pylori to fucosylated Lewis B (Leb) blood group antigens on gastric epithelium [29]. Humans are polymorphic for Lewis antigen expression

in all tissues [30]. H. pylori is similarly polymorphic for expression of its INCB024360 cell line own Lewis antigens [31]. Following up on earlier work by Solnick et al. [32] and other groups showing that the babA gene locus is subject to both antigenic and phase variation in vivo, the groups of Solnick and Blaser have now presented additional evidence demonstrating that positive and negative selective forces shape the expression of both the adhesin, BabA, and H. pylori’s own Lewis B antigens. Hypothesizing that host phenotype selects for H. pylori’s Lewis B phenotype, Pohl et al. infected Leb transgenic mice with Lex and Ley expressing H. pylori. After 8 months of infection, most reisolates had lost Lex and gained Leb expression, a phenomenon that was not observed after colonization of wild-type mice [33]. Styer et al. [34] confirmed previous results obtained by experimental infection of rhesus macaques showing that BabA expression is lost in the animals because of a single-base-pair mutation generating http://www.selleckchem.com/products/Everolimus(RAD001).html a stop codon or because of gene conversion of babA with a duplicate copy of babB. Similar mechanisms

operated in mice and gerbils to turn off BabA expression altogether or to mutate the Lewis antigen binding sites, indicating that strong selective forces shape BabA expression independent of the host species [34]. A novel mechanism generating MCE公司 diversity in H. pylori was revealed by whole-genome sequencing of the patient isolate P12 [35]. The P12 genome contains three plasticity zones, two of which encode T4SSs and

have typical features of genomic islands [35]. Remarkably, one of the three plasticity zones has the ability to self-excise through the activity of a XerD recombinase and to be horizontally transferred by a conjugative process, suggesting a novel mechanism generating genetic diversity [35]. Using deep sequencing technology to address the genetic variation of H. pylori within one host over time, Kennemann et al. [36] compared pairs of isolates obtained at two different time points from four chronically infected Colombians. At least 16 and up to 441 imported clusters of polymorphisms resulting from recombination were detectable between sequential isolates from the same individual; these import events were particularly abundant at loci of outer membrane proteins [36]. A similar approach by Morelli et al. [37] examining on average 39,300 bp in 78 gene fragments of 34 sequential isolates allowed the estimation of short-term mutation rates of around 1.4 × 10−6 per nucleotide per year. Both studies confirm once again the unusual genetic diversity of this pathogen. Several recent reports have investigated the mechanisms that allow H. pylori to persist in its human host in the face of a robust innate and adaptive immune response.

pylori to fucosylated Lewis B (Leb) blood group antigens on gastric epithelium [29]. Humans are polymorphic for Lewis antigen expression

in all tissues [30]. H. pylori is similarly polymorphic for expression of its Buparlisib mouse own Lewis antigens [31]. Following up on earlier work by Solnick et al. [32] and other groups showing that the babA gene locus is subject to both antigenic and phase variation in vivo, the groups of Solnick and Blaser have now presented additional evidence demonstrating that positive and negative selective forces shape the expression of both the adhesin, BabA, and H. pylori’s own Lewis B antigens. Hypothesizing that host phenotype selects for H. pylori’s Lewis B phenotype, Pohl et al. infected Leb transgenic mice with Lex and Ley expressing H. pylori. After 8 months of infection, most reisolates had lost Lex and gained Leb expression, a phenomenon that was not observed after colonization of wild-type mice [33]. Styer et al. [34] confirmed previous results obtained by experimental infection of rhesus macaques showing that BabA expression is lost in the animals because of a single-base-pair mutation generating selleck a stop codon or because of gene conversion of babA with a duplicate copy of babB. Similar mechanisms

operated in mice and gerbils to turn off BabA expression altogether or to mutate the Lewis antigen binding sites, indicating that strong selective forces shape BabA expression independent of the host species [34]. A novel mechanism generating MCE diversity in H. pylori was revealed by whole-genome sequencing of the patient isolate P12 [35]. The P12 genome contains three plasticity zones, two of which encode T4SSs and

have typical features of genomic islands [35]. Remarkably, one of the three plasticity zones has the ability to self-excise through the activity of a XerD recombinase and to be horizontally transferred by a conjugative process, suggesting a novel mechanism generating genetic diversity [35]. Using deep sequencing technology to address the genetic variation of H. pylori within one host over time, Kennemann et al. [36] compared pairs of isolates obtained at two different time points from four chronically infected Colombians. At least 16 and up to 441 imported clusters of polymorphisms resulting from recombination were detectable between sequential isolates from the same individual; these import events were particularly abundant at loci of outer membrane proteins [36]. A similar approach by Morelli et al. [37] examining on average 39,300 bp in 78 gene fragments of 34 sequential isolates allowed the estimation of short-term mutation rates of around 1.4 × 10−6 per nucleotide per year. Both studies confirm once again the unusual genetic diversity of this pathogen. Several recent reports have investigated the mechanisms that allow H. pylori to persist in its human host in the face of a robust innate and adaptive immune response.

Indeed, diabetes might represent a different pathogenic category in the heterogeneous sets of iron overload syndromes. Categorizations of patients with fatty liver and iron overload syndrome may be particularly important, in terms of therapeutic procedures, to discriminate patients who can benefit from blood letting, which

has been demonstrated to be useful in most of these syndromes.5-7 We congratulate the authors on their excellent work; however, by adding the above information important insights may be provided. Melania Manco M.D., Ph.D., F.A.C.N.*, Anna Alisi Ph.D.*, Antonella Mosca M.D.*, Valerio Nobili M.D.*, * Laboratorio di Malattie Epatiche Auto-Immuni e Metaboliche Ospedale Pediatrico Bambino Gesù IRCCS, Centro buy Belnacasan di Nutrizione e Dietetica Dipartimento di Pediatria Università La Sapienza Roma, Italia. “
“One

of the vexing questions in clinical hepatology Selleck SRT1720 is defining the specific and independent contribution of the liver to systemic metabolic dysregulation, defined operationally by the term metabolic syndrome. The latter comprises a spectrum of disorders including obesity, insulin resistance, hypertension, and dyslipidemia. Clarifying the conundrum is difficult, as we tend to practice in silos as hepatologists or diabetic specialists, rather than as physicians. Ideally, defining the role of the liver to cardiometabolic risk requires prospective, well-defined, large patient cohorts with baseline liver histology, determinations of fat depots, an assessment of endocrine function and insulin sensitivity, together with long-term follow-up and regular liver assessments. Nevertheless, some progress has been made. Several cross-sectional studies have described an association between the presence of nonalcoholic fatty liver disease (NAFLD) and markers of atherosclerosis

such as carotid artery thickness, endothelial dysfunction, coronary artery calcification, and stenosis.[1] Epidemiological studies have also demonstrated an association between an imaging-based medchemexpress diagnosis of NAFLD and an increased risk of coronary, cerebrovascular and peripheral vascular disease, and mortality. While some of these associations persist after adjusting for traditional cardiovascular risk factors,[2, 3] in others the association is lost.[4, 5] The latter, however, does not negate a role for the liver since, for example, atherogenic dyslipidemia is, in large part, liver-dependent. Numerous mechanisms have been proposed to explain the contribution of NAFLD to cardiovascular risk, including hepatic insulin resistance, atherogenic dyslipidemia, hepatic inflammation, and a prothrombotic milieu.[6] In fatty liver, the accumulation of diacylglycerol and sphingolipids enhances hepatic insulin resistance.

Indeed, diabetes might represent a different pathogenic category in the heterogeneous sets of iron overload syndromes. Categorizations of patients with fatty liver and iron overload syndrome may be particularly important, in terms of therapeutic procedures, to discriminate patients who can benefit from blood letting, which

has been demonstrated to be useful in most of these syndromes.5-7 We congratulate the authors on their excellent work; however, by adding the above information important insights may be provided. Melania Manco M.D., Ph.D., F.A.C.N.*, Anna Alisi Ph.D.*, Antonella Mosca M.D.*, Valerio Nobili M.D.*, * Laboratorio di Malattie Epatiche Auto-Immuni e Metaboliche Ospedale Pediatrico Bambino Gesù IRCCS, Centro CH5424802 manufacturer di Nutrizione e Dietetica Dipartimento di Pediatria Università La Sapienza Roma, Italia. “
“One

of the vexing questions in clinical hepatology NVP-LDE225 is defining the specific and independent contribution of the liver to systemic metabolic dysregulation, defined operationally by the term metabolic syndrome. The latter comprises a spectrum of disorders including obesity, insulin resistance, hypertension, and dyslipidemia. Clarifying the conundrum is difficult, as we tend to practice in silos as hepatologists or diabetic specialists, rather than as physicians. Ideally, defining the role of the liver to cardiometabolic risk requires prospective, well-defined, large patient cohorts with baseline liver histology, determinations of fat depots, an assessment of endocrine function and insulin sensitivity, together with long-term follow-up and regular liver assessments. Nevertheless, some progress has been made. Several cross-sectional studies have described an association between the presence of nonalcoholic fatty liver disease (NAFLD) and markers of atherosclerosis

such as carotid artery thickness, endothelial dysfunction, coronary artery calcification, and stenosis.[1] Epidemiological studies have also demonstrated an association between an imaging-based medchemexpress diagnosis of NAFLD and an increased risk of coronary, cerebrovascular and peripheral vascular disease, and mortality. While some of these associations persist after adjusting for traditional cardiovascular risk factors,[2, 3] in others the association is lost.[4, 5] The latter, however, does not negate a role for the liver since, for example, atherogenic dyslipidemia is, in large part, liver-dependent. Numerous mechanisms have been proposed to explain the contribution of NAFLD to cardiovascular risk, including hepatic insulin resistance, atherogenic dyslipidemia, hepatic inflammation, and a prothrombotic milieu.[6] In fatty liver, the accumulation of diacylglycerol and sphingolipids enhances hepatic insulin resistance.

Indeed, diabetes might represent a different pathogenic category in the heterogeneous sets of iron overload syndromes. Categorizations of patients with fatty liver and iron overload syndrome may be particularly important, in terms of therapeutic procedures, to discriminate patients who can benefit from blood letting, which

has been demonstrated to be useful in most of these syndromes.5-7 We congratulate the authors on their excellent work; however, by adding the above information important insights may be provided. Melania Manco M.D., Ph.D., F.A.C.N.*, Anna Alisi Ph.D.*, Antonella Mosca M.D.*, Valerio Nobili M.D.*, * Laboratorio di Malattie Epatiche Auto-Immuni e Metaboliche Ospedale Pediatrico Bambino Gesù IRCCS, Centro AZD0530 order di Nutrizione e Dietetica Dipartimento di Pediatria Università La Sapienza Roma, Italia. “
“One

of the vexing questions in clinical hepatology Selleck AP24534 is defining the specific and independent contribution of the liver to systemic metabolic dysregulation, defined operationally by the term metabolic syndrome. The latter comprises a spectrum of disorders including obesity, insulin resistance, hypertension, and dyslipidemia. Clarifying the conundrum is difficult, as we tend to practice in silos as hepatologists or diabetic specialists, rather than as physicians. Ideally, defining the role of the liver to cardiometabolic risk requires prospective, well-defined, large patient cohorts with baseline liver histology, determinations of fat depots, an assessment of endocrine function and insulin sensitivity, together with long-term follow-up and regular liver assessments. Nevertheless, some progress has been made. Several cross-sectional studies have described an association between the presence of nonalcoholic fatty liver disease (NAFLD) and markers of atherosclerosis

such as carotid artery thickness, endothelial dysfunction, coronary artery calcification, and stenosis.[1] Epidemiological studies have also demonstrated an association between an imaging-based 上海皓元 diagnosis of NAFLD and an increased risk of coronary, cerebrovascular and peripheral vascular disease, and mortality. While some of these associations persist after adjusting for traditional cardiovascular risk factors,[2, 3] in others the association is lost.[4, 5] The latter, however, does not negate a role for the liver since, for example, atherogenic dyslipidemia is, in large part, liver-dependent. Numerous mechanisms have been proposed to explain the contribution of NAFLD to cardiovascular risk, including hepatic insulin resistance, atherogenic dyslipidemia, hepatic inflammation, and a prothrombotic milieu.[6] In fatty liver, the accumulation of diacylglycerol and sphingolipids enhances hepatic insulin resistance.

We provide evidence that this process promotes cell survival, but exceeding a certain threshold of mitochondrial dysfunction is associated with an autophagic overload or stress. This complex effect could be involved in EFV-related hepatic toxicity and may constitute a new mechanism

implicated in the genesis of drug-generated buy Cabozantinib liver damage. AIDS, acquired immunodeficiency syndrome; ΔΨm, mitochondrial transmembrane potential; EFV, Efavirenz; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; LC3, microtubule-associated protein 1A/1B light chain 3; 3MA, 3-methyladenine; MPT, mitochondrial permeability transition; NAO, 10-N-nonyl acridine orange; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; Pol-γ, DNA polymerase gamma; PI, propidium iodide; STS, staurosporine; TEM, transmission electron microscopy. Unless stated otherwise, chemical reagents and fluorochromes were purchased from

Sigma-Aldrich (Steinheim, Germany). Efavirenz (Sustiva 600 mg, Bristol-Myers Squibb) was acquired in its clinically available form and dissolved in methanol (3 mg/mL) once insoluble substances had been removed by filtration. The purity (98%-100%) and stability were evaluated by high-performance liquid chromatography (HPLC) and compared with a control solution of EFV (Sequoia Research Products, Pangbourne, UK). The employed range of EFV (10, 25, AZD6738 nmr and 50 μM) MCE is clinically relevant and was chosen considering the important interindividual variability in its pharmacokinetics.16 Although the therapeutic plasma levels of EFV are believed to be 3.17-12.67 μM, as many as

20% of patients exhibit higher levels, with values of 30-50 μM being documented.17-19 0.5% methanol was employed in all EFV treatments and vehicle control experiments, versus which statistical analysis was performed. In most experiments the vehicle-treated were compared to untreated cells and no significant differences in any of the parameters were detected. We used Hep3B cells (American Type Culture Collection [ATCC] HB-8064), which despite constituting a transformed cell line, is considered metabolically competent and, unlike other human hepatoma cell lines, such as HepG2, has an active cytochrome P450 system. Confirmatory experiments were performed in primary human hepatocytes and for gene overexpression we used the human cervical carcinoma cell line HeLa (ATCC CCL-2), as these cells also possess a high mitochondrial content and are frequently employed for transfection (details in Supporting Material). WB was performed using whole-cell protein extracts as described.13 Primary antibodies: anti-Beclin (Abcam), anti-microtubule-associated protein 1A/1B light chain 3 (LC3), and anti-actin (both from Sigma-Aldrich, Steinheim, Germany), all at 1:1,000, and a secondary antibody peroxidase-labeled antirabbit IgG (Vector Laboratories, Burlingame, CA) at 1:5,000.

We provide evidence that this process promotes cell survival, but exceeding a certain threshold of mitochondrial dysfunction is associated with an autophagic overload or stress. This complex effect could be involved in EFV-related hepatic toxicity and may constitute a new mechanism

implicated in the genesis of drug-generated find more liver damage. AIDS, acquired immunodeficiency syndrome; ΔΨm, mitochondrial transmembrane potential; EFV, Efavirenz; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; LC3, microtubule-associated protein 1A/1B light chain 3; 3MA, 3-methyladenine; MPT, mitochondrial permeability transition; NAO, 10-N-nonyl acridine orange; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; Pol-γ, DNA polymerase gamma; PI, propidium iodide; STS, staurosporine; TEM, transmission electron microscopy. Unless stated otherwise, chemical reagents and fluorochromes were purchased from

Sigma-Aldrich (Steinheim, Germany). Efavirenz (Sustiva 600 mg, Bristol-Myers Squibb) was acquired in its clinically available form and dissolved in methanol (3 mg/mL) once insoluble substances had been removed by filtration. The purity (98%-100%) and stability were evaluated by high-performance liquid chromatography (HPLC) and compared with a control solution of EFV (Sequoia Research Products, Pangbourne, UK). The employed range of EFV (10, 25, this website and 50 μM) MCE公司 is clinically relevant and was chosen considering the important interindividual variability in its pharmacokinetics.16 Although the therapeutic plasma levels of EFV are believed to be 3.17-12.67 μM, as many as

20% of patients exhibit higher levels, with values of 30-50 μM being documented.17-19 0.5% methanol was employed in all EFV treatments and vehicle control experiments, versus which statistical analysis was performed. In most experiments the vehicle-treated were compared to untreated cells and no significant differences in any of the parameters were detected. We used Hep3B cells (American Type Culture Collection [ATCC] HB-8064), which despite constituting a transformed cell line, is considered metabolically competent and, unlike other human hepatoma cell lines, such as HepG2, has an active cytochrome P450 system. Confirmatory experiments were performed in primary human hepatocytes and for gene overexpression we used the human cervical carcinoma cell line HeLa (ATCC CCL-2), as these cells also possess a high mitochondrial content and are frequently employed for transfection (details in Supporting Material). WB was performed using whole-cell protein extracts as described.13 Primary antibodies: anti-Beclin (Abcam), anti-microtubule-associated protein 1A/1B light chain 3 (LC3), and anti-actin (both from Sigma-Aldrich, Steinheim, Germany), all at 1:1,000, and a secondary antibody peroxidase-labeled antirabbit IgG (Vector Laboratories, Burlingame, CA) at 1:5,000.

2011). The connection between the two areas has previously been supported by the direct movement between the habitats of seven find more individuals identified with DNA profiles (Carroll et al. 2011). Here we add a further eight photo-ID matches and three DNA profile matches between the two areas. We also provide evidence for within-year movement between the NZ subantarctic and mainland NZ, based on the matching of a photo-identified whale. This is consistent

with previous satellite tag data showing the movement of a SRW between the NZ subantarctic and the South Island of NZ in the winter of 2009 (Carroll et al. 2011). The mainland NZ wintering habitat appears to be increasing in importance for NZ SRWs. Sightings of cows with calves are now recorded every year, and we provide evidence of short-term residency by cow-calf pairs,

as well as fidelity to the calving ground over multiple years. In addition we provide further evidence of connectivity between the NZ mainland and subantarctic wintering grounds, building on previous work (Carroll et al. 2011). We thank all individuals GSK126 who contributed sighting data and images. We thank Rebecca Pirzl (Skadia Pty Ltd) and Saras Kumar (South Australia Department of Environment & Heritage) for use of BigFish and Laura Wakelin (New Zealand Department of 上海皓元医药股份有限公司 Conservation) for providing access to the sightings database and images. Thank you to Trudi Webster for confirming photo-ID matches. Biopsy

sample collection around mainland New Zealand (NZ) was made possible by Dan Engelhaupt and NZ Department of Conservation staff, including Jim Fyfe, Pete McClelland, Paul Brady, Jamie Quirk, Don Neale, Brian Williams, Mike Morrissey, and Mike Ogle. Lab work was funded by the Marsden Fund of New Zealand (to CSB), NZ Department of Conservation, the Heseltine Trust and an OMV New Zealand Ltd. Scholarship (to EC). EC was supported by a Tertiary Education Commission Top Achiever Scholarship and a University of Auckland PBRF writing grant. WR was supported by a Foundation for Research, Science and Technology post-doctoral fellowship. “
“Body length and axillary girth measurements of more than 600 free-ranging Hawaiian monk seals from 1 to 20 yr old were analyzed. Comparison of fitted von Bertalanffy growth models confirmed there is no evidence of sexual dimorphism in this species. Substantial differences in growth patterns were detected among seven subpopulations representing the species entire geographic range. The age at which seals would be expected to attain a reference length of 180 cm ranged from just over 3 yr up to almost 7 yr at the various sites. Subpopulations exhibiting slower growth have previously been found to also exhibit lower age-specific reproductive rates.

2011). The connection between the two areas has previously been supported by the direct movement between the habitats of seven Selleck MG-132 individuals identified with DNA profiles (Carroll et al. 2011). Here we add a further eight photo-ID matches and three DNA profile matches between the two areas. We also provide evidence for within-year movement between the NZ subantarctic and mainland NZ, based on the matching of a photo-identified whale. This is consistent

with previous satellite tag data showing the movement of a SRW between the NZ subantarctic and the South Island of NZ in the winter of 2009 (Carroll et al. 2011). The mainland NZ wintering habitat appears to be increasing in importance for NZ SRWs. Sightings of cows with calves are now recorded every year, and we provide evidence of short-term residency by cow-calf pairs,

as well as fidelity to the calving ground over multiple years. In addition we provide further evidence of connectivity between the NZ mainland and subantarctic wintering grounds, building on previous work (Carroll et al. 2011). We thank all individuals GDC-0068 research buy who contributed sighting data and images. We thank Rebecca Pirzl (Skadia Pty Ltd) and Saras Kumar (South Australia Department of Environment & Heritage) for use of BigFish and Laura Wakelin (New Zealand Department of MCE Conservation) for providing access to the sightings database and images. Thank you to Trudi Webster for confirming photo-ID matches. Biopsy

sample collection around mainland New Zealand (NZ) was made possible by Dan Engelhaupt and NZ Department of Conservation staff, including Jim Fyfe, Pete McClelland, Paul Brady, Jamie Quirk, Don Neale, Brian Williams, Mike Morrissey, and Mike Ogle. Lab work was funded by the Marsden Fund of New Zealand (to CSB), NZ Department of Conservation, the Heseltine Trust and an OMV New Zealand Ltd. Scholarship (to EC). EC was supported by a Tertiary Education Commission Top Achiever Scholarship and a University of Auckland PBRF writing grant. WR was supported by a Foundation for Research, Science and Technology post-doctoral fellowship. “
“Body length and axillary girth measurements of more than 600 free-ranging Hawaiian monk seals from 1 to 20 yr old were analyzed. Comparison of fitted von Bertalanffy growth models confirmed there is no evidence of sexual dimorphism in this species. Substantial differences in growth patterns were detected among seven subpopulations representing the species entire geographic range. The age at which seals would be expected to attain a reference length of 180 cm ranged from just over 3 yr up to almost 7 yr at the various sites. Subpopulations exhibiting slower growth have previously been found to also exhibit lower age-specific reproductive rates.

Two hundred and twenty-five patients with severe and moderate forms of haemophilia A and B from three centres were invited

to participate in the study. Spearman’s rank correlation test was used for validation, and internal consistency of the HAL was calculated with Cronbach’s alpha. Eighty-four patients (39%) (18–80 years old) filled out the questionnaires. The internal consistency of the Swedish version of HAL was high, with Cronbach’s alpha being 0.98–0.71. Function of the legs had the highest consistency and transportation had the lowest. The correlation was excellent between the HAL sum score and AIMS 2 physical (r = 0.84, P < 0.01), IPA autonomy indoors (r = 0.83, P < 0.01) and autonomy outdoors (r = 0.89, NVP-BEZ235 P < 0.01). The Swedish version of HAL has both internal consistency and convergent

validity and may complement other functional tests to gather information on the patient’s self-perceived ability. “
“The objective of the present study was to evaluate the Selleckchem GSK1120212 pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the new recombinant FVIII compound turoctocog alfa and a Glyco-PEGylated FVIII derivative thereof (N8-GP) in Haemophilia A dogs. Six haemophilic dogs divided into two groups were included in the study. Each dog was administered a dose of 125 U kg−1, blood samples were collected at predetermined time points for both pharmacokinetic (FVIII measured by one-stage aPTT assay) and pharmacodynamic [whole blood clotting time (WBCT)] evaluations. After intravenous administration to haemophilic dogs, the plasma concentration at the first sampling point was comparable for turoctocog alfa and N8-GP, and the clearance was estimated to be 6.5 and 3.9 mL h−1kg−1 for turoctocog alfa and N8-GP respectively. Both turoctocog alfa and N8-GP

were able to reduce the WBCT time to normal levels (<20 min), however, the reduced clearance was reflected in the WBCT, 上海皓元医药股份有限公司 which returned to baseline at a later time point for N8-GP as compared with dogs dosed with turoctocog alfa. The clearance was 40% reduced for N8-GP as compared with turoctocog alfa. Simulations of a multiple dosing regimen in dogs, suggest that to maintain WBCT <20 min N8-GP can be dosed at reduced intervals, e.g. with 4 days between doses, whereas turoctocog alfa will have to be dosed with 2½ day between doses. Data thereby supports N8-GP as an alternative to standard rFVIII replacement therapy, with a more convenient dosing regimen. "
“Summary.  A predictive standardized bleeding questionnaire (Vicenza score), previously validated for identifying individuals with type 1 von Willebrand’s disease (VWD), has never been prospectively validated in tertiary care paediatric settings.