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BACKGROUND: Deep brain stimulation (DBS) has been increasingly used in the management of dyskinetic cerebral palsy (DCP). Data on long-term effects and the safety profile are rare. OBJECTIVES: We assessed the efficacy and safety of pallidal DBS in pediatric patients with DCP. METHODS: The STIM-CP trial was a prospective, single-arm, multicenter study in which patients from the parental trial agreed to be followed-up for up to 36 months. Assessments included motor and non-motor domains. RESULTS: Of the 16 patients included initially, 14 (mean inclusion age 14 years) were assessed. There was a significant change in the (blinded) ratings of the total Dyskinesia Impairment Scale at 36 months. Twelve serious adverse events (possibly) related to treatment were documented. CONCLUSION: DBS significantly improved dyskinesia, but other outcome parameters did not change significantly. Investigations of larger homogeneous cohorts are needed to further ascertain the impact of DBS and guide treatment decisions in DCP. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Paralisia Cerebral , Estimulação Encefálica Profunda , Discinesias , Transtornos dos Movimentos , Humanos , Criança , Adolescente , Paralisia Cerebral/terapia , Seguimentos , Estudos Prospectivos , Discinesias/etiologia , Discinesias/terapia , Globo Pálido , Transtornos dos Movimentos/terapia , Resultado do TratamentoRESUMO
BACKGROUND: Patients with dyskinetic cerebral palsy are often severely impaired with limited treatment options. The effects of deep brain stimulation (DBS) are less pronounced than those in inherited dystonia but can be associated with favorable quality of life outcomes even in patients without changes in dystonia severity. OBJECTIVE: The aim is to assess DBS effects in pediatric patients with pharmacorefractory dyskinetic cerebral palsy with focus on quality of life. METHODS: The method used is a prospective, single-arm, multicenter study. The primary endpoint is improvement in quality of life (CPCHILD [Caregiver Priorities & Child Health Index of Life with Disabilities]) from baseline to 12 months under therapeutic stimulation. The main key secondary outcomes are changes in Burke-Fahn-Marsden Dystonia Rating Scale, Dyskinesia Impairment Scale, Gross Motor Function Measure-66, Canadian Occupational Performance Measure (COPM), and Short-Form (SF)-36. After 12 months, patients were randomly assigned to a blinded crossover to receive active or sham stimulation for 24 hours each. Severity of dystonia and chorea were blindly rated. Safety was assessed throughout. The trial was registered at ClinicalTrials.gov, number NCT02097693. RESULTS: Sixteen patients (age: 13.4 ± 2.9 years) were recruited by seven clinical sites. Primary outcome at 12-month follow-up is as follows: mean CPCHILD increased by 4.2 ± 10.4 points (95% CI [confidence interval] -1.3 to 9.7; P = 0.125); among secondary outcomes: improvement in COPM performance measure of 1.1 ± 1.5 points (95% CI 0.2 to 1.9; P = 0.02) and in the SF-36 physical health component by 5.1 ± 6.2 points (95% CI 0.7 to 9.6; P = 0.028). Otherwise, there are no significant changes. CONCLUSION: Evidence to recommend DBS as routine treatment to improve quality of life in pediatric patients with dyskinetic cerebral palsy is not yet sufficient. Extended follow-up in larger cohorts will determine the impact of DBS further to guide treatment decisions in these often severely disabled patients. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Paralisia Cerebral , Estimulação Encefálica Profunda , Distonia , Distúrbios Distônicos , Adolescente , Canadá , Paralisia Cerebral/terapia , Criança , Estimulação Encefálica Profunda/métodos , Globo Pálido , Humanos , Estudos Prospectivos , Qualidade de Vida , Resultado do TratamentoRESUMO
BACKGROUND: Dystonia is clinically and genetically heterogeneous. Despite being a first-line testing tool for heterogeneous inherited disorders, whole-exome sequencing has not yet been evaluated in dystonia diagnostics. We set up a pilot study to address the yield of whole-exome sequencing for early-onset generalized dystonia, a disease subtype enriched for monogenic causation. METHODS: Clinical whole-exome sequencing coupled with bioinformatics analysis and detailed phenotyping of mutation carriers was performed on 16 consecutive cases with genetically undefined early-onset generalized dystonia. Candidate pathogenic variants were validated and tested for cosegregation. The whole-exome approach was complemented by analyzing 2 mutated yet unestablished causative genes in another 590 dystonia cases. RESULTS: Whole-exome sequencing detected clinically relevant mutations of known dystonia-related genes in 6 generalized dystonia cases (37.5%), among whom 3 had novel variants. Reflecting locus heterogeneity, identified unique variants were distributed over 5 genes (GCH1, THAP1, TOR1A, ANO3, ADCY5), of which only 1 (ANO3) was mutated recurrently. Three genes (GCH1, THAP1, TOR1A) were associated with isolated generalized dystonia, whereas 2 (ANO3, ADCY5) gave rise to combined dystonia-myoclonus phenotypes. Follow-up screening of ANO3 and ADCY5 revealed a set of distinct variants of interest, the pathogenicity of which was supported by bioinformatics testing and cosegregation work. CONCLUSIONS: Our study identified whole-exome sequencing as an effective strategy for molecular diagnosis of early-onset generalized dystonia and offers insights into the heterogeneous genetic architecture of this condition. Furthermore, it provides confirmatory evidence for a dystonia-relevant role of ANO3 and ADCY5, both of which likely associate with a broader spectrum of dystonic expressions than previously thought. © 2016 International Parkinson and Movement Disorder Society.
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Distonia/genética , Exoma/genética , Mutação/genética , Adenilil Ciclases/genética , Adulto , Anoctaminas , Proteínas Reguladoras de Apoptose/genética , Canais de Cloreto/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Saúde da Família , Feminino , Seguimentos , GTP Cicloidrolase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Chaperonas Moleculares/genética , Proteínas Nucleares/genética , Adulto JovemRESUMO
Laser Assisted in Situ Keratomileusis (LASIK) is a proven treatment method for corneal refractive surgery. Surgically induced higher order optical aberrations were a major reason why the method was only rarely used to treat presbyopia, an age-related near-vision loss. In this study, a novel customization algorithm for designing multifocal ablation patterns, thereby minimizing induced optical aberrations, was used to treat 36 presbyopic subjects. Results showed that most candidates went from poor visual acuity to uncorrected 20/20 vision or better for near (78%), intermediate (92%), and for distance (86%) vision, six months after surgery. All subjects were at 20/25 or better for distance and intermediate vision, and a majority (94%) were also better for near vision. Even though further studies are necessary, our results suggest that the employed methodology is a safe, reliable, and predictable refractive surgical treatment for presbyopia.
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Presbiopia , Humanos , Hiperopia , Ceratomileuse Assistida por Excimer Laser In Situ , Lasers de Excimer , Resultado do Tratamento , Acuidade VisualRESUMO
A prospective comparative study assessing the importance of the intra-operative dynamic rotational tracking-especially in the treatment of astigmatisms in corneal refractive Excimer laser correction-concerning clinical outcomes is presented. The cyclotorsion from upright to supine position was measured using iris image comparison. The Group 1 of patients was additionally treated with cyclorotational control and Group 2 only with X-Y control. Significant differences were observed between the groups regarding the mean postoperative cylinder refraction (p < 0.05). The mean cyclotorsion can be calculated to 3.75° with a standard deviation of 3.1°. The total range of torsion was from -14.9° to +12.6°. Re-treatment rate was 2.2% in Group 1 and 8.2% in Group 2, which is highly significant (p < 0.01). The investigation confirms that the dynamic rotational tracking system used for LASIK results in highly predictable refraction quality with significantly less postoperative re-treatments.
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Lasers de Excimer , Humanos , Iris , Miopia , Estudos Prospectivos , Refração Ocular , Resultado do TratamentoRESUMO
OBJECTIVES: Recent studies suggest that oscillatory beta activity could be used as a state biomarker in patients with Parkinson's disease for subthalamic closed-loop stimulation with the intention of improving clinical benefit. Here we investigate the feasibility of subthalamic recordings via a novel chronically implanted pulse generator. METHODS: Subthalamic local field potential recordings were obtained from eight patients before and during deep brain stimulation (DBS). All data were analyzed in the frequency domain using Fourier transform-based methods and compared between ON and OFF stimulation conditions. RESULTS: Distinct peaks of oscillatory beta band activity were found in 12 of 15 electrodes. DBS induced a significant frequency specific suppression of oscillatory beta activity (p = 0.002). CONCLUSION: The results of the study suggest that oscillatory beta band synchronization and its modulation by DBS is recordable with a system suitable for chronic implantation and may serve as a biomarker for subthalamic closed-loop stimulation in patients with Parkinson's disease.
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Estimulação Encefálica Profunda/métodos , Potenciais Evocados/fisiologia , Doença de Parkinson/terapia , Núcleo Subtalâmico/citologia , Núcleo Subtalâmico/fisiologia , Idoso , Biofísica , Eletrodos Implantados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise EspectralRESUMO
Background: Cervical dystonia (CD) is the most common form of focal dystonia in adults. Studies show that physiotherapy (PT) in combination with BoNT has an effect on pain in cervical dystonia. We intended to test this hypothesis in a real-world setting to answer the question of whether pain is a good target symptom for prescribing PT. We also aimed to assess which form of PT is most appropriate for the treatment of pain. Methods: Study design: cross-sectional survey-based study of 91 patients with a confirmed diagnosis of cervical dystonia. The survey consisted of a questionnaire on type, frequency and content of physiotherapy, an assessment of quality of life with the Craniocervical Dystonia Questionnaire 24 (CDQ 24) and subjective pain scores. Results: 53.8% of patients received physiotherapy, mostly a mixture of exercises to either correct the abnormal posture or to reduce the muscle tone. Additional therapies included stress-reducing exercises (14.3%), psychotherapy (9.9%) and EMG biofeedback (2.2%). Patients who received PT showed a non-significant tendency towards higher pain scores. The severity of dystonia-associated pain was significantly associated with the patients' quality of life (F (1,54) = 22.9, adjusted R2 = 0.286, p < 0.001). Discussion: Pain is a frequent problem in patients with CD and severely affects quality of life. Physiotherapy could therefore be a valuable treatment option for patients with CD and pain. Highlights: Our uncontrolled study illustrates the high frequency of physiotherapy in addition to BoNT treatment in a real-life cohort of patients with cervical dystonia. We were able to show that PT reduces patients' perceived pain in a patient reported outcome measure. This highlights the importance of PT in reducing CD-related pain, which considerably impairs quality of life.
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Distúrbios Distônicos , Torcicolo , Adulto , Humanos , Torcicolo/complicações , Torcicolo/terapia , Qualidade de Vida , Estudos Transversais , Modalidades de Fisioterapia , DorRESUMO
Dystonia is a neurological movement disorder characterised by abnormal involuntary movements and postures, particularly affecting the head and neck. However, current clinical assessment methods for dystonia rely on simplified rating scales which lack the ability to capture the intricate spatiotemporal features of dystonic phenomena, hindering clinical management and limiting understanding of the underlying neurobiology. To address this, we developed a visual perceptive deep learning framework that utilizes standard clinical videos to comprehensively evaluate and quantify disease states and the impact of therapeutic interventions, specifically deep brain stimulation. This framework overcomes the limitations of traditional rating scales and offers an efficient and accurate method that is rater-independent for evaluating and monitoring dystonia patients. To evaluate the framework, we leveraged semi-standardized clinical video data collected in three retrospective, longitudinal cohort studies across seven academic centres. We extracted static head angle excursions for clinical validation and derived kinematic variables reflecting naturalistic head dynamics to predict dystonia severity, subtype, and neuromodulation effects. The framework was also applied to a fully independent cohort of generalised dystonia patients for comparison between dystonia sub-types. Computer vision-derived measurements of head angle excursions showed a strong correlation with clinically assigned scores. Across comparisons, we identified consistent kinematic features from full video assessments encoding information critical to disease severity, subtype, and effects of neural circuit interventions, independent of static head angle deviations used in scoring. Our visual perceptive machine learning framework reveals kinematic pathosignatures of dystonia, potentially augmenting clinical management, facilitating scientific translation, and informing personalized precision neurology approaches.
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OBJECTIVE: Main objective of this study was to examine the chemosensory effects of formaldehyde on hyposensitive and hypersensitive males at concentrations relevant to the workplace. Attention focused on objective effects on and subjective symptoms of the mucous membranes of the eyes, the nose, the upper respiratory tract and olfactory function. METHODS: Forty-one male volunteers were exposed for 5 days (4 h per day) in a randomised schedule to the control condition (0 ppm) and to formaldehyde concentrations of 0.5 and 0.7 ppm and to 0.3 ppm with peak exposures of 0.6 ppm, and to 0.4 ppm with peak exposures of 0.8 ppm, respectively. Peak exposures were carried out four times a day over a 15-min period of time. Subjective pain perception induced by nasal application of carbon dioxide served as indicator for sensitivity to sensory nasal irritation. The following parameters were examined before and after exposure: subjective rating of symptoms and complaints (Swedish Performance Evaluation System), conjunctival redness, eye-blinking frequency, self-reported tear film break-up time and nasal flow rates. In addition, the influence of personality factors on the volunteer's subjective scoring was examined (Positive And Negative Affect Schedule). RESULTS: Formaldehyde exposures to 0.7 ppm for 4 h and to 0.4 ppm for 4 h with peaks of 0.8 ppm for 15 min caused no significant sensory irritation of the measured conjunctival and nasal parameters. No differences between hypo- and hypersensitive subjects were seen. Nevertheless, statistically significant differences were noted for olfactory symptoms, especially for the 'perception of impure air'. These subjective complaints were more pronounced in hypersensitive subjects. CONCLUSIONS: Formaldehyde concentrations of 0.7 ppm for 4 h and of 0.4 ppm for 4 h with peaks of 0.8 ppm for 15 min did not cause adverse effects related to irritation, and no differences between hypo- and hypersensitive subjects were observed.
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Olho/efeitos dos fármacos , Formaldeído/toxicidade , Irritantes/toxicidade , Nariz/efeitos dos fármacos , Adulto , Relação Dose-Resposta a Droga , Feminino , Formaldeído/administração & dosagem , Formaldeído/análise , Humanos , Irritantes/administração & dosagem , MasculinoRESUMO
Patients with immune thrombocytopenia (ITP) under eltrombopag therapy are vulnerable to thrombotic disbalance, both due to the disease itself and therapy-related hypercoagulability. Vascular events such as the development of a free-floating carotid thrombus are known rare complications of acute COVID-19 infections due to endothelial inflammation and presumptive underlying hypercoagulable state. In patients at risk, the onset of new focal neurological symptoms should prompt immediate angiographic diagnostics and, if necessary, appropriate treatment. Here, we report a case of a 38-year-old female with a medical history of ITP and the presence of COVID-19 infection presenting an acute sensorimotor hemiparesis of the right side while on eltrombopag therapy. Initial CT angiography revealed a free-floating thrombus in the left common carotid artery. Upon admission, the patient's platelet count was significantly elevated at 896 × 109/l. After systemic lysis therapy, the thrombus was fully dissolved. Follow-up diffusion-weighted imaging revealed multilocular cortical infarction of the left MCA territory. The patient soon recovered and was discharged with residual mild sensorimotor deficits in the right arm. Eltrombopag was paused at admission, and the patient's platelet count was quickly returning to normal. She was discharged with a daily intake of acetylsalicylic acid, a reduced daily dose of eltrombopag, and weekly monitoring of her platelet count for the next three months. This unique case highlights the need for caution in patients at vascular risk who contract COVID-19 and discusses thrombocytic derailment under thrombopoietin receptor agonist therapy in the context of an acute COVID-19 infection.
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Advancing novel immunotherapy strategies requires refined tools in preclinical research to thoroughly assess drug targets, biodistribution, safety, and efficacy. Light sheet fluorescence microscopy (LSFM) offers unprecedented fast volumetric ex vivo imaging of large tissue samples in high resolution. Yet, to date laborious and unstandardized tissue processing procedures have limited throughput and broader applications in immunological research. Therefore, we developed a simple and harmonized protocol for processing, clearing and imaging of all mouse organs and even entire mouse bodies. Applying this Rapid Optical Clearing Kit for Enhanced Tissue Scanning (ROCKETS) in combination with LSFM allowed us to comprehensively study the in vivo biodistribution of an antibody targeting Epithelial Cell Adhesion Molecule (EpCAM) in 3D. Quantitative high-resolution scans of whole organs did not only reveal known EpCAM expression patterns but, importantly, uncovered several new EpCAM-binding sites. We identified gustatory papillae of the tongue, choroid plexi in the brain and duodenal papillae as previously unanticipated locations of high EpCAM expression. Subsequently, we confirmed high EpCAM expression also in human tongue and duodenal specimens. Choroid plexi and duodenal papillae may be considered as particularly sensitive sites due to their importance for liquor production or as critical junctions draining bile and digestive pancreatic enzymes into the small bowel, respectively. These newly gained insights appear highly relevant for clinical translation of EpCAM-addressing immunotherapies. Thus, ROCKETS in combination with LSFM may help to set new standards for preclinical evaluation of immunotherapeutic strategies. In conclusion, we propose ROCKETS as an ideal platform for a broader application of LSFM in immunological research optimally suited for quantitative co-localization studies of immunotherapeutic drugs and defined cell populations in the microanatomical context of organs or even whole mice.
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Descoberta de Drogas , Receptores Proteína Tirosina Quinases , Animais , Humanos , Camundongos , Molécula de Adesão da Célula Epitelial , Distribuição Tecidual , Microscopia de Fluorescência/métodos , FosforilaçãoRESUMO
Botulinum Toxin injections into salivary glands (SG) up to a total dose of 100 units IncobotulinumtoxinA (IncoA) represent the treatment of choice for sialorrhea. However, BTX might also protect SG against sialotoxic radioligand cancer therapies. The radioligand Actinium-225-PSMA effectively targets Prostate Cancer (PCa) metastases but inevitably destroys SG due to unintended gland uptake. A preliminary case series with regular-dose IncoA failed to reduce SG PSMA-radioligand uptake. We therefore increased IncoA dosage in combination with transdermal scopolamine until a clinically relevant SG PSMA-radioligand uptake reduction was achieved. Ten consecutive men with metastasized PCa refractory to all other cancer therapies received gradually increasing IncoA dosages as part of a compassionate use PSMA-radioligand-therapy trial. The parotid gland received six and the submandibular gland three injection points under ultrasound control, up to a maximum of 30 units IncoA per injection point. A maximum total dose of 250 units IncoA was applied with up to 170 units per parotid and 80 units per submandibular gland. Treatment was well tolerated and all side-effects were non-serious. The most frequent side-effect was dry mouth of mild severity. No dysphagia, facial weakness, chewing difficulties or systemic side-effects were observed. SG injections with IncoA up to a total dose of 250 units are safe when distributed among several injection-points under ultrasound control by an experienced physician. These preliminary findings lay the basis for future trials including BTX as major component for SG protection in established as well as newly emerging radioligand cancer therapies.
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Toxinas Botulínicas Tipo A/efeitos adversos , Glândula Parótida/efeitos dos fármacos , Glândula Submandibular/efeitos dos fármacos , Idoso , Relação Dose-Resposta a Droga , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
T-cell bispecific antibodies (TCB) are engineered molecules that bind both the T-cell receptor and tumor-specific antigens. Epidermal growth factor receptor variant III (EGFRvIII) mutation is a common event in glioblastoma (GBM) and is characterized by the deletion of exons 2-7, resulting in a constitutively active receptor that promotes cell proliferation, angiogenesis, and invasion. EGFRvIII is expressed on the surface of tumor cells and is not expressed in normal tissues, making EGFRvIII an ideal neoantigen target for TCBs. We designed and developed a novel 2+1 EGFRvIII-TCB with optimal pharmacologic characteristics and potent antitumor activity. EGFRvIII-TCB showed specificity for EGFRvIII and promoted tumor cell killing as well as T-cell activation and cytokine secretion only in patient-derived models expressing EGFRvIII. Moreover, EGFRvIII-TCB promoted T-cell recruitment into intracranial tumors. EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft models. Our results warrant the clinical testing of EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.
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Anticorpos Biespecíficos , Neoplasias Encefálicas , Glioblastoma , Animais , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Citocinas , Receptores ErbB/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/metabolismoRESUMO
Forty-one volunteers (male non-smokers) were exposed to formaldehyde (FA) vapours for 4 h/day over a period of five working days under strictly controlled conditions. For each exposure day, different exposure concentrations were used in a random order ranging from 0 up to 0.7 p.p.m. At concentrations of 0.3 and 0.4 p.p.m., four peaks of 0.6 or 0.8 p.p.m. for 15 min each were applied. During exposure, subjects had to perform bicycle exercises (â¼80 W) four times for 15 min. Blood samples, exfoliated nasal mucosa cells and nasal biopsies were taken before the first and after the last exposure. Nasal epithelial cells were additionally sampled 1, 2 and 3 weeks after the end of the exposure period. The alkaline comet assay, the sister chromatid exchange test and the cytokinesis-block micronucleus test were performed with blood samples. The micronucleus test was also performed with exfoliated nasal mucosa cells. The expression (mRNA level) of the glutathione (GSH)-dependent formaldehyde dehydrogenase (FDH, identical to alcohol dehydrogenase 5; ADH5; EC 1.2.1.46) was measured in blood samples by quantitative real-time reverse transcription-polymerase chain reaction with TaqMan probes. DNA microarray analyses using a full-genome human microarray were performed on blood samples and nasal biopsies of selected subgroups with the highest FA exposure at different days. Under the experimental conditions of this study, inhalation of FA did not lead to genotoxic effects in peripheral blood cells and nasal mucosa and had no effect on the expression of the FDH gene. Inhalation of FA did also not cause alterations in the expression of genes in a microarray analysis with nasal biopsies and peripheral blood cells.
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Formaldeído/intoxicação , Regulação da Expressão Gênica/efeitos dos fármacos , Mutagênicos/intoxicação , Hipersensibilidade Respiratória/genética , Biópsia , Ensaio Cometa , Formaldeído/efeitos adversos , Formaldeído/sangue , Perfilação da Expressão Gênica , Humanos , Exposição por Inalação , Masculino , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Testes de Mutagenicidade , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/patologia , Hipersensibilidade Respiratória/sangue , Troca de Cromátide Irmã/efeitos dos fármacos , Fatores de TempoRESUMO
Forty-one volunteers (male non-smokers, aged 32 ± 9.6yrs) were tested for susceptibility towards unspecific nasal irritation (sensitivity towards CO(2)) in order to define subgroups of hypersensitive and hyposensitive subjects. Blood samples were taken and the expression (mRNA level) of the GSH-dependent formaldehyde dehydrogenase gene (FDH, identical to alcohol dehydrogenase 5, ADH5; EC 1.2.1.46) was measured in leukocytes by quantitative real-time RT-PCR with TaqMan probes. FDH is the most important enzyme for the metabolic inactivation of FA. Blood samples were exposed to 150µM formaldehyde (FA) for 2h and the induction of DNA-protein crosslinks (DPX) in leukocytes was measured by means of a modification of the alkaline comet assay (i.e., by assessing the reduction of DNA migration induced by γ-radiation). Removal of DPX was determined by the abolition of FA-induced reduction in DNA migration within 4h after the end of the exposure. Furthermore, the induction of sister chromatid exchange (SCE) in cultured lymphocytes was studied after treatment of whole blood cultures with FA (150µM). A correlation analysis was performed for all parameters tested for the whole study group and for hypersensitive and hyposensitive subgroups. The results indicate that despite large differences in CO(2)-sensitivity, the susceptibility towards nasal irritation was not related to the induction of genotoxic effects (DPX, SCE) in peripheral blood or to the protection of blood cells against FA-induced effects (expression of FDH, repair capacity for FA-induced DPX). There was no correlation between CO(2)-sensitivity and the expression of FDH. There was also no close correlation between the various indicators of cellular sensitivity towards FA-induced genotoxic effects and no subgroups were identified with particular mutagen sensitivity towards FA.
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Formaldeído/metabolismo , Formaldeído/toxicidade , Mutagênicos/toxicidade , Hipersensibilidade Respiratória/induzido quimicamente , Adulto , Aldeído Oxirredutases/metabolismo , Células Sanguíneas/efeitos dos fármacos , Dióxido de Carbono/farmacologia , Ensaio Cometa , Reparo do DNA , Humanos , Técnicas In Vitro , Leucócitos/efeitos dos fármacos , Masculino , Troca de Cromátide Irmã , Nervo Trigêmeo/efeitos dos fármacosRESUMO
OBJECTIVE: Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. METHODS: Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. RESULTS: Four clusters were identified and validated. Three were pathologic, representing "inflammatory," "lymphoid," and "interferon" patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. CONCLUSION: Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases.
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Doenças Autoimunes/classificação , Doenças Autoimunes/genética , Epigenoma , Perfilação da Expressão Gênica , Adulto , Idoso , Síndrome Antifosfolipídica/genética , Síndrome Antifosfolipídica/imunologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Estudos de Casos e Controles , Análise por Conglomerados , Estudos Transversais , Epigenômica , Feminino , Humanos , Inflamação/imunologia , Interferons/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Doença Mista do Tecido Conjuntivo/genética , Doença Mista do Tecido Conjuntivo/imunologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Doenças do Tecido Conjuntivo Indiferenciado/genética , Doenças do Tecido Conjuntivo Indiferenciado/imunologiaAssuntos
Proteínas Reguladoras de Apoptose/genética , Proteínas de Ligação a DNA/genética , Distúrbios Distônicos/genética , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Chaperonas Moleculares/genética , Mutação/genética , Proteínas Nucleares/genética , Áustria , Análise Mutacional de DNA , Feminino , Humanos , MasculinoRESUMO
Endometriosis is a common gynaecological disease of women in reproductive age, and is thought to arise from retrograde menstruation and implantation of endometrial tissue, mostly into the peritoneal cavity. The condition is characterized by a chronic, unresolved inflammatory process thereby contributing to pain as cardinal symptom in endometriosis. Elevated reactive oxygen species (ROS) and oxidative stress have been postulated as factors in endometriosis pathogenesis. We here set out for a systematic study to identify novel mechanisms and pathways relating to oxidative stress in ectopic peritoneal lesions. Using combined proteomic and transcriptomic approaches, we identified novel targets including upregulated pro-oxidative enzymes, such as amine oxidase 3/vascular adhesion protein 1 (AOC3/VAP1) as well as downregulated protective factors, in particular alkenal reductase PTGR1 and methionine sulfoxide reductase. Consistent with an altered ROS landscape, we observed hemoglobin / iron overload, ROS production and lipid peroxidation in ectopic lesions. ROS-derived 4-hydroxy-2-nonenal induced interleukin IL-8 release from monocytes. Notably, AOC3 inhibitors provoked analgesic effects in inflammatory pain models in vivo, suggesting potential translational applicability.
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Amina Oxidase (contendo Cobre)/metabolismo , Moléculas de Adesão Celular/metabolismo , Endometriose/metabolismo , Doenças Peritoneais/metabolismo , Aldeídos/metabolismo , Compostos Alílicos/farmacologia , Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Analgésicos/farmacologia , Animais , Biomarcadores/metabolismo , Moléculas de Adesão Celular/antagonistas & inibidores , Modelos Animais de Doenças , Endometriose/genética , Endometriose/patologia , Feminino , Perfilação da Expressão Gênica , Heme/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-8/metabolismo , Ferro/metabolismo , Peroxidação de Lipídeos , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos BALB C , Células Mieloides/patologia , Estresse Oxidativo , Doenças Peritoneais/genética , Doenças Peritoneais/patologia , Fagocitose , Sulfonamidas/farmacologiaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Sensory gestes (SG) are a pathognomonic sign of dystonia, which can be detected in up to two thirds of patients with cervical dystonia (CD). They reduce dystonia severity markedly but transiently. We report a patient whose CD substantially worsened with sensory input to the back of the head and neck in different body postures, a phenomomen recently termed "reverse" sensory geste (rSG) in craniocervical dystonia. In a cohort of CD outpatients, screening for "reverse" effects of SG on dystonia yielded a prevalence of 12.8% (n = 6/47). The most frequent rSG pattern was increased dystonic activity in a supine, resting position while trying to fall asleep. The response to rSG persisted throughout the course of the disease arguing for an impairment of central integration of neck proprioception. Assessment of rSG should be included in the routine examination of CD patients, since BTX treatment may have to beadjusted accordingly to be efficacious.