RESUMO
We previously molecularly and clinically characterized Mazzanti syndrome, a RASopathy related to Noonan syndrome that is mostly caused by a single recurrent missense variant (c.4A > G, p.Ser2Gly) in SHOC2, which encodes a leucine-rich repeat-containing protein facilitating signal flow through the RAS-mitogen-associated protein kinase (MAPK) pathway. We also documented that the pathogenic p.Ser2Gly substitution causes upregulation of MAPK signaling and constitutive targeting of SHOC2 to the plasma membrane due to the introduction of an N-myristoylation recognition motif. The almost invariant occurrence of the pathogenic c.4A > G missense change in SHOC2 is mirrored by a relatively homogeneous clinical phenotype of Mazzanti syndrome. Here, we provide new data on the clinical spectrum and molecular diversity of this disorder and functionally characterize new pathogenic variants. The clinical phenotype of six unrelated individuals carrying novel disease-causing SHOC2 variants is delineated, and public and newly collected clinical data are utilized to profile the disorder. In silico, in vitro and in vivo characterization of the newly identified variants provides evidence that the consequences of these missense changes on SHOC2 functional behavior differ from what had been observed for the canonical p.Ser2Gly change but converge toward an enhanced activation of the RAS-MAPK pathway. Our findings expand the molecular spectrum of pathogenic SHOC2 variants, provide a more accurate picture of the phenotypic expression associated with variants in this gene and definitively establish a gain-of-function behavior as the mechanism of disease.
Assuntos
Anormalidades Múltiplas , Peptídeos e Proteínas de Sinalização Intracelular , Síndrome dos Cabelos Anágenos Frouxos , Anormalidades Múltiplas/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Síndrome dos Cabelos Anágenos Frouxos/genética , Fenótipo , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
Upregulated signal flow through RAS and the mitogen-associated protein kinase (MAPK) cascade is the unifying mechanistic theme of the RASopathies, a family of disorders affecting development and growth. Pathogenic variants in more than 20 genes have been causally linked to RASopathies, the majority having a dominant role in promoting enhanced signaling. Here, we report that SPRED2 loss of function is causally linked to a recessive phenotype evocative of Noonan syndrome. Homozygosity for three different variants-c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95)-were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behavior. When overexpressed in cells, all variants were unable to negatively modulate EGF-promoted RAF1, MEK, and ERK phosphorylation, and time-course experiments in primary fibroblasts (p.Leu100Pro and p.Leu381Hisfs∗95) documented an increased and prolonged activation of the MAPK cascade in response to EGF stimulation. Morpholino-mediated knockdown of spred2a and spred2b in zebrafish induced defects in convergence and extension cell movements indicating upregulated RAS-MAPK signaling, which were rescued by expressing wild-type SPRED2 but not the SPRED2Leu381Hisfs∗95 protein. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome. These features, in part, characterize the phenotype of Spred2-/- mice. Our findings identify the second recessive form of Noonan syndrome and document pleiotropic consequences of SPRED2 loss of function in development.
Assuntos
Mutação com Perda de Função , Síndrome de Noonan/genética , Fenótipo , Proteínas Repressoras/genética , Alelos , Animais , Células COS , Chlorocebus aethiops , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Knockout , Peixe-ZebraRESUMO
Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.
Assuntos
Carcinogênese/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Transtornos do Neurodesenvolvimento/genética , Síndrome de Noonan/genética , Pré-Escolar , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/patologia , Síndrome de Noonan/fisiopatologia , Fenótipo , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Transdução de Sinais , Sequenciamento do Exoma , Proteínas ras/genéticaRESUMO
Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.
Assuntos
Mutação com Ganho de Função , Guanosina Trifosfato/metabolismo , Proteínas de Membrana/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Síndrome de Noonan/etiologia , Adulto , Criança , Feminino , Estudos de Associação Genética , Células HEK293 , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Proteínas Monoméricas de Ligação ao GTP/química , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Síndrome de Noonan/patologia , Linhagem , Conformação ProteicaRESUMO
Vertebral osteomyelitis (VO) is a primary infection of the endplates of the vertebral bodies with secondary infection of the adjacent intervertebral discs. Diagnosis is often delayed due to unspecific symptoms and a lack of specific infection markers. In this prospective study, we determined the suitability of 27 cytokines for the discrimination of VO and degenerative diseases of the spine and compared its diagnostic potential in relation to the C-reactive protein (CRP), which is widely used as a non-specific inflammation marker in clinical diagnostics. The patients included in this study underwent surgical stabilization of the lumbar and/or thoracic spine with removal of 1 or more affected intervertebral discs, as therapy for VO (n = 16) or for erosive osteochondrosis (EO, control group, n = 20). We evaluated the cytokine and CRP concentrations before (pre-OP = -20-0d where 0 means the day of surgery) and after surgery (post-OP) on days 3-5, 6-11, 40-56, and 63-142. Compared to the control patients pre-OP, a significantly higher elevation of the 4 cytokines IL-6, IL-8, IL-12 (p70), and VEGF as well as CRP were found in the VO patients, showing an area under the curve > 0.80 pre-OP. No significant differences were observed between VO patients with high and low virulent bacteria with respect to all 5 elevated biomarkers. This is the first prospective study in which a broad spectrum of 27 cytokines was analysed via multiplex assay using sera from patients with and without VO. Our results show that, in addition to CRP, 4 different cytokines were significantly altered in VO but not control patients. The results implicate that these candidate cytokines may be used in a multiplex assay for discrimination between VO and degenerative diseases of the spine.
Assuntos
Citocinas , Osteomielite , Citocinas/uso terapêutico , Humanos , Interleucina-12 , Osteomielite/diagnóstico , Osteomielite/tratamento farmacológico , Osteomielite/microbiologia , Estudos Prospectivos , Coluna Vertebral/microbiologia , Coluna Vertebral/cirurgiaRESUMO
Germline PTPN11 mutations cause Noonan syndrome (NS), the most common disorder among RASopathies. PTPN11 encodes SHP2, a protein tyrosine-phosphatase controlling signaling through the RAS-MAPK and PI3K-AKT pathways. Generally, NS-causing PTPN11 mutations are missense changes destabilizing the inactive conformation of the protein or enhancing its binding to signaling partners. Here, we report on two PTPN11 variants resulting in the deletion or duplication of one of three adjacent glutamine residues (Gln255 -to-Gln257 ). While p.(Gln257dup) caused a typical NS phenotype in carriers of a first family, p.(Gln257del) had incomplete penetrance in a second family. Missense mutations involving Gln256 had previously been reported in NS. This poly-glutamine stretch is located on helix B of the PTP domain, a region involved in stabilizing SHP2 in its autoinhibited state. Molecular dynamics simulations predicted that changes affecting this motif perturb the SHP2's catalytically inactive conformation and/or substrate recognition. Biochemical data showed that duplication and deletion of Gln257 variably enhance SHP2's catalytic activity, while missense changes involving Gln256 affect substrate specificity. Expression of mutants in HEK293T cells documented their activating role on MAPK signaling, uncoupling catalytic activity and modulation of intracellular signaling. These findings further document the relevance of helix B in the regulation of SHP2's function.
Assuntos
Síndrome de Noonan/genética , Peptídeos/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Adolescente , Criança , Pré-Escolar , Feminino , Glutamina/genética , Células HEK293 , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Domínios Proteicos , Transdução de SinaisRESUMO
Noonan syndrome-like disorder with loose anagen hair (NS/LAH) is one of the RASopathies, a group of clinically related developmental disorders caused by germline mutations in genes that encode components acting in the RAS/MAPK pathway. Among RASopathies, NS/LAH (OMIM 607721) is an extremely rare, multiple anomaly syndrome characterized by dysmorphic facial features similar to those observed in Noonan syndrome along with some distinctive ectodermal findings including easily pluckable, sparse, thin, and slow-growing hair. ADA2 deficiency (DADA2, OMIM 615688) is a monogenic autoinflammatory disorder caused by homozygous or compound heterozygous mutations in ADA2, with clinical features including recurrent fever, livedo racemosa, hepatosplenomegaly, and strokes as well as immune dysregulation. This is the first report of NS/LAH and ADA2 deficiency in the same individual. We report on a patient presenting with facial features, recurrent infections and ectodermal findings in whom both the clinical and molecular diagnoses of NS/LAH and ADA2 deficiency were established, respectively.
Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Síndrome dos Cabelos Anágenos Frouxos/diagnóstico , Síndrome dos Cabelos Anágenos Frouxos/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Fenótipo , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Adenosina Desaminase/genética , Alelos , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Genótipo , Humanos , Mutação , Radiografia , Avaliação de SintomasRESUMO
PURPOSE: To characterize the molecular genetics of autosomal recessive Noonan syndrome. METHODS: Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction. RESULTS: Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings. CONCLUSION: These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.
Assuntos
Predisposição Genética para Doença , Síndrome de Noonan/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Exoma/genética , Feminino , Ligação Genética , Genótipo , Heterozigoto , Humanos , Lactente , Masculino , Mutação , Síndrome de Noonan/patologia , Linhagem , Isoformas de Proteínas/genética , Splicing de RNA/genética , IrmãosRESUMO
Noonan syndrome is characterized by typical craniofacial dysmorphism, postnatal growth retardation, congenital heart defect, and learning difficulties and belongs to the RASopathies, a group of neurodevelopmental disorders caused by germline mutations in genes encoding components of the RAS-MAPK pathway. Mutations in the RAF1 gene are associated with Noonan syndrome, with a high prevalence of hypertrophic cardiomyopathy (HCM). RAF1 mutations cluster in exons encoding the conserved region 2 (CR2), the kinase activation segment of the CR3 domain, and the C-terminus. We present two boys with Noonan syndrome and the identical de novo RAF1 missense variant c.1082G>C/p.(Gly361Ala) affecting the CR3, but located outside the kinase activation segment. The p.(Gly361Ala) mutation has been identified as a RAF1 allele conferring resistance to RAF inhibitors. This amino acid change favors a RAF1 conformation that allows for enhanced RAF dimerization and increased intrinsic kinase activity. Both patients with Noonan syndrome showed typical craniofacial dysmorphism, macrocephaly, and short stature. One individual developed HCM and was diagnosed with a disseminated oligodendroglial-like leptomeningeal tumor (DOLT) of childhood at the age of 9 years. While there is a well-established association of NS with malignant tumors, especially childhood hemato-oncological diseases, brain tumors have rarely been reported in Noonan syndrome. Our data demonstrate that mutation scanning of the entire coding region of genes associated with Noonan syndrome is mandatory not to miss rare variants located outside the known mutational hotspots.
Assuntos
Neoplasias Encefálicas/genética , Cardiomiopatia Hipertrófica/genética , Síndrome de Noonan/genética , Proteínas Proto-Oncogênicas c-raf/genética , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/fisiopatologia , Cardiomiopatia Hipertrófica/fisiopatologia , Criança , Sequência Conservada/genética , Éxons/genética , Mutação em Linhagem Germinativa , Humanos , Lactente , Masculino , Síndrome de Noonan/complicações , Síndrome de Noonan/fisiopatologia , Sequenciamento do ExomaRESUMO
INTRODUCTION: Incidence and mortality for bladder cancer has changed very little over the past 20 years. Approximately 40% of patients with high-risk nonmuscle invasive bladder cancer eventually recur/progress. It is important to understand the economic impact of disease recurrence/progression in bladder cancer. Our aim was to estimate and understand the direct costs associated with the treatment of bladder cancer from the payer's perspective in the USA, in the year of 2021, including costs for both newly diagnosed bladder cancer (stages 0a-IV) and recurrent patients. METHODS: An economic model was constructed to calculate the number of patients receiving each treatment modality at every stage of disease and their respective costs. Epidemiological data were based on the CancerMPact Patient Metrics (PM) database and treatment modality data retrieved from CMP Treatment Architecture (TA), 2021 version. Resource utilization and costs were obtained from medical literature and public data sources. Only direct costs were considered. RESULTS: There were an estimated 83,532 newly diagnosed patients with bladder cancer of all stages in 2021 with a projected total cost of treatment of ~$2.6 billion. Average cost per newly diagnosed patient varied from $19,521 (stage 0a) to $169,533 (metastatic disease). Cost profile differed substantially among the stages of disease. For the 75,760 patients that were expected to have a recurrence in 2021, an additional cost of ~$3.9 billion was estimated at an average cost per patient of $52,179. The expected total cost to treat newly diagnosed and newly recurrent patients is reported in this model, with the total cost in 2021 estimated to exceed $6.5 billion. CONCLUSIONS: Treatment and resource costs increase for bladder cancer as the disease recurs/progresses. More effective treatments that can delay recurrence/progression may reduce the economic burden associated with bladder cancer.
The costs of treating bladder cancer in the USA are high, expected to have exceeded $6.5 billion in the year 2021. The average cost for newly diagnosed patients ranges from $19,521 for the earliest stage of disease to $169,533 for metastatic disease. Average costs per patient increase upon disease recurrence and more effective initial treatments to delay disease recurrence or progression may reduce the costs associated with bladder cancer.
RESUMO
Transurethral resection of bladder tumor followed by intravesical Bacillus Calmette-Guérin (BCG) is the standard of care in high-risk, non-muscle-invasive bladder cancer (NMIBC). Although many patients respond, recurrence and progression are common. In addition, patients may be unable to receive inductionâ¯+â¯maintenance due to intolerance or supply issues. Therefore, alternative treatment options are urgently required. Programmed cell death (ligand) 1 (PD-[L]1) inhibitors show clinical benefit in phase 1/2 trials in BCG-unresponsive NMIBC patients. This review presents the status of PD-(L)1 inhibition in high-risk NMIBC and discusses future directions. PubMed and Google scholar were searched for articles relating to NMIBC immunotherapy and ClinicalTrials.gov for planned and ongoing clinical trials. Preclinical and early clinical studies show that BCG upregulates PD-L1 expression in bladder cancer cells and, when combined with a PD-(L)1 inhibitor, a potent antitumor response is activated. Based on this mechanism, several PD-(L)1 inhibitors are in phase 3 trials in BCG-naïve, high-risk NMIBC in combination with BCG. Whereas PD-(L)1 inhibitors are well characterized in patients with advanced malignancies, the impact of immune-related adverse events (irAE) on the benefit/risk ratio in NMIBC should be determined. Alternative routes to intravenous administration, like subcutaneous and intravesical administration, may facilitate adherence and access. The outcomes of combination of PD-(L)1 inhibitors and BCG in NMIBC are highly anticipated. There will be a need to address treatment resources, optimal management of irAEs and education and training related to use of this therapy in clinical practice.
Assuntos
Neoplasias não Músculo Invasivas da Bexiga , Neoplasias da Bexiga Urinária , Humanos , Adjuvantes Imunológicos/uso terapêutico , Vacina BCG/farmacologia , Vacina BCG/uso terapêutico , Neoplasias da Bexiga Urinária/patologia , Medição de Risco , Administração Intravesical , Invasividade Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
BACKGROUND: Identification of variable epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer (NSCLC) is important for the selection of appropriate targeted therapies. This meta-analysis was conducted to provide a worldwide overview of EGFR mutation and submutation (specifically exon 19 deletions, exon 21 L858R substitutions, and others) prevalence, and identify important covariates that influence EGFR mutation status in patients with advanced NSCLC to address this clinical data gap. METHODS: Embase® and MEDLINE® in Ovid were searched for studies published between 2004 and 2019 with cohorts of ≥ 50 adults with EGFR mutations, focusing on stage III/IV NSCLC (≤ 20% of patients with stage I/II NSCLC). Linear mixed-effects models were fitted to EGFR mutation endpoints using logistic transformation (logit), assuming a binomial distribution. The model included terms for an intercept reflecting European studies and further additive terms for other continents. EGFR submutations examined were exon 19 deletions, exon 21 L858R substitutions, and others. RESULTS: Of 3969 abstracts screened, 57 studies were included in the overall EGFR mutation analysis and 74 were included in the submutation analysis relative to the overall EGFR mutation population (Europe, n = 12; Asia, n = 51; North America, n = 5; Central America, n = 1; South America, n = 1; Oceania, n = 1; Global, n = 3). The final overall EGFR mutations model estimated Asian and European prevalence of 49.1% and 12.8%, respectively, and included an additive covariate for the proportion of male patients in a study. There were no significant covariates in the submutation analyses. Most submutations were actionable: exon 19 deletions (49.2% [Asia]; 48.4% [Europe]); exon 21 L858R substitutions (41.1% [Asia]; 29.9% [Europe]). CONCLUSIONS: Although EGFR mutation prevalence was higher in Asian than Western countries, data support worldwide testing for EGFR overall and submutations to inform appropriate targeted treatment decisions.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Masculino , Mutação , Prevalência , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
The RASopathies are a group of clinically and genetically heterogeneous developmental disorders caused by dysregulation of the RAS/MAPK signalling pathway. Variants in several components and regulators of this pathway have been identified as the pathogenetic cause. In 2015, missense variants in A2ML1 were reported in three unrelated families with clinical diagnosis of Noonan syndrome (NS) and a zebrafish model was presented showing heart and craniofacial defects similar to those caused by a NS-associated Shp2 variant. However, a causal role of A2ML1 variants in NS has not been confirmed since. Herein, we report on 15 individuals who underwent screening of RASopathy-associated genes and were found to carry rare variants in A2ML1, including variants previously proposed to be causative for NS. In cases where parental DNA was available, the respective A2ML1 variant was found to be inherited from an unaffected parent. Seven index patients carrying an A2ML1 variant presented with an alternate disease-causing genetic aberration. These findings underscore that current evidence is insufficient to support a causal relation between variants in A2ML1 and NS, questioning the inclusion of A2ML1 screening in diagnostic RASopathy testing.
Assuntos
Mutação , Síndrome de Noonan/genética , Fenótipo , alfa-Macroglobulinas/genética , Testes Genéticos/normas , Humanos , Síndrome de Noonan/patologiaRESUMO
RASopathies are caused by variants in genes encoding components or modulators of the RAS/MAPK signaling pathway. Noonan syndrome is the most common entity among this group of disorders and is characterized by heart defects, short stature, variable developmental delay, and typical facial features. Heterozygous variants in SOS2, encoding a guanine nucleotide exchange factor for RAS, have recently been identified in patients with Noonan syndrome. The number of published cases with SOS2-related Noonan syndrome is still limited and little is known about genotype-phenotype correlations. We collected previously unpublished clinical and genotype data from 17 individuals carrying a disease-causing SOS2 variant. Most individuals had one of the previously reported dominant pathogenic variants; only four had novel changes at the established hotspots for variants that affect protein function. The overall phenotype of the 17 patients fits well into the spectrum of Noonan syndrome and is most similar to the phenotype observed in patients with SOS1-related Noonan syndrome, with ectodermal anomalies as common features and short stature and learning disabilities as relatively infrequent findings compared to the average Noonan syndrome phenotype. The spectrum of heart defects in SOS2-related Noonan syndrome was consistent with the known spectrum of cardiac anomalies in RASopathies, but no specific heart defect was particularly predominating. Notably, lymphatic anomalies were extraordinarily frequent, affecting more than half of the patients. We therefore conclude that SOS2-related Noonan syndrome is associated with a particularly high risk of lymphatic complications that may have a significant impact on morbidity and quality of life.
Assuntos
Sistema Linfático/patologia , Síndrome de Noonan/genética , Fenótipo , Proteínas Son Of Sevenless/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação , Síndrome de Noonan/patologiaRESUMO
INTRODUCTION: Peripheral artery disease (PAD) is the third most prevalent cardiovascular disease worldwide, with smoking and diabetes being the strongest risk factors. The most prominent symptom is leg pain while walking, known as intermittent claudication. To improve mobility, first-line treatment for intermittent claudication is supervised exercise programmes, but these remain largely unavailable and economically impractical, which has led to the development of structured home-based exercise programmes. This trial aims to determine the effectiveness and cost advantage of TeGeCoach, a 12-month long home-based exercise programme, compared with usual care of PAD. It is hypothesised that TeGeCoach improves walking impairment and lowers the need of health care resources that are spent on patients with PAD. METHODS AND ANALYSIS: The investigators conduct a prospective, pragmatic randomised controlled clinical trial in a health insurance setting. 1760 patients diagnosed with PAD at Fontaine stage II are randomly assigned to either TeGeCoach or care-as-usual. TeGeCoach consists of telemonitored intermittent walking exercise with medical supervision by a physician and telephone health coaching. Participants allocated to the usual care group receive information leaflets and can access supervised exercise programmes, physical therapy and a variety of programmes for promoting a healthy lifestyle. The primary outcome is patient reported walking ability based on the Walking Impairment Questionnaire. Secondary outcome measures include quality of life, health literacy and health behaviour. Claims data are used to collect total health care costs, healthcare resource use and (severe) adverse events. Outcomes are measured at baseline, 12 and 24 months. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Medical Association Hamburg. Findings are disseminated through peer-reviewed journals, reports to the funding body, conference presentations and media press releases. Data from this trial are made available to the public and researchers upon reasonable request.NCT03496948 (www.clinicaltrials.gov), Pre-results.
Assuntos
Terapia por Exercício/economia , Terapia por Exercício/métodos , Monitores de Aptidão Física , Tutoria , Doença Arterial Periférica/fisiopatologia , Doença Arterial Periférica/terapia , Telefone , Caminhada , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: There is still a challenge in discriminating between vertebral osteomyelitis and degenerative diseases of the spine. To this end, we determined the suitability of soluble urokinase-type plasminogen activator receptor (suPAR) and compared the diagnostic potential of suPAR to CRP. METHODS: Patients underwent surgical stabilization of the lumbar and/or thoracic spine with removal of one or more affected intervertebral discs, as therapy for vertebral osteomyelitis (n = 16) or for erosive osteochondrosis (control group, n = 20). In this prospective study, we evaluated the suPAR and CRP levels before (pre-OP) and after surgery (post-OP) on days 3-5, 6-11, 40-56, and 63-142. RESULTS: The suPAR levels in vertebral osteomyelitis patients were significantly higher than those from controls pre-OP, 3-5 days post-OP, and 6-11 days post-OP. Significantly higher CRP levels were observed in the vertebral osteomyelitis group than in the controls pre-OP and 6-11 days post-OP. Levels of suPAR and CRP correlated positively in all patients in the pre-OP period: r = 0.63 (95% CI: 0.37-0.79), p < 0.0001. The values for the area under the receiver operating characteristics curve (AUC) for pre-OP and the overall model post-OP were 0.88 (95% CI: 0.76-1.00) and 0.84 (95% CI: 0.71-0.97) for suPAR, 0.93 (95% CI: 0.85-1.00) and 0.77 (95% CI: 0.62-0.93) for CRP, and 0.98 (95% CI: 0.96-1.00) and 0.91 (95% CI: 0.82-1.00) for the combination of suPAR and CRP. The AUC for suPAR pre-OP revealed an optimum cut-off value, sensitivity, specificity, NPV, and PPV of 2.96 ng/mL, 0.69, 1.00, 0.80, and 1.00, respectively. For CRP, these values were 11.58 mg/L, 0.88, 0.90, 0.90, and 0.88, respectively. CONCLUSION: The present results show that CRP is more sensitive than suPAR whereas suPAR is more specific than CRP. Moreso, our study demonstrated that improvement in the diagnostic power for discrimination of vertebral osteomyelitis and degenerative diseases of the spine can be achieved by a combination of both suPAR and CRP. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02554227, posted Sept. 18, 2015, and updated Aug. 13, 2019.
Assuntos
Proteína C-Reativa/metabolismo , Osteocondrose/diagnóstico , Osteomielite/diagnóstico , Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , Doenças da Coluna Vertebral/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Discotomia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteocondrose/sangue , Osteocondrose/cirurgia , Osteomielite/sangue , Osteomielite/cirurgia , Estudos Prospectivos , Doenças da Coluna Vertebral/sangue , Doenças da Coluna Vertebral/cirurgiaRESUMO
Cardiovascular risk rapidly increased following exposure to air pollution. Changes in human autonomic regulation have been implicated based on epidemiological associations between exposure estimates and indirect autonomic nervous system measurements. We conducted a mechanistic study to test the hypothesis that, in healthy older individuals, well-defined experimental exposure to ultrafine carbon particles (UFP) increases sympathetic nervous system activity and more so with added ozone (O3). Eighteen participants (age >50 years, 6 women) were exposed to filtered air (Air), UFP, and UFP + O3 combination for 3 hours during intermittent bicycle ergometer training in a randomized, crossover, double-blind fashion. Two hours following exposure, respiration, electrocardiogram, blood pressure, and muscle sympathetic nerve activity (MSNA) were recorded at supine rest, during deep breathing, and during a Valsalva manoeuvre. Catechols and inflammatory marker levels were measured in venous blood samples. Induced sputum was obtained 3.5 h after exposure. Combined exposure to UFP + O3 but not UFP alone, caused a significant increase in sputum neutrophils and circulating leucocytes. Norepinephrine was modestly increased while the ratio between plasma dihydroxyphenylglycol (DHPG) and norepinephrine levels, a marker for norepinephrine clearance, was reduced with UFP + O3. Resting MSNA was not different (47 ± 12 with Air, 47 ± 14 with UFP, and 45 ± 14 bursts/min with UFP + O3). Indices of parasympathetic heart rate control were unaffected by experimental air pollution. Our study suggests that combined exposure to modest UFP and O3 levels increases peripheral norepinephrine availability through decreased clearance rather than changes in central autonomic activity. Pulmonary inflammatory response may have perturbed pulmonary endothelial norepinephrine clearance.
Assuntos
Poluentes Atmosféricos/efeitos adversos , Exposição por Inalação/efeitos adversos , Norepinefrina/metabolismo , Ozônio/efeitos adversos , Material Particulado/efeitos adversos , Pneumonia/induzido quimicamente , Sistema Nervoso Simpático/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/metabolismo , Pneumonia/patologiaRESUMO
Bilateral bipolar electric carotid sinus stimulation acutely reduced muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in patients with resistant arterial hypertension but is no longer available. The second-generation device uses a smaller unilateral unipolar disk electrode to reduce invasiveness while saving battery life. We hypothesized that the second-generation device acutely lowers BP and MSNA in treatment-resistant hypertensive patients. Eighteen treatment-resistant hypertensive patients (9 women/9 men; 53±11 years; 33±5 kg/m(2)) on stable medications have been included in the study. We monitored finger and brachial BP, heart rate, and MSNA. Without stimulation, BP was 165±31/91±18 mm Hg, heart rate was 75±17 bpm, and MSNA was 48±14 bursts per minute. Acute stimulation with intensities producing side effects that were tolerable in the short term elicited interindividually variable changes in systolic BP (-16.9±15.0 mm Hg; range, 0.0 to -40.8 mm Hg; P=0.002), heart rate (-3.6±3.6 bpm; P=0.004), and MSNA (-2.0±5.8 bursts per minute; P=0.375). Stimulation intensities had to be lowered in 12 patients to avoid side effects at the expense of efficacy (systolic BP, -6.3±7.0 mm Hg; range, 2.8 to -14.5 mm Hg; P=0.028 and heart rate, -1.5±2.3 bpm; P=0.078; comparison against responses with side effects). Reductions in diastolic BP and MSNA (total activity) were correlated (r(2)=0.329; P=0.025). In our patient cohort, unilateral unipolar electric baroreflex stimulation acutely lowered BP. However, side effects may limit efficacy. The approach should be tested in a controlled comparative study.
Assuntos
Pressão Sanguínea/fisiologia , Seio Carotídeo/inervação , Resistência a Medicamentos , Estimulação Elétrica/métodos , Hipertensão/terapia , Sistema Nervoso Simpático/fisiopatologia , Vasodilatação/fisiologia , Anti-Hipertensivos/farmacologia , Barorreflexo/fisiologia , Feminino , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/fisiopatologiaRESUMO
BACKGROUND: Sympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization-activated cyclic nucleotide-gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact. METHODS AND RESULTS: We treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute (P<0.001) with unaffected blood pressure and muscle sympathetic nerve activity. On ivabradine, cardiac and sympathetic baroreflex gains and blood pressure responses to vasoactive drugs were unchanged. Ivabradine aggravated bradycardia during baroreflex loading. CONCLUSIONS: HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865917.
Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Benzazepinas/administração & dosagem , Relógios Biológicos/efeitos dos fármacos , Fármacos Cardiovasculares/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Nó Sinoatrial/efeitos dos fármacos , Adulto , Sistema Nervoso Autônomo/fisiologia , Benzazepinas/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Bradicardia/induzido quimicamente , Bradicardia/fisiopatologia , Fármacos Cardiovasculares/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Eletrocardiografia , Alemanha , Voluntários Saudáveis , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/antagonistas & inibidores , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Ivabradina , Masculino , Proteínas Musculares/antagonistas & inibidores , Proteínas Musculares/metabolismo , Músculo Esquelético/inervação , Canais de Potássio/metabolismo , Nó Sinoatrial/inervação , Nó Sinoatrial/metabolismo , Fatores de Tempo , Adulto JovemRESUMO
Aortic pulse wave velocity (aPWV) can be measured with different methodologies, including applanation tonometry. These pilot study findings suggest that impedance cardiography combined with thigh oscillometry provides comparable results. Intra- and inter-observer variability was tested by two observers in two subjects. We instrumented 41 patients and 12 healthy normotensive controls for impedance cardiography and consecutive applanation tonometry and compared methods using the Bland-Altman method. Observer variability for the impedance-thigh cuff method (range, 3.61%-7.77%) was comparable with the tonometric method (range, 2.93%-7.37%). Comparison of the two methods based on the Bland-Altman plot revealed a good agreement between methods. The bias between impedance and tonometric measurements was -0.28 ± 0.37 m/s. Both measurements were significantly correlated (r(2) = 0.94; P < .0001; slope = 1.038).Impedance cardiography combined with thigh oscillometry is an easy to use approach which, in addition to providing hemodynamic information, yields aPWV measurements comparable to applanation tonometry. Following full validation according to current guidelines, the methodology could prove useful in cardiovascular risk stratification.