Successful immune tolerance induction using turoctocog alfa in an adult haemophilia A patient.

We present here the first known case of successful immune tolerance induction (ITI) using recombinant factor VIII (rFVIII), turoctocog alfa, in a patient with severe haemophilia A. The 38-year-old patient with a long-standing inhibitor required urgent surgery for severe arthropathy. rFVIII was administered throughout the surgical period. Surgery was considered successful, but on day 7 after surgery, an increased level of FVIII inhibitors were detected. ITI was attempted immediately thereafter according to the Bonn protocol. Inhibitors were no longer detected on day 17; 13 months later, successful ITI was achieved. This case suggests that a long-time interval between inhibitor appearance and the start of ITI therapy may not necessarily indicate poor prognosis.

Former Very Preterm Infants Show an Unfavorable Cardiovascular Risk Profile at a Preschool Age.

Cardiovascular disease is the leading cause of death worldwide. Evidence points towards an unfavorable cardiovascular risk profile of former preterm infants in adolescence and adulthood. The aim of this study was to determine whether cardiovascular risk predictors are detectable in former very preterm infants at a preschool age. Five- to seven-year-old children born at <32 weeks' gestational age were included in the study. Same-aged children born at term served as controls. Basic data of study participants were collected by means of follow-up databases and standardized questionnaires. At study visit, anthropometric data, blood pressure readings and aortic intima-media thickness were assessed. Blood samples were obtained after an overnight fast. In comparison to children born at term, former preterm infants had higher systolic and diastolic blood pressure readings (odds ratio [95% confidence interval] per 1-SD higher blood pressure level 3.2 [2.0-5.0], p<0.001 and 1.6 [1.1-1.2], p = 0.008), fasting glucose levels (OR [95% CI] 5.2 [2.7-10.1], p<0.001), homeostasis model assessment index (OR [95% CI] 1.6 [1.0-2.6], p = 0.036), and cholesterol levels (OR [95% CI] 2.1 [1.3-3.4], p = 0.002). Systolic prehypertension (23.7% vs. 2.2%; OR [95% CI] 13.8 [3.1-60.9], p = 0.001), elevated glucose levels (28.6% vs. 5.9%; OR [95% CI] 6.4 [1.4-28.8], p = 0.016), and hypercholesterolemia (77.4% vs. 52.9%; OR [95% CI] 3.0 [1.3-7.1], p = 0.010) were significantly more prevalent in the preterm group. As former very preterm infants display an unfavorable cardiovascular risk profile already at a preschool age, implementation of routine cardiovascular follow-up programs might be warranted.

Choice of High-Dose Intravenous Iron Preparation Determines Hypophosphatemia Risk.

BACKGROUND: Ferric carboxymaltose (FCM) and iron isomaltoside 1000 (IIM) are increasingly used because they allow correction of severe iron deficiency in a single infusion. A transient decrease in serum phosphate concentrations is a frequent side effect of FCM. AIM: To characterize this adverse event and search for its predictors in a gastroenterology clinic patient cohort. METHODS: Electronic medical records of patients attending the University Hospital of Innsbruck were searched for the keywords ferric carboxymaltose or iron isomaltoside. Eighty-one patients with documented administration of FCM or IIM with plasma phosphate concentrations before and after treatment were included. RESULTS: The prevalence of hypophosphatemia (<0.8 mmol/L) increased from 11% to 32.1% after treatment with i.v. iron. The hypophosphatemia risk was greater after FCM (45.5%) compared with IIM (4%). Severe hypophosphatemia (<0.6 mmol/L) occurred exclusively after FCM (32.7%). The odds for hypophosphatemia after i.v. iron treatment were independently determined by baseline phosphate and the choice of i.v. iron preparation (FCM vs. IIM-OR = 20.8; 95% CI, 2.6-166; p = 0.004). The median time with hypophosphatemia was 41 days, but prolonged hypophosphatemia of ≥ 2 months was documented in 13 of 17 patients in whom follow-up was available. A significant increase in the phosphaturic hormone intact FGF-23 in hypophosphatemic patients shows that this adverse event is caused by FCM-induced hormone dysregulation. CONCLUSION: Treatment with FCM is associated with a high risk of developing severe and prolonged hypophosphatemia and should therefore be monitored. Hypophosphatemia risk appears to be substantially lower with IIM.

Remote ischemic preconditioning in the prevention of ischemic brain damage during intracranial aneurysm treatment (RIPAT): study protocol for a randomized controlled trial.

BACKGROUND: The treatment of intracranial aneurysms may be associated with cerebral ischemia. We hypothesize that pre-interventional remote ischemic preconditioning (RIPC) reduces ischemic cerebral tissue damage in patients undergoing elective intracranial aneurysm treatment. METHODS/DESIGN: This study is a single-center, prospective, randomized, double-blind explorative trial. Patients with an unruptured intracranial aneurysm admitted to Innsbruck Medical University Hospital for coiling or clipping will be consecutively randomized to either the intervention group (= RIPC by inflating an upper extremity blood-pressure cuff for 3 x 5 min to 200 mmHg) or the control group after induction of anesthesia. Participants will be randomized 1:1 to either the preconditioning group or the sham group using a random allocation sequence and block randomization. The precalculated sample size is n = 24 per group. The primary endpoint is the area-under-the-curve concentration of serum biomarkers (S100B, NSE, GFAP, MMP9, MBP, and cellular microparticles) in the first five days after treatment. Secondary endpoints are the number and volume of new ischemic lesions in magnetic resonance imaging and clinical outcome evaluated with the National Institutes of Health Stroke Scale, the modified Rankin Scale, and neuropsychological tests at six and twelve months. All outcome variables will be determined by observers blinded to group allocation. This study was approved by the local institutional Ethics Committee (UN5164), version 3.0 of the study protocol, dated 20 October 2013. DISCUSSION: This study uses the elective treatment of intracranial aneurysms as a paradigmatic situation to explore the neuroprotective effects of RIPC. If effects are demonstrable in this pilot trial, a larger, prospective phase III trial will be considered.

Influence of Acute Normobaric Hypoxia on Hemostasis in Volunteers with and without Acute Mountain Sickness.

INTRODUCTION: The aim of the present study was to investigate whether a 12-hour exposure in a normobaric hypoxic chamber would induce changes in the hemostatic system and a procoagulant state in volunteers suffering from acute mountain sickness (AMS) and healthy controls. MATERIALS AND METHODS: 37 healthy participants were passively exposed to 12.6% FiO2 (simulated altitude hypoxia of 4,500 m). AMS development was investigated by the Lake Louise Score (LLS). Prothrombin time, activated partial thromboplastin time, fibrinogen, and platelet count were measured and specific methods (i.e., thromboelastometry and a thrombin generation test) were used. RESULTS: AMS prevalence was 62.2% (LLS cut off of 3). For the whole group, paired sample t-tests showed significant increase in the maximal concentration of generated thrombin. ROTEM measurements revealed a significant shortening of coagulation time and an increase of maximal clot firmness (InTEM test). A significant increase in maximum clot firmness could be shown (FibTEM test). CONCLUSIONS: All significant changes in coagulation parameters after exposure remained within normal reference ranges. No differences with regard to measured parameters of the hemostatic system between AMS-positive and -negative subjects were observed. Therefore, the hypothesis of the acute activation of coagulation by hypoxia can be rejected.

Identification of Aspergillus fumigatus Surface Components That Mediate Interaction of Conidia and Hyphae With Human Platelets.

BACKGROUND: Platelets were recently identified as a part of innate immunity. They are activated by contact with Aspergillus fumigatus; putative consequences include antifungal defense but also thrombosis, excessive inflammation, and thrombocytopenia. We aimed to identify those fungal surface structures that mediate interaction with platelets. METHODS: Human platelets were incubated with Aspergillus conidia and hyphae, isolated wall components, or fungal surface mutants. Interaction was visualized microscopically; activation was quantified by flow cytometry of specific markers. RESULTS: The capacity of A. fumigatus conidia to activate platelets is at least partly due to melanin, because this effect can be mimicked with "melanin ghosts"; a mutant lacking melanin showed reduced platelet stimulating potency. In contrast, conidial hydrophobin masks relevant structures, because an A. fumigatus mutant lacking the hydrophobin protein induced stronger platelet activation than wild-type conidia. A. fumigatus hyphae also contain surface structures that interact with platelets. Wall proteins, galactomannan, chitin, and ß-glucan are not the relevant hyphal components; instead, the recently identified fungal polysaccharide galactosaminogalactan potently triggered platelet activation. CONCLUSIONS: Conidial melanin and hydrophobin as well as hyphal galactosaminogalactan represent important pathogenicity factors that modulate platelet activity and thus might influence immune responses, inflammation, and thrombosis in infected patients.

Evaluation of the performance of a tandem mass spectral library with mass spectral data extracted from literature.

MSforID represents a database of tandem mass spectral data obtained from (quasi-)molecular ions produced by atmospheric pressure ionization methods. At the current stage of development the library contains 12 122 spectra of 1208 small (bio-)organic molecules. The present work was aimed to evaluate the performance of the MSforID library in terms of accuracy and transferability with a collection of fragment ion mass spectra from various compounds acquired on multiple instruments. A literature survey was conducted to collect the set of sample spectra. A total number of 554 spectra covering 291 compounds were extracted from 109 publications. The majority of spectra originated from publications on applications of LC/MS/MS in drug monitoring, pharmacokinetics, environmental analysis, forensic analysis as well as food analysis. Almost all types of tandem mass spectrometric instruments distributed by the five most important instrument vendors were included in the study. The overall sensitivity of library search was found to be 96.4%, which clearly proves that the MSforID library can successfully handle data from a huge variety of mass spectrometric instruments to allow accurate compound identification. Only for spectra containing three or more fragment ions, however, the rate of classified matches (= matches with a relative average match probability (ramp) score > 40.0) was 95%. Ambiguous or unclassified results were mainly obtained for searches with single precursor-to-fragment ion transitions due to the insufficient specificity of such a low amount of structural information to unequivocally define a single compound.