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1.
Haemophilia ; 24(2): 236-244, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29388742

ABSTRACT

INTRODUCTION: Following a provincial tender, most subjects with haemophilia A in Quebec switched their treatment to a third-generation recombinant B-domain-deleted factor VIII (FVIII). AIM: Our objective was to evaluate the incidence of inhibitor development and FVIII recovery in patients following the switch of factor replacement therapy. METHODS: One hundred and thirty-five subjects were enrolled and tested for FVIII activity and inhibitors every 6 months during 1 year. Subjects with mild haemophilia A or current inhibitors were excluded. Data on demographics, bleeds and FVIII usage were collected. RESULTS: A total of 125 switchers and 10 non-switchers were enrolled. Most subjects had severe haemophilia A (95.6%) and were on prophylaxis (89.6%). Mean FVIII recovery was similar at 0, 6 and 12 months postswitch. Two switchers developed de novo inhibitors in the 6 months postswitch, one of which was transient. No recurrent inhibitor was observed. A small but significant increase in FVIII usage was observed for adult switchers and the whole cohort of switchers and non-switchers. There was an increase in the annualized bleeding rate (ABR) for non-joint bleeds for the whole cohort of switchers. However, no significant differences were observed in ABR for joint bleeds. CONCLUSION: Our surveillance study shows comparable inhibitor development to similar published studies. A significant increase in FVIII utilization was noted for the whole cohort, switchers and non-switchers. Lastly, no clinically significant changes were observed in ABR for joint bleeds, but a difference for non-joint bleed ABRs was observed in switchers.


Subject(s)
Factor VIII/therapeutic use , Hemophilia A/drug therapy , Adult , Female , Humans , Male , Prospective Studies
2.
Breast ; 31: 197-201, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27894048

ABSTRACT

BACKGROUND: HER2-overexpressing breast cancer (BC) is common among young patients and poses a public health burden. Adjuvant anti-HER2/neu therapy with trastuzumab reduces the risk of recurrence and improves survival. METHODS: A web-based survey was sent to 386 physicians of the "TEACH" trial in 2011 to determine access to HER2/neu testing and treatment patterns for HER2-overexpressing BC. RESULTS: There were 151 responders (39%) from 28 countries. Ninety-seven percent reported HER2/neu expression is routinely measured in their institutions by immunohistochemistry (85%), FISH (80%) and other methods (16%). Twenty percent of responders from Asia reported that the test was not routinely available. Forty-eight percent of participants reported instances when adjuvant HER2-directed therapy was recommended to a patient who eventually did not receive it. Reasons for not receiving trastuzumab was cost (73%, p < 0.0001) in low- and middle-income countries and co-morbidities in high-income countries (43%, p = 0.003). CONCLUSIONS: This survey reflects the availability of HER2/neu testing and anti-HER2/neu therapy among physicians who participated in TEACH. A high proportion of women with HER2-overexpressing BC may not receive standard adjuvant therapy due to unavailability of the test and cost of therapy. Despite having some limitations, such as a possible selection bias of participating physicians, variable definitions of access to healthcare among respondents, and changes in trastuzumab availability since 2011, our results demonstrate that access to care and region of practice impact the implementation of cancer treatments.


Subject(s)
Breast Neoplasms/therapy , Developed Countries/statistics & numerical data , Developing Countries/statistics & numerical data , Practice Patterns, Physicians' , Antineoplastic Agents/supply & distribution , Antineoplastic Agents/therapeutic use , Breast Neoplasms/chemistry , Clinical Trials, Phase III as Topic , Female , Health Care Surveys , Health Services Accessibility/statistics & numerical data , Humans , Insurance, Health/statistics & numerical data , Mastectomy, Segmental/statistics & numerical data , Randomized Controlled Trials as Topic , Receptor, ErbB-2/analysis , Trastuzumab/therapeutic use
3.
Haemophilia ; 22(5): e401-5, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27481574

ABSTRACT

INTRODUCTION: Standard prophylaxis has been shown to be an effective treatment for severe haemophilia A. According to pharmacokinetic principles, daily factor infusions of smaller doses can maintain similar trough factor VIII (FVIII) levels, and perhaps the same protection as standard prophylaxis. AIM: This multicentre study examined the feasibility of daily prophylaxis for youth and young adults with severe haemophilia A in Montreal and Toronto. METHODS: Bleeding rates, joint status, quality of life and physical activity were monitored for 14 patients during this study. At baseline, subjects continued their regular treatment regimen and switched to daily prophylaxis after 4 months; nine had begun daily prophylaxis before enrolment. Additional visits occurred at 8 and 12 months which included a physical examination, inhibitor testing, HJHS and FISH assessments, the CHO-KLAT/Haemo-QoL-A and PDPAR. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication ver.II and perceived difficulty questions at the end of study. RESULTS AND CONCLUSIONS: There were no significant changes in quality of life except for concerns with the demanding daily infusion schedule. The number of bleeds did not statistically differ from the initial 4 months of the study to the last 8 months. Monthly bleeding rates from the year prior to the study and during the intervention phase were not statistically different. It was also found that daily prophylaxis used 24% less FVIII compared to standard prophylaxis. Taking all of this into account, we have found that providing daily prophylaxis is feasible and that it is feasible to prospectively study daily prophylaxis in youth and young adults.


Subject(s)
Factor VIII/therapeutic use , Hemophilia A/drug therapy , Hemorrhage/prevention & control , Adolescent , Adult , Canada , Disease Progression , Feasibility Studies , Follow-Up Studies , Hemophilia A/complications , Hemorrhage/etiology , Humans , Pilot Projects , Quality of Life , Surveys and Questionnaires , Treatment Outcome , Young Adult
4.
BMC Hematol ; 16: 13, 2016.
Article in English | MEDLINE | ID: mdl-27158500

ABSTRACT

BACKGROUND: This study was undertaken to explore the longitudinal patterns of health-related quality of life (HRQoL) among youth and young adults with Hemophilia A (HA) over a 3-year period. This report presents the baseline characteristics of the study cohort. METHODS: Males, 14 to 29 years of age, with predominantly severe HA were recruited from six treatment centres in Canada. Subjects completed a comprehensive survey. HRQoL was measured using: the CHO-KLAT2.0 (youth), Haemo-QoL-A (young adults) and the SF-36v2 (all). RESULTS: 13 youth (mean age = 15.7, range = 12.9-17.9 years) and 33 young adults (mean age = 23.6; range = 18.4 -28.7 years) with moderate (7 %) and severe (93 %) HA were enrolled. All were on a prophylactic regimen with antihemophilic factor (Helixate FS®) during the study. The youth had minimal joint damage (mean HJHS = 5.2) compared to young adults (mean HJHS = 13.3). The mean HRQoL scores for youth were: 79.2 (SD = 11.9) for the CHO-KLAT, and 53.0 (5.5) and 52.3 (6.8) for the SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores respectively. The mean HRQoL scores for young adults were: 85.8 (9.5) for the Haemo-Qol-A, and 50.8 (6.4) and 50.9 (8.8) for PCS and MCS respectively. PCS and MCS scores were comparable to published Canadian norms, however significant differences were found for the domains of Physical Functioning and Bodily Pain. The disease-specific HRQoL scores were weakly correlated with the PCS for youth (CHO-KLAT vs. PCS r = 0.28, p = 0.35); and moderately correlated for the MCS (r = 0.39, p = 0.19). Haemo-QoL-A scores for young adults were strongly correlated with the PCS (r = 0.53, p = 0.001); and weakly correlated with the MCS (r = 0.26, p = 0.13). Joint status as assessed by HJHS was correlated with PCS scores. A history of lifelong prophylaxis resulted in better PCS but worse MCS scores. CONCLUSION: Despite having hemophilia, the youth in this cohort have minimal joint disease and good HRQoL. The young adults demonstrated more joint disease and slightly worse HRQoL in the domains of physical functioning and pain. The data presented here provide new information to inform the selection of Health Related Quality of Life (HRQoL) instruments for use in future clinical trials involving persons with hemophilia. TRIAL REGISTRATION: ClinicalTrials.gov : NCT01034904. Study funded by CSL Behring Canada.

5.
Haemophilia ; 22(3): e177-83, 2016 May.
Article in English | MEDLINE | ID: mdl-26988074

ABSTRACT

INTRODUCTION: In persons with severe haemophilia A (pwshA), infused factor VIII (FVIII) half-life can vary according to such determinants as blood group, von Willebrand factor (VWF) level or age; however, FVIII pharmacokinetics (PK) has not been well studied in pwshA during exercise. AIM: To investigate FVIII PK in pwshA performing moderate-intensity aerobic exercise. METHODS: Twelve young-adult pwshA with the intron-22 inversion mutation, on relatively low-dose FVIII prophylaxis regimens, and relatively good musculoskeletal status were recruited. Abbreviated PK of FVIII activity and von Willebrand factor antigen (VWF:Ag) level were compared - during rest, and with 60-min exercise (2 × 15 min each of moderate-intensity stationary cycling and treadmill walking). During rest and exercise visits, a baseline blood specimen was drawn, routine prophylaxis FVIII infused; then six blood specimens were taken over the following 24 h. RESULTS: For all subjects, mean half-life of infused FVIII did not change significantly with exercise vs. at rest (577 ± 190 vs. 614 ± 163 min; P = 0.4131). VWF:Ag rose transiently by 40-50% for 6-8 h with exercise (P < 0.01), particularly in non-O blood group subjects. No musculoskeletal bleeds occurred during the study. CONCLUSION: Four × 15 min of moderate-intensity aerobic exercise increased VWF:Ag levels for 6-8 h, and showed no evidence of accelerated FVIII clearance or of musculoskeletal bleeding in these young-adult pwshA with relatively good musculoskeletal status, on relatively low-dose FVIII prophylaxis regimens. However, O blood group impact would merit larger studies, with longer durations of similar or more vigorous exercise intensities.


Subject(s)
Exercise , Factor VIII/pharmacokinetics , Hemophilia A/drug therapy , von Willebrand Factor/pharmacokinetics , Adolescent , Adult , Blood Coagulation Tests , Blood Group Antigens/metabolism , Disease Progression , Factor VIII/therapeutic use , Female , Half-Life , Humans , Male , Pilot Projects , Young Adult , von Willebrand Factor/therapeutic use
6.
Haemophilia ; 21(2): 162-170, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25623166

ABSTRACT

Acquired haemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against human factor VIII (hFVIII). OBI-1 is an investigational, B-domain deleted, recombinant FVIII, porcine sequence, with low cross-reactivity to anti-hFVIII antibodies. Efficacy can be monitored with FVIII activity levels in addition to clinical assessments. This prospective, open label, phase 2/3 study was designed to evaluate the efficacy of OBI-1 treatment for bleeding episodes in subjects with AHA. After an initial dose of 200 U kg(-1) , OBI-1 was titrated to maintain target FVIII activity levels, in correlation with clinical assessments, throughout the treatment phase. All 28 subjects with AHA had a positive response to OBI-1 treatment 24 h after initiation despite inhibition of FVIII activity levels immediately after infusion in 10 subjects with baseline anti-porcine FVIII inhibitors. Control of the qualifying bleed was ultimately achieved in 24 of 28 subjects. No related serious adverse events, thrombotic events, allergic reactions or thrombocytopaenia occurred. The results of this study indicate that OBI-1 is safe and effective in treating bleeding episodes in subjects with AHA. The ability to safely and effectively titrate dosing based on FVIII activity levels in this study demonstrates that OBI-1 fulfils the unmet medical need to monitor the key coagulation parameter in AHA patients.


Subject(s)
Factor VIII/therapeutic use , Hemophilia A/drug therapy , Recombinant Proteins/therapeutic use , Adult , Aged , Aged, 80 and over , Animals , Antibodies, Neutralizing , Autoantibodies/immunology , Cross Reactions/immunology , Factor VIII/administration & dosage , Factor VIII/adverse effects , Factor VIII/immunology , Female , Hemophilia A/immunology , Humans , Male , Middle Aged , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/immunology , Swine , Time Factors , Treatment Outcome
7.
Haemophilia ; 20(4): e251-9, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24948405

ABSTRACT

The Canadian Hemophilia Assessment and Resource Management System (CHARMS) tracks factor concentrates (FC) from the sole suppliers, Canadian Blood Services (CBS) and Hema-Quebec (HQ), to hospitals and to patients' homes. Patients FC infusion data are entered into CHARMS at Canadian Hemophilia Treatment Centres (HTCs) then exported to the national database (CentrePoint). From 2000 to 2009, 2260 registered haemophilia A or B patients received FVIII (1,009,097,765 IU) and FIX (272,406,859 IU). Over 91% of FVIII and over 84% of FIX was infused at home. Utilization of FVIII progressively increased; this was accounted for by an increase in the number of patients treated (r = 0.97; P < 0.001), there being a linear relationship between the increase in utilization and the increase in number of patients treated (P < 0.001). There was also a correlation with the annual amount used per patient (r = 0.95; P < 0.001). Utilization of FIX did not increase over time. The highest proportional utilization of both FVIII and FIX was for prophylaxis, and this proportion progressively increased being, in year 10 (2009), 77% and 66% for FVIII and FIX respectively. The proportion used for bleeding remained steady; in year 10 that proportion was 14% for FVIII and 26% for FIX, the use per patient for bleeding decreasing. The HTC-based CHARMS tracking system is essential, in Canada, for analysing indications for infusion, for predicting utilization and planning for future needs.


Subject(s)
Blood Coagulation Factors/therapeutic use , Health Resources/statistics & numerical data , Health Resources/trends , Hemophilia A/drug therapy , Blood Coagulation Factors/administration & dosage , Canada , Female , Humans , Male
8.
Haemophilia ; 20(3): e199-204, 2014 May.
Article in English | MEDLINE | ID: mdl-24589126

ABSTRACT

From a young age patients with severe and moderately severe FIX deficiency (haemophilia B) can experience spontaneous or traumatic bleeding and joint destruction may result. The use of coagulation factor IX concentrate to prevent anticipated bleeding, as primary or secondary prophylaxis, has become a common and recommended practice in children. The current practice of using tertiary prophylaxis, in the presence of established joint arthropathy, in adults with haemophilia B is not well characterized. This observational study was conducted to gain a better understanding of the recent Canadian experience with tertiary prophylaxis in adults with severe and moderately severe haemophilia B. Data were collected from all eligible adult (≥ 18 years of age) males with baseline FIX:C ≤ 2% from seven Canadian Hemophilia Treatment centres over a 2-year observation period from 2009 to 2011. Thirty-four per cent of the 67 subjects with moderately severe haemophilia B were exposed to prophylaxis with the majority as continuous prophylaxis (≥45 weeks year(-1) ). The severe subgroup (FIX:C < 1%) demonstrated a 52% exposure rate. None had primary prophylaxis exposure in childhood. Eighty-one per cent used once or twice weekly infusion regimens and reported a median annual bleeding rate of five bleeds per year versus four bleeds per year for those using on-demand treatment. Annual median factor utilization for all subjects using prophylaxis was 196,283 U year(-1) compared to 46,361 U year(-1) for on demand. Approximately 50% of adults with severe haemophilia B are using continuous tertiary prophylaxis in Canada, a practice likely to increase which warrants further study.


Subject(s)
Hemophilia B/drug therapy , Hemorrhage/prevention & control , Adult , Aged , Aged, 80 and over , Canada , Factor IX/administration & dosage , Female , Hemarthrosis/pathology , Hemophilia B/pathology , Humans , Male , Middle Aged , Young Adult
9.
Haemophilia ; 19(3): 385-91, 2013 May.
Article in English | MEDLINE | ID: mdl-22994803

ABSTRACT

von Willebrand disease (VWD) is a bleeding disorder that occurs in up to 1% of the general population. The great majority of females with VWD experience menorrhagia. The morbidity burden in females with VWD may relate to iron deficiency resulting from menorrhagia. To explore relationships between bleeding disorders, menorrhagia, iron deficiency and the outcomes of health-related quality of life (HRQL) and educational attainment. All subjects with VWD, and females with other bleeding disorders, in the Canadian national registry who were more than 12 years of age were eligible for survey. Survey measures included the HEALTH UTILITIES INDEX(®); abridged Clinical History Assessment Tool; socio-demographic questions and serum ferritin. Statistical analyses included testing differences among groups of means using analysis of variance and of proportions using chi-squared test. Significant size differences in mean HRQL scores were detected between VWD females and both females with other bleeding disorders [diff = (-0.08); P = 0.017] and VWD males [diff = (-0.07); P = 0.039]. Mean HRQL scores differed between females with and without menorrhagia (P < 0.001). Mean HRQL scores were not significantly different between females with and without iron deficiency. Educational attainment was not associated with disease group, menorrhagia status or iron status. Females with VWD have a greater morbidity burden than females in the general population, females with other bleeding disorders and males with VWD. Menorrhagia is associated with low HRQL scores in females with bleeding disorders, including VWD. Further investigation should assess how menorrhagia impacts HRQL in females with bleeding disorders.


Subject(s)
Anemia, Iron-Deficiency/psychology , Menorrhagia/psychology , Quality of Life , von Willebrand Diseases/psychology , Adolescent , Adult , Anemia, Iron-Deficiency/complications , Anemia, Iron-Deficiency/epidemiology , Child , Cross-Sectional Studies , Female , Ferritins/blood , Health Status , Humans , Iron/metabolism , Male , Menorrhagia/epidemiology , Menorrhagia/etiology , Prevalence , Surveys and Questionnaires , Young Adult , von Willebrand Diseases/complications
10.
Exp Physiol ; 98(1): 183-92, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22848078

ABSTRACT

Regulation of the sodium pump during normal pregnancy and its effect on the function of cardiomyocytes is poorly understood. Our objective was to evaluate the possible implication of the Na(+)-K(+)-ATPase, the sodium pump which controls cellular ionic and metabolic homeostasis, in the adaptations of cardiomyocytes to normal pregnancy. We have used Western blots and patch-clamp measurements to identify changes in the sodium pump proteins. Confocal microscopy was applied to estimate intracellular sodium concentration. Time-resolved spectroscopy was employed to measure mitochondrial NAD(P)H fluorescence and estimate oxidative metabolic state. Optical microscopy was adopted to study the contractility responses of cardiomyocytes. Cells from non-pregnant and pregnant rats (1 day prior parturition) were studied. Our results showed lower protein expression of the α1 Na(+)-K(+)-ATPase isoform in cardiomyocytes in pregnant rats, decreased sodium pump membrane current and elevated steady-state sodium concentration. In addition, ouabain, the inhibitor of the sodium pump capable of increasing cardiomyocyte contractility in non-pregnant rats in a concentration-dependent manner, failed to affect cell contractions in pregnant rats. We also noted modified responsiveness of the mitochondrial metabolic state to ouabain in cardiac cells. The gathered data confirmed that in pregnant rats, the sodium pump protein content and transmembrane flux are decreased, while the sensitivity of cardiomyocyte contractility and the sensitivity of mitochondrial metabolic redox state to ouabain are modified, pointing to regulation of the Na(+)-K(+)-ATPase during cardiac cell adaptations to normal pregnancy.


Subject(s)
Adaptation, Physiological , Myocytes, Cardiac/physiology , Pregnancy, Animal/physiology , Sodium-Potassium-Exchanging ATPase/physiology , Animals , Female , Muscle Contraction/drug effects , NADP/metabolism , Ouabain/pharmacology , Pregnancy , Rats , Rats, Sprague-Dawley , Sodium-Potassium-Exchanging ATPase/biosynthesis
11.
Am J Physiol Heart Circ Physiol ; 302(5): H1195-201, 2012 Mar 01.
Article in English | MEDLINE | ID: mdl-22198172

ABSTRACT

The renin-angiotensin-aldosterone (RAA) system is markedly activated in pregnancy. We evaluated if mineralocorticoid receptors (MR), a major component of the RAA system, are involved in the reduced vascular reactivity associated with pregnancy. Canrenoate (MR antagonist; 20 mg·kg(-1)·day(-1)) was administered to nonpregnant (NP) rats for 7 days and to pregnant rats from day 15 to 22 of gestation. These were killed on day 17, 19, or 22 of gestation and, for NP rats, after 7 days treatment. Constrictor responses to phenylephrine (PhE) and KCl were measured in endothelium-denuded thoracic aortic rings under the influence of modulators of potassium (activators) and calcium (blocker) channels. Responses to the constrictors were blunted from days 17 to 22 of gestation. Although canrenoate increased responses to PhE and KCl, it did not reverse their blunted responses in gestation. NS-1619 and cromakalim (respectively, high-conductance calcium-activated potassium channels and ATP-sensitive potassium channel activators) diminished responses to both PhE and KCl. Inhibition by NS-1619 on responses to both agonists was decreased under canrenoate treatment in NP, but the reduced influence of NS-1619 during gestation was reversed by the mineralocorticoid antagonist. Cromakalim reduced the response to PhE significantly in the pregnant groups; this effect was enhanced by canrenoate. Finally, nifedipine (calcium channel blocker) markedly reduced KCl responses but to a lesser extent at the end of pregnancy, an inhibiting effect that was increased with canrenoate treatment. These data demonstrate that treating rats with a MR antagonist increased vascular reactivity but that it differentially affected potassium and calcium channel activity in aortas of NP and pregnant animals. This suggests that aldosterone is one of the components involved in vascular adaptations to pregnancy.


Subject(s)
Aorta, Thoracic/physiology , Mineralocorticoids/pharmacology , Renin-Angiotensin System/physiology , Aldosterone/pharmacology , Animals , Aorta, Thoracic/drug effects , Benzimidazoles/pharmacology , Calcium Channel Blockers/pharmacology , Canrenoic Acid/pharmacology , Cromakalim/pharmacology , Female , KATP Channels/antagonists & inhibitors , Mineralocorticoid Receptor Antagonists/pharmacology , Muscle, Smooth, Vascular/drug effects , Nifedipine/pharmacology , Phenylephrine/pharmacology , Potassium Channels, Calcium-Activated/antagonists & inhibitors , Potassium Chloride/pharmacology , Pregnancy , Rats , Rats, Sprague-Dawley , Receptors, Mineralocorticoid/physiology , Vasoconstrictor Agents/pharmacology , Vasodilator Agents/pharmacology
12.
Haemophilia ; 18(3): e254-9, 2012 May.
Article in English | MEDLINE | ID: mdl-22077390

ABSTRACT

Annual reporting of inhibitors to factors (FVIII) and IX (FIX) to the Canadian Haemophilia Registry has suggested a lower prevalence than that published in the literature. We performed a prospective study to determine the prevalence of patients with inhibitors directed against either FVIII or FIX. Patients with inhibitors were classified as: (i) inhibitor test positive; (ii) inhibitor test negative but on immune tolerance induction (ITI); (iii) inhibitor test negative but bypass treatment recommended; or (iv) inhibitor resolved. One year later, the cohort was re-classified. The prevalence of inhibitors on 1 May, 2007 was 3.3% for haemophilia A, 0.6% for haemophilia B and 8.9% and 2.1% for severe haemophilia A and B. One year later 17 individuals gained and 11 individuals lost inhibitor status (10 of these with ITI). This study suggests that the prevalence of inhibitors in our population is lower than that was previously published. We hypothesize that this is primarily due to the increased use of ITI, but other factors may be the unselected nature of the cohort and the restriction of the study to one date thereby conforming as close as practical to the definition of prevalence rather than incidence. The classification system used in this study was easy for clinics to apply and was important in defining the population with inhibitors.


Subject(s)
Factor IX/immunology , Factor VIII/immunology , Hemophilia A/immunology , Hemophilia B/immunology , Isoantibodies/blood , Adolescent , Adult , Canada , Child , Child, Preschool , Humans , Middle Aged , Prospective Studies , Young Adult
13.
Haemophilia ; 18(3): 353-7, 2012 May.
Article in English | MEDLINE | ID: mdl-22103664

ABSTRACT

Multi-site studies are necessary in the field of haemophilia to ensure adequate sample sizes. Quality of life (QoL) instruments need to be harmonized across languages and cultures to facilitate their inclusion. The purpose of this study was to adapt the Canadian Haemophilia Outcomes - Kids Life Assessment Tool (CHO-KLAT(©)) and HAEMO-QoL-A(©) to French for Canada. The CHO-KLAT and the HAEMO-QoL-A are haemophilia-specific measures of QoL for boys and men respectively. Both measures originated in English, were translated into Canadian French by clinicians with expertise in haemophilia care, back-translated by expert translators and harmonized by a multi-disciplinary team. The harmonized versions were evaluated through a cognitive debriefing process with 6 boys with haemophilia, their parents and 10 men with haemophilia. The final versions were validated in a sample of 19 boys with haemophilia, 19 parents, and 22 men with haemophilia along with a generic QoL scale: the PedsQL for children; and the SF-36 for adults. The translation and cognitive debriefing processes resulted in a preliminary version that maintained the intent of the original questions. The validation study estimated the mean score for the child-reported CHO-KLAT at 71.9 (SD 10.4), and the adult-reported HAEMO-QoL-A at 79.1 (SD 21.3). The CHO-KLAT correlated 0.64 with the PedsQL and the HAEMO-QoL-A correlated 0.78 with the SF-36 physical component summary score. The French-Canadian version of the CHO-KLAT and HAEMO-QoL-A are valid. These measures are available for use in multi-site haemophilia trials and clinical practices to capture QoL data from French Canadians.


Subject(s)
Hemophilia A/psychology , Hemophilia B/psychology , Outcome Assessment, Health Care/methods , Quality of Life , Adult , Aged , Canada , Child , Child, Preschool , Cross-Cultural Comparison , France/ethnology , Humans , Language , Male , Reproducibility of Results , Surveys and Questionnaires/standards , Translations
14.
Placenta ; 32(12): 941-8, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22015024

ABSTRACT

As the placenta is devoid of autonomic innervation, umbilical-placental vascular tone should be under the control of tissue and humoral factors. Among the numerous stimuli capable of challenging the placental circulation, we propose that prostanoids could be responsible for the regulation of placental vascular tone. Consequently, we measured vasomotor responses to the thromboxane A(2) (TXA(2)) mimetic U-46619 and the isoprostane 8-iso-prostaglandin E(2) (8-isoPGE(2)) in the human placental vasculature. Placental tissues were collected from normotensive women after elective caesarean delivery. Cotyledons were set up in a perfusion system, whereas chorionic arteries were prepared as rings and installed in glass-jacketed tissue baths. The effects of U-46619 and 8-isoPGE(2) were measured in the absence and presence of blockers of TXA(2) receptors (TP), SQ29,548 and ICI192,605, and of PGE(2) receptors (EP), AH6809. The influence of nitric oxide (NO) was assessed with NG-nitro-L-arginine methyl ester (L-NAME). U-46619 and 8-isoPGE(2) markedly increased perfusion pressure in cotyledons and tension in chorionic arteries. Dose-response curves to both prostanoids were competitively shifted to the right by all antagonists, but to different extents. L-NAME had no significant impact on the dose-response curves to U-46619. The effects of U-46619 and 8-isoPGE(2) were found to be mediated by both TP and EP. The presence of these receptors and the actions exerted by their agonists support our postulate that prostanoids play an important regulatory role in placental vascular tone and resistance. NO, however, does not seem to be involved.


Subject(s)
Placenta/blood supply , Prostaglandins/pharmacology , Receptors, Prostaglandin E/physiology , Receptors, Thromboxane A2, Prostaglandin H2/physiology , Thromboxanes/pharmacology , 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology , Adult , Bridged Bicyclo Compounds, Heterocyclic , Dinoprostone/analogs & derivatives , Dinoprostone/pharmacology , Dioxanes/pharmacology , Fatty Acids, Unsaturated , Female , Humans , Hydrazines/pharmacology , In Vitro Techniques , Isoprostanes/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/physiology , Perfusion , Placenta/drug effects , Pregnancy , Receptors, Prostaglandin E/antagonists & inhibitors , Receptors, Thromboxane A2, Prostaglandin H2/antagonists & inhibitors , Xanthones/pharmacology
17.
Haemophilia ; 15(1): 227-39, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18752535

ABSTRACT

All but essential surgery is generally avoided in haemophilia patients with inhibitor antibodies, because of concern about the reliability with which haemostasis can be achieved and maintained in such patients. Orthopaedic surgical procedures which are not required to preserve life fall under this category. As a result, patients with inhibitors may be denied operations, which could greatly enhance their quality of life, and which are routinely offered to other haemophilia patients. While caution is appropriate in recommending surgery in any circumstance, we believe that the threshold for offering validated surgical procedures to patients with inhibitors should be re-evaluated in the light of current surgical and rehabilitative techniques, and the long experience with safe and effective factor VIII inhibitor bypassing agents, namely activated prothrombin complex concentrates and recombinant activated factor FVII. In this article, we review the haematological, surgical and rehabilitative considerations relevant to orthopaedic surgery in haemophilia patients with inhibitors, and provide recommendations for carrying out such procedures.


Subject(s)
Factor VIII/immunology , Hemophilia A/therapy , Hemostasis, Surgical/methods , Isoantibodies/blood , Orthopedic Procedures/methods , Blood Coagulation Factors/therapeutic use , Factor VIIa/therapeutic use , Hemophilia A/immunology , Humans , Male , Orthopedic Procedures/rehabilitation , Perioperative Care/methods , Recombinant Proteins/therapeutic use
18.
Pediatr Cardiol ; 28(4): 311-3, 2007.
Article in English | MEDLINE | ID: mdl-17563826

ABSTRACT

Pentalogy of Cantrell is a rare anomaly characterized by midline closure defects, including a defect in the lower sternum, supraumbilical abdominal wall defect, deficiency of the anterior portion of the diaphragm, deficiency in the diaphragmatic portion of the pericardium with free communication between the pericardial and peritoneal cavities, and congenital heart defects. The long-term prognosis for children with this anomaly depends to a great extent on the complexity of the associated congenital heart defect. We describe the previously unreported association of pentalogy of Cantrell with hypoplastic left heart syndrome.


Subject(s)
Abdominal Wall/abnormalities , Abnormalities, Multiple/epidemiology , Diaphragm/abnormalities , Hypoplastic Left Heart Syndrome/etiology , Pericardium/abnormalities , Sternum/abnormalities , Collagen/therapeutic use , Fatal Outcome , Female , Hernia, Umbilical/etiology , Hernia, Umbilical/surgery , Humans , Hypoplastic Left Heart Syndrome/surgery , Infant, Newborn , Skin, Artificial , Syndrome
19.
Placenta ; 28(1): 52-8, 2007 Jan.
Article in English | MEDLINE | ID: mdl-16469376

ABSTRACT

The onset of preeclampsia is associated with increased maternal insult that could affect placental function. By increasing sodium intake (0.9% or 1.8% NaCl in drinking water) during the last week of gestation in the rat, we developed an animal model that shows many characteristics of preeclampsia such as increased blood pressure, decreased circulatory volume and diminished activity of the renin-angiotensin-aldosterone system. The aim of the present study was to determine in this model whether maternal perturbations in pregnancy lead to placental oxidative stress. Sprague-Dawley pregnant rats receiving salted-water were compared to not-supplemented pregnant rats. Markers of oxidative stress, ensuing cell death, and changes in the production of vasoactive substances (prostanoids: thromboxane, TxB(2); and prostacyclin, PGF(1alpha)) and the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) were measured in the placenta. In tissue from pregnant rats on 1.8% NaCl supplement, 8-iso-PGF(2alpha) levels, TxB(2)/6-keto-PGF(1alpha) ratios, total TNF-alpha RNA expression, as well as the apoptotic index (Bax/Bcl-2 ratio) and endothelial nitric oxide synthase protein expression increase while total glutathione content decreases. These findings demonstrate that maternal insult during gestation induced an imbalance in the oxidative environment in the placenta favouring oxidation. This was accompanied by an increased synthesis of vasoconstrictive substances and TNF-alpha by the placenta as well as the increased rate of placental cell apoptosis.


Subject(s)
Oxidative Stress , Placenta/metabolism , Pre-Eclampsia/metabolism , Animals , Apoptosis , Dinoprost/analogs & derivatives , Dinoprost/analysis , Disease Models, Animal , Female , Gene Expression , Glutathione/analysis , Nitric Oxide Synthase Type III/metabolism , Placenta/chemistry , Pre-Eclampsia/pathology , Pregnancy , Prostaglandins/analysis , Rats , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/metabolism
20.
Haemophilia ; 12(1): 7-18, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16409170

ABSTRACT

When a high titre inhibitor develops in a patient with haemophilia, attempts are made to eradicate it through immune tolerance induction therapy (ITI) involving the frequent and regular administration of factor, usually for months to years. ITI is successful in only two thirds of patients prompting investigators to explore alternate regimens to use in haemophiliacs failing conventional ITI. Rituximab is an anti-CD20 monoclonal antibody, which has shown promise in the treatment of B-cell-mediated disorders. We developed a protocol for the use of rituximab in haemophilia A (HA) patients failing conventional ITI or in those haemophiliacs where the likelihood of success of conventional ITI is poor. Patients receive 375 mg m(-2) of intravenous rituximab weekly for 4 weeks followed by monthly (up to 5 months) until inhibitor disappearance and establishment of normal FVIII pharmacokinetics (recovery and half-life). Patients are concurrently placed on recombinant FVIII (100 U kg(-1) day(-1)). We have placed five haemophiliacs (four children with severe HA, and one adult with mild HA) on this protocol. In three patients (two with severe HA and one with mild HA) inhibitors disappeared although in neither severe haemophiliac did FVIII pharmacokinetics completely normalize. The fourth patient had a significant drop in inhibitor titres although not a complete disappearance of the inhibitor. All four of these patients ceased bleeding following rituximab. The fifth patient had no response to rituximab. This non-responding patient was not placed on concurrent FVIII. Our five cases suggest that rituximab may hold promise in the eradication of inhibitors. Prospective randomized studies are required to determine the value of this agent in inhibitor management.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Hemophilia A/therapy , Immunologic Factors/administration & dosage , Adolescent , Aged , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal, Murine-Derived , Child , Clinical Protocols , Drug Administration Schedule , Factor VIII/antagonists & inhibitors , Factor VIII/immunology , Factor VIII/pharmacokinetics , Factor VIII/therapeutic use , Hemophilia A/genetics , Humans , Immune Tolerance/immunology , Immunologic Factors/immunology , Immunotherapy/methods , Male , Mutation , Rituximab , Treatment Outcome
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