PulmoStent: <Emphasis Type="Italic">In Vitro</Emphasis> to <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of a Tissue Engineered Endobronchial Stent

Currently, there is no optimal treatment available for end stage tumour patients with airway stenosis. The PulmoStent concept aims on overcoming current hurdles in airway stenting by combining a nitinol stent with a nutrient-permeable membrane, which prevents tumour ingrowth. Respiratory epithelial cells can be seeded onto the cover to restore mucociliary clearance. In this study, a novel hand-braided dog bone stent was developed, covered with a polycarbonate urethane nonwoven and mechanically tested. Design and manufacturing of stent and cover were improved in an iterative process according to predefined requirements for permeability and mechanical properties and finally tested in a proof of concept animal study in sheep for up to 24 weeks. In each animal two stents were implanted, one of which was cell-seeded by endoscopic spraying in situ. We demonstrated the suitability of this membrane for our concept by glucose transport testing and in vitro culture of respiratory epithelial cells. In the animal study, no migration occurred in any of the twelve stents. There was only mild granulation tissue formation and tissue reaction; no severe mucus plugging was observed. Thus, the PulmoStent concept might be a step forward for palliative treatment of airway stenosis with a biohybrid stent device.     

Meta‐analysis of digital game and study characteristics eliciting physiological stress responses

Digital games have been used as stressors in a range of disciplines for decades. Nonetheless, the underlying characteristics of these stressors and the study in which the stressor was applied are generally not recognized for their moderating effect on the measured physiological stress responses. We have therefore conducted a meta‐analysis that analyzes the effects of characteristics of digital game stressors and study design on heart rate, systolic and diastolic blood pressure, in studies carried out from 1976 to 2012. In order to assess the differing quality between study designs, a new scale is developed and presented, coined reliability of effect size. The results show specific and consistent moderating functions of both game and study characteristics, on average accounting for around 43%, and in certain cases up to 57% of the variance found in physiological stress responses. Possible cognitive and physiological processes underlying these moderating functions are discussed, and a new model integrating these processes with the moderating functions is presented. These findings indicate that a digital game stressor does not act as a stressor by virtue of being a game, but rather derives its stressor function from its characteristics and the methodology in which it is used. This finding, together with the size of the associated moderations, indicates the need for a standardization of digital game stressors.     

Online Quantitative Aortographic Assessment of Aortic Regurgitation After TAVR: Results of the OVAL Study

ObjectivesThe aim of this study was to investigate the online assessment feasibility of aortography using videodensitometry in the catheterization laboratory during transcatheter aortic valve replacement (TAVR).BackgroundQuantitative assessment of regurgitation after TAVR through aortography using videodensitometry is simple, reproducible, and validated in vitro, in vivo, in clinical trials, and in “real-world” patients. However, thus far the assessment has been done offline.MethodsThis was a single center, prospective, proof-of-principle, feasibility study. One hundred consecutive patients with aortic stenosis and indications to undergo TAVR were enrolled. All final aortograms were analyzed immediately after acquisition in the catheterization laboratory and were also sent to an independent core laboratory for blinded offline assessment. The primary endpoint of the study was the feasibility of the online assessment of regurgitation (percentage of analyzable cases). The secondary endpoint was the reproducibility of results between the online assessment and the offline analysis by the core laboratory.ResultsPatients’ mean age was 81 ± 7 years, and 56% were men. The implanted valves were either SAPIEN 3 (97%) or SAPIEN 3 Ultra (3%). The primary endpoint of online feasibility of analysis was 92% (95% confidence interval [CI]: 86% to 97%) which was the same feasibility encountered by the core laboratory (92%; 95% CI: 86% to 97%). Reproducibility assessment showed a high correlation between online and core laboratory evaluations (R² = 0.87, p < 0.001), with an intraclass correlation coefficient of 0.962 (95% CI: 0.942 to 0.975; p < 0.001).ConclusionsThis study showed high feasibility of online quantitative assessment of regurgitation and high agreement between the online examiner and core laboratory. These results may pave the way for the application of videodensitometry in the catheterization laboratory after TAVR. (Online Videodensitometric Assessment of Aortic Regurgitation in the Cath-Lab [OVAL]; NCT04047082)     

Preclinical Safety and Efficacy of Human CD34+ Cells Transduced With Lentiviral Vector for the Treatment of Wiskott-Aldrich Syndrome

Gene therapy with ex vivo-transduced hematopoietic stem/progenitor cells may represent a valid therapeutic option for monogenic immunohematological disorders such as Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency associated with thrombocytopenia. We evaluated the preclinical safety and efficacy of human CD34⁺ cells transduced with lentiviral vectors (LV) encoding WAS protein (WASp). We first set up and validated a transduction protocol for CD34⁺ cells derived from bone marrow (BM) or mobilized peripheral blood (MPB) using a clinical grade, highly purified LV. Robust transduction of progenitor cells was obtained in normal donors and WAS patients'' cells, without evidence of toxicity. To study biodistribution of human cells and exclude vector release in vivo, LV-transduced CD34⁺ cells were transplanted in immunodeficient mice, showing a normal engraftment and differentiation ability towards transduced lymphoid and myeloid cells in hematopoietic tissues. Vector mobilization to host cells and transmission to germline cells of the LV were excluded by different molecular assays. Analysis of vector integrations showed polyclonal integration patterns in vitro and in human engrafted cells in vivo. In summary, this work establishes the preclinical safety and efficacy of human CD34⁺ cells gene therapy for the treatment of WAS.     

Long-term result of guided nerve regeneration with an inert microporous polytetrafluoroethylene conduit

Thedevelopmentinmicrosurgicaltechniqueshasgreatlyimprovednervefunctionalrecovery .However ,owingtotheinabilitytocoaptateandsuturethousandsofnervefiberstotheirfunctionallysimilarnervefibersandinaccuratesutureofthenervestumps ,regeneratednervefiberspartiallylosethechancetoselectivelyregrowintotheirtargetendoneurialtubes,1 4whichresultsinaninevitablemismatchofmotorandsensorynervefibers .Thus,thecontact guidance basedmicrosurgicalnerverepairhasfailedtoachieveconsistentsatisfactoryfunctionalrecover…     

Ovarian Sertoli-Leydig cell tumour with raised serum alpha fetoprotein

Summary A case of ovarian Sertoli-Leydig cell tumour with a raised serum alpha fetoprotein in reported. The patient first presented at the age of 27 years with a history of 6 years' amenorrhoea followed by 3 months irregular vaginal bleeding. A ovarian tumour was found and excised and shown microscopically to be a spindle cell malignant tumour. The patient was treated with chemotherapy and had a complete response. Thirty months after first presentation there was a recurrence in the pelvis which microscopically showed the typical features of a Sertoli-Leydig cell tumour. Six months later a second recurrence had the microscopic appearance of a lipid cell tumour. A raised serum alpha fetoprotein was found at the time of the second recurrence and immunohistochemistry showed this protein in the Leydig and luteinized cells of the recurrent tumours but not in the spindle cells of the original ovarian neoplasm.     

Mood correlates with blood serotonin, but not with glucose measures in patients with recurrent suicidal behavior

Depressive mood and impulsive-aggressive behavior are relevant to suicidal behavior and have been associated with decreased central serotonergic function. Impulsive behavior and aggression have also been related to abnormal glucose metabolism. To investigate these relationships further, blood serotonin (5-HT), blood glucose measures (glycated hemoglobin (HbA_1C) and fructosamine) and self-reported depressive symptoms and anger were repeatedly measured, during a 1-year follow-up, in 106 patients who had recently attempted suicide for at least a second time. A major DSM-III-R Axis I diagnosis or use of antidepressants were reasons for exclusion. Intra-individual variations in blood 5-HT were inversely correlated with variations in depressive mood, self-depreciation, and anger, and positively with variations in fructosamine. Intra-individual variations of HbA_1C or fructosamine were not correlated with mood. Mean blood 5-HT levels per patient were positively correlated with mean scores of depression and self-depreciation. The contrast between the intra-individual and the inter-individual correlations may reflect a difference between short- vs. long-term effects. The results do support an association between serotonergic function and mood, but not between glucose metabolism and mood, in recurrent suicide attempters.     

Expression of Angiogenesis-related Factors in Lungs of Patients with Congenital Diaphragmatic Hernia and Pulmonary Hypoplasia of Other Causes

Congenital diaphragmatic hernia (CDH) is a congenital disorder, complicated by pulmonary hypoplasia (PH) and pulmonary hypertension. Hypoplastic lungs have fewer and smaller airspaces than normal, with thicker interalveolar septa; the adventitia and media of pulmonary arteries are thickened, and the total size of the pulmonary vascular bed is decreased compared to normal. Although histological abnormalities in PH have been described, less is known about the underlying molecular mechanisms. Therefore, we have investigated a series of proteins, known to be involved in angiogenesis, including von Hippel-Lindau protein (pVHL), hypoxia-inducible factor-1a (HIF-1a), vascular endothelial growth factor (VEGF), fetal liver kinase 1 (Flk-1), and endothelial and inducible nitric oxide synthase (eNOS, iNOS) by immunohistochemistry on paraffin-embedded lung tissue of CDH patients ( n = 13), patients with lung hypoplasia due to other causes ( n = 20), and normal controls ( n = 33). pVHL was expressed more frequently in the arterial smooth muscle cells of CDH lungs compared with both other groups. Furthermore, HIF-1a was expressed less frequently in the endothelium of arteries, veins, and capillaries of CDH lungs as compared with both other groups. No differences were observed in the expression patterns of VEGF, Flk-1, eNOS, and iNOS between the different groups. Our data suggest a role for pVHL and HIF-1a in normal and abnormal pulmonary angiogenesis. The differential expression of these proteins may provide a molecular basis for the histological differences observed in the lung vessels of patients with CDH.