A novel application of capnography during controlled human exposure to air pollution

BACKGROUND: The objective was to determine the repeatability and stability of capnography interfaced with human exposure facility. METHODS: Capnographic wave signals were obtained from five healthy volunteers exposed to particle-free, filtered air during two consecutive 5 min intervals, 10 min apart, within the open and then the sealed and operational human exposure facility (HEF). Using a customized setup comprised of the Oridion Microcap(® )portable capnograph, DA converter and AD card, the signal was acquired and saved as an ASCII file for subsequent processing. The minute ventilation (VE), respiratory rate (RR) and expiratory tidal volume (V(TE)) were recorded before and after capnographic recording and then averaged. Each capnographic tracing was analyzed for acceptable waves. From each recorded interval, 8 to 19 acceptable waves were selected and measured. The following wave parameters were obtained: total length and length of phase II and III, slope of phase II and III, area under the curve and area under phase III. In addition, we recorded signal measures including the mean, standard deviation, mode, minimum, maximum – which equals end-tidal CO(2 )(EtCO(2)), zero-corrected maximum and true RMS. RESULTS: Statistical analysis using a paired t-test for means showed no statistically significant changes of any wave parameters and wave signal measures, corrected for RR and V(TE), comparing the measures when the HEF was open vs. sealed and operational. The coefficients of variation of the zero-corrected and uncorrected EtCO(2), phase II absolute difference, signal mean, standard deviation and RMS were less than 10% despite a sub-atmospheric barometric pressure, and slightly higher temperature and relative humidity within the HEF when operational. CONCLUSION: We showed that a customized setup for the acquisition and processing of the capnographic wave signal, interfaced with HEF was stable and repeatable. Thus, we expect that analysis of capnographic waves in controlled human air pollution exposure studies is a feasible tool for characterization of cardio-pulmonary effects of such exposures

Sensitivity and specificity of screening for pulmonary arteriovenous malformations

grantor: University of Toronto'Objective'. To determine sensitivity and specificity of contrast echocardiography (CE) for diagnosing pulmonary arteriovenous malformations (AVMs) in Hereditary Hemorrhagic Telangiectasia (HHT). 'Methods'. 143/164 (87%) consecutive patients seen between 98-02-01 and 99-10-31 at the Toronto HHT Clinic underwent CE, oxygen shunt test (OST) and chest radiography (CXR). Patients with positive screening underwent pulmonary angiography (gold standard). 'Results'. Sensitivity and specificity of CE were 93% and 40%, when verification bias ignored. CE was more sensitive than OST (p = 0.0006) and CXR (p = 0.0001), but less specific than CXR (p = 0.0008). Using logistic regression to impute data for unverified patients, sensitivity and specificity were both 79%. Using novel scenario analysis to address verification bias, the possible range of sensitivity was 34-94% and specificity was 29-84%. 'Conclusion'. CE is more sensitive than conventional screening tests for pulmonary AVMs in HHT, when verification bias ignored. However, verification bias effects on estimates of sensitivity and specificity may be large.M.Sc

Prevention of influenza in the general population

BACKGROUND: Although all jurisdictions in Canada offer annual influenza immunization to people at high risk of complications, only Ontario has provided universal annual immunization of healthy adults and children. Use of chemotherapy (amantidine, neuraminidase inhibitors) to prevent influenza varies among provinces. We sought to systematically review the evidence for the prevention of influenza infection in the general population. METHODS: The interventions reviewed were influenza vaccination and prophylactic use of neuraminidase inhibitors. The health outcomes of interest were rates of laboratory-confirmed influenza infection, clinical definitions of influenza-like illness and work absenteeism. MEDLINE and Cochrane databases were searched for relevant articles published between 1966 and March 2003. Only randomized controlled trials (RCTs) were selected. Evidence was appraised using the methodology of the Canadian Task Force on Preventive Health Care. RESULTS: Eighteen trials involving more than 33 000 healthy adults were identified that met the inclusion criteria; of these, 15 showed that influenza vaccination with either live-attenuated and inactivated vaccines was efficacious. Eleven trials were considered to be of “good” quality, and 7 were considered to be of “fair” quality. The relative risk reduction (RRR) associated with influenza immunization in adults ranged from 0% to 91%. Fifteen RCTs involving more than 45 000 healthy children aged 6 months to 19 years were identified, of which 9 were considered to contain “good” evidence and 6 “fair” evidence. Results from 12 of these trials showed protection against influenza. The RRR ranged from 0% to 93%. There were 6 RCTs of “good” quality showing that neuraminidase inhibitors are effective in preventing influenza infection. Side effects from both influenza vaccination and neuraminidase inhibitor administration were mild. INTERPRETATION: There are numerous RCTs of good quality in large populations that have consistently shown that influenza vaccination, using inactivated or live-attenuated vaccines, is moderately effective in preventing influenza in the general population (healthy adults and children over 6 months of age). There is good evidence that neuraminidase inhibitor prophylaxis in contacts given within 36 to 48 hours of symptom onset of the household index case is effective; appropriate use of this prevention method requires access to rapid diagnostic methods. Decisions about introduction of routine immunization programs must take into account the cost and cost-effectiveness of a universal program and the burden of illness associated with influenza in each jurisdiction

MicroRNA-132-3p, Downregulated in Myeloid Angiogenic Cells from Hereditary Hemorrhagic Telangiectasia Patients, Is Enriched in the TGFβ and PI3K/AKT Signalling Pathways

Background. Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant genetic disorder characterized by life-threatening vascular dysplasia. Myeloid angiogenic cells (MACs), alternatively called early endothelial progenitor cells or circulating angiogenic cells, do not directly incorporate into developing blood vessels, but augment angiogenesis in a paracrine manner. MAC dysfunction has been reported in HHT. MicroRNAs (miRNAs) regulate cellular function by modulating gene expression post-transcriptionally. To date, the role of miRNAs in HHT MAC dysfunction has not been documented. Objective. The goal of this study was to comparatively profile miRNAs in HHT patient and control MACs to identify dysregulated miRNAs that may be responsible for the observed MAC dysfunction in HHT. Methodology/Results. Twenty-three dysregulated miRNAs (twenty-one upregulated and two downregulated) in HHT MACs were identified with a TaqMan miRNA microarray. Pathway enrichment analysis showed that the dysregulated miRNAs were significantly enriched in pathways involved in HHT pathogenesis, such as the transforming growth factor β (TGFβ), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and Hippo signalling pathways. Furthermore, miR-132-3p was determined to be significantly reduced in HHT MACs compared with controls by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Bioinformatic analysis revealed that miR-132-3p is significantly enriched in the TGFβ and PI3K/AKT signalling pathways, targeting SMAD4, an effector of the TGFβ signalling pathway and RASA1, a negative regulator of the PI3K/AKT signalling pathway, respectively. Conclusion. MiRNA dysregulation, specifically reduced expression of miR-132-3p, in HHT MACs was identified. The dysregulated miRNAs are significantly enriched in the TGFβ, PI3K/AKT, and Hippo signalling pathways. These data suggest that alteration in miRNA expression may impair these pathways and contribute to MAC dysfunction in HHT

Decreased Levels of MicroRNAs-28-5p, -361-3p and Increased Insulin-Like Growth Factor 1 mRNA Levels in Mononuclear Cells from Hereditary Hemorrhagic Telangiectasia Patients

Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disorder inherited in an autosomal dominant manner. Patients with HHT can develop vascular dysplasias called telangiectasias and arteriovenous malformations (AVMs). Our objective was to profile and characterize microRNAs (miRs), short-noncoding RNAs that regulate gene expression post-transcriptionally, in HHT patient derived peripheral blood mononuclear cells (PBMCs). PBMCs, comprised mostly of lymphocytes and monocytes, have been reported to be dysfunctional in HHT. A total of 40 clinically confirmed HHT patients and 22 controls were enrolled in this study. PBMCs were isolated from 16 ml of peripheral blood and purified for total RNA. MiR expression profiling was conducted with a human miR array analysis. Select dysregulated miRs and miR targets were validated with RT-qPCR. Of the 377 miRs screened, 41 dysregulated miRs were identified. MiR-28-5p and miR-361-3p, known to target insulin-like growth factor 1 (IGF1), a potent angiogenic growth factor, were found to be significantly downregulated in patients. Consequently, IGF1 mRNA levels were found to be significantly elevated. Our research successfully identified miR dysregulation and elevated IGF1 mRNA levels in HHT PBMCs. This novel discovery represents a potential pathogenic mechanism that could be targeted to alleviate clinical manifestations of HHT.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

MicroRNA-132-3p, Downregulated in Myeloid Angiogenic Cells from Hereditary Hemorrhagic Telangiectasia Patients, Is Enriched in the TGFβ and PI3K/AKT Signalling Pathways

Background. Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant genetic disorder characterized by life-threatening vascular dysplasia. Myeloid angiogenic cells (MACs), alternatively called early endothelial progenitor cells or circulating angiogenic cells, do not directly incorporate into developing blood vessels, but augment angiogenesis in a paracrine manner. MAC dysfunction has been reported in HHT. MicroRNAs (miRNAs) regulate cellular function by modulating gene expression post-transcriptionally. To date, the role of miRNAs in HHT MAC dysfunction has not been documented. Objective. The goal of this study was to comparatively profile miRNAs in HHT patient and control MACs to identify dysregulated miRNAs that may be responsible for the observed MAC dysfunction in HHT. Methodology/Results. Twenty-three dysregulated miRNAs (twenty-one upregulated and two downregulated) in HHT MACs were identified with a TaqMan miRNA microarray. Pathway enrichment analysis showed that the dysregulated miRNAs were significantly enriched in pathways involved in HHT pathogenesis, such as the transforming growth factor β (TGFβ), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and Hippo signalling pathways. Furthermore, miR-132-3p was determined to be significantly reduced in HHT MACs compared with controls by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Bioinformatic analysis revealed that miR-132-3p is significantly enriched in the TGFβ and PI3K/AKT signalling pathways, targeting SMAD4, an effector of the TGFβ signalling pathway and RASA1, a negative regulator of the PI3K/AKT signalling pathway, respectively. Conclusion. MiRNA dysregulation, specifically reduced expression of miR-132-3p, in HHT MACs was identified. The dysregulated miRNAs are significantly enriched in the TGFβ, PI3K/AKT, and Hippo signalling pathways. These data suggest that alteration in miRNA expression may impair these pathways and contribute to MAC dysfunction in HHT

Embolization of a Duodenal Arteriovenous Malformation in Hereditary Hemorrhagic Telangiectasia: Case Report and Review of the Literature

A 68-year-old man with hereditary hemorrhagic telangiectasia presented with recurrent, intermittent gastrointestinal hemorrhage. Transfusion of a total of 27 units of red blood cells was required over the three months before admission. Upper and lower endoscopy did not reveal a source of bleeding and a technetium-labelled red blood cell scan was noncontributory. Angiography demonstrated a duodenal arteriovenous malformation originating from a superior mesenteric artery branch. Embolization of the arteriovenous malformation was performed with resolution of gastrointestinal hemorrhage and reduced requirement for blood transfusion. The utility of trans-catheter embolization in the management of duodenal arteriovenous malformations in hereditary hemorrhagic telangiectasia is discussed