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1.
Sci Rep ; 13(1): 20476, 2023 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-37993490

RESUMO

Navigating the challenges of data-driven speech processing, one of the primary hurdles is accessing reliable pathological speech data. While public datasets appear to offer solutions, they come with inherent risks of potential unintended exposure of patient health information via re-identification attacks. Using a comprehensive real-world pathological speech corpus, with over n[Formula: see text]3800 test subjects spanning various age groups and speech disorders, we employed a deep-learning-driven automatic speaker verification (ASV) approach. This resulted in a notable mean equal error rate (EER) of [Formula: see text], outstripping traditional benchmarks. Our comprehensive assessments demonstrate that pathological speech overall faces heightened privacy breach risks compared to healthy speech. Specifically, adults with dysphonia are at heightened re-identification risks, whereas conditions like dysarthria yield results comparable to those of healthy speakers. Crucially, speech intelligibility does not influence the ASV system's performance metrics. In pediatric cases, particularly those with cleft lip and palate, the recording environment plays a decisive role in re-identification. Merging data across pathological types led to a marked EER decrease, suggesting the potential benefits of pathological diversity in ASV, accompanied by a logarithmic boost in ASV effectiveness. In essence, this research sheds light on the dynamics between pathological speech and speaker verification, emphasizing its crucial role in safeguarding patient confidentiality in our increasingly digitized healthcare era.


Assuntos
Fenda Labial , Fissura Palatina , Patologia da Fala e Linguagem , Adulto , Humanos , Criança , Inteligibilidade da Fala , Medida da Produção da Fala , Fala
2.
J Thromb Haemost ; 21(2): 269-275, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36700507

RESUMO

BACKGROUND: Sickle cell disease (SCD) is an inherited red blood cell disorder with a causative substitution in the beta-globin gene that encodes beta-globin in hemoglobin. Furthermore, the ensuing vasculopathy in the microvasculature involves heightened endothelial cell adhesion, inflammation, and coagulopathy, all of which contribute to vaso-occlusive crisis (VOC) and the sequelae of SCD. In particular, dysregulation of the von Willebrand factor (VWF) and a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) axis has been implicated in human SCD pathology. OBJECTIVES: To investigate the beneficial potential of treatment with recombinant ADAMTS13 (rADAMTS13) to alleviate VOC. METHODS: Pharmacologic treatment with rADAMTS13 in vitro or in vivo was performed in a humanized mouse model of SCD that was exposed to hypoxia/reoxygenation stress as a model of VOC. Then, pharmacokinetic, pharmacodynamic, and behavioral analyses were performed. RESULTS: Administration of rADAMTS13 to SCD mice dose-dependently increased plasma ADAMTS13 activity, reduced VWF activity/antigen ratios, and reduced baseline hemolysis (free hemoglobin and total bilirubin) within 24 hours. rADAMTS13 was administered in SCD mice, followed by hypoxia/reoxygenation stress, and reduced VWF activity/antigen ratios in parallel to significantly (p < .01) improved recovery during the reoxygenation phase. Consistent with the results in SCD mice, we demonstrate in a human in vitro system that treatment with rADAMTS13 counteracts the inhibitory activity of hemoglobin on the VWF/ADAMTS13-axis. CONCLUSION: Collectively, our data provide evidence that relative ADAMTS13 insufficiency in SCD mice is corrected by pharmacologic treatment with rADAMTS13 and provides an effective disease-modifying approach in a human SCD mouse model.


Assuntos
Anemia Falciforme , Doenças Vasculares , Compostos Orgânicos Voláteis , Humanos , Animais , Camundongos , Fator de von Willebrand/metabolismo , Anemia Falciforme/tratamento farmacológico , Hemólise , Proteína ADAMTS13/genética
3.
J Speech Lang Hear Res ; 65(12): 4623-4636, 2022 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-36417788

RESUMO

PURPOSE: The aim of this study was to investigate the speech prosody of postlingually deaf cochlear implant (CI) users compared with control speakers without hearing or speech impairment. METHOD: Speech recordings of 74 CI users (37 males and 37 females) and 72 age-balanced control speakers (36 males and 36 females) are considered. All participants are German native speakers and read Der Nordwind und die Sonne (The North Wind and the Sun), a standard text in pathological speech analysis and phonetic transcriptions. Automatic acoustic analysis is performed considering pitch, loudness, and duration features, including speech rate and rhythm. RESULTS: In general, duration and rhythm features differ between CI users and control speakers. CI users read slower and have a lower voiced segment ratio compared with control speakers. A lower voiced ratio goes along with a prolongation of the voiced segments' duration in male and with a prolongation of pauses in female CI users. Rhythm features in CI users have higher variability in the duration of vowels and consonants than in control speakers. The use of bilateral CIs showed no advantages concerning speech prosody features in comparison to unilateral use of CI. CONCLUSIONS: Even after cochlear implantation and rehabilitation, the speech of postlingually deaf adults deviates from the speech of control speakers, which might be due to changed auditory feedback. We suggest considering changes in temporal aspects of speech in future rehabilitation strategies. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.21579171.


Assuntos
Implante Coclear , Implantes Cocleares , Surdez , Percepção da Fala , Adulto , Masculino , Feminino , Humanos , Surdez/reabilitação , Audição , Acústica
4.
Haematologica ; 107(11): 2650-2660, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35443560

RESUMO

Sickle cell disease (SCD) is an inherited red blood cell disorder that occurs worldwide. Acute vaso-occlusive crisis is the main cause of hospitalization in patients with SCD. There is growing evidence that inflammatory vasculopathy plays a key role in both acute and chronic SCD-related clinical manifestations. In a humanized mouse model of SCD, we found an increase of von Willebrand factor activity and a reduction in the ratio of a disintegrin and metalloproteinase with thrombospondin type 1 motif, number 13 (ADAMTS13) to von Willebrand factor activity similar to that observed in the human counterpart. Recombinant ADAMTS13 was administered to humanized SCD mice before they were subjected to hypoxia/reoxygenation (H/R) stress as a model of vaso-occlusive crisis. In SCD mice, recombinant ADAMTS13 reduced H/R-induced hemolysis and systemic and local inflammation in lungs and kidneys. It also diminished H/R-induced worsening of inflammatory vasculopathy, reducing local nitric oxidase synthase expression. Collectively, our data provide for the firsttime evidence that pharmacological treatment with recombinant ADAMTS13 (TAK-755) diminished H/R-induced sickle cell-related organ damage. Thus, recombinant ADAMTS13 might be considered as a potential effective disease-modifying treatment option for sickle cell-related acute events.


Assuntos
Proteína ADAMTS13 , Anemia Falciforme , Doenças Vasculares , Animais , Humanos , Camundongos , Proteína ADAMTS13/uso terapêutico , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Modelos Animais de Doenças , Eritrócitos Anormais , Hipóxia , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/etiologia , Fator de von Willebrand , Proteínas Recombinantes/uso terapêutico
5.
Front Allergy ; 3: 829898, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35386654

RESUMO

Background: Chronic rhinosinusitis is a common disease with a significant impact on the quality of life. Topical drug delivery to the paranasal sinuses is not efficient to prevent sinus surgery or expensive biologic treatment in a lot of cases as the affected mucosa is not reached. More efficient approaches for topical drug delivery are, therefore, necessary. In the current study, dual-energy CT (DECT) imaging was used to examine sinus ventilation before and after sinus surgery using a pulsating xenon gas ventilator in a cadaver head. Methods: Xenon gas was administered to the nasal cavity of a cadaver head with a laminar flow of 7 L/min and with pulsating xenon-flow (45 Hz frequency, 25 mbar amplitude). Nasal cavity and paranasal sinuses were imaged by DECT. This procedure was repeated after functional endoscopic sinus surgery (FESS). Based on the enhancement levels in the different sinuses, regional xenon concentrations were calculated. Results: Xenon-related enhancement could not be detected in most of the sinuses during laminar gas flow. By superimposing laminar flow with pulsation, DECT imaging revealed a xenon wash-in and wash-out in the sinuses. After FESS, xenon enhancement was immediately seen in all sinuses and reached higher concentrations than before surgery. Conclusion: Xenon-enhanced DECT can be used to visualize and quantify sinus ventilation. Pulsating air-/gas flow was superior to laminar flow for the administration of xenon to the paranasal sinuses. FESS leads to successful ventilation of all paranasal sinuses.

6.
Laryngorhinootologie ; 101(10): 797-804, 2022 10.
Artigo em Alemão | MEDLINE | ID: mdl-35016249

RESUMO

BACKGROUND: During the SARS-CoV2-pandemic, people working in healthcare such as caregives for the elderly face additional burden, e.g. by the use of face masks. METHODS: In a prospective study, the emotional and physical wellbeing as well as the vocal tract discomfort of caregivers of two municipal homes for the elderly were assessed by questionnaires, the Mini-SCL and the Vocal Tract Discomfort Scale (VTDS), and one on personal data (sex, age, lung disease, previous SARS-CoV2-infection) and on voice symptoms. RESULTS: 67% of the questionnaires were answered by 56 women and 11 men aged 45.2 ± 11.5. In the Mini-SCL, increased scores were found in depression in 23.8%, anxiety in 49.3%, somatization in 55.2% and in the global score in 44.7%. 52% showed increased scores in the VTDS. Significant correlations were found in between the subscales of the Mini-SCL and the VTDS as well as to dysphonia symptoms. DISCUSSION: Psychological problems, somatization and vocal tract discomfort is more frequently reported by caregivers for the elderly than in the normal population. The VTDS, voice symptoms and the Mini-SCL scales are significantly related. Training on vocal hygiene should be included in workplace health promotion during the pandemic.


Assuntos
COVID-19 , Disfonia , Distúrbios da Voz , Idoso , COVID-19/epidemiologia , Cuidadores , Disfonia/diagnóstico , Feminino , Humanos , Masculino , Pandemias , Estudos Prospectivos , RNA Viral , SARS-CoV-2 , Distúrbios da Voz/diagnóstico , Distúrbios da Voz/epidemiologia , Distúrbios da Voz/etiologia , Qualidade da Voz
7.
Eur Arch Otorhinolaryngol ; 279(6): 2845-2855, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34318333

RESUMO

OBJECTIVES: In pediatric audiology, objective techniques for hearing threshold estimation in infants and children with profound or severe hearing loss play a key role. Auditory brainstem responses (ABR) and auditory steady-state responses (ASSR) are available for frequency-dependent hearing threshold estimations and both techniques show strong correlations but sometimes with considerable differences. The aim of the study was to compare hearing threshold estimations in children with and without cochlear and cochlear nerve malformations. METHODS: Two groups with profound or severe hearing loss were retrospectively compared. In 20 ears (15 children) with malformation of the inner ear and/or cochlear nerve hypoplasia and a control group of 20 ears (11 children) without malformation, ABR were measured with the Interacoustics Eclipse EP25 ABR system® (Denmark) with narrow-band CE-chirps® at 500, 1000, 2000 and 4000 Hz and compared to ASSR at the same center frequencies under similar conditions. RESULTS: ABR and ASSR correlated significantly in both groups (r = 0.413 in malformation group, r = 0.82 in control group). The malformation group showed a significantly lower percentage of "equal" hearing threshold estimations than the control group. In detail, patients with isolated cochlear malformation did not differ significantly from the control group, whereas patients with cochlear nerve hypoplasia showed significantly greater differences. CONCLUSION: ABR and ASSR should be used jointly in the diagnostic approach in children with suspected profound or severe hearing loss. A great difference in hearing threshold estimation between these techniques could hint at the involvement of cochlear nerve or cochlear nerve hypoplasia itself.


Assuntos
Potenciais Evocados Auditivos do Tronco Encefálico , Perda Auditiva , Estimulação Acústica/métodos , Limiar Auditivo/fisiologia , Criança , Nervo Coclear , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Perda Auditiva/diagnóstico , Humanos , Lactente , Estudos Retrospectivos
8.
Blood Coagul Fibrinolysis ; 33(1): 56-60, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34267062

RESUMO

Insufficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motif repeats-13) is the cause of thrombotic thrombocytopenic purpura (TTP) and contributes in microangiopathy in sickle cell disease (SCD). Recombinant ADAMTS13 effectively cleaves prothrombotic ultra-large von Willebrand factor (VWF) multimers. It is being tested as replacement therapy for TTP, and at supra-physiologic concentrations, for moderating vaso-occlusive crisis in SCD. Deficiencies of VWF, or concomitant treatment with antithrombotic drugs, could pose risks for increased bleeds in these patient populations. The purpose of the experiments was to evaluate the potential of exaggerated pharmacology and temporary bleeding risks associated with rADAMTS13 administration. We utilized safety studies in monkey and tested the effects of administering maximum-feasible doses of rADAMTS13 on nonclinical safety and spontaneous or aggressive bleeds in the rat model. Evaluation of pharmacokinetics, toxicity profiles, and challenge in a tail-tip bleeding model show that treatment with rADAMTS13 did not increase bleeding tendency, either alone, or in combination with enoxaparin or acetylsalicylic-acid. These novel findings demonstrate absence of rADAMTS13 exaggerated pharmacology without spontaneous or aggravated bleeds even at supra-physiologic (>100-fold) plasma concentrations.


Assuntos
Proteínas ADAM , Púrpura Trombocitopênica Trombótica , Proteína ADAMTS13 , Animais , Haplorrinos , Humanos , Ratos , Fator de von Willebrand
9.
Logoped Phoniatr Vocol ; 47(3): 194-201, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33988080

RESUMO

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, professional caregivers caring for the elderly may experience more vocal tract problems in addition to regular high vocal demands while wearing face masks/coverings. METHODS AND PARTICIPANTS: Vocal tract discomfort (VTD) was assessed in 64 caregivers in one home for the elderly (64% participation rate) in June 2020 using the German version of the VTD scale. RESULTS: More than one-half of the participating caregivers experienced VTD, described mostly as dryness, irritability, and tightness. Approximately, 80% reported that sensations were not perceived before enhanced infection prevention standards were implemented. CONCLUSIONS: Among caregivers caring for the elderly during the COVID-19 pandemic, special care should be focused on the voice and vocal tract well-being.


Assuntos
COVID-19 , Distúrbios da Voz , Idoso , COVID-19/epidemiologia , Cuidadores , Humanos , Pandemias , Distúrbios da Voz/diagnóstico , Distúrbios da Voz/epidemiologia , Distúrbios da Voz/etiologia , Qualidade da Voz
10.
STAR Protoc ; 2(4): 100999, 2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34917978

RESUMO

The adrenal gland consists of two tissues, cortex and medulla, united under one capsule. Adrenal stem/progenitor cells play a key role in development and homeostasis. Here, we describe a protocol for generating primary cultures of adrenal cells from mice. We describe techniques for separating the cortex and medulla, generating spheroid cultures containing stem- and progenitor cells, and for the differentiation into steroidogenic and chromaffin cells, respectively. This protocol enables analysis of various treatments before, during, or after differentiation. For complete details on the use and execution of this protocol, please refer to Rubin de Celis et al. (2015), Steenblock et al. (2018), and Werdermann et al. (2021).


Assuntos
Glândulas Suprarrenais/citologia , Técnicas de Cultura de Células/métodos , Separação Celular/métodos , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Células Cromafins/citologia , Feminino , Masculino , Camundongos , Esferoides Celulares/citologia , Células-Tronco/citologia
11.
Mov Disord ; 36(12): 2862-2873, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34390508

RESUMO

BACKGROUND: Dysarthric symptoms in Parkinson's disease (PD) vary greatly across cohorts. Abundant research suggests that such heterogeneity could reflect subject-level and task-related cognitive factors. However, the interplay of these variables during motor speech remains underexplored, let alone by administering validated materials to carefully matched samples with varying cognitive profiles and combining automated tools with machine learning methods. OBJECTIVE: We aimed to identify which speech dimensions best identify patients with PD in cognitively heterogeneous, cognitively preserved, and cognitively impaired groups through tasks with low (reading) and high (retelling) processing demands. METHODS: We used support vector machines to analyze prosodic, articulatory, and phonemic identifiability features. Patient groups were compared with healthy control subjects and against each other in both tasks, using each measure separately and in combination. RESULTS: Relative to control subjects, patients in cognitively heterogeneous and cognitively preserved groups were best discriminated by combined dysarthric signs during reading (accuracy = 84% and 80.2%). Conversely, patients with cognitive impairment were maximally discriminated from control subjects when considering phonemic identifiability during retelling (accuracy = 86.9%). This same pattern maximally distinguished between cognitively spared and impaired patients (accuracy = 72.1%). Also, cognitive (executive) symptom severity was predicted by prosody in cognitively preserved patients and by phonemic identifiability in cognitively heterogeneous and impaired groups. No measure predicted overall motor dysfunction in any group. CONCLUSIONS: Predominant dysarthric symptoms appear to be best captured through undemanding tasks in cognitively heterogeneous and preserved cohorts and through cognitively loaded tasks in patients with cognitive impairment. Further applications of this framework could enhance dysarthria assessments in PD. © 2021 International Parkinson and Movement Disorder Society.


Assuntos
Disfunção Cognitiva , Doença de Parkinson , Cognição , Disartria/diagnóstico , Disartria/etiologia , Humanos , Aprendizado de Máquina , Fala
12.
MMW Fortschr Med ; 163(9): 9, 2021 05.
Artigo em Alemão | MEDLINE | ID: mdl-33961234
14.
Neurodegener Dis Manag ; 10(3): 137-157, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32571150

RESUMO

Aim: This paper introduces Apkinson, a mobile application for motor evaluation and monitoring of Parkinson's disease patients. Materials & methods: The App is based on previously reported methods, for instance, the evaluation of articulation and pronunciation in speech, regularity and freezing of gait in walking, and tapping accuracy in hand movement. Results: Preliminary experiments indicate that most of the measurements are suitable to discriminate patients and controls. Significance is evaluated through statistical tests. Conclusion: Although the reported results correspond to preliminary experiments, we think that Apkinson is a very useful App that can help patients, caregivers and clinicians, in performing a more accurate monitoring of the disease progression. Additionally, the mobile App can be a personal health assistant.


Assuntos
Aplicativos Móveis , Doença de Parkinson/fisiopatologia , Smartphone , Idoso , Idoso de 80 Anos ou mais , Feminino , Marcha , Humanos , Masculino , Pessoa de Meia-Idade , Movimento , Índice de Gravidade de Doença , Fala
15.
PLoS One ; 15(2): e0227791, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32040514

RESUMO

The objective investigation of the dynamic properties of vocal fold vibrations demands the recording and further quantitative analysis of laryngeal high-speed video (HSV). Quantification of the vocal fold vibration patterns requires as a first step the segmentation of the glottal area within each video frame from which the vibrating edges of the vocal folds are usually derived. Consequently, the outcome of any further vibration analysis depends on the quality of this initial segmentation process. In this work we propose for the first time a procedure to fully automatically segment not only the time-varying glottal area but also the vocal fold tissue directly from laryngeal high-speed video (HSV) using a deep Convolutional Neural Network (CNN) approach. Eighteen different Convolutional Neural Network (CNN) network configurations were trained and evaluated on totally 13,000 high-speed video (HSV) frames obtained from 56 healthy and 74 pathologic subjects. The segmentation quality of the best performing Convolutional Neural Network (CNN) model, which uses Long Short-Term Memory (LSTM) cells to take also the temporal context into account, was intensely investigated on 15 test video sequences comprising 100 consecutive images each. As performance measures the Dice Coefficient (DC) as well as the precisions of four anatomical landmark positions were used. Over all test data a mean Dice Coefficient (DC) of 0.85 was obtained for the glottis and 0.91 and 0.90 for the right and left vocal fold (VF) respectively. The grand average precision of the identified landmarks amounts 2.2 pixels and is in the same range as comparable manual expert segmentations which can be regarded as Gold Standard. The method proposed here requires no user interaction and overcomes the limitations of current semiautomatic or computational expensive approaches. Thus, it allows also for the analysis of long high-speed video (HSV)-sequences and holds the promise to facilitate the objective analysis of vocal fold vibrations in clinical routine. The here used dataset including the ground truth will be provided freely for all scientific groups to allow a quantitative benchmarking of segmentation approaches in future.


Assuntos
Endoscopia , Glote/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador , Laringe/diagnóstico por imagem , Redes Neurais de Computação , Gravação em Vídeo , Prega Vocal/diagnóstico por imagem , Adulto , Algoritmos , Pontos de Referência Anatômicos , Bases de Dados como Assunto , Feminino , Humanos , Fatores de Tempo
16.
Int J Pediatr Otorhinolaryngol ; 131: 109864, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31927147

RESUMO

INTRODUCTION: Objective techniques for hearing threshold estimation in infants and children with profound or severe hearing loss play a key role in pediatric audiology to prevent speech acquisition disorders by choosing the adequate therapy. Auditory brainstem responses and auditory steady-state responses are available for frequency-dependent hearing threshold estimations and both techniques show strong correlations. However, various systems and stimuli are available, which is one reason why comparison is challenging, and, so far, no single "gold standard" could be established for hearing threshold estimation in children suffering from profound or severe hearing loss. The aim of the study was to compare hearing threshold estimations in children with profound or severe hearing loss derived with narrow-band CE-chirps evoked auditory brainstem responses and auditory steady-state response. SUBJECTS: and Methods: 71 children (121 ears) with an age from 3 month to 15 years were measured with the Interacoustics Eclipse EP25 ABR system® (Denmark) with narrow-band CE-chirps® at 500, 1000, 2000 and 4000 Hz under identical conditions. RESULTS: Auditory brainstem responses and auditory steady-state responses highly correlate (r = 0.694, p < 0.001). Correlation coefficients differ depending on the center frequency and patient age. Generally, auditory steady-state responses show a better hearing threshold than auditory brainstem responses or a remaining hearing threshold when auditory brainstem responses could not be obtained. In approximately 15% of cases this would have affected the therapeutic strategy when only taking one technique into account. CONCLUSION: Auditory brainstem responses and auditory steady-state responses should be jointly used in the diagnostic approach in children with suspected profound or severe hearing loss.


Assuntos
Limiar Auditivo , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Potenciais Evocados Auditivos , Perda Auditiva/diagnóstico , Adolescente , Limiar Auditivo/fisiologia , Criança , Pré-Escolar , Surdez/diagnóstico , Surdez/fisiopatologia , Feminino , Audição/fisiologia , Perda Auditiva/fisiopatologia , Humanos , Lactente , Masculino , Distúrbios da Fala/prevenção & controle
17.
J Pharmacol Exp Ther ; 371(1): 95-105, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31366602

RESUMO

Extended half-life (EHL) factor therapies are needed to reduce the burden of prophylaxis and improve treatment adherence in patients with hemophilia. BAX 826 is a novel polysialylated full-length recombinant factor VIII [polysialyic acid (PSA) rFVIII] with improved pharmacokinetics (PK), prolonged pharmacology, and maintained safety attributes to enable longer-acting rFVIII therapy. In factor VIII (FVIII)-deficient hemophilic mice, PSArFVIII showed a substantially higher mean residence time (>2-fold) and exposure (>3-fold), and prolonged efficacy in tail-bleeding experiments (48 vs. 30 hours) compared with unmodified recombinant FVIII (rFVIII), as well as a potentially favorable immunogenicity profile. Reduced binding to a scavenger receptor (low-density lipoprotein receptor-related protein 1) and von Willebrand factor (VWF) as well as a largely VWF-independent circulation time in mice provide a rationale for prolonged BAX 826 activity. The significantly improved PK profile versus rFVIII was confirmed in cynomolgus monkeys [mean residence time: 23.4 vs. 10.1 hours; exposure (area under the curve from time 0 to infinity): 206 vs. 48.2 IU/ml⋅h] and is in line with results from rodent studies. Finally, safety and toxicity evaluations did not indicate increased thrombogenic potential, and repeated administration of BAX 826 to monkeys and rats was well tolerated. The favorable profile and mechanism of this novel experimental therapeutic demonstrated all of the requirements for an EHL-rFVIII candidate, and thus BAX 826 was entered into clinical assessment for the treatment of hemophilia A. SIGNIFICANCE STATEMENT: Prolongation of FVIII half-life aims to reduce the burden of prophylaxis and improve treatment outcomes in patients with hemophilia. This study shows that polysialylation of PSArFVIII resulted in prolongations of rFVIII circulation time and procoagulant activity, together with a favorable nonclinical safety profile of the experimental therapeutic.


Assuntos
Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Absorção Fisiológica , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Fator VIII/efeitos adversos , Fator VIII/farmacocinética , Feminino , Meia-Vida , Humanos , Macaca fascicularis , Masculino , Ácido N-Acetilneuramínico/química , Ligação Proteica , Ratos , Receptores Depuradores/metabolismo , Fator de von Willebrand/metabolismo
18.
Laryngorhinootologie ; 98(6): 388-397, 2019 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-31167292

RESUMO

Hypersalivation describes a relatively excessive salivary flow, which wets the patient himself and his surroundings. It may result because of insufficient oro-motor function, dysphagia, decreased central control and coordination. This update presents recent changes and innovation in the treatment of hypersalivation.Multidisciplinary diagnostic and treatment evaluation is recommended already at early stage and focus on dysphagia, saliva aspiration, and oro-motor deficiencies. Clinical screening tools and diagnostics such as fiberoptic endoscopic evaluation of swallowing generate important data on therapy selection and control. Many cases profit from swallowing therapy programmes in order to activate compensation mechanisms as long compliances is given. In children with hypotonic oral muscles, oral stimulation plates can induce a relevant symptom release because of the improved lip closure. The pharmacologic treatment improved for pediatric cases as glycopyrrolate fluid solution (Sialanar®) is now indicated for hypersalivation within the E. U. The injection of botulinum toxin into the salivary glands has shown safe and effective results with long lasting saliva reduction. Here, a phase III trial is completed for Incobotulinum toxin A and, in the U. S., is indicated for the treatment of adult patients with chronic hypersalivation. Surgical treatment should be reserved for isolated cases. External radiation is judged as a safe and effective therapy when using modern 3 D techniques to minimize tissue damage. Therapy effects and symptom severity has to be followed, especially in cases with underlying neurodegenerative disease.


Assuntos
Sialorreia , Toxinas Botulínicas Tipo A , Transtornos de Deglutição , Glicopirrolato , Humanos , Doenças Neurodegenerativas , Glândulas Salivares
19.
J Steroid Biochem Mol Biol ; 191: 105360, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31028792

RESUMO

Activation of the adrenal gland stress response is of utmost importance to survive sepsis. Experimental and clinical evidence exists demonstrating that adrenal gland often develops functional and structural damage due to sepsis with mechanisms remaining largely unknown. In the present study, we have used RNA Sequencing (RNA-Seq) technology to analyze changes in adrenal transcriptome elucidated by bacterial LPS. We aimed to find particularly alterations in genes that were previously not reported to be involved in the adrenal gland dysregulation in contexts of sepsis. Our results demonstrate that systemic administration of LPS significantly altered expression of 8458 genes as compared to saline injected animals. The subsequent quality and functional analysis of these gene signatures revealed that LPS-induced highly homogenous transcriptional response in total upregulating 4312 and downregulating 4146 genes. Furthermore, functional annotation analysis together with gene enrichment set analysis (GSEA) clearly demonstrated that adrenal response to LPS involved alterations in multiple pathways related to the inflammatory response along with previously unexplored activation of the hypoxia pathway. In addition, LPS strongly downregulated genes involved in the adrenal homeostasis, development, and regeneration. Those alterations were subsequently verified in clinically relevant cecal ligation and puncture (CLP)-induced sepsis model. Collectively, our study demonstrates that RNA-seq is a very useful method that can be applied to search for new unexplored pathways potentially involved in adrenal gland dysregulation during sepsis.


Assuntos
Sepse/genética , Transcriptoma , Glândulas Suprarrenais/imunologia , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/fisiopatologia , Animais , Regulação da Expressão Gênica , Lipopolissacarídeos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Sepse/imunologia , Sepse/fisiopatologia , Análise de Sequência de RNA
20.
J Neural Transm (Vienna) ; 126(7): 853-862, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30972507

RESUMO

Hypersalivation describes a relatively excessive salivary flow, which wets the patient himself and his surroundings. It may result because of insufficient oro-motor function, dysphagia, decreased central control and coordination. This update presents recent changes and innovation in the treatment of hypersalivation. Multidisciplinary diagnostic and treatment evaluation is recommended already at early stage and focus on dysphagia, saliva aspiration, and oro-motor deficiencies. Clinical screening tools and diagnostics such as fiberoptic endoscopic evaluation of swallowing generate important data on therapy selection and control. Many cases profit from swallowing therapy programmes to activate compensation mechanisms as long compliances are given. In children with hypotonic oral muscles, oral stimulation plates can induce a relevant symptom release because of the improved lip closure. The pharmacologic treatment improved for pediatric cases as glycopyrrolate fluid solution (Sialanar®) is now indicated for hypersalivation within the EU. The injection of botulinum toxin into the salivary glands has shown safe and effective results with long-lasting saliva reduction. Here, a phase III trial is completed for incobotulinum toxin A and, in the US, is indicated for the treatment of adult patients with chronic hypersalivation. Surgical treatment should be reserved for isolated cases. External radiation is judged as a safe and effective therapy when using modern 3D techniques to minimize tissue damage. Therapy effects and symptom severity have to be followed, especially in cases with underlying neurodegenerative disease.


Assuntos
Sialorreia , Alemanha , Humanos
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