with the CoQ10 pathway.
2007-03-21T07:00:00Z
article
https://ir.lib.uwo.ca/vascularpub/9
http://www.lipidworld.com/content/6/1/7
Robarts Vascular Research Publications
Scholarship@Western
Adult
Aged
Alkyl and Aryl Transferases
Female
Genetic Predisposition to Disease
Haplotypes
Homozygote
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Male
Middle Aged
Muscular Diseases
Myoglobinuria
Myositis
Polymorphism
Single Nucleotide
Rhabdomyolysis
Risk Factors
Polymorphism, Single Nucleotide
Medical Genetics
Medical Microbiology
oai:ir.lib.uwo.ca:vascularpub-1009
2023-03-16T14:08:08Z
publication:vascularpub
publication:fammedpub
publication:fammed
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:epidem
publication:biochempub
publication:robarts
publication:biochem
publication:institutes
publication:epidempub
Relationship of the Metabolic Syndrome to Carotid Ultrasound Traits
Pollex, Rebecca L.
Al-Shali, Khalid Z.
House, Andrew A.
Spence, J. David
Fenster, Aaron
Mamakeesick, Mary
Zinman, Bernard
Harris, Stewart B.
Hanley, Anthony J. G.
Hegele, Robert A.
Background: The metabolic syndrome is associated with increased vascular disease risk. We evaluated two carotid ultrasound measurements, namely intima media thickness and total plaque volume, in a Canadian Oji-Cree population with a high metabolic syndrome prevalence rate. Methods: As part of the Sandy Lake Complications Prevalence and Risk Factor Study, 166 Oji-Cree subjects (baseline metabolic syndrome prevalence, 44.0%, according to the National Cholesterol Education Program Adult Treatment Panel III guidelines) were examined using a high-resolution duplex ultrasound scanner. Results: Image analysis showed that mean intima media thickness was elevated in subjects with the metabolic syndrome (818 +/- 18 vs 746 +/- 20 microm), as was total plaque volume (125 +/- 26 vs 77.3 +/- 17.0 mm3). However, after adjustment for age and sex, the differences were significant only for intima media thickness (P = 0.039). Furthermore, a significant trend towards increased intima media thickness was observed with increasing numbers of metabolic syndrome components: mean intima media thickness was highest among individuals with all five metabolic syndrome components compared to those with none (866 +/- 55 vs 619 +/- 23 microm, P = 0.0014). A similar, but non-significant trend was observed for total plaque volume. Conclusion: This is the first study of the relationship between the metabolic syndrome and two distinct carotid ultrasound traits measured in the same individuals. The results suggest that standard intima media thickness measurement shows a more consistent and stronger association with the metabolic syndrome than does total plaque volume.
2006-07-07T07:00:00Z
article
https://ir.lib.uwo.ca/vascularpub/10
info:doi/10.1186/1476-7120-4-28
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1533865/
Robarts Vascular Research Publications
Scholarship@Western
Adult
Canada
Comorbidity
Coronary Artery Disease
Female
Humans
Incidence
Male
Metabolic Syndrome X
Prognosis
Risk Assessment
Risk Factors
Sensitivity and Specificity
Tunica Intima
Cardiology
Medical Microbiology
oai:ir.lib.uwo.ca:vascularpub-1010
2009-09-25T00:29:45Z
publication:vascularpub
publication:fammedpub
publication:fammed
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:epidem
publication:biochempub
publication:robarts
publication:biochem
publication:institutes
publication:epidempub
Association Between the -455T>C Promoter Polymorphism of the APOC3 Gene and the Metabolic Syndrome in a Multi-ethnic Sample
Pollex, Rebecca L.
Ban, Matthew R.
Young, T. Kue
Bjerregaard, Peter
Anand, Sonia S.
Yusuf, Salim
Zinman, Bernard
Harris, Stewart B.
Hanley, Anthony J. G.
Connelly, Philip W.
Huff, Murray W.
Hegele, Robert A.
Background: Common polymorphisms in the promoter of the APOC3 gene have been associated with hypertriglyceridemia and may impact on phenotypic expression of the metabolic syndrome (MetS). The rs7566605 marker, located near the INSIG2 gene, has been found to be associated with obesity, making it also a potential genetic determinant for MetS. The objective of this study is to examine the APOC3 -455T>C and the INSIG2 rs7566605 polymorphisms as potential genetic determinants for MetS in a multi-ethnic sample.
Methods: Subjects were genotyped for both the APOC3 -455T>C and INSIG2 rs7566605 polymorphisms, and classified for the presence or absence of MetS (NCEP ATP III and IDF definitions). The total study population included 2675 subjects (> or =18 years of age) from six different geographical ancestries.
Results: For the overall study population, the prevalence of MetS was 22.6% (NCEP ATP III definition). Carriers of > or =1 copy of APOC3 -455C were more likely to have MetS (NCEP ATP III definition) than noncarriers (carrier odds ratio 1.73, 95% CI 1.40 to 2.14, adjusting for age and study group). The basis of the association was related not only to a higher proportion of -455C carriers meeting the triglyceride and high-density lipoprotein cholesterol criteria, but also the blood pressure criteria compared with wild-type homozygotes. Plasma apo C-III concentrations were not associated with APOC3 -455T>C genotype. The INSIG2 rs7566605 polymorphism was not associated with MetS or measures of obesity.
Conclusion: Meta-analysis of the sample of multiple geographic ancestries indicated that the functional -455T>C promoter polymorphism in APOC3 was associated with an approximately 2-fold increased risk of MetS, whereas the INSIG2 rs7566605 polymorphism was not associated with MetS.
2007-11-20T08:00:00Z
article
https://ir.lib.uwo.ca/vascularpub/11
http://www.biomedcentral.com/1471-2350/8/80
Robarts Vascular Research Publications
Scholarship@Western
Adult
Apolipoprotein C-III
Canada
Ethnic Groups
Female
Genetic Predisposition to Disease
Humans
Male
Metabolic Syndrome X
Polymorphism
Genetic
Promoter Regions
Genetic
Polymorphism, Genetic
Promoter Regions, Genetic
Medical Genetics
oai:ir.lib.uwo.ca:vascularpub-1012
2023-03-16T14:09:27Z
publication:vascularpub
publication:fammedpub
publication:fammed
publication:robartspub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:epidem
publication:biochempub
publication:robarts
publication:biochem
publication:institutes
publication:epidempub
A Comparison of Ultrasound Measurements to Assess Carotid Atherosclerosis Development in Subjects with and without Type 2 Diabetes
Pollex, Rebecca L.
Spence, J. David
House, Andrew A.
Fenster, Aaron
Hanley, Anthony J. G.
Zinman, Bernard
Harris, Stewart B.
Hegele, Robert A.
Background: Subjects with type 2 diabetes are at an increased risk of vascular complications. The use of carotid ultrasound remains an attractive, non-invasive method to monitor atherosclerotic disease progression and/or response to treatment in patients with type 2 diabetes, with intima-media thickness routinely used as the gold standard to detect pathology. However, alternative measurements, such as plaque area or volume, may represent a potentially more powerful approach. Thus, the objective of this study was to compare the traditional intima-media thickness measurement against the novel total plaque volume measurement in analyzing carotid atherosclerosis development in individuals with type 2 diabetes. Methods: The case-control study included 49 Oji-Cree adults with diabetes or impaired glucose tolerance, aged 21-69, and 49 sex- and age-matched normoglycemic subjects. At baseline, metabolic variables were measured, including body mass index, waist circumference, total cholesterol: high density lipoprotein ratio, plasma triglycerides, plasma glucose, and serum insulin. Carotid ultrasound measurements, 7 years later, assessed carotid arterial intima-media thickness and total plaque volume. Results: At baseline, the two groups were well matched for smoking habits, hypertension, body mass index, and waist circumference. Differences were noted in baseline measurements of total cholesterol:high density lipoprotein (P = 0.0006), plasma triglycerides (P < 0.0001) and fasting glucose (P < 0.0001). After seven years, carotid ultrasound scans revealed that total plaque volume measurements (P = 0.037), but not intima-media thickness measurements, were higher in subjects with diabetes/impaired glucose tolerance compared to the normoglycemic controls. Correlation between intima-media thickness and total plaque volume was moderate. Based on our study findings, to achieve power levels > 0.70 when comparing intima-media thickness measurements for diabetics versus non-diabetics, thousands of study subjects are required. For comparing total plaque volume measurements, only hundreds of study subjects are required. Conclusion: The development of atherosclerotic plaque is greater in subjects with diabetes/impaired glucose tolerance. Total plaque volume appears to capture the atherosclerotic disease burden more effectively in subjects with type 2 diabetes, and would be an appropriate outcome measure for studies aimed at changing the diabetic milieu.
2005-06-15T07:00:00Z
article
https://ir.lib.uwo.ca/vascularpub/13
info:doi/10.1186/1476-7120-3-15
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1184090/
Robarts Vascular Research Publications
Scholarship@Western
Adult
Aged
Anatomy
Cross-Sectional
Canada
Carotid Artery Diseases
Diabetes Mellitus
Type 2
Echocardiography
Female
Humans
Image Interpretation
Computer-Assisted
Imaging
Three-Dimensional
Incidence
Male
Middle Aged
Prognosis
Reproducibility of Results
Risk Assessment
Risk Factors
Sensitivity and Specificity
Single-Blind Method
Anatomy, Cross-Sectional
Diabetes Mellitus, Type 2
Image Interpretation, Computer-Assisted
Imaging, Three-Dimensional
Cardiology
Medical Microbiology
oai:ir.lib.uwo.ca:vascularpub-1011
2009-09-26T00:00:46Z
publication:vascularpub
publication:fammedpub
publication:fammed
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:epidem
publication:biochempub
publication:robarts
publication:biochem
publication:institutes
publication:epidempub
Methylenetetrahydrofolate Reductase Polymorphism 677C>T is Associated with Peripheral Arterial Disease in Type 2 Diabetes
Pollex, Rebecca L.
Mamakeesick, Mary
Zinman, Bernard
Harris, Stewart B.
Hanley, Anthony J. G.
Hegele, Robert A.
Background: Individuals with diabetes are twice as likely to develop peripheral arterial disease (PAD), the manifestation of extensive atherosclerosis throughout the lower extremities. One putative determinant of PAD is the 677C>T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR), which has previously been found to associate with various diabetic complications including retinopathy, nephropathy, atherosclerosis and coronary heart disease. The objective of this study was to investigate a possible role for the MTHFR 677C>T gene polymorphism with PAD in subjects with type 2 diabetes from an isolated aboriginal Canadian population.
Methods: The 677C>T MTHFR gene polymorphism was genotyped in 138 subjects of Oji-Cree descent. Participants were selected from a community-wide survey that included PAD assessment by ankle-brachial index (ABI) measurement, and also intermittent claudication assessment by the Rose questionnaire.
Results: MTHFR 677T allele carriers had an increased risk of PAD with an odds ratio of 3.54 (95% CI 1.01, 12.4), P = 0.049, after adjustment for age, sex, duration of diabetes, hypertension, current smoking habits, and use of insulin or oral treatment for diabetes. None of these additional co-variables was significantly associated with PAD. No association was found between MTHFR genotype and intermittent claudication.
Conclusion: The genetic influence of the MTHFR 677C>T genotype on diabetic PAD is modest, yet for the Oji-Cree it is a major risk factor in comparison to other traditional risk factors.
2005-11-07T08:00:00Z
article
https://ir.lib.uwo.ca/vascularpub/12
http://www.cardiab.com/content/4/1/17
Robarts Vascular Research Publications
Scholarship@Western
Brachial Artery
Canada
Diabetes Mellitus
Type 2
Diabetic Angiopathies
Genotype
Humans
Indians
North American
Intermittent Claudication
Methylenetetrahydrofolate Reductase (NADPH2)
Odds Ratio
Polymorphism
Genetic
Risk Factors
Diabetes Mellitus, Type 2
Indians, North American
Methylenetetrahydrofolate Reductase (NADPH2)
Polymorphism, Genetic
Cardiology
Medical Microbiology
oai:ir.lib.uwo.ca:robartspub-1001
2023-03-16T14:07:28Z
publication:robartspub
publication:rwkex_researcharticles
publication:biophysicspub
publication:pmid
publication:medimaging
publication:faculties
publication:medpub
publication:rwkex
publication:med
publication:biophysics
publication:medimagingpub
publication:robarts
publication:institutes
Carotid Ultrasound Phenotypes in Vulnerable Populations
Riccio, Silvia A.
House, Andrew A.
Spence, J. David
Fenster, Aaron
Parraga, Grace
Background: Biomarkers of carotid atherosclerosis range from those that are widely available and relatively simple to measure such as serum cholesterol levels, and B-mode Ultrasound measurement of intima media thickness (IMT) to those that are more complex and technologically demanding but perhaps potentially more sensitive and specific to disease such as total plaque volume and total plaque area measured from 3-dimensional ultrasound images. In this study we measured and compared intima media thickness (IMT), total plaque volume (TPV) and total plaque area (TPA) in two separate populations, both vulnerable to carotid atherosclerosis. Methods: In total, 88 subjects (mean age 72.8) with carotid stenosis of at least 60%, based on a peak Doppler flow, and 82 subjects (mean age 60.9) with diabetic nephropathy were assessed in a cross-sectional study. Conventional atherosclerotic risk factors were examined and the associations and correlations between these and carotid ultrasound phenotypes measured from B-mode and 3-dimensional ultrasound images were assessed. Results: IMT and TPV were only modestly correlated in the two separate populations (r = .6, p < .01). ANOVA analyses indicated that both IMT and TPV were significantly associated with age (p < .001) and Framingham score (p < .05), but only TPV was associated with diabetes (p < .001) and presence of plaque ulcerations (p < .01) Conclusion: IMT and TPV were modestly correlated in a diabetic patient population and only TPV was associated with diabetes and the presence of plaque ulcerations in a diabetic population and carotid stenosis group. The 3-dimensional information provided by TPV can be critically important in unmasking association with risk factors not observed with less complex single-dimension assessments of carotid atherosclerosis such as those provided by IMT.
2006-11-13T08:00:00Z
article
https://ir.lib.uwo.ca/robartspub/2
info:doi/10.1186/1476-7120-4-44
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1657034/
Robarts Imaging Publications
Scholarship@Western
Aged
Carotid Stenosis
Diabetic Nephropathies
Female
Humans
Image Interpretation
Computer-Assisted
Male
Phenotype
Prognosis
Reproducibility of Results
Risk Assessment
Risk Factors
Sensitivity and Specificity
Ultrasonography
Doppler
Color
Image Interpretation, Computer-Assisted
Ultrasonography, Doppler, Color
Bioimaging and Biomedical Optics
Biomedical Engineering and Bioengineering
oai:ir.lib.uwo.ca:oncpub-1003
2009-09-27T21:17:27Z
publication:oncpub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:epidem
publication:onc
publication:epidempub
Psychometric Properties of a Prostate Cancer Radiation Late Toxicity Questionnaire
Rodrigues, George
Bauman, Glenn
Lock, Michael
D'Souza, David
Mahon, Jeff
Background: To construct a short prostate cancer radiation late toxicity (PCRT) questionnaire with health-related quality-of-life (HRQoL) domains.
Methods: The PCRT was developed by item generation, questionnaire construction (n = 7 experts, n = 8 focus group patients), pilot testing (n = 37), item reduction (n = 100), reliability testing (n = 237), and validity testing (n = 274).
Results: Reliability of the three item-reduced subscales demonstrated intraclass correlation coefficients (CC) of 0.811 (GU), 0.842 (GI), and 0.740 (sexual). Discriminant validity demonstrated Pearson CC of 0.449 (GU-GI), 0.200 (sexual-GU), and 0.09 (sexual-GI). Content validity correlations between PCRT-PCQoL were 0.35-0.78, PCRT-FACT-G(c) were 0.19-0.39, and PCRT-SF-36(R) were 0.03-0.34.
Conclusion: We successfully generated a PCRT HRQoL questionnaire including subscales with very good psychometric properties.
2007-05-31T07:00:00Z
article
https://ir.lib.uwo.ca/oncpub/3
http://www.hqlo.com/content/5/1/29
Oncology Publications
Scholarship@Western
Aged
Aged
80 and over
Brachytherapy
Focus Groups
Follow-Up Studies
Humans
Male
Middle Aged
Ontario
Outcome Assessment (Health Care)
Pilot Projects
Prostatic Neoplasms
Psychometrics
Quality of Life
Questionnaires
Radiation Oncology
Radiation
Ionizing
Radiotherapy
Sickness Impact Profile
Aged, 80 and over
Outcome Assessment (Health Care)
Radiation, Ionizing
Epidemiology
Oncology
oai:ir.lib.uwo.ca:medpub-1013
2009-10-02T00:51:40Z
publication:vascularpub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:biochempub
publication:robarts
publication:biochem
publication:institutes
Treatment of Dyslipidemia with Lovastatin and Ezetimibe in an Adolescent with Cholesterol Ester Storage Disease
Tadiboyina, Venu T.
Liu, Dora M.
Miskie, Brooke A.
Wang, Jian
Hegele, Robert A.
Background: Cholesterol ester storage disease (CESD) is an autosomal recessive illness that results from mutations in the LIPA gene encoding lysosomal acid lipase. CESD patients present in childhood with hepatomegaly and dyslipidemia characterized by elevated total and low-density lipoprotein cholesterol (LDL-C), with elevated triglycerides and depressed high-density lipoprotein cholesterol (HDL-C). Usual treatment includes a low fat diet and a statin drug.
Results: In an 18-year old with CESD, we documented compound heterozygosity for two LIPA mutations: a novel frameshift nonsense mutation and a deletion of exon 8. The patient had been treated with escalating doses of lovastatin for approximately 80 months, with approximately 15% decline in mean LDL-C. The addition of ezetimibe 10 mg to lovastatin 40 mg resulted in an additional approximately 16% decline in mean LDL-C.
Conclusion: These preliminary anecdotal findings in a CESD patient with novel LIPA mutations support the longer term safety of statins in an adolescent patient and provide new data about the potential efficacy and tolerability of ezetimibe in this patient group.
2005-10-28T07:00:00Z
article
https://ir.lib.uwo.ca/medpub/9
http://www.lipidworld.com/content/4/1/26
Department of Medicine Publications
Scholarship@Western
Adolescent
Amino Acid Sequence
Azetidines
Base Sequence
Child
Child
Preschool
Cholesterol Ester Storage Disease
Drug Therapy
Combination
Dyslipidemias
Humans
Lipoproteins
Lovastatin
Male
Molecular Sequence Data
Sterol Esterase
Child, Preschool
Drug Therapy, Combination
Medical Sciences
oai:ir.lib.uwo.ca:vascularpub-1013
2009-10-12T02:54:16Z
publication:vascularpub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:biochempub
publication:robarts
publication:biochem
publication:institutes
Homozygous Missense Mutation (G56R) in Glycosylphosphatidylinositol-anchored High-density Lipoprotein-binding Protein 1 (GPI-HBP1) in Two Siblings with Fasting Chylomicronemia (MIM 144650)
Wang, Jian
Hegele, Robert A.
Background: Mice with a deleted Gpihbp1 gene encoding glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1) develop severe chylomicronemia. We screened the coding regions of the human homologue--GPIHBP1--from the genomic DNA of 160 unrelated adults with fasting chylomicronemia and plasma triglycerides >10 mmol/L, each of whom had normal sequence of the LPL and APOC2 genes.
Results: One patient with severe type 5 hyperlipoproteinemia (MIM 144650), fasting chylomicronemia and relapsing pancreatitis resistant to standard therapy was found to be homozygous for a novel GPIHBP1 missense variant, namely G56R. This mutation was absent from the genomes of 600 control subjects and 610 patients with hyperlipidemia. The GPIHBP1 G56 residue has been conserved throughout evolution and the G56R mutation was predicted to have compromised function. Her homozygous brother also had refractory chylomicronemia and relapsing pancreatitis together with early coronary heart disease. G56R heterozygotes in the family had fasting mild hypertriglyceridemia.
Conclusion: Thus, a very rare GPIHBP1 missense mutation appears to be associated with severe hypertriglyceridemia and chylomicronemia.
2007-09-20T07:00:00Z
article
https://ir.lib.uwo.ca/vascularpub/14
http://www.lipidworld.com/content/6/1/23
Robarts Vascular Research Publications
Scholarship@Western
Amino Acid Substitution
Animals
Carrier Proteins
Chylomicrons
Conserved Sequence
Evolution
Molecular
Female
Genetic Variation
Homozygote
Humans
Lipid Metabolism
Inborn Errors
Male
Mice
Mutation
Missense
Pedigree
Receptors
Lipoprotein
Siblings
Evolution, Molecular
Lipid Metabolism, Inborn Errors
Mutation, Missense
Receptors, Lipoprotein
Medical Microbiology
oai:ir.lib.uwo.ca:medpub-1016
2009-10-12T04:11:55Z
publication:anatomy
publication:biophysicspub
publication:pmid
publication:faculties
publication:medpub
publication:anatomypub
publication:med
publication:biophysics
Cell Tracking and Therapy Evaluation of Bone Marrow Monocytes and Stromal Cells Using SPECT and CMR in a Canine Model of Myocardial Infarction
Wisenberg, Gerald
Lekx, Katie
Zabel, Pam
Kong, Huafu
Mann, Rupinder
Zeman, Peter R.
Datta, Sudip
Culshaw, Caroline N.
Merrifield, Peter
Bureau, Yves
Wells, Glenn
Sykes, Jane
Prato, Frank S.
Background: The clinical application of stem cell therapy for myocardial infarction will require the development of methods to monitor treatment and pre-clinical assessment in a large animal model, to determine its effectiveness and the optimum cell population, route of delivery, timing, and flow milieu.
Objectives: To establish a model for a) in vivo tracking to monitor cell engraftment after autologous transplantation and b) concurrent measurement of infarct evolution and remodeling.
Methods: We evaluated 22 dogs (8 sham controls, 7 treated with autologous bone marrow monocytes, and 7 with stromal cells) using both imaging of 111Indium-tropolone labeled cells and late gadolinium enhancement CMR for up to12 weeks after a 3 hour coronary occlusion. Hearts were also examined using immunohistochemistry for capillary density and presence of PKH26 labeled cells.
Results: In vivo Indium imaging demonstrated an effective biological clearance half-life from the injection site of ~5 days. CMR demonstrated a pattern of progressive infarct shrinkage over 12 weeks, ranging from 67-88% of baseline values with monocytes producing a significant treatment effect. Relative infarct shrinkage was similar through to 6 weeks in all groups, following which the treatment effect was manifest. There was a trend towards an increase in capillary density with cell treatment.
Conclusion: This multi-modality approach will allow determination of the success and persistence of engraftment, and a correlation of this with infarct size shrinkage, regional function, and left ventricular remodeling. There were overall no major treatment effects with this particular model of transplantation immediately post-infarct.
2009-04-27T07:00:00Z
article
https://ir.lib.uwo.ca/medpub/10
http://www.jcmr-online.com/content/11/1/11
Department of Medicine Publications
Scholarship@Western
Analysis of Variance
Animals
Bone Marrow Transplantation
Cell Survival
Dogs
Female
Image Processing
Computer-Assisted
Indium Radioisotopes
Magnetic Resonance Imaging
Cine
Monocytes
Myocardial Infarction
Organic Chemicals
Stromal Cells
Tomography
Emission-Computed
Single-Photon
Transplantation
Autologous
Ventricular Dysfunction
Left
Image Processing, Computer-Assisted
Magnetic Resonance Imaging, Cine
Tomography, Emission-Computed, Single-Photon
Transplantation, Autologous
Ventricular Dysfunction, Left
Cardiology
oai:ir.lib.uwo.ca:medpub-1017
2009-10-12T05:01:19Z
publication:physpharmpub
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:physpharm
Variation in Red Cell Transfusion Practice in the Intensive Care Unit: A Multicentre Cohort Study
Hébert, Paul C.
Wells, George
Martin, Claudio
Tweeddale, Martin
Marshall, John
Blajchman, Morris
Pagliarello, Giuseppe
Sandham, Dean
Schweitzer, Irwin
Boisvert, Denis
Calder, Lisa
Objectives: To determine the degree of interinstitutional transfusion practice variation and reasons why red cells are administered in critically ill patients.
Study Design: Multicentre cohort study combined with a cross-sectional survey of physicians requesting red cell transfusions for patients in the cohort.
Study Population: The cohort included 5298 consecutive patients admitted to six tertiary level intensive care units in addition to administering a survey to 223 physicians requesting red cell transfusions in these units.
Measurements: Haemoglobin concentrations were collected, along with the number and reasons for red cell transfusions plus demographic, diagnostic, disease severity (APACHE II score), intensive care unit (ICU) mortality and lengths of stay in the ICU.
Results: Twenty five per cent of the critically ill patients in the cohort study received red cell transfusions. The overall number of transfusions per patient-day in the ICU averaged 0.95 +/- 1.39 and ranged from 0.82 +/- 1.69 to 1.08 +/- 1.27 between institutions (P < 0.001). Independent predictors of transfusion thresholds (pre-transfusion haemoglobin concentrations) included patient age, admission APACHE II score and the institution (P < 0.0001). A very significant institution effect (P < 0.0001) persisted even after multivariate adjustments for age, APACHE II score and within four diagnostic categories (cardiovascular disease, respiratory failure, major surgery and trauma) (P < 0.0001). The evaluation of transfusion practice using the bedside survey documented that 35% (202 of 576) of pre-transfusion haemoglobin concentrations were in the range of 95-105 g/l and 80% of the orders were for two packed cell units. The most frequent reasons for administering red cells were acute bleeding (35%) and the augmentation of O2 delivery (25%).
Conclusions: There is significant institutional variation in critical care transfusion practice, many intensivists adhering to a 100g/l threshold, and opting to administer multiple units despite published guidelines to the contrary. There is a need for prospective studies to define optimal practice in the critically ill.
1999-04-29T07:00:00Z
article
https://ir.lib.uwo.ca/medpub/11
http://ccforum.com/content/3/2/57
Department of Medicine Publications
Scholarship@Western
Red Cells
Transfusions
Haemoglobin
Intensive Care
Medicine and Health Sciences
oai:ir.lib.uwo.ca:medpub-1018
2009-10-12T05:06:28Z
publication:pmid
publication:faculties
publication:medpub
publication:med
Intra-aortic Balloon Counterpulsation Pump Therapy: A Critical Appraisal of the Evidence for Patients with Acute Myocardial Infarction
Peterson, John C.
Cook, Deborah J.
1998-03-12T08:00:00Z
article
https://ir.lib.uwo.ca/medpub/12
http://ccforum.com/content/2/1/3
Department of Medicine Publications
Scholarship@Western
Myocardial Infarction
Cardiogenic Shock
Intra-Aortic Balloon Counterpulsation Pump
Cardiology
oai:ir.lib.uwo.ca:immunologypub-1004
2009-10-10T02:37:46Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Characterization of Oligomers Induced by Inverse Agonists of CTLA-4
Teft, Wendy A.
Madrenas, Joaquín
Although cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibits T cell activation when ligated by B7 molecules on antigen-presenting cells, it can also act as an activating receptor when binding certain soluble recombinant ligands known as inverse agonists. Following ligation with an inverse agonist, we observed CTLA-4 microclusters evenly distributed on the T cell surface over a 60-min period. We have previously shown that the inverse agonist properties of these ligands correlate with their capacity to induce the formation of large CTLA-4 oligomers that are distinctly different from those resulting by CTLA-4 engagement with membrane-bound B7. These oligomers are composed of CTLA-4 molecules expressed on the cell surface and decrease from both the soluble cell lysate and lipid rafts upon cellular fractionation. Formation of these inverse agonist-induced CTLA-4 oligomers does not require an intact actin cytoskeleton. However, modulation of these oligomers was partially blocked upon actin depolymerization. Retention of CTLA-4 oligomers on the cell surface correlated with enhanced T cell signaling. Together, our data further characterize the structural basis of inverse agonist properties for CTLA-4 ligands that may be used in the design and screening of therapeutic biologicals targeting this receptor.
2008-10-30T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/4
http://dx.doi.org/10.1016/j.imlet.2008.06.005
Robarts Immunology and Transplantation Publications
Scholarship@Western
Actins
Antibodies
Bispecific
Antigens
CD
Antigens
CD86
Antigens
Surface
Gene Expression Regulation
Humans
Immunoglobulin Variable Region
Jurkat Cells
Membrane Microdomains
T-Lymphocytes
Antibodies, Bispecific
Antigens, CD
Antigens, CD86
Antigens, Surface
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1002
2009-10-10T01:56:54Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Structure-function Analysis of the CTLA-4 Interaction with PP2A
Teft, Wendy A.
Chau, Thu A.
Madrenas, Joaquín
Background: CTLA-4 functions primarily as an inhibitor of T cell activation. There are several candidate explanations as to how CTLA-4 modulates T cell responses, but the exact mechanism remains undefined. The tail of CTLA-4 does not have any intrinsic enzymatic activity but is able to associate with several signaling molecules including the serine/threonine phosphatase PP2A. PP2A is a heterotrimeric molecule comprised of a regulatory B subunit associated with a core dimer of a scaffolding (A) and a catalytic (C) subunit.
Results: Here, we performed an analysis of the human CTLA-4 interface interacting with PP2A. We show that PP2A interacts with the cytoplasmic tail of CTLA-4 in two different sites, one on the lysine rich motif, and the other on the tyrosine residue located at position 182 (but not the tyrosine 165 of the YVKM motif). Although the interaction between CTLA-4 and PP2A was not required for inhibition of T cell responses, it was important for T cell activation by inverse agonists of CTLA-4. Such an interaction was functionally relevant because the inverse agonists induced IL-2 production in an okadaic acid-dependent manner.
Conclusion: Our studies demonstrate that PP2A interacts with the cytoplasmic tail of human CTLA-4 through two motifs, the lysine rich motif centered at lysine 155 and the tyrosine residue 182. This interaction and the phosphatase activity of PP2A are important for CTLA-4-mediated T cell activation.
2009-04-30T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/2
http://www.biomedcentral.com/1471-2172/10/23
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antigens
CD
Enzyme Activation
Humans
Jurkat Cells
Lymphocyte Activation
Mutagenesis
Site-Directed
Mutation
Okadaic Acid
Protein Binding
Protein Interaction Domains and Motifs
Protein Phosphatase 2
Protein Structure
Tertiary
Structure-Activity Relationship
T-Lymphocytes
Transgenes
Antigens, CD
Mutagenesis, Site-Directed
Protein Structure, Tertiary
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:mnipub-1006
2009-10-10T01:29:52Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Attenuation of Massive Cytokine Response to the Staphylococcal Enterotoxin B Superantigen by the Innate Immunomodulatory Protein Lactoferrin
Hayworth, J. L.
Kasper, K. J.
Leon-Ponte, M.
Herfst, C. A.
Yue, D.
Brintnell, W. C.
Mazzuca, D. M.
Heinrichs, D. E.
Cairns, E.
Madrenas, J.
Hoskin, D. W.
McCormick, J. K.
Haeryfar, S. M. M.
Staphylococcal enterotoxin B (SEB) is a pyrogenic exotoxin and a potent superantigen which causes massive T cell activation and cytokine secretion, leading to profound immunosuppression and morbidity. The inhibition of SEB-induced responses is thus considered a goal in the management of certain types of staphylococcal infections. Lactoferrin (LF) is a multi-functional glycoprotein with both bacteriostatic and bactericidal activities. In addition, LF is known to have potent immunomodulatory properties. Given the anti-microbial and anti-inflammatory properties of this protein, we hypothesized that LF can modulate T cell responses to SEB. Here, we report that bovine LF (bLF) was indeed able to attenuate SEB-induced proliferation, interleukin-2 production and CD25 expression by human leucocyte antigen (HLA)-DR4 transgenic mouse T cells. This inhibition was not due to bLF's iron-binding capacity, and could be mimicked by the bLF-derived peptide lactoferricin. Cytokine secretion by an engineered SEB-responsive human Jurkat T cell line and by peripheral blood mononuclear cells from healthy donors was also inhibited by bLF. These findings reveal a previously unrecognized property of LF in modulation of SEB-triggered immune activation and suggest a therapeutic potential for this naturally occurring protein during toxic shock syndrome.
2009-07-01T07:00:00Z
article
https://ir.lib.uwo.ca/mnipub/6
http://www3.interscience.wiley.com/journal/122350147/abstract
Microbiology & Immunology Publications
Scholarship@Western
Animals
Anti-Bacterial Agents
Apoproteins
Cattle
Cell Proliferation
Enterotoxins
Female
Flow Cytometry
HLA-DR4 Antigen
Humans
Interleukin-2
Jurkat Cells
Lactoferrin
Lymphocyte Activation
Male
Mice
Mice
Inbred C57BL
Mice
Transgenic
Serum Albumin
Staphylococcal Infections
Superantigens
T-Lymphocytes
Transferrin
Mice, Inbred C57BL
Mice, Transgenic
Immunology and Infectious Disease
Microbiology
oai:ir.lib.uwo.ca:immunologypub-1001
2009-10-10T01:57:37Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Toll-like Receptor 2 Ligands on the Staphylococcal Cell Wall Downregulate Superantigen-induced T Cell Activation and Prevent Toxic Shock Syndrome
Chau, Thu A.
McCully, Michelle L.
Brintnell, William
An, Gary
Kasper, Katherine J.
Vinés, Enrique D.
Kubes, Paul
Haeryfar, S. M. Mansour
McCormick, John K.
Cairns, Ewa
Heinrichs, David E.
Madrenas, Joaquín
Staphylococcal superantigens are pyrogenic exotoxins that cause massive T cell activation leading to toxic shock syndrome and death. Despite the strong adaptive immune response induced by these toxins, infections by superantigen-producing staphylococci are very common clinical events. We hypothesized that this may be partly a result of staphylococcal strains having developed strategies that downregulate the T cell response to these toxins. Here we show that the human interleukin-2 response to staphylococcal superantigens is inhibited by the simultaneous presence of bacteria. Such a downregulatory effect is the result of peptidoglycan-embedded molecules binding to Toll-like receptor 2 and inducing interleukin-10 production and apoptosis of antigen-presenting cells. We corroborated these findings in vivo by showing substantial prevention of mortality after simultaneous administration of staphylococcal enterotoxin B with either heat-killed staphylococci or Staphylococcus aureus peptidoglycan in mouse models of superantigen-induced toxic shock syndrome.
2009-06-01T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/1
http://www.nature.com/nm/journal/v15/n6/abs/nm.1965.html
Robarts Immunology and Transplantation Publications
Scholarship@Western
Animals
Antigen-Presenting Cells
Antigens
Bacterial
Apoptosis
Cell Wall
Down-Regulation
Humans
Interleukin-2
Ligands
Lymphocyte Activation
Mice
NF-kappa B
Shock
Septic
Staphylococcus aureus
Superantigens
T-Lymphocytes
Toll-Like Receptor 2
Antigens, Bacterial
Shock, Septic
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1005
2009-10-12T01:26:57Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
The Future of RIP2/RICK/CARDIAK as a Biomarker of the Inflammatory Response to Infection
McCully, Michelle L.
Fairhead, Todd
Blake, Peter G.
Madrenas, Joaquin
Biological markers of disease have become increasingly important for the clinician to diagnose, predict and monitor progression, and assess the therapeutic effect of interventions on underlying pathogenic mechanisms. Robust and specific biomarkers would be very useful in inflammation, where they may facilitate early identification of tissue injury, predict disease progression and help to modify disease outcomes. However, at present, there are no robust biomarkers to predict the course of inflammation. Here, we discuss emerging data indicating that RIP2, a putative serine/threonine protein kinase, may serve as a biomarker for the resolution of peritoneal dialysis-associated peritonitis and, more generally, of the acute inflammatory response to infection.
2008-05-01T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/5
http://www.expert-reviews.com/doi/abs/10.1586/14737159.8.3.257
Robarts Immunology and Transplantation Publications
Scholarship@Western
Biological Markers
Humans
Infection
Inflammation
Peritoneal Dialysis
Peritonitis
Receptor-Interacting Protein Serine-Threonine Kinase 2
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:mnipub-1009
2009-10-11T20:49:19Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Mesenchymal Stem Cells and Their Use as Cell Replacement Therapy and Disease Modelling Tool
García-Castro, J.
Trigueros, C.
Madrenas, Joaquin
Pérez-Simón, J. A.
Rodriguez, R.
Menendez, P.
Mesenchymal stem cells (MSCs) from adult somatic tissues may differentiate in vitro and in vivo into multiple mesodermal tissues including bone, cartilage, adipose tissue, tendon, ligament or even muscle. MSCs preferentially home to damaged tissues where they exert their therapeutic potential. A striking feature of the MSCs is their low inherent immunogenicity as they induce little, if any, proliferation of allogeneic lymphocytes and antigen-presenting cells. Instead, MSCs appear to be immunosuppressive in vitro. Their multilineage differentiation potential coupled to their immuno-privileged properties is being exploited worldwide for both autologous and allogeneic cell replacement strategies. Here, we introduce the readers to the biology of MSCs and the mechanisms underlying immune tolerance. We then outline potential cell replacement strategies and clinical applications based on the MSCs immunological properties. Ongoing clinical trials for graft-versus-host-disease, haematopoietic recovery after co-transplantation of MSCs along with haematopoietic stem cells and tissue repair are discussed. Finally, we review the emerging area based on the use of MSCs as a target cell subset for either spontaneous or induced neoplastic transformation and, for modelling non-haematological mesenchymal cancers such as sarcomas.
2008-12-01T08:00:00Z
article
https://ir.lib.uwo.ca/mnipub/9
http://www3.interscience.wiley.com/journal/121449056/abstract
Microbiology & Immunology Publications
Scholarship@Western
Animals
Clinical Trials as Topic
Disease
Humans
Immune Tolerance
Mesenchymal Stem Cell Transplantation
Mesenchymal Stem Cells
Models
Biological
Models, Biological
Immunology and Infectious Disease
Microbiology
oai:ir.lib.uwo.ca:immunologypub-1007
2009-10-12T01:29:01Z
publication:mnipub
publication:patholpub
publication:surgerypub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:pathol
publication:med
publication:mni
publication:robarts
publication:surgery
publication:institutes
RIP2 Is Required for NOD Signaling But Not for Th1 Cell Differentiation and Cellular Allograft Rejection
Fairhead, T.
Lian, D.
McCully, Michelle L.
Garcia, B.
Zhong, R.
Madrenas, J.
Two previous reports that receptor-interacting protein (RIP)-2 knockout (RIP2-/-) mice had defective nuclear factor-kappa B (NF-kappaB) signaling and T helper (Th)1 immune responses had led us to believe that this putative serine-threonine kinase might be a possible target for transplant immunosuppression. Thus, we tested whether RIP2-/- mice were able to reject vascularized allografts. Surprisingly, we found that T cells from RIP2-/- mice proliferated and produced interferon (IFN)-gamma after allostimulation in vitro. Moreover, naïve RIP2-/- CD4+ T cells differentiated normally into Th1 or Th2 cells under appropriate cytokine microenvironments. Consistent with these findings, no difference in allograft survival was observed between wild-type and RIP2-/- recipient mice, and rejection had similar pathology and cytokine profiles in both types of recipients. RIP2 deficiency was associated with defective NOD signaling, but this did not affect T-cell receptor (TCR)-dependent activation of the canonical NF-kappaB signaling or expression of NF-kappaB genes in rejecting allografts. Our data demonstrate that RIP2-deficient mice have intact canonical NF-kappaB signaling and can mount Th1-mediated alloresponses and reject vascularized allografts as efficiently as wild-type mice, thus arguing against RIP2 as a primary target for immunosuppression.
2008-06-01T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/7
http://www3.interscience.wiley.com/journal/120089580/abstract
Robarts Immunology and Transplantation Publications
Scholarship@Western
Animals
Cell Differentiation
Disease Models
Animal
Graft Rejection
Mice
NF-kappa B
Oxygenases
Receptor-Interacting Protein Serine-Threonine Kinases
Signal Transduction
Th1 Cells
Disease Models, Animal
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1006
2009-10-12T01:28:01Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Receptor-interacting Protein-2 Deficiency Delays Macrophage Migration and Increases Intracellular Infection during Peritoneal Dialysis-associated Peritonitis
McCully, Michelle L.
Fairhead, Todd
Colmont, Chantal S.
Beasley, Federico C.
Heinrichs, David E.
Blake, Peter G.
Topley, Nicholas
Madrenas, Joaquín
Background: Early upregulation of receptor-interacting protein-2 (RIP2) expression during peritoneal dialysis (PD)-associated peritonitis correlates with a favorable clinical outcome, while failure to upregulate RIP2 correlates with a protracted course. We noticed that patients who do not upregulate RIP2 during PD-associated peritonitis have more peritoneal macrophages during the early phase of infection.
Methods: To study the mechanism behind this observation, we examined the role of RIP2 in the immune response to bacterial challenge in a mouse model of acute peritonitis. We injected RIP2(+/+) and RIP2(-/-) mice intraperitoneally with a Staphylococcus epidermidis cell free-preparation, and peritoneal cells were isolated 3, 6 and 24 h after challenge.
Results: Surprisingly, RIP2(-/-) mice had a comparable influx of inflammatory leukocytes, but had a significantly higher number of peritoneal macrophages at 3 h, indicating delayed emigration of these cells. No significant differences were seen at later times suggesting that migration was delayed but not inhibited. In addition, RIP2(-/-) macrophages were more permissive to intracellular infection by Staphylococcus aureus, indicating that, in the absence of RIP2, resident peritoneal macrophages could become reservoirs of bacteria.
Conclusion: These findings provide a mechanism for the observation that upregulation of RIP2 expression is required for rapid resolution of peritonitis, by decreasing intracellular infection and by regulating the migration of antigen-presenting cells in the early stages of an inflammatory response.
2008-10-01T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/6
http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowAbstract&ArtikelNr=141041&Ausgabe=239023&ProduktNr=223979
Robarts Immunology and Transplantation Publications
Scholarship@Western
Animals
Cell Movement
Cell-Free System
Humans
Infection
Inflammation
Macrophages
Mice
Mice
Transgenic
Models
Biological
Peritoneal Dialysis
Peritonitis
Receptor-Interacting Protein Serine-Threonine Kinase 2
Staphylococcus epidermidis
Time Factors
Mice, Transgenic
Models, Biological
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1009
2011-10-25T05:12:32Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Receptor-interacting Protein 2 Is a Marker for Resolution of Peritoneal Dialysis-associated Peritonitis
McCully, Michelle L.
Baroja, M. L.
Chau, T. A.
Jain, A. K.
Barra, L.
Salgado, A.
Blake, P. G.
Madrenas, Joaquin
There are no predictive factors for peritoneal dialysis-associated peritonitis; however, its resolution correlates with a cell-mediated Th1 immune response. We tested the hypothesis that induction of receptor-interacting protein 2 (RIP2), an assumed kinase linked with Th1 responses, is a useful marker in this clinical setting. Basal RIP2 expression was measured in human immune cells and during dialysis-associated peritonitis. RIP2 increased with bacterial toxin cell activation and the temporal profile for this differed depending on immune cell involvement in the innate or adaptive phases of the response. Importantly, RIP2 expression increased in peritoneal immune cells during dialysis-associated peritonitis and this upregulation correlated with clinical outcome. An early induction in peritoneal CD14(+) cells correlated with rapid resolution, whereas minimal induction correlated with protracted infection and with catheter loss in 36% of patients. These latter patients had higher levels of MCP-1 consistent with a delayed transition from innate to adaptive immunity. Our study shows that upregulation of RIP2 is a useful marker to monitor dialysis-associated peritonitis and in predicting the clinical outcome of these infections.
2007-11-01T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/9
info:doi/10.1159/000141041
http://dx.doi.org/10.1159/000141041
Robarts Immunology and Transplantation Publications
Scholarship@Western
Adult
Aged
Antigens
CD14
Biological Markers
Female
Humans
Interleukin-12 Subunit p35
Leukocytes
Mononuclear
Lipopolysaccharides
Male
Middle Aged
Peptidoglycan
Peritoneal Dialysis
Peritonitis
RNA
Messenger
Receptor-Interacting Protein Serine-Threonine Kinase 2
Teichoic Acids
Tetradecanoylphorbol Acetate
Toll-Like Receptor 2
Toll-Like Receptor 4
Up-Regulation
Antigens, CD14
Leukocytes, Mononuclear
RNA, Messenger
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1008
2009-10-12T01:07:22Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Molecular Determinants of Inverse Agonist Activity of Biologicals Targeting CTLA-4
Teft, Wendy A.
Madrenas, Joaquín
Ligation of CD28 or CTLA-4 with some biologicals can activate T cells due to an unexpected superagonist or inverse agonist activity, respectively. The risk of such an outcome limits the therapeutic development of these reagents. Thus, identifying the molecular determinants of superagonist/inverse agonist properties for biologicals targeting costimulatory/inhibitory receptors has not only fundamental value but also important therapeutic implications. In this study, we show that ligation of CTLA-4 with either soluble B7.1 Ig (but not B7.2 Ig) or with a recombinant bispecific in-tandem single chain Fv known as 24:26 induces TCR-independent, T cell activation. Such an inverse agonist activity requires CD28 expression and high CTLA-4 expression and is not seen when CTLA-4 is ligated by membrane-bound B7.1 or B7.2. At the molecular level, the inverse agonist activity of B7.1 Ig or 24:26 correlates with their ability to induce the formation of unique dimer-based, CTLA-4 oligomers on the T cell surface and involves CTLA-4 signaling through its cytoplasmic domain. Our results provide a potential mechanism to explain and to predict inverse agonist activity for CTLA-4 ligands.
2007-09-15T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/8
http://www.jimmunol.org/cgi/content/abstract/179/6/3631
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antibodies
Bispecific
Antigens
CD
Antigens
CD80
Antigens
Differentiation
Cytoplasm
Dimerization
Doxycycline
Drug Delivery Systems
Growth Inhibitors
Humans
Jurkat Cells
Ligands
Lymphocyte Activation
Sequence Deletion
Signal Transduction
T-Lymphocytes
Antibodies, Bispecific
Antigens, CD
Antigens, CD80
Antigens, Differentiation
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1010
2009-10-12T22:31:54Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
T Cell Signalling Induced by Bacterial Superantigens
Bueno, Clara
Criado, Gabriel
McCormick, John K.
Madrenas, Joaquín
Bacterial superantigens (SAgs) constitute a large family of bacterial toxins that share the capacity to induce massive activation of the human immune system. Such a feature is based on the ability of these toxins to activate T cells that express Beta-chains of the T cell antigen receptor (TCR) containing variable regions (V) coded by specific families of VBeta genes. In addition, bacterial SAgs bypass the need for processing by antigen-presenting cells by directly binding to major histocompatibility complex class II molecules on the surface of these cells. Emerging work indicates that bacterial SAgs utilize not only the canonical pathways of TCR-mediated T cell activation but also other pathways. Here, we review the structural information on recognition of bacterial SAgs by T cells, the TCR signalling induced by this recognition event, and the effector functions that this recognition triggers. We analyze experimental evidence suggesting the existence of alternative receptors and coreceptors for bacterial SAgs, and outline future challenges in the research with these toxins.
2007-01-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/10
http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowAbstractBuch&ArtikelNr=100894&ProduktNr=232832
Robarts Immunology and Transplantation Publications
Scholarship@Western
Animals
Antigens
CD28
Histocompatibility Antigens Class II
Humans
Lymphocyte Activation
Receptors
Antigen
T-Cell
Signal Transduction
Staphylococcus
Streptococcus
Superantigens
T-Lymphocytes
Antigens, CD28
Receptors, Antigen, T-Cell
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1015
2009-10-12T23:32:06Z
publication:mnipub
publication:anatomy
publication:biophysicspub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:anatomypub
publication:med
publication:biophysics
publication:biochempub
publication:mni
publication:robarts
publication:biochem
publication:institutes
Wilms’ Tumor 1–Associating Protein Regulates the Proliferation of Vascular Smooth Muscle Cells
Small, Theodore W.
Bolender, Zuzana
Bueno, Clara
O'Neil, Caroline
Nong, Zengxuan
Rushlow, Walter
Rajakumar, Nagalingham
Kandel, Christopher
Strong, Jennifer
Madrenas, Joaquin
Pickering, J. Geoffrey
Smooth muscle cells (SMCs) are called on to proliferate during vascular restructuring but must return to a nonproliferative state if remodeling is to appropriately terminate. To identify mediators of the reacquisition of replicative quiescence, we undertook gene expression screening in a uniquely plastic human SMC line. As proliferating SMCs shifted to a contractile and nonproliferative state, expression of TIMP-3, Axl, and KIAA0098 decreased whereas expression of complement C1s, cathepsin B, cellular repressor of E1A-activated genes increased. Wilms' tumor 1-associating protein (WTAP), a nuclear constituent of unknown function, was also upregulated as SMCs became nonproliferative. Furthermore, WTAP in the intima of injured arteries was substantially upregulated in the late stages of repair. Introduction of WTAP complementary DNA into human SMCs inhibited their proliferation, with a corresponding decrease in DNA synthesis and an increase in apoptosis. Knocking down endogenous WTAP increased SMC proliferation, because of increased DNA synthesis and G(1)/S phase transition, together with reduced apoptosis. WTAP was found to associate with the Wilms' tumor-1 protein in human SMCs and WTAP overexpression inhibited the binding of WT1 to an oligonucleotide containing a consensus WT1 binding site, whereas WTAP knockdown accentuated this interaction. Expression of the WT1 target genes, amphiregulin and Bcl-2, was suppressed in WTAP-overexpressing SMCs and increased in WTAP-deficient SMCs. Moreover, exogenous amphiregulin rescued the antiproliferative effect of WTAP. These findings identify WTAP as a novel regulator of the cell cycle and cell survival and implicate a WTAP-WT1 axis as a novel pathway for controlling vascular SMC phenotype.
2006-12-08T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/14
http://circres.ahajournals.org/cgi/content/abstract/99/12/1338
Robarts Immunology and Transplantation Publications
Scholarship@Western
Angioplasty
Balloon
Animals
Aorta
Thoracic
Apoptosis
Carotid Artery Injuries
Carrier Proteins
Cell Division
Cell Line
DNA-Binding Proteins
Gene Silencing
Glycoproteins
Humans
Intercellular Signaling Peptides and Proteins
Male
Muscle
Smooth
Vascular
Nuclear Proteins
Rats
Rats
Inbred WKY
Rats
Sprague-Dawley
Transcription
Genetic
Up-Regulation
WT1 Proteins
Angioplasty, Balloon
Aorta, Thoracic
Muscle, Smooth, Vascular
Rats, Inbred WKY
Rats, Sprague-Dawley
Transcription, Genetic
Immunology and Infectious Disease
Medical Anatomy
Medical Biochemistry
Medical Biophysics
oai:ir.lib.uwo.ca:immunologypub-1013
2009-10-12T23:04:05Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
A Molecular Perspective of CTLA-4 Function
Teft, Wendy A.
Kirchhof, Mark G.
Madrenas, Joaquín
Within the paradigm of the two-signal model of lymphocyte activation, the interest in costimulation has witnessed a remarkable emergence in the past few years with the discovery of a large array of molecules that can serve this role, including some with an inhibitory function. Interest has been further enhanced by the realization of these molecules' potential as targets to modulate clinical immune responses. Although the therapeutic translation of mechanistic knowledge in costimulatory molecules has been relatively straightforward, the capacity to target their inhibitory counterparts has remained limited. This limited capacity is particularly apparent in the case of the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a major negative regulator of T cell responses. Because there have been several previous comprehensive reviews on the function of this molecule, we focus here on the physiological implications of its structural features. Such an exercise may ultimately help us to design immunotherapeutic agents that target CTLA-4.
2006-04-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/12
http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.immunol.24.021605.090535
Robarts Immunology and Transplantation Publications
Scholarship@Western
Amino Acid Sequence
Animals
Antigens
CD
Antigens
Differentiation
Biological Transport
Active
Dimerization
Evolution
Molecular
Humans
Ligands
Lymphocyte Activation
Models
Immunological
Molecular Biology
Molecular Sequence Data
Polymorphism
Genetic
Protein Structure
Quaternary
Sequence Homology
Amino Acid
Signal Transduction
T-Lymphocytes
Antigens, CD
Antigens, Differentiation
Biological Transport, Active
Evolution, Molecular
Models, Immunological
Polymorphism, Genetic
Protein Structure, Quaternary
Sequence Homology, Amino Acid
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1011
2009-10-12T22:40:24Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
The Immunological Synapse as a Novel Therapeutic Target
Teft, Wendy A.
Madrenas, Joaquin
The onset of adaptive immune responses includes the presentation of foreign antigenic peptides to T-cells, and the formation of a T-cell-antigen-presenting cell interface termed the immunological synapse (IS). Although the generation of a mature IS is thought to be the hallmark of T-cell activation, new evidence suggests that microclusters ofat signaling molecules at the periphery of the IS are responsible for initiating and maintaining T-cell activation while the core of the IS provides a platform for signal downregulation. In this context, costimulatory molecules and self-peptides contribute to sustain the signaling required for T-lymphocyte differentiation into effector cells. This review discusses these aspects in the identification of novel candidates for therapeutic modulation of immune responses.
2006-10-26T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/11
http://www.biomedcentral.com/1472-4472/7/1008/abstract
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antigen Presentation
Antigen-Presenting Cells
Drug Design
Epitopes
T-Lymphocyte
Humans
Lymphocyte Activation
Receptors
Antigen
T-Cell
Signal Transduction
Technology
Pharmaceutical
Epitopes, T-Lymphocyte
Receptors, Antigen, T-Cell
Technology, Pharmaceutical
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1014
2009-10-12T23:14:01Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Dendritic Cells as Arbiters of Peritoneal Immune Responses
McCully, Michelle L.
Madrenas, Joaquín
During the past few years, there has been a substantial increase in the understanding of innate immunity. Dendritic cells are emerging as key players in the orchestration of this early phase of immune responses, with a role that will translate into the subsequent type of adaptive immune response against infection. Here we provide an overview of dendritic cell differentiation and function, with particular emphasis on those features unique to the immune defense of the peritoneal cavity and in the context of peritoneal dialysis-associated immune responses. The reader is referred to the primary references included in the accompanying list for specific details in this fascinating field.
2006-01-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/13
http://www.pdiconnect.com/cgi/content/abstract/26/1/8
Robarts Immunology and Transplantation Publications
Scholarship@Western
Animals
Dendritic Cells
Humans
Immunity
Innate
Peritoneum
Immunity, Innate
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1017
2009-10-14T01:42:55Z
publication:mnipub
publication:physpharmpub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:physpharm
publication:mni
publication:robarts
publication:institutes
Bacterial Superantigens Bypass Lck-Dependent T Cell Receptor Signaling by Activating a Gα11-Dependent, PLC-β-Mediated Pathway
Bueno, Clara
Lemke, Caitlin D.
Criado, Gabriel
Baroja, Miren L.
Ferguson, Stephen S. G.
Rahman, A. K. M. Nur-Ur
Tsoukas, Constantine D.
McCormick, John K.
Madrenas, Joaquin
The paradigm to explain antigen-dependent T cell receptor (TCR) signaling is based on the activation of the CD4 or CD8 coreceptor-associated kinase Lck. It is widely assumed that this paradigm is also applicable to signaling by bacterial superantigens. However, these bacterial toxins can activate human T cells lacking Lck, suggesting the existence of an additional pathway of TCR signaling. Here we showed that this alternative pathway operates in the absence of Lck-dependent tyrosine-phosphorylation events and was initiated by the TCR-dependent activation of raft-enriched heterotrimeric Galpha11 proteins. This event, in turn, activated a phospholipase C-beta and protein kinase C-mediated cascade that turned on the mitogen-activated protein kinases ERK-1 and ERK-2, triggered Ca(2+) influx, and translocated the transcription factors NF-AT and NF-kappaB to the nucleus, ultimately inducing the production of interleukin-2 in Lck-deficient T cells. The triggering of this alternative pathway by superantigens suggests that these toxins use a G protein-coupled receptor as a coreceptor on T cells.
2006-07-01T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/17
http://www.cell.com/immunity/abstract/S1074-7613%2806%2900299-8
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antigens
Bacterial
Antigens
CD4
Calcium
Cells
Cultured
Enterotoxins
Enzyme Activation
Extracellular Signal-Regulated MAP Kinases
GTP-Binding Protein alpha Subunits
Gq-G11
Humans
Interleukin-2
Isoenzymes
Lymphocyte Activation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Phospholipase C beta
Phosphoserine
Protein Kinase C
Receptors
Antigen
T-Cell
Signal Transduction
Superantigens
Type C Phospholipases
Antigens, Bacterial
Antigens, CD4
Cells, Cultured
GTP-Binding Protein alpha Subunits, Gq-G11
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Receptors, Antigen, T-Cell
Immunology and Infectious Disease
Medical Physiology
oai:ir.lib.uwo.ca:nursingpub-1144
2010-02-01T02:14:36Z
publication:kin
publication:pmid
publication:faculties
publication:medpub
publication:kinpub
publication:med
publication:healthstudies
publication:nursing
publication:nursingpub
publication:healthstudiespub
Perceiving Falls within a Family Context: A Focused Ethnographic Approach
Kilian, Christine
Salmoni, Alan
Ward-Griffin, Catherine
Kloseck, Marita
The purpose of the present research was to examine the perceptions of risk regarding falling held by older adults and their adult children. Using a focused ethnographic approach, older adults and adult children were interviewed in depth. Thematic analysis was conducted to identify themes within groups and to compare the perspectives of older adults and adult children. Findings highlighted differences in perceptions and approaches to action between older adults and their adult children. There were three approaches to action adopted by these families, which focused around whose actions were dominant: parents' actions, shared actions, and children's secret actions. The results emphasize the value placed on independence by older adults and the impact of multiple family relations taking action to prevent falls. The present study points to the importance of including multiple family perspectives in research concerning injury prevention for older adults.
2008-01-01T08:00:00Z
article
https://ir.lib.uwo.ca/nursingpub/135
info:doi/10.1353/cja.0.0039
http://muse.jhu.edu/journals/canadian_journal_on_aging/summary/v027/27.4.kilian.html
Nursing Publications
Scholarship@Western
aging
risk perception
falls
falls prevention
focused ethnography
family dynamics
Nursing
oai:ir.lib.uwo.ca:immunologypub-1018
2009-10-19T23:44:28Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Complement Regulatory Protein Crry/p65-mediated Signaling in T Lymphocytes: Role of Its Cytoplasmic Domain and Partitioning into Lipid Rafts
Jiménez-Periañez, Arturo
Ojeda, Gloria
Criado, Gabriel
Sánchez, Alejandra
Pini, Eliana
Madrenas, Joaquín
Rojo, Jose Maria
Portolés, Pilar
Crry/p65 is a type I glycoprotein, which protects mouse T cells from complement attack. We have previously shown that complement receptor I-related protein Crry/p65 (Crry) ligation has a costimulatory effect on mouse CD4+ T cell activation. Here, we have examined the mechanisms responsible for Crry costimulation, addressing the question of whether Crry potentiates signal transduction starting at the T cell receptor (TCR)/CD3 complex or promotes distinct costimulatory signals. We show that Crry increases early TCR-dependent activation signals, including p56lck-, zeta-associated protein-70 (ZAP-70), Vav-1, Akt, and extracellular signal-regulated kinase (ERK) phosphorylation but also costimulation-dependent mitogen-activated protein kinases (MAPK), such as the stress-activated c-Jun N-terminal kinase (JNK). It is intriguing that Crry costimulus enhanced p38 MAPK activation in T helper cell type 1 (Th1) but not in Th2 cells. A fraction of Crry is found consistently in the detergent-insoluble membrane fraction of Th1 or Th2 cells or CD4+ lymphoblasts. Crry costimulation induced clustering of lipid rafts, increasing their content in Crry, CD3epsilon, and p59-60 forms of p56lck, and caused actin polymerization close to the site of activation in Th2 cells. Such events were inhibited by wortmannin, suggesting a role for phosphatidylinositol-3 kinase in these effects. The Crry cytoplasmic domain was required for JNK activation and interleukin-4 secretion but not for the presence of Crry in rafts or activation of p56lck, ZAP-70, Akt, Vav-1, or ERK. This suggests that Crry costimulation involves two different but not mutually exclusive signal transduction modules. The dual function of Crry as a complement regulatory protein and as a T cell costimulator illustrates the importance of complement regulatory proteins as links between innate and adaptive immunity.
2005-12-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/18
http://www.jleukbio.org/cgi/content/abstract/78/6/1386
Robarts Immunology and Transplantation Publications
Scholarship@Western
Animals
Antigens
CD3
Cell Line
Cytoplasm
Extracellular Signal-Regulated MAP Kinases
Immunity
Innate
JNK Mitogen-Activated Protein Kinases
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Membrane Microdomains
Mice
Oncogene Protein v-akt
Protein Structure
Tertiary
Proto-Oncogene Proteins c-vav
Receptors
Complement
Signal Transduction
T-Lymphocytes
Th1 Cells
ZAP-70 Protein-Tyrosine Kinase
p38 Mitogen-Activated Protein Kinases
Antigens, CD3
Immunity, Innate
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Protein Structure, Tertiary
Receptors, Complement
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1019
2009-10-19T23:55:03Z
publication:mnipub
publication:hismed
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:hismedpub
publication:med
publication:mni
publication:robarts
publication:institutes
publication:campusunits
Giving Credit Where Credit Is Due: John Hunter and the Discovery of Erythrocyte Sedimentation Rate
Madrenas, Joaquín
Potter, Paul
Cairns, Ewa
2005-12-17T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/19
http://dx.doi.org/10.1016/S0140-6736(05)67337-0
Robarts Immunology and Transplantation Publications
Scholarship@Western
Blood Sedimentation
Great Britain
History
18th Century
History, 18th Century
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:medpub-1019
2010-07-26T15:52:40Z
publication:pmid
publication:faculties
publication:medpub
publication:med
Quantitative Gait Analysis under Dual-task in Older People with Mild Cognitive Impairment: A Reliability Study
Montero-Odasso, Manuel
Casas, Alvaro
Hansen, Kevin T.
Bilski, Patricia
Gutmanis, Iris
Wells, Jennie L.
Borrie, Michael J.
Background: Reliability of quantitative gait assessment while dual-tasking (walking while doing a secondary task such as talking) in people with cognitive impairment is unknown. Dual-tasking gait assessment is becoming highly important for mobility research with older adults since better reflects their performance in the basic activities of daily living. Our purpose was to establish the test-retest reliability of assessing quantitative gait variables using an electronic walkway in older adults with mild cognitive impairment (MCI) under single and dual-task conditions.
Methods: The gait performance of 11 elderly individuals with MCI was evaluated using an electronic walkway (GAITRite System) in two sessions, one week apart. Six gait parameters (gait velocity, step length, stride length, step time, stride time, and double support time) were assessed under two conditions: single-task (sG: usual walking) and dual-task (dG: counting backwards from 100 while walking). Test-retest reliability was determined using intra-class correlation coefficient (ICC). Gait variability was measured using coefficient of variation (CoV).
Results: Eleven participants (average age = 76.6 years, SD = 7.3) were assessed. They were high functioning (Clinical Dementia Rating Score = 0.5) with a mean Mini-Mental Status Exam (MMSE) score of 28 (SD = 1.56), and a mean Montreal Cognitive Assessment (MoCA) score of 22.8 (SD = 1.23). Under dual-task conditions, mean gait velocity (GV) decreased significantly (sGV = 119.11 +/- 20.20 cm/s; dGV = 110.88 +/- 19.76 cm/s; p = 0.005). Additionally, under dual-task conditions, higher gait variability was found on stride time, step time, and double support time. Test-retest reliability was high (ICC>0.85) for the six parameters evaluated under both conditions.
Conclusion: In older people with MCI, variability of time-related gait parameters increased with dual-tasking suggesting cognitive control of gait performance. Assessment of quantitative gait variables using an electronic walkway is highly reliable under single and dual-task conditions. The presence of cognitive impairment did not preclude performance of dual-tasking in our sample supporting that this methodology can be reliably used in cognitive impaired older individuals.
2009-09-21T07:00:00Z
article
https://ir.lib.uwo.ca/medpub/14
info:doi/10.1186/1743-0003-6-35
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754991/
Department of Medicine Publications
Scholarship@Western
Senior
Cognitive impairment
Elderly
Geriatrics
Neurology
oai:ir.lib.uwo.ca:medpub-1020
2009-11-10T17:08:42Z
publication:pmid
publication:faculties
publication:medpub
publication:med
Dual-tasking and Gait in People with Mild Cognitive Impairment. The Effect of Working Memory
Montero-Odasso, Manuel
Bergman, Howard
Phillips, Natalie A.
Wong, Chek H.
Sourial, Nadia
Chertkow, Howard
Background: Cognition and mobility in older adults are closely associated and they decline together with aging. Studies evaluating associations between cognitive factors and gait performance in people with Mild Cognitive Impairment (MCI) are scarce. In this study, our aim was to determine whether specific cognitive factors have a more identifiable effect on gait velocity during dual-tasking in people with MCI.
Methods: Fifty-five participants, mean age 77.7 (SD = 5.9), 45% women, with MCI were evaluated for global cognition, working memory, executive function, and attention. Gait Velocity (GV) was measured under a single-task condition (single GV) and under two dual-task conditions: 1) while counting backwards (counting GV), 2) while naming animals (verbal GV). Multivariable linear regression analysis was used to examine associations with an alpha-level of 0.05.
Results: Participants experienced a reduction in GV while engaging in dual-task challenges (p < 0.005). Low executive function and working memory performances were associated with slow single GV (p = 0.038), slow counting GV (p = 0.017), and slow verbal GV (p = 0.031). After adjustments, working memory was the only cognitive factor which remained significantly associated with a slow GV.
Conclusion: In older adults with MCI, low working memory performance was associated with slow GV. Dual-task conditions showed the strongest associations with gait slowing. Our findings suggest that cortical control of gait is associated with decline in working memory in people with MCI.
2009-09-01T07:00:00Z
article
https://ir.lib.uwo.ca/medpub/13
http://www.biomedcentral.com/1471-2318/9/41
Department of Medicine Publications
Scholarship@Western
Cognitive Impairment
working memory
Geriatrics
Neurology
oai:ir.lib.uwo.ca:medpub-1021
2009-11-14T09:04:30Z
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:epidem
publication:epidempub
Can Cognitive Enhancers Reduce the Risk of Falls in Older People with Mild Cognitive Impairment? A Protocol for a Randomised Controlled Double Blind Trial
Montero-Odasso, Manuel
Wells, Jennie L.
Borrie, Michael J.
Speechley, Mark
Background: Older adults with cognitive problems have a higher risk of falls, at least twice that of cognitively normal older adults. The consequences of falls in this population are very serious: fallers with cognitive problems suffer more injuries due to falls and are approximately five times more likely to be admitted to institutional care. Although the mechanisms of increased fall risk in cognitively impaired people are not completely understood, it is known that impaired cognitive abilities can reduce attentional resource allocation while walking. Since cognitive enhancers, such as cholinesterase inhibitors, improve attention and executive function, we hypothesise that cognitive enhancers may reduce fall risk in elderly people in the early stages of cognitive decline by improving their gait and balance performance due to an enhancement in attention and executive function.
Method/Design: Double blinded randomized controlled trial with 6 months follow-up in 140 older individuals with Mild Cognitive Impairment (MCI). Participants will be randomized to the intervention group, receiving donepezil, and to the control group, receiving placebo. A block randomization by four and stratification based on fall history will be performed. Primary outcomes are improvements in gait velocity and reduction in gait variability. Secondary outcomes are changes in the balance confidence, balance sway, attention, executive function, and number of falls.
Discussion: By characterizing and understanding the effects of cognitive enhancers on fall risk in older adults with cognitive impairments, we will be able to pave the way for a new approach to fall prevention in this population. This RCT study will provide, for the first time, information regarding the effect of a medication designed to augment cognitive functioning have on the risk of falls in older adults with Mild Cognitive Impairment. We expect a significant reduction in the risk of falls in this vulnerable population as a function of the reduced gait variability achieved by treatment with cognitive enhancers. This study may contribute to a new approach to prevent and treat fall risk in seniors in early stages of dementia.
Trial Registration: The protocol for this study is registered with the Clinical Trials Registry, identifier number: NCT00934531 http://www.clinicaltrials.gov.
2009-08-12T07:00:00Z
article
https://ir.lib.uwo.ca/medpub/15
info:doi/10.1186/1471-2377-9-42
http://www.biomedcentral.com/1471-2377/9/42
Department of Medicine Publications
Scholarship@Western
Accidental Falls
Aged
Aged
80 and over
Cholinesterase Inhibitors
Clinical Protocols
Cognition Disorders
Community-Based Participatory Research
Double-Blind Method
Female
Gait
Humans
Indans
Male
Patient Selection
Piperidines
Treatment Outcome
Aged, 80 and over
Cognition and Perception
Neurology
oai:ir.lib.uwo.ca:medpub-1022
2009-11-21T00:51:00Z
publication:pmid
publication:faculties
publication:medpub
publication:med
Tenecteplase for ST-elevation Myocardial Infarction in a Patient treated with Drotrecogin Alfa (Activated) for Severe Sepsis: A Case Report
Barra, Lillian
Shum, Jeffrey
Pickering, J Geoffrey
Kao, Raymond
Introduction: Drotrecogin alfa (activated) (DrotAA), an activated protein C, promotes fibrinolysis in patients with severe sepsis. There are no reported cases or studies that address the diagnosis and treatment of myocardial infarction in septic patients treated with DrotAA.
Case presentation: A 59-year-old Caucasian man with septic shock secondary to community-acquired pneumonia treated with DrotAA, subsequently developed an ST-elevation myocardial infarction 12 hours after starting DrotAA. DrotAA was stopped and the patient was given tenecteplase thrombolysis resulting in complete resolution of ST-elevation and no adverse bleeding events. DrotAA was restarted to complete the 96-hour course. The sepsis resolved and the patient was discharged from hospital.
Conclusion: In patients with severe sepsis or septic shock complicated by myocardial infarction, it is difficult to determine if the myocardial infarction is an isolated event or caused by the sepsis process. The efficacy and safety of tenecteplase thrombolysis in septic patients treated with DrotAA need further study.
2009-11-05T08:00:00Z
article
https://ir.lib.uwo.ca/medpub/16
info:doi/10.1186/1752-1947-3-109
http://www.jmedicalcasereports.com/content/3/1/109
Department of Medicine Publications
Scholarship@Western
myocardial infarction
Tenecteplase
sepsis
Medicine and Health Sciences
oai:ir.lib.uwo.ca:medpub-1023
2009-11-23T06:57:17Z
publication:pmid
publication:faculties
publication:medpub
publication:med
The Utilization of Appropriate Osteoporosis Medications Improves following a Multifaceted Educational Intervention: The Canadian Quality Circle Project (CQC)
Ioannidis, George
Papaioannou, Alexandra
Thabane, Lehana
Gafni, Amiram
Hodsman, Anthony
Kvern, Brent
Walsh, Aleksandra
Jiwa, Famida
Adachi, Jonathan D.
Background: Osteoporosis is a serious but treatable condition. However, appropriate therapy utilization of the disease remains suboptimal. Thus, the objective of the study was to change physicians' therapy administration behavior in accordance with the Osteoporosis Canada 2002 guidelines.
Methods: The Project was a two year cohort study that consisted of five Quality Circle (QC) phases that included: 1) Training & Baseline Data Collection, 2) First Educational Intervention & First Follow-Up Data Collection 3) First Strategy Implementation Session, 4) Final Educational Intervention & Final Follow-up Data Collection, and 5) Final Strategy Implementation Session. A total of 340 family physicians formed 34 QCs and participated in the study. Physicians evaluated a total of 8376, 7354 and 3673 randomly selected patient charts at baseline, follow-up #1 and the final follow-up, respectively. Patients were divided into three groups; the high-risk, low-risk, and low-risk without fracture groups. The generalized estimating equations technique was utilized to model the change over time of whether physicians
Results: The odds of appropriate therapy was 1.29 (95% CI: 1.13, 1.46), and 1.41 (95% CI: 1.20, 1.66) in the high risk group, 1.15 (95% CI: 0.97, 1.36), and 1.16 (95% CI: 0.93, 1.44) in the low risk group, and 1.20 (95% CI: 1.01, 1.43), and 1.23 (95% CI: 0.97, 1.55) in the low risk group without fractures at follow-up #1 and the final follow-up, respectively.
Conclusion: QCs methodology was successful in increasing physicians' appropriate use of osteoporosis medications in accordance with Osteoporosis Canada guidelines.
2009-08-06T07:00:00Z
article
https://ir.lib.uwo.ca/medpub/17
info:doi/10.1186/1472-6920-9-54
http://www.biomedcentral.com/1472-6920/9/54
Department of Medicine Publications
Scholarship@Western
Canadian quality circle
osteoporosis
Medicine and Health Sciences
oai:ir.lib.uwo.ca:kinpub-1004
2012-02-11T23:57:13Z
publication:kin
publication:fammedpub
publication:fammed
publication:rwkex_researcharticles
publication:physpharmpub
publication:pmid
publication:faculties
publication:medpub
publication:rwkex
publication:kinpub
publication:physmed
publication:med
publication:physpharm
publication:healthstudies
publication:physmedpub
publication:healthstudiespub
The Use of Group Dynamics Strategies to Enhance Cohesion in a Lifestyle Intervention Program for Obese Children
Martin, Luc J.
Burke, Shauna M.
Shapiro, Sheree
Carron, Albert V.
Irwin, Jennifer D.
Petrella, Robert
Prapavessis, Harry
Shoemaker, Kevin
Background: Most research pertaining to childhood obesity has assessed the effectiveness of preventative interventions, while relatively little has been done to advance knowledge in the treatment of obesity. Thus, a 4-week family- and group-based intervention utilizing group dynamics strategies designed to increase cohesion was implemented to influence the lifestyles and physical activity levels of obese children.
Methods/Design: This paper provides an overview of the rationale for and implementation of the intervention for obese children and their families. Objectives of the intervention included the modification of health behaviors and cohesion levels through the use of group dynamics strategies. To date, a total of 15 children (7 boys and 8 girls, mean age = 10.5) and their families have completed the intervention (during the month of August 2008). Physiological and psychological outcomes were assessed throughout the 4-week intervention and at 3-, 6-, and 12-month follow-up periods.
Discussion: It is believed that the information provided will help researchers and health professionals develop similar obesity treatment interventions through the use of evidence-based group dynamics strategies. There is also a need for continued research in this area, and it is our hope that the Children's Health and Activity Modification Program (C.H.A.M.P.) will provide a strong base from which others may build.
2009-07-31T07:00:00Z
article
https://ir.lib.uwo.ca/kinpub/5
info:doi/10.1186/1471-2458-9-277
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2723112/
Kinesiology Publications
Scholarship@Western
Group dynamics
Obesity
Children
Lifestyle intervention
Kinesiology
Public Health
oai:ir.lib.uwo.ca:medpub-1024
2010-06-21T23:59:10Z
publication:fammedpub
publication:clinicalpub
publication:fammed
publication:philosophy
publication:pmid
publication:faculties
publication:philosophypub
publication:medpub
publication:med
publication:epidem
publication:robarts
publication:rotman
publication:rotmanpub
publication:institutes
publication:epidempub
Ethical and Policy Issues in Cluster Randomized Trials: Rationale and Design of a Mixed Methods Research Study
Taljaard, Monica
Weijer, Charles
Grimshaw, Jeremy M.
Brown, Judith Belle
Binik, Ariella
Boruch, Robert
Brehaut, Jamie C.
Chaudhry, Shazia H.
Eccles, Martin P.
McRae, Andrew
Saginur, Raphael
Zwarenstein, Merrick
Donner, Allan
Background: Cluster randomized trials are an increasingly important methodological tool in health research. In cluster randomized trials, intact social units or groups of individuals, such as medical practices, schools, or entire communities--rather than individual themselves--are randomly allocated to intervention or control conditions, while outcomes are then observed on individual cluster members. The substantial methodological differences between cluster randomized trials and conventional randomized trials pose serious challenges to the current conceptual framework for research ethics. The ethical implications of randomizing groups rather than individuals are not addressed in current research ethics guidelines, nor have they even been thoroughly explored. The main objectives of this research are to: (1) identify ethical issues arising in cluster trials and learn how they are currently being addressed; (2) understand how ethics reviews of cluster trials are carried out in different countries (Canada, the USA and the UK); (3) elicit the views and experiences of trial participants and cluster representatives; (4) develop well-grounded guidelines for the ethical conduct and review of cluster trials by conducting an extensive ethical analysis and organizing a consensus process; (5) disseminate the guidelines to researchers, research ethics boards (REBs), journal editors, and research funders.
Methods: We will use a mixed-methods (qualitative and quantitative) approach incorporating both empirical and conceptual work. Empirical work will include a systematic review of a random sample of published trials, a survey and in-depth interviews with trialists, a survey of REBs, and in-depth interviews and focus group discussions with trial participants and gatekeepers. The empirical work will inform the concurrent ethical analysis which will lead to a guidance document laying out principles, policy options, and rationale for proposed guidelines. An Expert Panel of researchers, ethicists, health lawyers, consumer advocates, REB members, and representatives from low-middle income countries will be appointed. A consensus conference will be convened and draft guidelines will be generated by the Panel; an e-consultation phase will then be launched to invite comments from the broader community of researchers, policy-makers, and the public before a final set of guidelines is generated by the Panel and widely disseminated by the research team.
2009-07-28T07:00:00Z
article
https://ir.lib.uwo.ca/medpub/18
info:doi/10.1186/1745-6215-10-61
http://dx.doi.org/10.1186/1745-6215-10-61
Department of Medicine Publications
Scholarship@Western
Clinical Trials Data Monitoring Committees
Focus Groups
Guidelines as Topic
Health Policy
Humans
Randomized Controlled Trials as Topic
Research Design
Ethics and Political Philosophy
Medicine and Health Sciences
Philosophy of Science
oai:ir.lib.uwo.ca:medpub-1025
2010-07-09T20:20:16Z
publication:pmid
publication:faculties
publication:medpub
publication:med
Stopping Randomized Trials Early for Benefit: A Protocol of the Study Of Trial Policy Of Interim Truncation-2 (STOPIT-2)
Briel, Matthias
Lane, Melanie
Montori, Victor M.
Bassler, Dirk
Glasziou, Paul
Malaga, German
Akl, Elie A.
Ferreira-Gonzalez, Ignacio
Alonso-Coello, Pablo
Urrutia, Gerard
Kunz, Regina
Culebro, Carolina Ruiz
da Silva, Suzana Alves
Flynn, David N.
Elamin, Mohamed B.
Strahm, Brigitte
Murad, M. Hassan
Djulbegovic, Benjamin
Adhikari, Neill K. J.
Mills, Edward J.
Gwadry-Sridhar, Femida
Kirpalani, Haresh
Soares, Heloisa P.
Abu Elnour, Nisrin O.
You, John J.
Karanicolas, Paul J.
Bucher, Heiner C.
Lampropulos, Julianna F.
Nordmann, Alain J.
Burns, Karen E. A.
Mulla, Sohail M.
Raatz, Heike
Sood, Amit
Kaur, Jagdeep
Bankhead, Clare R.
Mullan, Rebecca J.
Nerenberg, Kara A.
Vandvik, Per Olav
Coto-Yglesias, Fernando
Schünemann, Holger
Tuche, Fabio
Chrispim, Pedro Paulo M.
Cook, Deborah J.
Lutz, Kristina
Ribic, Christine M.
Vale, Noah
Erwin, Patricia J.
Perera, Rafael
Zhou, Qi
Heels-Ansdell, Diane
Ramsay, Tim
Walter, Stephen D.
Guyatt, Gordon H.
Background: Randomized clinical trials (RCTs) stopped early for benefit often receive great attention and affect clinical practice, but pose interpretational challenges for clinicians, researchers, and policy makers. Because the decision to stop the trial may arise from catching the treatment effect at a random high, truncated RCTs (tRCTs) may overestimate the true treatment effect. The Study Of Trial Policy Of Interim Truncation (STOPIT-1), which systematically reviewed the epidemiology and reporting quality of tRCTs, found that such trials are becoming more common, but that reporting of stopping rules and decisions were often deficient. Most importantly, treatment effects were often implausibly large and inversely related to the number of the events accrued. The aim of STOPIT-2 is to determine the magnitude and determinants of possible bias introduced by stopping RCTs early for benefit.
Methods/Design: We will use sensitive strategies to search for systematic reviews addressing the same clinical question as each of the tRCTs identified in STOPIT-1 and in a subsequent literature search. We will check all RCTs included in each systematic review to determine their similarity to the index tRCT in terms of participants, interventions, and outcome definition, and conduct new meta-analyses addressing the outcome that led to early termination of the tRCT. For each pair of tRCT and systematic review of corresponding non-tRCTs we will estimate the ratio of relative risks, and hence estimate the degree of bias. We will use hierarchical multivariable regression to determine the factors associated with the magnitude of this ratio. Factors explored will include the presence and quality of a stopping rule, the methodological quality of the trials, and the number of total events that had occurred at the time of truncation.Finally, we will evaluate whether Bayesian methods using conservative informative priors to "regress to the mean" overoptimistic tRCTs can correct observed biases.
Discussion: A better understanding of the extent to which tRCTs exaggerate treatment effects and of the factors associated with the magnitude of this bias can optimize trial design and data monitoring charters, and may aid in the interpretation of the results from trials stopped early for benefit.
2009-07-06T07:00:00Z
article
https://ir.lib.uwo.ca/medpub/19
info:doi/10.1186/1745-6215-10-49
http://dx.doi.org/10.1186/1745-6215-10-49
Department of Medicine Publications
Scholarship@Western
Bayes Theorem
Bias (Epidemiology)
Clinical Trials Data Monitoring Committees
Decision Making
Evidence-Based Medicine
Humans
Randomized Controlled Trials as Topic
Treatment Outcome
Bias (Epidemiology)
Medicine and Health Sciences
oai:ir.lib.uwo.ca:immunologypub-1020
2009-11-29T09:58:43Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Virus Attachment and Replication Are Promoted after Acquisition of Host CD28 and CD152 by HIV-1
Giguere, Jean-Francois
Diou, Juliette
Madrenas, Joaquim
Tremblay, Michel J.
CD28 is constitutively expressed on CD4(+) cells, but its homologue CD152 is only weakly expressed after cell activation. To determine whether these 2 costimulatory molecules can be inserted into human immunodeficiency virus type 1 (HIV-1), virus was produced in CD28- and CD152-expressing Jurkat-derived cells. Both molecules were efficiently acquired by virions. Virus attachment and infectivity were more affected by CD152 than by CD28. Given that CD28/CD152-CD80/CD86 interactions play a dominant role in antigen presentation, it can thus be proposed that the association between virus-anchored host CD28/CD152 and cell-surface CD80/CD86 on target cells might have consequences for the transmission and pathogenesis of HIV-1.
2005-10-01T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/20
info:doi/10.1086/444426
http://www.journals.uchicago.edu/doi/abs/10.1086/444426
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antigens
CD
Antigens
CD28
Antigens
Differentiation
Down-Regulation
HIV-1
Humans
Jurkat Cells
Up-Regulation
Virion
Antigens, CD
Antigens, CD28
Antigens, Differentiation
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1021
2009-11-29T10:05:18Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Hierarchical Regulation of CTLA-4 Dimer-based Lattice Formation and its Biological Relevance for T cell Inactivation
Darlington, Peter J.
Kirchhof, Mark G.
Criado, Gabriel
Sondhi, Jitin
Madrenas, Joaquín
CTLA-4 is an activation-induced, homodimeric inhibitory receptor in T cells. Recent crystallographic reports have suggested that it may form lattice-like arrays on the cell surface upon binding B7.1/B7.2 (CD80, CD86) molecules. To test the biological relevance of these CTLA-4-B7 lattices, we introduced a C122A point mutation in human CTLA-4, because this residue was shown to be essential for dimerization in solution. Surprisingly, we found that up to 35% of C122A CTLA-4 dimerized in human T lymphocytes. Moreover, C122A CTLA-4 partitioned within lipid rafts, colocalized with the TCR in the immunological synapse, and inhibited T cell activation. C122-independent dimerization of CTLA-4 involved N-glycosylation, because further mutation of the N78 and N110 glycosylation sites abrogated dimerization. Despite being monomeric, the N78A/N110A/C122A triple mutant CTLA-4 localized in the immunological synapse and inhibited T cell activation. Such functionality correlated with B7-induced dimerization of these mutant molecules. Based on these data, we propose a model of hierarchical regulation of CTLA-4 oligomerization by which B7 binding ultimately determines the formation of dimer-dependent CTLA-4 lattices that may be necessary for triggering B7-dependent T cell inactivation.
2005-07-15T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/21
http://www.jimmunol.org/cgi/content/abstract/175/2/996
Robarts Immunology and Transplantation Publications
Scholarship@Western
Alanine
Antigens
CD
Antigens
CD80
Antigens
CD86
Antigens
Differentiation
Cell Line
Transformed
Cysteine
Dimerization
Disulfides
Glycosylation
Humans
Immunosuppressive Agents
Jurkat Cells
Ligands
Lymphocyte Activation
Membrane Glycoproteins
Membrane Microdomains
Point Mutation
Protein Binding
T-Lymphocytes
Antigens, CD
Antigens, CD80
Antigens, CD86
Antigens, Differentiation
Cell Line, Transformed
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1022
2009-11-29T10:14:22Z
publication:mnipub
publication:surgerypub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:surgery
publication:institutes
Characterization of Human Peritoneal Dendritic Cell Precursors and Their Involvement in Peritonitis
McCully, M. L.
Chau, T. A.
Luke, P.
Blake, P. G.
Madrenas, J.
Scattered evidence suggests that the human peritoneal cavity contains cells of the dendritic cell (DC) lineage but their characterization is missing. Here, we report that the peritoneal cavity of normal subjects and of stable patients on peritoneal dialysis (PD) contains a population of CD14(+) cells that can differentiate into DCs or macrophages. Within this pool, we characterized a CD14(+)CD4(+) cell subset (2.2% of the peritoneal cells) fulfilling the definition of myeloid DC precursors or pre-DC1 cells. These cells expressed high levels of HLA-DR, CD13, CD33, and CD86, and low levels of CD40, CD80, CD83, CD123, CD209, TLR-2 and TLR-4. These cells retained CD14 expression until late stages of differentiation, despite concomitant up-regulation of DC-SIGN (CD209), CD1a, CD80 and CD40. Peritoneal pre-DC1 cells had endocytic capacity that was down-regulated upon LPS/IFN-gamma stimulation, were more potent allo-stimulators than peritoneal CD14(+)CD4(-/lo) cells and monocyte-derived macrophages, and induced Th1 cytokine responses. More importantly, the number of peritoneal pre-DC1 cells increased during PD-associated peritonitis, with a different profile for Gram positive and Gram negative peritonitis, suggesting that these cells participate in the induction of peritoneal adaptive immune responses, and may be responsible for the bias towards Th1 responses during peritonitis.
2005-03-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/22
info:doi/10.1111/j.1365-2249.2005.02713.x
http://www3.interscience.wiley.com/journal/118683683/abstract
Robarts Immunology and Transplantation Publications
Scholarship@Western
Adult
Aged
Analysis of Variance
Antigens
CD14
Case-Control Studies
Cell Differentiation
Cytokines
Dendritic Cells
Endocytosis
Female
Flow Cytometry
Humans
Immunophenotyping
Lymphocyte Count
Macrophages
Male
Microscopy
Confocal
Middle Aged
Peritoneal Dialysis
Peritoneum
Peritonitis
Th1 Cells
Antigens, CD14
Microscopy, Confocal
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1026
2009-11-29T10:26:07Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Mechanism of Modulation of T Cell Responses by N-palmitoylated Peptides
Bueno, Clara
Lee, Kenneth K.
Chau, Luan A.
Lee-Chan, Edwin
Singh, Bhagirath
Strejan, Gill H.
Madrenas, Joaquín
Small structural changes in the antigenic peptides recognized by TCR can alter the biological properties of those peptides and convert them into weak agonists, partial agonists, or antagonists of these receptors. These altered peptide ligands (APL) are usually generated by conservative amino acid substitutions at TCR contact residues. Here, we show that APL with therapeutic properties can also be generated by attachment of palmitic acid at the N terminus of the peptide without the need to modify the peptide's primary sequence. Using N-palmitoylated pigeon cytochrome-c peptide 81-104 (PALPCC(81-104)), we were able to induce T cell hyporesponsiveness to the wild-type peptide in vitro. More importantly, administration of the PALPCC(81-104 )to mice reduced the responsiveness to the native peptide when tested ex vivo. Biochemical and functional experiments indicated that the action of N-palmitoylated peptides was due to the conversion of the native peptide into a weak agonist that could then induce T cell anergy. Our results demonstrate that N-palmitoylation of antigenic peptides is a feasible strategy to generate APL, as it avoids the need to screen multiple amino acid variants of each specific antigen to identify those with therapeutic properties.
2004-12-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/24
info:doi/10.1002/eji.200425369
http://www3.interscience.wiley.com/journal/109717311/abstract
Robarts Immunology and Transplantation Publications
Scholarship@Western
Animals
Female
Immune Tolerance
Mice
Palmitic Acid
Peptide Fragments
Receptors
Antigen
T-Cell
Signal Transduction
T-Lymphocytes
Receptors, Antigen, T-Cell
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1023
2009-11-29T10:19:41Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Polycationic Lipids Inhibit the Pro-inflammatory Response to LPS
Leon-Ponte, Matilde
Kirchhof, Mark G.
Sun, Tina
Stephens, Tracey
Singh, Bhagirath
Sandhu, Shabaz
Madrenas, Joaquín
Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria. As such, it signals monocytes, macrophages and neutrophils to up-regulate phagocytic functions and to release pro-inflammatory cytokines. Despite the established role of CD14 as the main LPS receptor, the precise nature of the LPS signalling complex and its compartmentalization remain unknown. Interactions of LPS with other cell surface molecules such as TLR-4 and MD-2, and its subsequent internalization are required for LPS signalling. Here, we show that the polycationic lipid LipoFectamine causes inhibition of the LPS-induced MAPK activation and lack of pro-inflammatory cytokine production, despite proper localization of CD14 within lipid rafts and massive LPS internalization. The ability of LipoFectamine to inhibit LPS induced pro-inflammatory responses may be due to uncoupling of CD14 from TLR-4/MD-2 in the LPS signalling complex of mouse macrophages/microglial cells, as suggested by inhibition of LPS-induced concomitant internalization of these surface molecules. Thus, LipoFectamine may be a useful tool to dissect the molecular interactions leading to LPS signalling, and identifies a potential therapeutic strategy for LPS clearance.
2005-01-15T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/23
info:doi/10.1016/j.imlet.2004.07.019
http://dx.doi.org/10.1016/j.imlet.2004.07.019
Robarts Immunology and Transplantation Publications
Scholarship@Western
Animals
Antigens
CD14
Cations
Cytokines
Flow Cytometry
Immune System
Immune Tolerance
Lipids
Lipopolysaccharides
Membrane Glycoproteins
Mice
Mice
Inbred BALB C
Microscopy
Confocal
Mitogen-Activated Protein Kinases
Receptors
Cell Surface
Toll-Like Receptor 4
Toll-Like Receptors
Antigens, CD14
Mice, Inbred BALB C
Microscopy, Confocal
Receptors, Cell Surface
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1025
2010-01-25T01:09:39Z
publication:mnipub
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Lymphocytes: Antigen-induced Gene Activation
Criado, Gabriel
Madrenas, Joaquín
Lymphocytes are activated upon antigen recognition by their clone-specific surface antigen receptors. Lymphocyte activation includes multiple signalling cascades that converge in the cell nucleus to cause significant changes in the pattern of gene expression that determine the phenotype of activated lymphocytes and ultimately, the type of immune response.
2005-01-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/80
info:doi/10.1038/npg.els.0004033
http://mrw.interscience.wiley.com/emrw/9780470015902/els/article/a0001191/current/abstract
Robarts Immunology and Transplantation Publications
Scholarship@Western
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1027
2010-11-17T00:20:10Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Human Embryonic Stem Cells Possess Immune-privileged Properties
Li, Li
Baroja, Miren L.
Majumdar, Anish
Chadwick, Kristin
Rouleau, Anne
Gallacher, Lisa
Ferber, Iris
Lebkowski, Jane
Martin, Tanya
Madrenas, Joaquin
Bhatia, Mickie
Human embryonic stem cells (hESCs) are envisioned to be a major source for cell-based therapies. Efforts to overcome rejection of hESCs include nuclear transfer and collection of hESC banks representing the broadest diversity of major histocompatability complex (MHC) polymorphorisms. Surprisingly, immune responses to hESCs have yet to be experimentally evaluated. Here, injection of hESCs into immune-competent mice was unable to induce an immune response. Undifferentiated and differentiated hESCs failed to stimulate proliferation of alloreactive primary human T cells and inhibited third-party allogeneic dendritic cell-mediated T-cell proliferation via cellular mechanisms independent of secreted factors. Upon secondary rechallenge, T cells cocultured with hESCs were still responsive to allogeneic stimulators but failed to proliferate upon re-exposure to hESCs. Our study demonstrates that hESCs possess unique immune-privileged characteristics and provides an unprecedented opportunity to further investigate the mechanisms of immune response to transplantation of hESCs that may avoid immune-mediated rejection.
2004-07-01T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/25
info:doi/10.1634/stemcells.22-4-448
http://dx.doi.org/10.1634/stemcells.22-4-448
Robarts Immunology and Transplantation Publications
Scholarship@Western
Animals
Cell Differentiation
Cell Line
Tumor
Dendritic Cells
Embryo
Mammalian
Graft Rejection
Humans
Major Histocompatibility Complex
Mice
Stem Cells
T-Lymphocytes
Transplantation Immunology
Transplantation
Heterologous
Cell Line, Tumor
Embryo, Mammalian
Transplantation, Heterologous
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1029
2009-11-29T10:39:39Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Conversion of CTLA-4 from Inhibitor to Activator of T cells with a Bispecific Tandem Single-chain Fv Ligand
Madrenas, Joaquín
Chau, Luan A.
Teft, Wendy A.
Wu, Paul W.
Jussif, Jason
Kasaian, Marion
Carreno, Beatriz M.
Ling, Vincent
Abs or their recombinant fragments against surface receptors of the Ig superfamily can induce or block the receptors' native function depending on whether they induce or prevent the assembly of signalosomes on their cytoplasmic tails. In this study, we introduce a novel paradigm based on the observation that a bispecific tandem single-chain variable region fragment ligand of CTLA-4 by itself converts this inhibitory receptor into an activating receptor for primary human T lymphocytes. This reversal of function results from increased recruitment of the serine/threonine phosphatase 2A to the cytoplasmic tail of CTLA-4, consistent with a role of this phosphatase in the regulation of CTLA-4 function, and assembly of a distinct signalosome that activates an lck-dependent signaling cascade and induces IL-2 production. Our data demonstrate that the cytoplasmic domain of CTLA-4 has an inherent plasticity for signaling that can be exploited therapeutically with recombinant ligands for this receptor.
2004-05-15T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/27
http://www.jimmunol.org/cgi/content/abstract/172/10/5948
Robarts Immunology and Transplantation Publications
Scholarship@Western
Adjuvants
Immunologic
Antibodies
Bispecific
Antigens
CD
Antigens
CD28
Antigens
Differentiation
Binding Sites
Antibody
Enzyme Activation
Humans
Immunoconjugates
Immunoglobulin Fragments
Jurkat Cells
Ligands
Lymphocyte Activation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Phosphoprotein Phosphatases
Protein Phosphatase 2
Receptor-CD3 Complex
Antigen
T-Cell
Signal Transduction
Suppressor Factors
Immunologic
T-Lymphocyte Subsets
Adjuvants, Immunologic
Antibodies, Bispecific
Antigens, CD
Antigens, CD28
Antigens, Differentiation
Binding Sites, Antibody
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Receptor-CD3 Complex, Antigen, T-Cell
Suppressor Factors, Immunologic
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1028
2009-11-29T10:34:30Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Insertion of Host-derived Costimulatory Molecules CD80 (B7.1) and CD86 (B7.2) into Human Immunodeficiency Virus Type 1 affects the Virus Life Cycle
Giguère, Jean-François
Bounou, Salim
Paquette, Jean-Sébastien
Madrenas, Joaquín
Tremblay, Michel J.
Human immunodeficiency virus type 1 (HIV-1) carries virus-encoded and host-derived proteins. Recent advances in the functional characterization of host molecules inserted into mature virus particles have revealed that HIV-1 biology is influenced by the acquisition of host cell membrane components. The CD28/B7 receptor/ligand system is considered one of the fundamental elements of the normal immune response. Two major cell types that harbor HIV-1 in vivo, i.e., monocytes/macrophages and CD4+ T cells, express the costimulatory molecules CD80 (B7.1) and CD86 (B7.2). We investigated whether CD80 and CD86 are efficiently acquired by HIV-1, and if so, whether these host-encoded molecules can contribute to the virus life cycle. Here we provide the first evidence that the insertion of CD80 and CD86 into HIV-1 increases virus infectivity by facilitating the attachment and entry process due to interactions with their two natural ligands, CD28 and CTLA-4. Moreover, we demonstrate that NF-kappaB is induced by CD80- and CD86-bearing virions when they are combined with the engagement of the T-cell receptor/CD3 complex, an event that is inhibited upon surface expression of CTLA-4. Finally, both CD80 and CD86 were found to be efficiently incorporated into R5- and X4-tropic field strains of HIV-1 expanded in cytokine-treated macrophages. Thus, besides direct interactions between the virus envelope glycoproteins and cell surface constituents, such as CD4 and some specific chemokine coreceptors, HIV-1 may attach to target cells via interactions between cell-derived molecules incorporated into virions and their natural ligands. These findings support the theory that HIV-1-associated host proteins alter virus-host dynamics.
2004-06-01T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/26
info:doi/10.1128/JVI.78.12.6222-6232.2004
http://jvi.asm.org/cgi/content/abstract/78/12/6222
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antigens
CD
Antigens
CD28
Antigens
CD3
Antigens
CD80
Antigens
CD86
Antigens
Differentiation
Cell Line
HIV-1
Humans
Jurkat Cells
Macrophages
Membrane Glycoproteins
NF-kappa B
T-Lymphocytes
Virion
Virus Replication
Antigens, CD
Antigens, CD28
Antigens, CD3
Antigens, CD80
Antigens, CD86
Antigens, Differentiation
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1031
2009-11-29T10:48:24Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Superantigen Stimulation Reveals the Contribution of Lck to Negative Regulation of T Cell Activation
Criado, Gabriel
Madrenas, Joaquín
The conventional paradigm of T cell activation through the TCR states that Lck plays a critical activating role in this signaling process. However, the T cell response to bacterial superantigens does not require Lck. In this study we report that not only is Lck dispensable for T cell activation by superantigens, but it actively inhibits this signaling pathway. Disruption of Lck function, either by repression of Lck gene expression or by selective pharmacologic inhibitors of Lck, led to increased IL-2 production in response to superantigen stimulation. This negative regulatory effect of Lck on superantigen-induced T cell responses required the kinase activity of Lck and correlated with early TCR signaling, but was independent of immunological synapse formation and TCR internalization. Our data demonstrate that the multistage role of Lck in T cell signaling includes the activation of a negative regulatory pathway of T cell activation.
2004-01-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/29
http://www.jimmunol.org/cgi/content/abstract/172/1/222
Robarts Immunology and Transplantation Publications
Scholarship@Western
Cell Line
Cell Line
Transformed
Cytokines
DNA-Binding Proteins
Down-Regulation
Enterotoxins
Humans
Jurkat Cells
Lymphocyte Activation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Membrane Proteins
NFATC Transcription Factors
Nuclear Proteins
Pyrimidines
Receptors
Antigen
T-Cell
Signal Transduction
Staphylococcus aureus
Superantigens
T-Lymphocytes
Transcription Factors
Cell Line, Transformed
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Receptors, Antigen, T-Cell
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1030
2009-11-29T10:44:22Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Lck is Required for Activation-induced T Cell Death after TCR Ligation with Partial Agonists
Yu, Xue-Zhong
Levin, Steven D.
Madrenas, Joaquin
Anasetti, Claudio
TCR engagement can induce either T cell proliferation and differentiation or activation-induced T cell death (AICD) through apoptosis. The intracellular signaling pathways that dictate such a disparate fate after TCR engagement have only been partially elucidated. Non-FcR-binding anti-CD3 mAbs induce a partial agonist TCR signaling pattern and cause AICD on Ag-activated, cycling T cells. In this study, we examined TCR signaling during the induction of AICD by anti-CD3 fos, a non-FcR-binding anti-CD3 mAb. This mAb activates Fyn, Lck, and extracellular signal-regulated kinase, and induces phosphorylation of Src-like adapter protein, despite the inability to cause calcium mobilization or TCR polarization. Anti-CD3 fos also fails to effectively activate zeta-associated protein of 70 kDa or NF-kappaB. Using Ag-specific T cells deficient for Fyn or Lck, we provide compelling evidence that activation of Lck is required for the induction of AICD. Our data indicate that a selective and distinct TCR signaling pattern is required for AICD by TCR partial agonist ligands.
2004-02-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/28
http://www.jimmunol.org/cgi/content/abstract/172/3/1437
Robarts Immunology and Transplantation Publications
Scholarship@Western
Amino Acid Sequence
Animals
Antibodies
Monoclonal
Antigens
Antigens
CD3
Antigens
CD95
Apoptosis
Calcium
Cells
Cultured
Enzyme Activation
Fas Ligand Protein
Immunoglobulin Fab Fragments
Ligands
Lymphocyte Activation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Membrane Glycoproteins
Mice
Mice
Inbred BALB C
Mice
Inbred C57BL
Mice
Inbred MRL lpr
Mice
Knockout
Mice
Transgenic
Mitogen-Activated Protein Kinases
Molecular Sequence Data
NF-kappa B
Ovalbumin
Peptide Fragments
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-fos
Proto-Oncogene Proteins c-fyn
Receptors
Antigen
T-Cell
Solubility
T-Lymphocyte Subsets
Up-Regulation
src-Family Kinases
Antibodies, Monoclonal
Antigens, CD3
Antigens, CD95
Cells, Cultured
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred MRL lpr
Mice, Knockout
Mice, Transgenic
Receptors, Antigen, T-Cell
Immunology and Infectious Disease
Oncology
oai:ir.lib.uwo.ca:immunologypub-1032
2009-11-29T10:55:52Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
TCR Subunit Specificity of CTLA-4-mediated Signaling
Siu, Eric
Carreno, Beatriz M.
Madrenas, Joaquín
Cytotoxic T-lymphocyte-associated antigen (CTLA)-4 is an activation-induced receptor that down-regulates T cell responses by antagonizing B7-dependent costimulation and/or by transducing a negative signal. The mechanism of CTLA-4-mediated negative signaling is unknown. Recently, it has been postulated that CTLA-4 inhibits T cell activation by causing specific dephosphorylation of the T cell receptor (TCR)-zeta chain of the antigen-receptor complex through an lck-dependent recruitment of the Src homology-2-containing tyrosine phosphatase-2. To test this hypothesis, we generated stably transfected T cell clones expressing doxycycline-inducible CTLA-4 with CD25:TCR-zeta (CD25-zeta) or CD25:CD3-epsilon (CD25-epsilon) fusion proteins. In these clones, ligation of CD25-zeta or of CD25-epsilon with antibodies against CD25 induced full T cell activation, as illustrated by extracellular signal-regulated kinase (ERK) activation and interleukin (IL)-2 production. More importantly, coligation of CTLA-4 with CD25-zeta or of CTLA-4 with CD25-epsilon in the respectively transfected clones inhibited ERK activation and IL-2 production, demonstrating that CTLA-4 does not specifically inhibit signals from TCR-zeta but can also inhibit signals from CD3-epsilon. Our results suggest that the target specificity of CTLA-4 is determined by its coligation with any given transmembrane receptor rather than by its intracellular mediators.
2003-12-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/30
info:doi/10.1189/jlb.0503198
http://www.jleukbio.org/cgi/content/abstract/74/6/1102
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antigens
CD
Antigens
CD3
Antigens
Differentiation
Down-Regulation
Humans
Interleukin-2
Jurkat Cells
Lymphocyte Activation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Membrane Proteins
Mitogen-Activated Protein Kinases
Protein Phosphatase 2
Protein Tyrosine Phosphatases
Receptors
Antigen
T-Cell
Receptors
Interleukin-2
Signal Transduction
T-Lymphocytes
Antigens, CD
Antigens, CD3
Antigens, Differentiation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Receptors, Antigen, T-Cell
Receptors, Interleukin-2
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1033
2009-11-29T11:01:03Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:biochempub
publication:mni
publication:robarts
publication:biochem
publication:institutes
Regulation of T-cell Activation by Phosphodiesterase 4B2 Requires its Dynamic Redistribution during Immunological Synapse Formation
Arp, Jacqueline
Kirchhof, Mark G.
Baroja, Miren L.
Nazarian, Steven H.
Chau, Thu A.
Strathdee, Craig A.
Ball, Eric H.
Madrenas, Joaquín
Stimulation of T cells through their antigen receptors (TCRs) causes a transient increase in the intracellular concentration of cyclic AMP (cAMP). However, sustained high levels of cAMP inhibit T-cell responses, suggesting that TCR signaling is coordinated with the activation of cyclic nucleotide phosphodiesterases (PDEs). The molecular basis of such a pathway is unknown. Here we show that TCR-dependent signaling activates PDE4B2 and that this enhances interleukin-2 production. Such an effect requires the regulatory N terminus of PDE4B2 and correlates with partitioning within lipid rafts, early targeting of this PDE to the immunological synapse, and subsequent accumulation in the antipodal pole of the T cell as activation proceeds.
2003-11-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/31
info:doi/10.1128/MCB.23.22.8042-8057.2003
http://mcb.asm.org/cgi/content/abstract/23/22/8042
Robarts Immunology and Transplantation Publications
Scholarship@Western
3'
5'-Cyclic-AMP Phosphodiesterases
Cell Compartmentation
Cyclic Nucleotide Phosphodiesterases
Type 4
Enzyme Activation
Humans
Interleukin-2
Jurkat Cells
Lymphocyte Activation
Membrane Microdomains
Protein Structure
Tertiary
Receptors
Antigen
T-Cell
Recombinant Fusion Proteins
Sequence Deletion
Signal Transduction
T-Lymphocytes
3',5'-Cyclic-AMP Phosphodiesterases
Cyclic Nucleotide Phosphodiesterases, Type 4
Protein Structure, Tertiary
Receptors, Antigen, T-Cell
Immunology and Infectious Disease
Medical Biochemistry
oai:ir.lib.uwo.ca:immunologypub-1034
2009-11-29T11:07:15Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Peritoneal Dialysis Solutions Inhibit the Differentiation and Maturation of Human Monocyte-derived Dendritic Cells: Effect of Lactate and Glucose-degradation Products
Puig-Kröger, Amaya
Pello, Oscar Muñiz
Selgas, Rafael
Criado, Gabriel
Bajo, M-Auxiliadora
Sánchez-Tomero, Jose A.
Alvarez, Vicente
del Peso, Gloria
Sánchez-Mateos, Paloma
Holmes, Clifford
Faict, Dirk
López-Cabrera, Manuel
Madrenas, Joaquín
Corbí, Angel L.
Peritoneal dialysis (PD) is a well-established therapy for end-stage renal failure, but its efficiency is limited by recurrent peritonitis. As PD solutions impair local inflammatory responses within the peritoneal cavity, we have analyzed their influence on the in vitro maturation of human monocyte-derived dendritic cells (MDDC). Evaluation of MDDC maturation parameters [expression of adhesion and costimulatory molecules, receptor-mediated endocytosis, allogeneic T cell activation, production of tumor necrosis factor alpha, interleukin (IL)-6 and IL-12 p70, and nuclear factor (NF)-kappaB activation] revealed that currently used PD solutions differentially inhibit the lipopolysaccharide (LPS)-induced maturation of MDDC, an inhibition that correlated with their ability to impair the LPS-stimulated NF-kappaB activation. Evaluation of PD components revealed that sodium lactate and glucose-degradation products impaired the acquisition of maturation parameters and NF-kappaB activation in a dose-dependent manner. Moreover, PD solutions impaired monocyte-MDDC differentiation, inhibiting the acquisition of DC markers such as CD1a and DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (CD209). These findings have important implications for the initiation of immune responses under high lactate conditions, such as those occurring within tumor tissues or after macrophage activation.
2003-04-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/32
info:doi/10.1189/jlb.0902451
http://www.jleukbio.org/cgi/content/abstract/73/4/482
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antigens
CD1
Blotting
Western
Cell Adhesion Molecules
Cell Differentiation
Cell Division
DNA
Dendritic Cells
Dialysis Solutions
Electrophoretic Mobility Shift Assay
Flow Cytometry
Glycosylation End Products
Advanced
Humans
Interleukin-12
Interleukin-6
Lectins
C-Type
Lipopolysaccharides
Monocytes
NF-kappa B
Peritoneal Dialysis
Receptors
Cell Surface
Sodium Lactate
Tumor Necrosis Factor-alpha
Antigens, CD1
Blotting, Western
Glycosylation End Products, Advanced
Lectins, C-Type
Receptors, Cell Surface
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1036
2009-11-29T11:17:31Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
A SLAT in the Th2 Signalosome
Madrenas, Joaquín
There is abundant information on the distinguishing features of TCR-mediated signaling in Th1 and Th2 cells. However, the primary signals that determine the commitment and differentiation of naive T cells toward those T helper subsets, especially prior to the contribution of polarizing cytokines, remain elusive. This minireview discusses the potential contribution of SLAT in favoring differentiation along the Th2 lineage and how this may bring us closer to a framework model for Th1/Th2 differentiation.
2003-04-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/34
info:doi/10.1016/S1074-7613(03)00089-X
http://www.cell.com/immunity/abstract/S1074-7613(03)00089-X
Robarts Immunology and Transplantation Publications
Scholarship@Western
Animals
Cell Differentiation
Cell Lineage
DNA-Binding Proteins
Humans
Nuclear Proteins
Receptors
Antigen
T-Cell
Signal Transduction
Th1 Cells
Th2 Cells
Receptors, Antigen, T-Cell
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1039
2009-11-29T11:31:43Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Inhibition of CTLA-4 Function by the Regulatory Subunit of Serine/Threonine Phosphatase 2A
Baroja, Miren L.
Vijayakrishnan, Lalitha
Bettelli, Estelle
Darlington, Peter J.
Chau, Thu A.
Ling, Vincent
Collins, Mary
Carreno, Beatriz M.
Madrenas, Joaquín
Kuchroo, Vijay K.
The catalytic subunit of the serine/threonine phosphatase 2A (PP2A) can interact with the cytoplasmic tail of CTLA-4. However, the molecular basis and the biological significance of this interaction are unknown. In this study, we report that the regulatory subunit of PP2A (PP2AA) also interacts with the cytoplasmic tail of CTLA-4. Interestingly, TCR ligation induces tyrosine phosphorylation of PP2AA and its dissociation from CTLA-4 when coligated. The association between PP2AA and CTLA-4 involves a conserved three-lysine motif in the juxtamembrane portion of the cytoplasmic tail of CTLA-4. Mutations of these lysine residues prevent the binding of PP2AA and enhance the inhibition of IL-2 gene transcription by CTLA-4, indicating that PP2A represses CTLA-4 function. Our data imply that the lysine-rich motif in CTLA-4 may be used to identify small molecules that block its binding to PP2A and act as agonists for CTLA-4 function.
2002-05-15T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/37
http://www.jimmunol.org/cgi/content/abstract/168/10/5070
Robarts Immunology and Transplantation Publications
Scholarship@Western
Amino Acid Motifs
Animals
Antigens
CD
Antigens
Differentiation
Cell Line
Transformed
Cytoplasm
Down-Regulation
Humans
Immunoconjugates
Immunosuppressive Agents
Jurkat Cells
Ligands
Lymphocyte Activation
Lysine
Mice
Mutagenesis
Site-Directed
Phosphoprotein Phosphatases
Phosphorylation
Protein Binding
Protein Phosphatase 2
Protein Structure
Tertiary
Receptors
Antigen
T-Cell
T-Lymphocytes
Antigens, CD
Antigens, Differentiation
Cell Line, Transformed
Mutagenesis, Site-Directed
Protein Structure, Tertiary
Receptors, Antigen, T-Cell
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1035
2009-11-29T11:13:05Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Viewpoint: Therapeutic Implications of CTLA-4 Compartmentalization
Baroja, Miren L.
Madrenas, Joaquín
Understanding the regulatory events involved in the activation and inactivation of T cells is crucial to develop therapeutic approaches for autoimmune diseases and for organ transplantation. Co-stimulatory signals delivered through the CD28 receptor and inhibitory signals through CTLA-4 are required for the proper modulation of T cell responses and the induction and maintenance of peripheral tolerance. Manipulation of these signals is emerging as a potential strategy to prevent allograft rejection in different animal models. Recent data on the compartmentalization and the structural features of CTLA-4 within T cells provides critical information not only on the molecular basis of T cell inactivation by CTLA-4, but also on the key requirements for the successful development of therapeutic strategies targeting this molecule.
2003-08-01T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/33
info:doi/10.1034/j.1600-6143.2003.00182.x
http://www3.interscience.wiley.com/journal/118901817/abstract
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antigens
CD
Antigens
Differentiation
Cell Compartmentation
Humans
Signal Transduction
T-Lymphocytes
Antigens, CD
Antigens, Differentiation
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1037
2009-11-29T11:22:06Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Clustering of a Lipid-raft Associated Pool of ERM Proteins at the Immunological Synapse upon T cell Receptor or CD28 Ligation
Tomas, Elizabeth M.
Chau, Thu A.
Madrenas, Joaquín
Although ezrin is tyrosine phosphorylated following TCR ligation, its biological role in T cell activation is not known. Here, we shhow that ezrin clusters at the immunological synapse upon T cell stimulation. Clustering of ezrin can be triggered by TCR ligation, or, more efficiently, by CD28 ligation. The clusters of ezrin at the immunological synapse include serine/threonine phosphorylated ezrin predominantly located within cell membrane lipid rafts. Based on these data, we propose that ezrin may play a role in the formation/stabilization of lipid raft signalosomes at the immunological synapse and therefore contribute to sustain TCR-dependent signalling.
2002-09-02T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/35
info:doi/10.1016/S0165-2478(02)00075-5
http://dx.doi.org/10.1016/S0165-2478(02)00075-5
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antigens
CD28
Cytoskeletal Proteins
DNA-Binding Proteins
Humans
Jurkat Cells
Membrane Microdomains
Microscopy
Confocal
Phosphoproteins
Phosphorylation
Receptors
Antigen
T-Cell
Transcription Factors
Antigens, CD28
Microscopy, Confocal
Receptors, Antigen, T-Cell
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1038
2009-11-29T11:26:15Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Surface Cytotoxic T Lymphocyte-associated Antigen 4 Partitions within Lipid Rafts and Relocates to the Immunological Synapse under Conditions of Inhibition of T cell Activation.
Darlington, Peter J.
Baroja, Miren L.
Chau, Thu A.
Siu, Eric
Ling, Vincent
Carreno, Beatriz M.
Madrenas, Joaquín
T cell activation through the T cell receptor (TCR) involves partitioning of receptors into discrete membrane compartments known as lipid rafts, and the formation of an immunological synapse (IS) between the T cell and antigen-presenting cell (APC). Compartmentalization of negative regulators of T cell activation such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is unknown. Recent crystal structures of B7-ligated CTLA-4 suggest that it may form lattices within the IS which could explain the mechanism of action of this molecule. Here, we show that after T cell stimulation, CTLA-4 coclusters with the TCR and the lipid raft ganglioside GM1 within the IS. Using subcellular fractionation, we show that most lipid raft-associated CTLA-4 is on the T cell surface. Such compartmentalization is dependent on the cytoplasmic tail of CTLA-4 and can be forced with a glycosylphosphatidylinositol-anchor in CTLA-4. The level of CTLA-4 within lipid rafts increases under conditions of APC-dependent TCR-CTLA-4 coligation and T cell inactivation. However, raft localization, although necessary for inhibition of T cell activation, is not sufficient for CTLA-4-mediated negative signaling. These data demonstrate that CTLA-4 within lipid rafts migrates to the IS where it can potentially form lattice structures and inhibit T cell activation.
2002-05-20T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/36
info:doi/10.1084/jem.20011868
http://jem.rupress.org/cgi/content/abstract/195/10/1337
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antigen-Presenting Cells
Antigens
CD
Antigens
Differentiation
Flow Cytometry
Glycosylphosphatidylinositols
Humans
Immunoconjugates
Interleukin-2
Jurkat Cells
Lymphocyte Activation
Membrane Microdomains
Microscopy
Confocal
Molecular Sequence Data
Protein Transport
Receptors
Antigen
T-Cell
Signal Transduction
T-Lymphocytes
Antigens, CD
Antigens, Differentiation
Microscopy, Confocal
Receptors, Antigen, T-Cell
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1040
2009-11-29T12:04:51Z
publication:mnipub
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Oral Administration of the Probiotic Combination Lactobacillus Rhamnosus GR-1 and L. Fermentum RC-14 for Human Intestinal Applications
Gardiner, Gillian E.
Heinemann, Christine
Baroja, Miren L.
Bruce, Andrew W.
Beuerman, Dee
Madrenas, Joaquín
Reid, Gregor
Lactobacillus rhamnosus GR-1 and L. fermentum RC-14, previously characterized as urogenital probiotics were evaluated for human intestinal applications. RC-14 and GR-1 were tolerant to 0.3 and 0.5% (w/v) bile, respectively. Both strains were suspended in skim milk, stored as a frozen concentrate and administered in combination to five healthy women twice daily for 14 days. Faecal samples were analyzed and the Lactobacillus flora assessed by Randomly Amplified Polymorphic DNA (RAPD). Both strains were recovered from all subjects during the 14-day administration period and GR-1 was detected for at least 7 days post-administration in some individuals. No notable increases in serum IgG, IgA or IgM were observed and IL-2 and IL-4 were undetectable. Although IL-6 and IFN-γ levels increased slightly in some individuals, concentrations remained within normal ranges. Thus, L. rhamnosus GR-1 and L. fermentum RC-14 are bile tolerant and survive gastrointestinal transit without induction of systemic immune or inflammatory responses. These data together with the previously demonstrated probiotic properties of GR-1 and RC-14 make this strain combination potentially useful for human intestinal applications.
2002-01-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/38
info:doi/10.1016/S0958-6946(01)00138-8
http://dx.doi.org/10.1016/S0958-6946(01)00138-8
Robarts Immunology and Transplantation Publications
Scholarship@Western
Probiotic
Lactobacilli
Gastrointestinal tract
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1041
2009-11-29T12:19:27Z
publication:mnipub
publication:patholpub
publication:surgerypub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:pathol
publication:med
publication:mni
publication:robarts
publication:surgery
publication:institutes
Thymic Re-entry of Mature Activated T cells and Increased Negative Selection in Vascularized Allograft Recipients
Chau, L. A.
Rohekar, S.
Wang, J.-J.
Lian, D.
Chakrabarti, S.
Zhang, L.
Zhong, R.
Madrenas, J.
Transplantation tolerance is a dynamic state that involves several homeostatic mechanisms intrinsic to the host. One of these mechanisms is activation-induced T cell death (AICD). However, it is unclear where AICD takes place during alloreactive responses. Since activated T cells can re-enter the thymus, we hypothesized that mature T cells activated by an allograft could be deleted upon re-entry into the thymus. To test this hypothesis, we used wild-type or 2C TCR transgenic mice receiving syngeneic or allogeneic heterotopic, vascularized heart grafts. First, we demonstrated that ex vivo CFSE-labelled T cells re-entered the thymus when transferred into allograft recipients but not when transferred into isograft recipients. Next, we compared the changes in cell subset numbers and incidence of apoptosis in the thymi and spleens of allograft or isograft recipients. Seven days after transplantation, at a time in which all the allografts were undergoing rejection, cells expressing donor-MHC class II molecules had migrated to the thymus and to the spleen. In the thymus of allograft recipients, overall cellularity was significantly reduced by 40% and associated with an increase in the number of double negative (CD4-CD8-) thymocytes and a decrease in double positive (CD4+CD8+) thymocytes, consistent with increased negative selection of thymocytes. Additionally, thymi of allograft recipients showed an increase in the number of recently activated, mature T cells (TCRhi, CD25+, CD44+) and a significant increase in the number of apoptotic cells, especially in the thymic medulla, that involved mature T cells as indicated by the TCRhi, CD44+, CD4 or CD8 single positive phenotype. Spleens of allograft recipients were increased in size and cellularity but did not show any of the changes in cell subsets seen in the thymi. Our data show that after allografting there is an increase in apoptotic cell death that is associated with negative selection of developing thymocytes as well as of alloreactive mature T cells that have re-entered the thymus upon activation in the periphery. This may occur upon migration of graft-derived antigen-presenting cells to the thymus.
2002-01-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/39
info:doi/10.1046/j.1365-2249.2002.01717.x
http://www3.interscience.wiley.com/journal/118939024/abstract
Robarts Immunology and Transplantation Publications
Scholarship@Western
Animals
Antigen Presentation
Cell Death
Cell Movement
Heart Transplantation
Lymphocyte Activation
Male
Mice
Mice
Inbred BALB C
Mice
Inbred C57BL
Neovascularization
Physiologic
T-Lymphocytes
Thymus Gland
Transplantation Immunology
Transplantation
Homologous
Mice, Inbred BALB C
Mice, Inbred C57BL
Neovascularization, Physiologic
Transplantation, Homologous
Immunology and Infectious Disease
Pathology
Surgery
oai:ir.lib.uwo.ca:immunologypub-1044
2009-11-29T12:23:36Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Generation of Partial Agonist Ligands of the T-cell Receptor by Engineering of Antibodies against CD3
Chau, L. A.
Tso, J. Y.
Madrenas, J.
2001-02-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/41
info:doi/10.1016/S0041-1345(00)02125-4
http://dx.doi.org/10.1016/S0041-1345(00)02125-4
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antibodies
Antigens
CD3
Cyclin-Dependent Kinase Inhibitor p21
Cyclins
Humans
Leukocytes
Mononuclear
Ligands
Muromonab-CD3
Phosphorylation
Protein-Tyrosine Kinases
Receptors
Antigen
T-Cell
ZAP-70 Protein-Tyrosine Kinase
Antigens, CD3
Leukocytes, Mononuclear
Receptors, Antigen, T-Cell
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1045
2009-11-29T12:27:29Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
The Role of Ezrin in T-cell Receptor-dependent Signaling
Tomas, E. M.
Darlington, P. J.
Chau, L. A.
Madrenas, J.
2001-02-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/42
info:doi/10.1016/S0041-1345(00)01976-X
http://dx.doi.org/10.1016/S0041-1345(00)01976-X
Robarts Immunology and Transplantation Publications
Scholarship@Western
Animals
Cell Line
Cytoskeletal Proteins
Cytoskeleton
Humans
Jurkat Cells
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Mice
Phosphoproteins
Phosphorylation
Protein-Tyrosine Kinases
Receptors
Antigen
T-Cell
ZAP-70 Protein-Tyrosine Kinase
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Receptors, Antigen, T-Cell
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1042
2009-11-29T12:15:16Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Zap-70-independent Ca(2+) Mobilization and Erk Activation in Jurkat T cells in Response to T-cell Antigen Receptor Ligation
Shan, X.
Balakir, R.
Criado, G.
Wood, J. S.
Seminario, M. C.
Madrenas, J.
Wange, R. L.
The tyrosine kinase ZAP-70 has been implicated as a critical intermediary between T-cell antigen receptor (TCR) stimulation and Erk activation on the basis of the ability of dominant negative ZAP-70 to inhibit TCR-stimulated Erk activation, and the reported inability of anti-CD3 antibodies to activate Erk in ZAP-70-negative Jurkat cells. However, Erk is activated in T cells receiving a partial agonist signal, despite failing to activate ZAP-70. This discrepancy led us to reanalyze the ZAP-70-negative Jurkat T-cell line P116 for its ability to support Erk activation in response to TCR/CD3 stimulation. Erk was activated by CD3 cross-linking in P116 cells. However, this response required a higher concentration of anti-CD3 antibody and was delayed and transient compared to that in Jurkat T cells. Activation of Raf-1 and MEK-1 was coincident with Erk activation. Remarkably, the time course of Ras activation was comparable in the two cell lines, despite proceeding in the absence of LAT tyrosine phosphorylation in the P116 cells. CD3 stimulation of P116 cells also induced tyrosine phosphorylation of phospholipase C-gamma1 (PLCgamma1) and increased the intracellular Ca(2+) concentration. Protein kinase C (PKC) inhibitors blocked CD3-stimulated Erk activation in P116 cells, while parental Jurkat cells were refractory to PKC inhibition. The physiologic relevance of these signaling events is further supported by the finding of PLCgamma1 tyrosine phosphorylation, Erk activation, and CD69 upregulation in P116 cells on stimulation with superantigen and antigen-presenting cells. These results demonstrate the existence of two pathways leading to TCR-stimulated Erk activation in Jurkat T cells: a ZAP-70-independent pathway requiring PKC and a ZAP-70-dependent pathway that is PKC independent.
2001-11-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/40
info:doi/10.1128/MCB.21.21.7137-7149.2001
http://mcb.asm.org/cgi/content/abstract/21/21/7137
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antigens
CD3
Calcium
Cell Line
Cross-Linking Reagents
DNA-Binding Proteins
Dose-Response Relationship
Drug
Enzyme Activation
Enzyme Inhibitors
Flow Cytometry
Genes
Reporter
Humans
Isoenzymes
Jurkat Cells
Kinetics
MAP Kinase Kinase 1
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinases
Models
Biological
NFATC Transcription Factors
Nuclear Proteins
Phospholipase C gamma
Phosphorylation
Precipitin Tests
Protein Binding
Protein Kinase C
Protein-Serine-Threonine Kinases
Protein-Tyrosine Kinases
Proto-Oncogene Proteins c-raf
Time Factors
Transcription Factors
Type C Phospholipases
Up-Regulation
ZAP-70 Protein-Tyrosine Kinase
Antigens, CD3
Dose-Response Relationship, Drug
Genes, Reporter
Models, Biological
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:mnipub-1014
2010-01-24T07:47:16Z
publication:mnipub
publication:surgerypub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:surgery
publication:institutes
CD40-deficient Dendritic Cells Producing Interleukin-10, but not Interleukin-12, Induce T-cell Hyporesponsiveness In Vitro and Prevent Acute Allograft Rejection
Gao, J. X.
Madrenas, J.
Zeng, W.
Cameron, M. J.
Zhang, Z.
Wang, J. J.
Zhong, R.
Grant, D.
The induction of an immune response or tolerance is mediated by corresponding subsets of dendritic cells (DC). However, the property of tolerogenic DC is not clear. Recently, we have characterized a population of CD11c+ splenic DC derived from long-term mixed leucocyte culture (LT-MLC), which are able to proliferate upon stimulation and have a strong primary mixed leucocyte reaction (MLR)-stimulating activity in conventional MLR. In this study, we show that, in contrast to the irradiated ones, non-irradiated LT-MLC-derived DC induce polyclonal antigen-specific T-cell hyporesponsiveness when cocultured with allogeneic splenocytes for 3-11 days. The degree of the hyporesponsiveness increased with the length of coculture. Although these DC expressed major histocompatibility complex class II and B7 costimulatory molecules, which are down-regulated during coculture, they expressed very low or undetectable CD40 before and after coculture, respectively. The CD40-deficient DC spontaneously produce interleukin-10 (IL-10), but not IL-12. The skewed balance between IL-10 and IL-12 is associated with their capability to induce T-cell hyporesponsiveness, because a neutralizing antibody to IL-10, exogenous recombinant IL-12 or lipopolysaccharide (LPS) significantly blocked the hyporesponsiveness. Accordingly, infusion of a small number of non-irradiated LT-MLC-derived DC (5x105) significantly prolonged the survival of a vascularized heterotopic murine heart transplant, whereas irradiated DC accelerated graft rejection. These data suggest that CD40-deficient DC producing IL-10, but not IL-12 can induce T-cell hyporesponsiveness in vitro and in vivo.
1999-10-01T07:00:00Z
article
https://ir.lib.uwo.ca/mnipub/17
info:doi/10.1046/j.1365-2567.1999.00863.x
http://www3.interscience.wiley.com/journal/119061760/abstract
Microbiology & Immunology Publications
Scholarship@Western
Adoptive Transfer
Animals
Antigens
CD40
Cells
Cultured
Dendritic Cells
Flow Cytometry
Graft Rejection
Immune Tolerance
Interleukin-10
Interleukin-12
Lipopolysaccharides
Male
Mice
Mice
Inbred BALB C
Mice
Inbred C3H
Mice
Inbred C57BL
T-Lymphocytes
Transplantation
Homologous
Antigens, CD40
Cells, Cultured
Mice, Inbred BALB C
Mice, Inbred C3H
Mice, Inbred C57BL
Transplantation, Homologous
Immunology and Infectious Disease
Microbiology
oai:ir.lib.uwo.ca:immunologypub-1046
2009-11-29T12:31:16Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
CTLA-4 (CD152) Can Inhibit T cell Activation by Two Different Mechanisms Depending on Its Level of Cell Surface Expression
Carreno, Beatriz M.
Bennett, Frann
Chau, Thu A.
Ling, Vincent
Luxenberg, Deborah
Jussif, Jason
Baroja, Miren L.
Madrenas, Joaquin
CTLA-4 (CD152) engagement results in down-regulation of T cell activation. Two mechanisms have been postulated to explain CTLA-4 inhibition of T cell activation: negative signaling and competitive antagonism of CD28:B7-mediated costimulation. We assessed the contributions of these two mechanisms using a panel of T cell lines expressing human CTLA-4 with mutations in the cytoplasmic region. Under conditions of B7-independent costimulation, inhibition of IL-2 production following CTLA-4 engagement required the CTLA-4 cytoplasmic region. In contrast, under B7-dependent costimulation, inhibition of IL-2 production by CTLA-4 engagement was directly proportional to CTLA-4 cell surface levels and did not require its cytoplasmic region. Thus, CTLA-4 down-regulates T cell activation by two different mechanisms-delivery of a negative signal or B7 sequestration-that are operational depending on the levels of CTLA-4 surface expression. These two mechanisms may have distinct functional outcomes: rapid inhibition of T cell activation or induction of T cell anergy.
2000-08-01T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/43
http://www.jimmunol.org/cgi/content/abstract/165/3/1352
Robarts Immunology and Transplantation Publications
Scholarship@Western
Amino Acid Sequence
Antibodies
Monoclonal
Antigens
CD
Antigens
CD28
Antigens
CD3
Antigens
CD80
Antigens
CD86
Antigens
Differentiation
Cell Membrane
Cytoplasm
Down-Regulation
Doxycycline
Humans
Immunoconjugates
Immunoglobulin Fc Fragments
Immunosuppressive Agents
Interleukin-2
Jurkat Cells
Lymphocyte Activation
Membrane Glycoproteins
Microspheres
Molecular Sequence Data
Peptide Fragments
Recombinant Fusion Proteins
Signal Transduction
T-Lymphocytes
Antibodies, Monoclonal
Antigens, CD
Antigens, CD28
Antigens, CD3
Antigens, CD80
Antigens, CD86
Antigens, Differentiation
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1047
2009-11-29T12:35:41Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Prevention of Diabetes Mellitus in the Non-obese Diabetic Mouse Strain with Monoclonal Antibodies against the CD45RB Molecule
Abu-Hadid, M. M.
Lazarovits, A. I.
Madrenas, J.
2000-07-01T07:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/44
info:doi/10.3109/08916930008995990
http://www.informaworld.com/smpp/content~db=all~content=a907297957
Robarts Immunology and Transplantation Publications
Scholarship@Western
Animals
Antibodies
Monoclonal
Antigens
CD45
Autoimmunity
Diabetes Mellitus
Female
Insulin
Mice
Mice
Inbred NOD
Pancrelipase
Antibodies, Monoclonal
Antigens, CD45
Mice, Inbred NOD
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:physpharmpub-1024
2010-01-07T07:37:27Z
publication:mnipub
publication:physpharmpub
publication:paed
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:physpharm
publication:mni
publication:robarts
publication:institutes
publication:paedpub
Cytotoxicity of Sulfonamide Reactive Metabolites: Apoptosis and Selective Toxicity of CD8(+) Cells by the Hydroxylamine of Sulfamethoxazole
Hess, David A.
Sisson, Margaret E.
Suria, Hamza
Wijsman, John
Puvanesasingham, Ram
Madrenas, Joaquín
Rieder, Michael J.
Treatment with sulfonamide antibiotics in HIV-infected patients is associated with a high incidence (> 40%) of adverse drug events, including severe hypersensitivity reactions. Sulfonamide reactive metabolites have been implicated in the pathogenesis of these adverse reactions. Sulfamethoxazole hydroxylamine (SMX-HA) induces lymphocyte toxicity and suppression of proliferation in vitro; the mechanism(s) of these immunomodulatory effects remain unknown. We investigated the cytotoxicity of SMX-HA via apoptosis on human peripheral blood mononuclear cells and purified cell subpopulations in vitro. CD19(+), CD4(+), and CD8(+) cells were isolated from human peripheral blood by positive selection of cell surface molecules by magnetic bead separation. SMX-HA induced significant CD8(+) cell death (67 +/- 7%) at 100 microM SMX-HA, with only minimal CD4(+) cell death (8 +/- 4%). No significant subpopulation toxicity was shown when incubated with parent drug (SMX). Flow cytometry measuring phosphatidylserine externalization 24 h after treatment with 100 microM and 400 microM SMX-HA revealed 14.1 +/- 0.7% and 25. 6 +/- 4.2% annexin-positive cells, respectively, compared to 3.7 +/- 1.2% in control PBMCs treated with 400 microM SMX. Internucleosomal DNA fragmentation was observed in quiescent and stimulated PBMCs 48 h after incubation with SMX-HA. Our data show that CD8(+) cells are highly susceptible to the toxic effects of SMX-HA through enhanced cell death by apoptosis.
1999-10-01T07:00:00Z
article
https://ir.lib.uwo.ca/physpharmpub/29
http://www.fasebj.org/cgi/content/abstract/13/13/1688
Physiology and Pharmacology Publications
Scholarship@Western
Apoptosis
CD8-Positive T-Lymphocytes
DNA Fragmentation
Dose-Response Relationship
Drug
Humans
Immunomagnetic Separation
Phosphatidylserines
Sulfamethoxazole
Sulfonamides
T-Lymphocyte Subsets
Dose-Response Relationship, Drug
Medical Immunology
Medical Microbiology
Pediatrics
Pharmacy and Pharmaceutical Sciences
oai:ir.lib.uwo.ca:immunologypub-1048
2009-12-03T06:39:07Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
The Inhibitory Function of CTLA-4 Does Not Require Its Tyrosine Phosphorylation
Baroja, Miren L.
Luxenberg, Deborah
Chau, Thu
Ling, Vincent
Strathdee, Craig A.
Carreno, Beatriz M.
Madrenas, Joaquín
CTLA-4 is a negative regulator of T cell responses. Sequence analysis of this molecule reveals the presence of two cytoplasmic tyrosine residues at positions 165 and 182 that are potential Src homology (SH)-2 domain binding sites. The role of phosphorylation of these residues in CTLA-4-mediated signaling is unknown. Here, we show that sole TCR ligation induces zeta-associated protein (ZAP)-70-dependent tyrosine phosphorylation of CTLA-4 that is important for cell surface retention of this molecule. However, CTLA-4 tyrosine phosphorylation is not required for down-regulation of T cell activation following CD3-CTLA-4 coengagement. Specifically, inhibition of extracellular signal-regulated kinase (ERK) activation and of IL-2 production by CTLA-4-mediated signaling occurs in T cells expressing mutant CTLA-4 molecules lacking the cytoplasmic tyrosine residues, and in lck-deficient or ZAP-70-deficient T cells. Therefore, CTLA-4 function involves interplay between two different levels of regulation: phosphotyrosine-dependent cell surface retention and phosphotyrosine-independent association with signaling molecules.
2000-01-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/45
http://www.jimmunol.org/cgi/content/abstract/164/1/49
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antigens
CD
Antigens
CD3
Antigens
Differentiation
Cell Membrane
Cytoplasm
Enzyme Activation
Humans
Immunoconjugates
Immunosuppressive Agents
Interleukin-2
Jurkat Cells
Ligands
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases
Mutagenesis
Site-Directed
Phosphorylation
Protein-Tyrosine Kinases
T-Lymphocytes
Tyrosine
ZAP-70 Protein-Tyrosine Kinase
Antigens, CD
Antigens, CD3
Antigens, Differentiation
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Mutagenesis, Site-Directed
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1049
2009-12-03T06:42:14Z
publication:mnipub
publication:physpharmpub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:physpharm
publication:mni
publication:robarts
publication:institutes
Identification of a Novel Mechanism for Endotoxin-mediated Down-modulation of CC Chemokine Receptor Expression
Xu, Luoling
Khandaker, Masud H.
Barlic, Jana
Ran, Longsi
Borja, Miren L.
Madrenas, Joaquín
Rahimpour, Rahbar
Chen, Kong
Mitchell, Gordon
Tan, Christopher M.
DeVries, Mark
Feldman, Ross D.
Kelvin, David J.
In the present study, we explored the molecular mechanisms by which bacterial endotoxin (LPS) mediates the down-regulation of CCR2 receptors on human monocytes. We found that LPS induced a marked reduction in CCR2 cell surface protein levels which was blocked by pretreatment with the tyrosine kinase inhibitors genistein and herbimycin A. The effector mechanism underlying LPS-induced CCR2 down-modulation appears to involve the enzymatic activity of proteinases since Western blot analysis of LPS-stimulated monocytes revealed the degradation of a 38-kDa species corresponding to the CCR2B monomer. In RBL cells expressing the CCR2B-green fluorescent protein (GFP) fusion chemokine receptor, LPS stimulated the internalization and degradation of CCR2. The serine proteinase inhibitor N-alpha-p-tosyl-L-lysine chloromethyl ketone blocked LPS-induced down-modulation of CCR2 in monocytes and CCR2B-GFP in RBL cells. This work describes a previously uncharacterized mechanism for CC chemokine receptor down-modulation that is dependent upon tyrosine kinase activation and serine proteinase-mediated receptor degradation and may provide further insight into the mechanisms of leukocyte regulation during immunological and inflammatory responses.
2000-01-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/46
info:doi/10.1002/1521-4141(200001)30:1<227::AID-IMMU227>3.0.CO;2-X
http://www3.interscience.wiley.com/journal/73000486/abstract
Robarts Immunology and Transplantation Publications
Scholarship@Western
Chemokine CCL2
Down-Regulation
Genistein
Humans
Lipopolysaccharides
Monocytes
Receptors
CCR2
Receptors
Chemokine
Receptors
Cytokine
Serine Endopeptidases
Serine Proteinase Inhibitors
Tosyllysine Chloromethyl Ketone
Receptors, CCR2
Receptors, Chemokine
Receptors, Cytokine
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:physpharmpub-1025
2010-01-07T07:42:37Z
publication:mnipub
publication:physpharmpub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:physpharm
publication:mni
publication:robarts
publication:institutes
CD45 Modulation of CXCR1 and CXCR2 in Human Polymorphonuclear Leukocytes
Mitchell, Gordon B.
Khandaker, Masud H.
Rahimpour, Rahbar
Xu, Luoling
Lazarovits, Andrew I.
Pickering, J. Geoffrey
Suria, Hamza
Madrenas, Joaquín
Pomerantz, David K.
Feldman, Ross D.
Kelvin, David J.
All leukocytes express the cell surface glycoprotein CD45, which has intrinsic intracellular protein tyrosine phosphatase activity. CD45 is known to play a regulatory role in activation-induced signaling in lymphocytes; however, little is known of its role in non-lymphoid leukocytes. Therefore, we examined the potential effect of CD45 on chemokine-induced signaling in human neutrophils (polymorphonuclear cells, PMN). Treating isolated PMN for 2 h with an anti-CD45RB antibody (Bra11) down-modulated expression of the chemokine receptors CXCR1 and CXCR2 to 44 +/- 10% and 47 +/- 9% of their respective controls. The tyrosine kinase inhibitors genistein and herbimycin A significantly inhibited the Bra11-induced down-modulation of CXCR1 and CXCR2. Furthermore, Bra11-treated PMN were functionally inhibited in their capacity to exhibit IL-8-induced transient intracellular Ca2+ increases. Selected targeting of CXC receptors is indicated by the fact that N-formyl-Met-Leu-Phe (fMLP) receptor expression and function were not lost following Bra11 treatment. The effect of Bra11 on IL-8-mediated function and receptor expression was paralleled by decreased tyrosine phosphorylation of a 54- to 60-kDa protein. These findings indicate that CD45 can act to modulate PMN responses to chemokines; thus agents regulating CD45 can potentially modulate leukocyte traffic and may represent a novel therapeutic approach towards the treatment of inflammatory diseases.
1999-05-01T07:00:00Z
article
https://ir.lib.uwo.ca/physpharmpub/30
info:doi/10.1002/(SICI)1521-4141(199905)29:05<1467::AID-IMMU1467>3.0.CO
http://www3.interscience.wiley.com/journal/62002682/abstract
Physiology and Pharmacology Publications
Scholarship@Western
Antibodies
Monoclonal
Antigens
CD
Antigens
CD45
Benzoquinones
Cells
Cultured
Chemokine CCL2
Chemokine CCL4
Down-Regulation
Genistein
Humans
Interleukin-8
Lactams
Macrocyclic
Macrophage Inflammatory Proteins
Neutrophils
Phosphorylation
Protein-Tyrosine Kinases
Quinones
Receptors
Chemokine
Receptors
Interleukin
Receptors
Interleukin-8A
Receptors
Interleukin-8B
Tyrosine
Antibodies, Monoclonal
Antigens, CD
Antigens, CD45
Cells, Cultured
Lactams, Macrocyclic
Receptors, Chemokine
Receptors, Interleukin
Receptors, Interleukin-8A
Receptors, Interleukin-8B
Medical Immunology
Medical Microbiology
Medical Physiology
oai:ir.lib.uwo.ca:mnipub-1013
2010-01-24T07:40:14Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Cytoskeletal Disruption Induces T Cell Apoptosis by a Caspase-3 Mediated Mechanism
Suria, Hamza
Chau, Luan A.
Negrou, Ella
Kelvin, David J.
Madrenas, Joaquín
T cell apoptosis can be triggered by different mechanisms that lead to distinctive features such as cell shrinkage, membrane blebbing, phosphatidylserine externalization, and internucleosomal DNA fragmentation. Prevailing models for the induction of apoptosis place the cytoskeleton as a distal target of the death effector molecules ('executioners'). However, the cytoskeleton can also play a role in the induction of apoptosis as suggested by the finding that cytoskeletal disruption can induce apoptosis. The mechanism by which this occurs is unknown. Here, we report that T cell apoptosis by cytoskeletal disruption involves a protein synthesis-independent mechanism leading to up-regulation of caspase-3 protease activity and increased accessibility of active caspase-3 to its substrate. Thus, cytoskeleton integrity may regulate the subcellular compartmentalization of death effector molecules.
1999-11-12T08:00:00Z
article
https://ir.lib.uwo.ca/mnipub/16
info:doi/10.1016/S0024-3205(99)00538-X
http://dx.doi.org/10.1016/S0024-3205(99)00538-X
Microbiology & Immunology Publications
Scholarship@Western
Animals
Annexin A5
Apoptosis
Caspase 3
Caspases
Cell Line
Cytochalasin B
Cytochalasin D
Cytochalasins
Cytoskeleton
DNA Fragmentation
Mice
Nucleic Acid Synthesis Inhibitors
T-Lymphocytes
Immunology and Infectious Disease
Microbiology
oai:ir.lib.uwo.ca:immunologypub-1050
2010-01-25T01:25:31Z
publication:mnipub
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Lymphocytes: Antigen-induced Gene Activation
Madrenas, Joaquin
1999-11-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/81
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antigen Receptor
Lymphocyte Activation
Signal Transduction
Transcription Factors
Cytokines
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1054
2009-12-12T02:15:07Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Specific CD3{varepsilon} Epsilon Association of a Phosphodiesterase 4B Isoform Determines Its Selective Tyrosine Phosphorylation after CD3 Ligation
Baroja, Miren L.
Cieslinski, Lenora B.
Torphy, Theodore J.
Wange, Ronald L.
Madrenas, Joaquín
cAMP-specific phosphodiesterases (PDE) comprise an extensive family of enzymes that control intracellular levels of cAMP and thus regulate T cell responses. It is not known how the function of these enzymes is altered by TCR engagement. We have examined this issue by studying one of the PDE isozymes (PDE4B). PDE4B RNA and protein were detected in resting PBLs, and the levels of PDE4B protein increased with cell cycling. In peripheral blood T cells, two previously reported PDE4B isoforms could be detected: one was 75–80 kDa (PDE4B1) and the other was 65–67 kDa (PDE4B2). These two isoforms differed in their N-terminal sequence, with the presence of four potential myristylation sites in the PDE4B2 that are absent in PDE4B1. Consequently, only PDE4B2 was found in association with the CD3{varepsilon} chain of the TCR. In addition, although both isoforms were phosphorylated in tyrosines in pervanadate-stimulated T cells, only the TCR-associated PDE4B2 was tyrosine-phosphorylated following CD3 ligation. The kinetics of phosphorylation of TCR-associated PDE4B2 correlated with changes in cAMP levels, suggesting that tyrosine phosphorylation of the TCR-associated PDE4B isoform upon engagement of this receptor may be an important regulatory step in PDE4B function. Our results reveal that selectivity of PDE4B activation can be achieved by differential receptor association and phosphorylation of the alternatively spliced forms of this PDE.
1999-02-15T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/50
http://www.jimmunol.org/cgi/content/abstract/162/4/2016
Robarts Immunology and Transplantation Publications
Scholarship@Western
3'
5'-Cyclic-AMP Phosphodiesterases
Antibodies
Monoclonal
Antigens
CD3
Blotting
Western
Cyclic Nucleotide Phosphodiesterases
Type 4
Humans
Interphase
Isoenzymes
Leukocytes
Mononuclear
Lymphocyte Activation
Phosphorylation
Precipitin Tests
Receptor-CD3 Complex
Antigen
T-Cell
Receptors
Antigen
T-Cell
T-Lymphocytes
Tyrosine
3',5'-Cyclic-AMP Phosphodiesterases
Antibodies, Monoclonal
Antigens, CD3
Blotting, Western
Cyclic Nucleotide Phosphodiesterases, Type 4
Leukocytes, Mononuclear
Receptor-CD3 Complex, Antigen, T-Cell
Receptors, Antigen, T-Cell
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:immunologypub-1053
2009-12-12T02:00:34Z
publication:mnipub
publication:physpharmpub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:physpharm
publication:mni
publication:robarts
publication:institutes
Metalloproteinases Are Involved in Lipopolysaccharide- and Tumor Necrosis Factor-alpha-mediated Regulation of CXCR1 and CXCR2 Chemokine Receptor Expression
Khandaker, Masud H.
Mitchell, Gordon
Xu, Luoling
Andrews, Joseph D.
Singh, Rajkumari
Leung, Harry
Madrenas, Joaquín
Ferguson, Stephen S. G.
Feldman, Ross D.
Kelvin, David J.
The neutrophil-specific G-protein-coupled chemokine receptors, CXCR1 and CXCR2, bind with high affinity to the potent chemoattractant interleukin-8 (IL-8). The mechanisms of IL-8 receptor regulation are not well defined, although previous studies have suggested a process of ligand-promoted internalization as a putative regulatory pathway. Herein, we provide evidence for two distinct processes of CXCR1 and CXCR2 regulation. Confocal microscopy data showed a redistribution of CXCR1 expression from the cell surface of neutrophils to internal compartments after stimulation with IL-8, whereas stimulation with bacterial lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha) did not induce CXCR1 internalization but instead mediated a significant loss of membrane-proximal CXCR1 staining intensity. To investigate whether proteolytic cleavage was the mechanism responsible for LPS- and TNF-alpha-induced downmodulation of IL-8 receptors, we tested a panel of proteinase inhibitors. The downmodulation of CXCR1 and CXCR2 by LPS and TNF-alpha was most dramatically inhibited by metalloproteinase inhibitors; 1, 10-phenanthroline and EDTA significantly attenuated LPS- and TNF-alpha-induced loss of CXCR1 and CXCR2 cell surface expression. Metalloproteinase inhibitors also blocked the release of CXCR1 cleavage fragments into the cell supernatants of LPS- and TNF-alpha-stimulated neutrophils. In addition, while treatment of neutrophils with LPS and TNF-alpha inhibited IL-8 receptor-mediated calcium mobilization and IL-8-directed neutrophil chemotaxis, both 1, 10-phenanthroline and EDTA blocked these inhibitory processes. In contrast, metalloproteinase inhibitors did not affect IL-8-mediated downmodulation of CXCR1 and CXCR2 cell surface expression or receptor signaling. Thus, these findings may provide further insight into the mechanisms of leukocyte regulation during immunologic and inflammatory responses.
1999-04-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/49
http://bloodjournal.hematologylibrary.org/cgi/content/abstract/93/7/2173
Robarts Immunology and Transplantation Publications
Scholarship@Western
Antigens
CD
Apoptosis
Calcium Signaling
Chemotaxis
Leukocyte
Dexamethasone
Down-Regulation
Edetic Acid
Endocytosis
GTP-Binding Proteins
Humans
Interleukin-8
Leucine
Leukocytes
Lipopolysaccharides
Metalloendopeptidases
Microscopy
Confocal
Phenanthrolines
Protease Inhibitors
Receptors
Chemokine
Receptors
Interleukin
Receptors
Interleukin-8A
Receptors
Interleukin-8B
Tumor Necrosis Factor-alpha
Antigens, CD
Chemotaxis, Leukocyte
Microscopy, Confocal
Receptors, Chemokine
Receptors, Interleukin
Receptors, Interleukin-8A
Receptors, Interleukin-8B
Immunology and Infectious Disease
oai:ir.lib.uwo.ca:psychologypub-1071
2011-09-06T00:46:56Z
publication:pmid
publication:faculties
publication:medpub
publication:med
publication:psychologypub
publication:psychology
Categorizing Patients in a Forced-Choice Triad Task: The Integration of Context in Patient Management
Devantier, Sarah L.
Minda, John Paul
Goldszmidt, Mark
Haddara, Wael
Background: Studies of experts' problem-solving abilities have shown that experts can attend to the deep structure of a problem whereas novices attend to the surface structure. Although this effect has been replicated in many domains, there has been little investigation into such effects in medicine in general or patient management in particular. Methodology/Principal Findings: We designed a 10-item forced-choice triad task in which subjects chose which one of two hypothetical patients best matched a target patient. The target and its potential matches were related in terms of surface features (e.g., two patients of a similar age and gender) and deep features (e.g., two diabetic patients with similar management strategies: a patient with arthritis and a blind patient would both have difficulty with self-injected insulin). We hypothesized that experts would have greater knowledge of management categories and would be more likely to choose deep matches. We contacted 130 novices (medical students), 11 intermediates (medical residents), and 159 experts (practicing endocrinologists) and 15, 11, and 8 subjects (respectively) completed the task. A linear mixed effects model indicated that novices were less likely to make deep matches than experts (t(68) = −3.63, p = .0006), while intermediates did not differ from experts (t(68) = −0.24, p = .81). We also found that the number of years in practice correlated with performance on diagnostic (r = .39, p = .02), but not management triads (r = .17, p = .34). Conclusions: We found that experts were more likely than novices to match patients based on deep features, and that this pattern held for both diagnostic and management triads. Further, management and diagnostic triads were equally salient for expert physicians suggesting that physicians recognize and may create management-oriented categories of patients.
2009-06-11T07:00:00Z
article
https://ir.lib.uwo.ca/psychologypub/48
info:doi/10.1371/journal.pone.0005881
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690657/
Psychology Publications
Scholarship@Western
Mental Health
Evidence-Based Healthcare
Non-Clinical Medicine
Medicine and Health Sciences
Psychology
oai:ir.lib.uwo.ca:surgerypub-1020
2010-01-28T06:24:42Z
publication:mnipub
publication:surgerypub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:surgery
publication:institutes
Surgical Technique for Vascularized Thymus Transplantation in Mice
Jiang, Jifu
Wang, Hao
Madrenas, Joaquin
Zhong, Robert
Traditionally, mouse nonvascularized thymus implants have been used to investigate various aspects of thymus function. However, these grafts are easily damaged by ischemia and fail to reproduce the normal anatomy of the thymus. In addition, the function of these grafts has not been fully examined. We have recently developed a vascularized thymus transplant model in mice. The donor operation consists of isolating the right lobe of the thymus and creating a single vascular pathway. In the recipient surgery, end-to-side anastomoses between donor brachycephalic artery and recipient right common carotid artery, and between donor superior caval vein and recipient right external jugular vein, were performed. We performed 10 consecutive isografts in BALB/c mice with a success rate of 90%. The thymus grafts had a normal histology and function. This study illustrates that it is technically possible to transplant a mouse vascular thymus graft. This model has several advantages that make it a useful tool to study many aspects of thymus function. We plan to use this model further to study the potential for induction of tolerance by thymus grafts.
1999-01-01T08:00:00Z
article
https://ir.lib.uwo.ca/surgerypub/22
http://www3.interscience.wiley.com/journal/45002064/abstract
Surgery Publications
Scholarship@Western
Animals
Endocrine Surgical Procedures
Flow Cytometry
Male
Mice
Mice
Inbred BALB C
Microsurgery
Postoperative Period
Random Allocation
Thymus Gland
Time Factors
Mice, Inbred BALB C
Medical Immunology
Surgery
oai:ir.lib.uwo.ca:mnipub-1015
2010-01-24T07:52:17Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Development of an I-Ag7-expressing Antigen-presenting Cell Line: Intrinsic Molecular Defect in Compact I-Ag7 Dimer Generation
Nabavieh, Ali
Chou, Henry
Volokhov, Irina
Lee, James E.
Purdy, Lisa E.
Elliott, John F.
Singh, Bhagirath
Madrenas, Joaquín
Insulin-dependent diabetes mellitus (IDDM) results from chronic, T-cell dependent, autoimmune destruction of the insulin-producing beta-cells in the Langerhans' islets of the pancreas. Non-obese diabetic (NOD) mice spontaneously develop IDDM that resembles human type I diabetes. The susceptibility to diabetes in the NOD strain is a complex polygenic trait that determines a phenotype of immune alterations. The unique MHC class II molecule expressed by NOD mice (I-Ag7) plays a major role in the development of disease. Recently, it has been reported that I-Ag7 molecules generate a lower proportion of compact alphabeta heterodimers, compared to other haplotypes. However, it is not clear whether this reflects an intrinsic defect of this molecule to bind peptide stably or is the result of abnormal processing and/or peptide loading into the I-Ag7 molecule. Our aim was to develop and characterize a suitable antigen-presenting cell (APC) that expressed I-Ag7 in the context of a non-diabetes-prone antigen processing and presentation machinery. Here, we report the generation of a mouse DAP.3 fibroblast cell line (DAP.3Ag7) that constitutively expresses high levels of I-Ag7. Using DAP.3 cells transfected with I-Ag7 or I-Ak, we show that the expression of compact dimers in the same cell type is proportionally less for I-Ag7 molecules than for I-Ak molecules, implying an intrinsic defect of the I-Ag7 molecule as the cause for the low generation of compact dimers. However, DAP.3Ag7 cells are able to process and present antigen, as indicated by I-Ag7-dependent IL-2 production by a GAD67-specific NDO T-cell hybridoma after stimulation with GAD and live, but not fixed, DAP.3Ag7 cells. The IL-2 response to GAD when presented by DAP.3Ag7 was significantly higher than the response to GAD presented by NOD splenocytes. Based on these data, we conclude that the low generations of compact dimers is an intrinsic feature of I-Ag7 molecules and not affected by other genes in the NOD background. The DAP.3Ag7 cell line should be a valuable tool with which to dissect the role of the I-Ag7 molecule in antigen presentation and T-cell activation in NOD mice, which clearly contributes to the development of IDDM.
1998-02-01T08:00:00Z
article
https://ir.lib.uwo.ca/mnipub/18
info:doi/10.1006/jaut.1997.0176
http://dx.doi.org/10.1006/jaut.1997.0176
Microbiology & Immunology Publications
Scholarship@Western
Animals
Antigen Presentation
Antigen-Presenting Cells
Cell Culture Techniques
Cell Line
Diabetes Mellitus
Type 1
Dimerization
Epitopes
Glutamate Decarboxylase
Histocompatibility Antigens Class II
Hybridomas
Immunophenotyping
L Cells (Cell Line)
Mice
Mice
Inbred BALB C
Mice
Inbred NOD
T-Lymphocytes
Transfection
Diabetes Mellitus, Type 1
L Cells (Cell Line)
Mice, Inbred BALB C
Mice, Inbred NOD
Immunology and Infectious Disease
Microbiology
oai:ir.lib.uwo.ca:immunologypub-1057
2009-12-12T05:49:24Z
publication:mnipub
publication:pmid
publication:immunologypub
publication:faculties
publication:medpub
publication:med
publication:mni
publication:robarts
publication:institutes
Differential Signaling through the T Cell Receptor: From Biochemistry to Transplantation Tolerance
Madrenas, J.
Lazarovits, A. I.
Recent advances in our understanding of the structural nature of T cell activation and signal transduction from the T cell receptor for antigen make possible the development of new tolerogenic strategies. Here, we summarize the evidence supporting a critical role for the co-receptor molecule (CD4 or CD8) and CD45 in determining the pattern of T cell receptor-mediated signaling. The consequences of this differential signaling can range from T cell proliferation and cytokine production to the establishment of a state of proliferative unresponsiveness known as T cell anergy. Inducing T cell anergy can be an alternative approach for the establishment of transplantation tolerance.
1998-01-01T08:00:00Z
article
https://ir.lib.uwo.ca/immunologypub/53
http://www.hh.um.es/Abstracts/Vol_13/13_1/13_1_24.htm
Robarts Immunology and Transplantation Publications
Scholarship@Western
Animals
Antigens
CD4
Antigens
CD45
Antigens
CD8
Clonal Anergy
Humans
Receptors
Antigen
T-Cell
Signal Transduction
Antigens, CD4
Antigens, CD45
Antigens, CD8
Receptors, Antigen, T-Cell
Immunology and Infectious Disease
834221/oai_dc/100//