We present clinical data on 558 patients with deletions within the DiGeorge syndrome critical region of chromosome 22qll. Twenty-eight percent of the cases where parents had been tested had inherited deletions, with a marked excess of maternally inherited deletions (maternal 61, paternal 18). Eight percent of the patients had died, over half of these within a month ofbirth and the majority within 6 months. All but one of the deaths were the result of congenital heart disease. Clinically significant immunological problems were very uncommon. Nine percent of patients had cleft palate and 32% had velopharyngeal insufficiency, 60% of patients were hypocalcaemic, 75% of patients had cardiac problems, and 36% of patients who had abdominal ultrasound had a renal abnormality. Sixty-two percent of surviving patients were developmentally normal or had only mild learning problems. The majority of patients were constitutionally small, with 36% of patients below the 3rd centile for either height or weight parameters. (JMed Genet 1997;34:798-804) Data collectionParticipating centres from Europe were sent data questionnaires relating to cases of proven deletions within chromosome band 22ql 1. The probes and microsatellite markers used varied between centres but all mapped within the DGS region.2 Centres were asked to send information on all their cases, whether previously published or not. The data for all UK centres was collected by one person (AR) who also entered information into the database from the returned questionnaires. Data were requested on heart, palate, renal, and thymus abnormalities, parathyroid function, growth, developmental status, behaviour, and psychiatric illness. All available patient information was entered into an anonymous central database. Some questionnaires did not provide information on all sections, for example, the heart section was completed in more questionnaires than the renal section. Hence, the total number of patients for which data were recorded is specified in each section of the results.

We explored the relationship between time to relapse and different exposure variables (serum methotrexate (S-MTX) 23, 36 and 42 h after start of administration, MTX elimination time and leucovorin (LV) dose) during high-dose MTX (HDM) treatment of 445 children with acute lymphoblastic leukemia. MTX was infused at 5 g/m 2 (non-high risk) or 8 g/m 2 (high risk) over 24 h, 2-9 times per patient. LV rescue dose was adjusted according to the S-MTX concentration. Time from end of the last HDM to relapse was analyzed by Cox regression analysis with the logarithms of S-MTX and LV dose as exposures. The combined results from all risk groups suggest that high LV dose is related to higher risk for relapse. Doubling of the LV dose increased the relapse risk by 22% (95% confidence interval 1-49%, P ¼ 0.037). High LV doses correlated with high MTX levels at 23, 36 and 42 h and longer elimination time. The results suggest that high doses of LV increase the risk for relapse despite the fact that they were correlated with high MTX levels and longer MTX elimination time. The choice of MTX and LV doses may be regarded as an intricate balance between effect and counter-effect.

BackgroundThe phenotypic diagnosis of von Willebrand disease (VWD) is a multistep process with classification dependent on the quantification of von Willebrand factor (VWF) multimeric structure. VWF multimer analysis is a technically challenging, lengthy and non‐standardised assay, usually performed in specialist laboratories. Recently, a new semi‐automated multimer assay, the Hydragel 5 von Willebrand multimers (H5VWM) has become available.ObjectivesThis study, performed in two European centres, compared existing in‐house multimer assays to the H5VWM in individuals with and without VWD.ResultsOverall agreement of 91.1% was observed in 74 individuals with normal VWF levels, 57 patients grouped as type 1 VWD, 33 type 2A, 16 type 2B, 28 type 2M, 11 type 2N. Patients tested following Desmopressin or VWF concentrate, with thrombotic thrombocytopenic purpura and acquired von Willebrand syndrome were also evaluated. Many of the discrepancies between methods were in patients with genetic mutations linked to more than one type of VWD including p.R1374C/H and p.R1315C. Quantifiable multimer results were available within one working day. Densitometry improved the interpretation of the multimers with slight structural variations that were not apparent by visual inspection of the in‐house method.Conclusions5VWM was a rapid, sensitive, standardised assay which used existing technology and could be included as an initial screen of VWF multimers in a VWD diagnostic algorithm in conjunction with traditional multimer analysis.

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Supplementary Material to Seidel et al. "Bleeding diathesis in patients with mast cell activation disease" (Thromb Haemost 2011; 106.5) Definition of mast cell activation disease The term mast cell activation disease (MCAD) denotes a collection of disorders characterized by accumulation of pathological mast cells in potentially any or all organs and tissues and/or aberrant release of variable subsets of mast cell mediators (1, 2). A classification has been proposed which differentiates several types and subclasses of MCAD. The traditionally recognized subclass termed systemic mastocytosis (SM) includes disorders characterized by certain pathological immunohistochemical and mutational findings (the WHO criteria; [3]) which are divided into several subtypes. On the other hand, mast cell activation syndrome (MCAS) presents a complex clinical picture of multiple mast cell mediator-induced symptoms, failure to meet the WHO criteria for diagnosis of SM, and exclusion of relevant differential diagnoses (1, 2, 4-7). Mast cell activation disease in general has long been thought to be rare. However, although SM is truly rare, recent findings suggest MCAS is a fairly common disorder ([2], further references therein). Symptoms observed in patients with MCAS are little, if any, different from those seen in patients with SM ([2], further references therein). The clinical manifestation results from episodic release of both preformed and newly-synthesized mast cell mediators either in response to trigger stimuli or spontaneously. The clinical presentation of MCAD is very diverse, since due to both the widespread distribution of mast cells and the great heterogeneity of aberrant mediator expression patterns, symptoms can occur in virtually all organs and tissues. Moreover, symptoms often occur in a temporally staggered fashion, waxing and waning over years to decades. Patients often have a history of chronic and acute mediator

BackgroundArgatroban or lepirudin anticoagulation therapy in patients with heparin induced thrombocytopenia (HIT) or HIT suspect is typically monitored using the activated partial thromboplastin time (aPTT). Although aPTT correlates well with plasma levels of argatroban and lepirudin in healthy volunteers, it might not be the method of choice in critically ill patients. However, in-vivo data is lacking for this patient population.Therefore, we studied in vivo whether ROTEM or global clotting times would provide an alternative for monitoring the anticoagulant intensity effects in critically ill patients.MethodsThis study was part of the double-blind randomized trial “Argatroban versus Lepirudin in critically ill patients (ALicia)”, which compared critically ill patients treated with argatroban or lepirudin. Following institutional review board approval and written informed consent, for this sub-study blood of 35 critically ill patients was analysed. Before as well as 12, 24, 48 and 72 h after initiation of argatroban or lepirudin infusion, blood was analysed for aPTT, aPTT ratios, thrombin time (TT), INTEM CT,INTEM CT ratios, EXTEM CT, EXTEM CT ratios and maximum clot firmness (MCF) and correlated with the corresponding plasma concentrations of the direct thrombin inhibitor.ResultsTo reach a target aPTT of 1.5 to 2 times baseline, median [IQR] plasma concentrations of 0.35 [0.01–1.2] μg/ml argatroban and 0.17 [0.1–0.32] μg/ml lepirudin were required. For both drugs, there was no significant correlation between aPTT and aPTT ratios and plasma concentrations. INTEM CT, INTEM CT ratios, EXTEM CT, EXTEM CT ratios, TT and TT ratios correlated significantly with plasma concentrations of both drugs. Additionally, agreement between argatroban plasma levels and EXTEM CT and EXTEM CT ratios were superior to agreement between argatroban plasma levels and aPTT in the Bland Altman analysis. MCF remained unchanged during therapy with both drugs.Conclusion In critically ill patients, TT and ROTEM parameters may provide better correlation to argatroban and lepirudin plasma concentrations than aPTT.Trial registrationClinicalTrials.gov, NCT00798525, registered on 25 Nov 2008Electronic supplementary materialThe online version of this article (10.1186/s12871-018-0475-y) contains supplementary material, which is available to authorized users.

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Cigarettes with similar design features but with either cellulose acetate or dual carbon filters were made at 1-mg and 13-mg “tar” levels, as determined under the ISO smoking procedure. Products were smoked under the ISO, Massachusetts and Canadian smoking regimes to provide per-cigarette and per-puff yields of twelve vapour phase (VP) smoke components. The yields generated at the lit end of the cigarette and the significant yield reductions caused by filter ventilation, selective (carbon) adsorption, tobacco rod ventilation and diffusion were estimated in a modelling approach. For a “1-mg tar” carbon-filtered product it was estimated that the VP generated at the lit end was reduced by 99.4% to a machine yield of 17 µg/cig under ISO smoking conditions. Under the Canadian regime with 100% vent blocking, the estimated total VP was lowered 20% by tobacco rod effects and 15% by carbon filter adsorption giving a machine yield of 3487 µg/cig. The carbon filter adsorbed less efficiently partly due to the artificially high smoke temperatures through the filter that would probably not be tolerated by human smokers. Under the Massachusetts regime with 50% vent blocking, conditions better associated with human smoking, the total VP was lowered 51% by filter ventilation, 22% by tobacco rod effects and 17% by carbon filter adsorption giving a machine yield of 659 µg/cig. Ventilation is used to achieve “tar”/nicotine/carbon monoxide yield ceilings at 10/1/10 mg based on the current ISO smoking method. If future regulations were to mandate further reductions in VP then this will only be selectively achieved by increasing filter or tobacco rod ventilation/porosity or by using selective adsorption. It is inevitable that manufacturers will need to add further ventilation into their product to comply with such regulations and this should be reflected in any smoking regime. Furthermore, regimes with 100% vent blocking, that do not produce data reflecting the significant reductions in VP yields, provided to the smoker by ventilation, are misleading and their results will not correlate with relevant biomarker data. When proposing a different smoking regime, it is essential to understand the generation and transfer of smoke within cigarettes and factors involved in the subsequent data interpretation as described in this work. For regulatory evaluation purposes, cigarette characterisation using a regime that removes ventilation, one of the main design tools, is more misleading than the current ISO regime or one with partial vent blocking.