187 research outputs found

    Cardiac perforation during minimally invasive repair of pectus excavatum : a rare complication

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    Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author(s) 2022.Life-threatening complications (LTCs) and negative results of surgical treatments often go unreported. Minimally invasive repair of pectus excavatum (MIRPE) represents a procedure with a low incidence of adverse outcomes. However, 15 potentially fatal cases of MIRPE-related heart injury have been published. We report a case of cardiac perforation (CP) during MIRPE. A 12-year-old female was admitted for elective repair of a severe asymmetric pectus excavatum. Preoperative computed tomography showed a Haller index of 4.9. MIRPE was performed under bilateral video-assisted thoracoscopy. After the placement of the pectus bar, cardiac arrhythmias, hypotension and bilateral hemothorax occurred. Emergency thoracotomy without pectus bar removal showed CP. The wound sites were repaired and the pectus bar was eventually successfully implanted. The patient was discharged on postoperative day 11. After 10 months, she remains asymptomatic. Reporting rare complications is essential for accurate calculations of the true prevalence of LTCs, maintaining high alertness in pediatric surgeons.publishersversionPeer reviewe

    Imbalanced Folate and Vitamin B12 in the Third Trimester of Pregnancy and its Association with Birthweight and Child Growth up to 2 Years

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    Scope: Folic acid supplementation during pregnancy may lead to an imbalance when vitamin B12 intake is low (folate trap) and may affect child’s growth. Methods: The authors study the association between third trimester maternal intakes of folate and B12 and birthweight and postnatal growth of 2632 infants from the KOALA Birth Cohort Study. Plasma vitamin biomarkers are measured in 1219 women. Results: Imbalanced total intakes (folate > 430 µg day−1 combined with B12 < 5.5 µg day−1) are not associated with birthweight [ adj (95% CI) = –14.87 (–68.87, 39.13)] compared with high intakes of both. Imbalanced intake is associated with a lower z score of weight at 1–2 years [ adj = –0.14 (–0.25, –0.03)]. Having red blood cell folate > 745 nmol L−1 and plasma B12 < 172 pmol L−1 is not associated with birthweight [ adj = –7.10 (–97.90, 83.71) g]. Maternal dietary B12 intake [ adj = –9.5 (–15.6, –3.3)] and plasma methylmalonic acid [ adj = 234 (43, 426)] are associated with birthweight. Conclusion: Low maternal dietary B12 intake and elevated methylmalonic acid rather than imbalanced vitamins are associated with higher birthweight, suggesting that low maternal B12 can predispose the infants for later obesity

    Sex-related differences of invasive therapy in patients with aneurysmal subarachnoid hemorrhage

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    Background: Sex-related differences in patients with aneurysmal subarachnoid hemorrhage (aSAH) exist. More females than males are affected. Aneurysm location is associated to sex. The relationship between sex and outcome, however, is unclear. Possible differences in management might influence the occurrence of primary and secondary brain injury and thus outcome. The study compares demographics, intensity of treatment, complications, and outcome among females and males with aSAH. Methods: All consecutive patients with aSAH admitted to the neurocritical care unit, University Hospital Zurich over a 5-year period were eligible in this retrospective study. Patients’ characteristics, comorbidities, aSAH severity, frequency of vasospasm/delayed cerebral ischemia, frequency of invasive interventions, and 3-month outcome were compared by sex. Univariate analysis was performed with the data dichotomized by sex, and outcome. Multivariate analysis for prediction of outcomes was performed. Results: Three hundred forty-eight patients were enrolled (64% females). Women were older than men. Comorbidities, scores at admission, and treatment modality were comparable among males and females. Vasospasm and DCI occurred similarly among females and males. Interventions and frequency of intraarterial spasmolysis were comparable between sexes. In the multivariate analysis, increasing age, female sex, increasing comorbidities, WFNS and Fisher grade, and presence of delayed cerebral ischemia were predictors of unfavorable outcome when considering all patients. However, after excluding death as a possible outcome, sex did not remain a predictor of unfavorable outcome. Conclusions: In the study population, women with aSAH might have present a worse outcome at 3 months. However, no differences by sex that might explain this difference were found in intensity of treatment and management

    Heparin-guided binding of vascular endothelial growth factor to supramolecular biomaterial surfaces

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    Growth factors can steer the biological response to a biomaterial post implantation. Heparin is a growth factor binding molecule that can coordinate growth factor presentation to cells and therefore is able to regulate many biological processes. One way to functionalize biomaterials with heparin and growth factors is via a supramolecular approach. Here, we show a proof-of-concept study in which a supramolecular approach based on ureido-pyrimidinone (UPy) was used, which allows for modular functionalization. PCLdiUPy was functionalized with a UPy-modified heparin binding peptide (UPy-HBP) to facilitates binding of heparin, which in turn can bind vascular endothelial growth factor (VEGF) via its heparin binding domain. The adsorption of both heparin and VEGF were studied in two different functionalization approaches (pre-complex and two-step) and at different molecular ratios. Quartz crystal microbalance with dissipation energy adsorption data showed that VEGF and pre-complexed heparin:VEGF adsorbed non-specifically, with no distinguish between non-specific adsorption and heparin guided-adsorption. On the biological side, heparin guided-adsorption of Heparin:VEGF enhanced HUVECs surface coverage as compared to non-specific adsorption. These results provide a detailed insight on the molecular sandwich which is useful for new design strategies of supramolecular biomaterials with well-controlled immobilization of different growth factors.</p

    Factor XII contact activation can be prevented by targeting 2 unique patches in its epidermal growth factor-like 1 domain with a nanobody

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    Background: Factor (F)XII triggers contact activation by binding to foreign surfaces, with the epidermal growth factor-like 1 (EGF-1) domain being the primary binding site. Blocking FXII surface-binding might hold therapeutic value to prevent medical device–induced thrombosis. Objectives: To unravel and prevent EGF-1–mediated FXII surface-binding with a variable domain of heavy chain–only antibody (VHH). Methods: FXII variants with glutamine substitutions of 2 positively charged amino acid patches within the EGF-1 domain were created. Their role in FXII contact activation was assessed using kaolin pull-down experiments, amidolytic activity assays, and clotting assays. FXII EGF-1 domain–specific VHHs were raised to inhibit EGF-1–mediated FXII contact activation while preserving quiescence. Results: Two unique, positively charged patches in the EGF-1 domain were identified (upstream, 73K74K76K78H81K82H; downstream, 87K113K). Neutralizing the charge of both patches led to a 99% reduction in FXII kaolin binding, subsequent decrease in autoactivation of 94%, and prolongation of clot formation in activated partial thromboplastin time assays from 36 (±2) to 223 (±13) seconds. Three FXII EGF-1–specific VHHs were developed that are capable of inhibiting kaolin binding and subsequent contact system activation in plasma. The most effective VHH “F2” binds the positively charged patches and thereby dose-dependently extends activated partial thromboplastin time clotting times from 29 (±2) to 43 (±3) seconds without disrupting FXII quiescence. Conclusion: The 2 unique, positively charged patches in FXII EGF-1 cooperatively mediate FXII surface-binding, making both patches crucial for contact activation. Targeting these with FXII EGF-1–specific VHHs can exclusively decrease FXII surface-binding and subsequent contact activation, while preserving zymogen quiescence. These patches thus have potential as druggable targets in preventing medical device–induced thrombosis

    Insight into the neurophysiological processes of melodically intoned language with functional MRI

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    Background: Melodic Intonation Therapy (MIT) uses the melodic elements of speech to improve language production in severe nonfluent aphasia. A crucial element of MIT is the melodically intoned auditory input: the patient listens to the therapist singing a target utterance. Such input of melodically intoned language facilitates production, whereas auditory input of spoken language does not. Methods: Using a sparse sampling fMRI sequence, we examined the differential auditory processing of spoken and melodically intoned language. Nineteen right-handed healthy volunteers performed an auditory lexical decision task in an event related design consisting of spoken and melodically intoned meaningful and meaningless items. The control conditions consisted of neutral utterances, either melodically intoned or spoken. Results: Irrespective of whether the items were normally spoken or melodically intoned, meaningful items showed greater activation in the supramarginal gyrus and inferior parietal lobule, predominantly in the left hemisphere. Melodically intoned language activated both temporal lobes rather symmetrically, as well as the right frontal lobe cortices, indicating that these regions are engaged in the acoustic complexity of melodically intoned stimuli. Compared to spoken language, melodically intoned language activated sensory motor regions and articulatory language networks in the left hemisphere, but only when meaningful language was used. Discussion: Our results suggest that the facilitatory effect of MIT may - in part - depend on an auditory input which combines melody and meaning. Conclusion: Combined melody and meaning provide a sound basis for the further investigation of melodic language processing in aphasic patients, and eventually the neurophysiological processes underlying MIT. Compared to spoken language, melodically intoned language activated sensory motor regions and articulatory language networks in the left hemisphere, but only when meaningful language was used. Our results suggest that the facilitatory effect of MIT may - in part - depend on an auditory input which combines melody and meaning. As such, they provide a sound basis for further investigation of melodic language processing in aphasic patients, and eventually the neurophysiological processes underlying MIT

    Оцінювання зволоженості гірських водозборів при математичному моделюванні дощових паводків

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    Розроблено процедуру оцінювання зволоженості водозбору, яка не потребує тривалого моделювання в оперативних умовах.Разработана процедура оценивания увлажненности водосбора, которая исключает необходимость продолжительного моделирования в оперативных условиях

    Plasmin-cleaved von Willebrand factor as a biomarker for microvascular thrombosis

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    von Willebrand factor (VWF) is an essential contributor to microvascular thrombosis. Physiological cleavage by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) limits its prothrombotic properties, explaining why ADAMTS13 deficiency leads to attacks of microthrombosis in patients with thrombotic thrombocytopenic purpura (TTP). We previously reported that plasminogen activation takes place during TTP attacks in these patients. Furthermore, stimulation of plasminogen activation attenuates pathogenesis in preclinical TTP models in vivo. This suggests that plasmin is an endogenous regulator of VWF thrombogenicity, in particular when ADAMTS13 falls short to prevent microvascular occlusions. VWF cleavage by plasmin is biochemically distinct from cleavage by ADAMTS13. We hypothesized that plasmin-cleaved VWF (cVWF) holds value as a biomarker of microvascular thrombosis. Here, we describe the development of a variable domain of heavy-chain-only antibody (VHH)-based bioassay that can distinguish cVWF from intact and ADAMTS13-cleaved VWF in plasma. We validate this assay by tracking cVWF release during degradation of microthombi in vitro. We demonstrate that endogenous cVWF formation takes place in patients with TTP during acute attacks of thrombotic microangiopathy but not in those in remission. Finally, we show that therapeutic plasminogen activation in a mouse model of TTP amplifies cVWF formation, which is accompanied by VWF clearance. Our combined findings indicate that cVWF is released from microthrombi in the context of microvascular occlusion

    Targeted SERPIN (TaSER): a dual-action antithrombotic agent that targets platelets for SERPIN delivery

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    Background: Occlusive thrombi are not homogeneous in composition. The core of a thrombus is rich in activated platelets and fibrin while the outer shell contains resting platelets. This core is inaccessible to plasma proteins. We produced a fusion protein (targeted SERPIN–TaSER), consisting of a function-blocking V HH against glycoprotein Ibα (GPIbα) and a thrombin-inhibiting serine protease inhibitor (SERPIN; α1-antitrypsin 355AIAR 358) to interfere with platelet-driven thrombin formation. Aim: To evaluate the antithrombotic properties of TaSER. Methods: Besides TaSER, we generated three analogous control variants with either a wild-type antitrypsin subunit, a non-targeting control V HH, or their combination. We investigated TaSER and controls in protease activity assays, (platelet-dependent) thrombin generation assays, and by western blotting. The effects of TaSER on platelet activation and von Willebrand factor (VWF) binding were studied by fluorescence-activated cell sorting, in agglutination studies, and in ATP secretion experiments. We studied the influence of TaSER in whole blood (1) on platelet adhesion on VWF, (2) aggregate formation on collagen, and (3) thrombus formation (after recalcification) on collagen and tissue factor. Results: TaSER binds platelets and inhibits thrombin activity on the platelet surface. It blocks VWF binding and disassembles platelet agglutinates. TaSER delays tissue factor-triggered thrombin generation and ATP secretion in platelet-rich plasma in a targeted manner. In flow studies, TaSER interferes with platelet adhesion and aggregate formation due to GPIbα blockade and limits thrombus formation due to targeted inhibition of platelet-dependent thrombin activity. Conclusion: The synergy between the individual properties of TaSER makes it a highly effective antithrombotic agent with possible clinical implications

    The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen

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    Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histological progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neo-angiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution towards an IDHwt-like phenotype
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