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1.
Dysphagia ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31440909

RESUMO

Respiratory-swallow coordination (RSC) is important for swallowing safety. Atypical RSC is common in Parkinson's disease (PD) and is associated with the presence of dysphagia and aspiration. Verbal cueing is known to affect RSC in healthy adults, yet an understanding of its effect on RSC in PD is unknown. Therefore, the aims of this study were to: (1) assess the effects of verbal cueing on respiratory-swallow patterning, lung volume initiation, and swallow apnea duration in PD; and (2) determine when during tidal breathing verbal cues should be given in order to increase the likelihood of eliciting optimal RSC. People with PD were prospectively recruited for respiratory-swallowing assessments during cued and non-cued swallowing conditions. Non-cued trials consisted of swallowing in an unprompted fashion, while cued trials consisted of swallowing only once participants were verbally instructed. Verbal cues were given at four specific points during tidal breathing. Nonparametric tests were used to compare differences in patterning, lung volume, and swallow apnea duration between the cued and non-cued swallows. Twenty-five people with PD were enrolled, yielding an analysis of 375 swallows. Verbal cueing significantly affected respiratory-swallow patterning (p < 0.0005), lung volume initiation (p < 0.0005), and swallow apnea duration (p < 0.0005). The effects of verbal cueing on RSC differed significantly depending on when during tidal breathing verbal cues were given. Cues given at high tidal inhalation were most likely to elicit optimal RSC, while cues given at low tidal exhalation were the least likely to elicit optimal RSC. The results of this study demonstrate that verbal cueing significantly affects RSC in PD. Depending on when verbal cues are given during tidal breathing, RSC can become more safe and coordinated or more atypical and risky. Clinicians should be cognizant of these effects by avoiding verbal cues if attempting to evaluate normal RSC during swallowing evaluations and cueing for swallows at the time of high tidal inhalation when targeting more optimal RSC in PD.

2.
Dysphagia ; 2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31446478

RESUMO

Pharyngeal area can increase as a function of normal healthy aging and muscle atrophy. These increases in pharyngeal area can negatively affect swallowing function in healthy older adults (HOA). However, the presence of pharyngeal area changes and their effects on swallowing function in Parkinson's disease (PD) remain unknown. Therefore, we compared the pharyngeal area of people with PD to HOA to determine if pharyngeal area changes were present in PD above and beyond what is seen in HOA. Within PD, we also evaluated if and how an increase in pharyngeal area affects swallowing kinematics, swallowing safety, and swallowing efficiency. A secondary analysis of videofluoroscopic swallow studies was completed comparing 41 HOA and 40 people with PD. Measures of pharyngeal area, swallowing kinematics, swallowing safety (penetration/aspiration), and swallowing efficiency (residue) were analyzed. An analysis of covariance (ANCOVA) was used to determine if pharyngeal area was significantly different between the HOA and PD groups while controlling for age, sex, and height. Regression analyses were used to examine if and how pharyngeal area influenced swallowing kinematics, swallowing safety, and swallowing efficiency in PD. Pharyngeal areas were significantly larger for people with PD when compared to HOA (p = .008). An increase in pharyngeal area was associated with less pharyngeal constriction (p = .022), shorter duration of airway closure (p = .017), worse swallowing safety (p < .0005), and worse swallowing efficiency (p = .037). This study revealed that pharyngeal areas are larger in people with PD when compared to HOA, and that this increase in pharyngeal area is associated with maladaptive changes to swallowing kinematics, residue, and penetration/aspiration. These findings support the notion that pharyngeal muscle atrophy may be exacerbated in PD above and beyond what is seen in normal, healthy aging group. Results from this study highlight the need to consider pharyngeal muscle atrophy as a source for swallowing dysfunction in PD, and as a potential treatment target for swallowing rehabilitation.

3.
Laryngoscope ; 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31254293

RESUMO

OBJECTIVES: When swallowing function is compromised in patients with Parkinson's disease (PD), cough plays a crucial role in clearing the airway and preventing pulmonary complications. The aim of this study was to determine the influence of vocal fold atrophy severity as measured by the bowing index (BI) on airway protection in PD. METHODS: Thirty participants with PD completed measures of voluntary and reflex cough. Flexible laryngoscopy with endoscopic evaluation of swallowing allowed for measurement of BI using ImageJ software. Swallowing safety was scored on the Penetration-Aspiration Scale (PAS). Regression and receiver operating characteristic (ROC) analyses were performed to test our study aim. RESULTS: Twenty-four of 30 participants had some degree of vocal fold atrophy (BI >0). When controlling for age, disease duration did not significantly influence BI. BI was not predictive of any sensorimotor parameters of cough including measures of cough airflow, reflex cough threshold, or urge to cough. BI discriminated participants with near-normal (PAS 1-3) swallowing safety from participants with impaired (PAS 4-8) swallowing safety (P = .01, sensitivity: 87.0%, specificity: 71.4%, cutoff value BI >4.6). CONCLUSION: Vocal fold atrophy is a potential factor contributing to poor swallowing safety in PD. BI was not associated with cough function in this PD cohort, contrary to prior studies that have shown improved cough measures after vocal fold augmentation. Vocal fold atrophy in PD remains an important area of study as a targetable intervention for patients with airway protective dysfunction. Future studies should include measures of glottic closure during vocal fold adduction. LEVEL OF EVIDENCE: Level 3 retrospective review Laryngoscope, 2019.

4.
J Allergy Clin Immunol ; 144(5): 1364-1376, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31201888

RESUMO

BACKGROUND: CCAAT enhancer-binding protein epsilon (C/EBPε) is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBPε is autosomal recessive neutrophil-specific granule deficiency leading to severely impaired neutrophil function and early mortality. OBJECTIVE: The aim of this study was to molecularly characterize the effects of C/EBPε transcription factor Arg219His mutation identified in a Finnish family with previously genetically uncharacterized autoinflammatory and immunodeficiency syndrome. METHODS: Genetic analysis, proteomics, genome-wide transcriptional profiling by means of RNA-sequencing, chromatin immunoprecipitation (ChIP) sequencing, and assessment of the inflammasome function of primary macrophages were performed. RESULTS: Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated noncanonical inflammasome activation caused by decreased association with transcriptional repressors, leading to increased chromatin occupancy and considerable changes in transcriptional activity, including increased expression of NLR family, pyrin domain-containing 3 protein (NLRP3) and constitutively expressed caspase-5 in macrophages. CONCLUSION: We describe a novel autoinflammatory disease with defective neutrophil function caused by a homozygous Arg219His mutation in the transcription factor C/EBPε. Mutated C/EBPε acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and noncanonical inflammasomopathy/immunodeficiency. The mechanism, including widely dysregulated transcription, is likely not unique for C/EBPε. Similar multiomics approaches should also be used in studying other transcription factor-associated diseases.

5.
Am J Speech Lang Pathol ; 28(2): 515-520, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-31136233

RESUMO

Purpose The aim of this study was to assess the effects of barium, blue dye, and green dye on the frequency and reliability of detecting airway invasion (penetration and aspiration) seen during flexible endoscopic evaluations of swallowing (FEES). Method Thirty patients with neurodegenerative disease and suspected dysphagia underwent an FEES. Patients were presented with 10-cc boluses of water colored with blue dye, green dye, and barium, within the same examination, in a randomized order. Airway protection outcomes were blindly analyzed by a panel of expert raters. Outcomes included the presence of residue on airway structures (epiglottis, laryngeal vestibule, vocal folds, subglottis) and abnormal Penetration-Aspiration Scale (PAS; Rosenbek, Robbins, Roecker, Coyle, & Wood, 1996 ) scores (PAS ≥ 3). Statistical analyses were performed to determine group differences in the frequency of airway residue and abnormal PAS scores, as well as reliability. Results Airway residue was observed most frequently with barium when compared to blue dye ( p < .05) or green dye ( p < .05). Abnormal PAS scores were also observed most frequently with barium when compared to blue dye ( p < .0005) and green dye ( p < .0005). There were no significant differences in the observed frequency of airway residue nor abnormal PAS scores when comparing blue and green dye ( p > .05). Intrapanel reliability scores for airway residue and PAS scores, respectively, were very good ( k = .83) and good ( k = .67) for barium, very good ( k = 1.00) and moderate ( k = .50) for green dye, and moderate ( k = .47) and fair ( k = .33) for blue dye. Conclusion Airway invasion was detected significantly more frequently and with greater reliability with barium when compared to blue and green dye. Given these findings, standardized use of barium is recommended at some point during FEES, especially when attempting to detect subtle signs of airway invasion.

6.
Am J Speech Lang Pathol ; 28(1): 148-154, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-31072163

RESUMO

Purpose The aims of this study were to (a) describe the development and utility of the Open Mouth-Maximal Isometric Press (OM-MIP), a tool designed for the quantitative assessment of suprahyoid-infrahyoid muscle strength; (b) examine the effects of age and sex on the OM-MIP; and (c) establish age- and sex-based OM-MIP norms. Method Two hundred sixteen healthy male and female volunteers were recruited. Participants performed the OM-MIP, and the maximum of 3 trials that were within 10% of each other was recorded. Rest between each trial was allowed to avoid fatigue. Multiple regression examined the influence of age and sex on the OM-MIP. Descriptive statistics outlined normative OM-MIP values for young adult (aged 18-39 years), middle-aged adult (aged 40-59 years), old adult (aged 60-79 years), and very old adult (aged ≥ 80 years) men and women. Two-way analysis of variance determined if normative data differed significantly between the age and sex groups. Results Age and sex significantly influenced the OM-MIP, although no significant interaction effect was identified. Women had lower mean OM-MIPs when compared with men ( p < .0005), and very old adults had lower mean OM-MIPs when compared with young ( p = .001), middle-aged ( p < .0005), and old ( p = .013) adults. Conclusions This study establishes age- and sex-based OM-MIP norms and outlines its potential utility during clinical swallowing evaluations and treatment. By providing these norms, clinicians can begin to quantitatively measure suprahyoid and infrahyoid strength, individualize resistance training programs to patients' OM-MIP 1 repetition maximum, and track strength changes over time in response to therapeutic interventions.

7.
Dysphagia ; 2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31028481

RESUMO

Dysphagia is a highly prevalent disorder in Parkinson's Disease (PD) characterized by changes in swallowing kinematics, residue, and airway invasion. These changes can lead to serious medical morbidities including malnutrition, aspiration pneumonia, and death. However, little is known about the most predictive causes of residue and airway invasion in this patient population. Therefore, the aims of this study were to (1) assess how disease severity affects residue, airway invasion, and swallowing kinematics in PD; and (2) determine which swallowing kinematic variables were most predictive of residue and airway invasion. A secondary analysis of forty videofluoroscopic swallow studies (VFSS) from individuals with early through mid-stage PD was performed. Airway invasion (Penetration-Aspiration Scale 'PAS'), residue (Bolus Clearance Ratio 'BCR'), and ten spatiotemporal swallowing kinematic variables were analyzed. Statistical analyses were used to determine if disease severity predicted residue, depth of airway invasion, and swallowing kinematics, and to examine which swallowing kinematic variables were most predictive of residue and the presence of airway invasion. Results revealed that residue and the presence of airway invasion were significantly predicted by swallowing kinematics. Specifically, airway invasion was primarily influenced by the extent and timing of airway closure, while residue was primarily influenced by pharyngeal constriction. However, disease severity did not significantly predict changes to swallowing kinematics, extent of residue, or depth of airway invasion during VFSS assessment. This study comprehensively examined the pathophysiology underlying dysphagia in people with early to mid-stage PD. The results of the present study indicate that disease severity alone does not predict swallowing changes in PD, and therefore may not be the best factor to identify risk for dysphagia in PD. However, the swallowing kinematics most predictive of residue and the presence of airway invasion were identified. These findings may help to guide the selection of more effective therapy approaches for improving swallowing safety and efficiency in people with early to mid-stage PD.

8.
Science ; 361(6404): 810-813, 2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30026316

RESUMO

RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.


Assuntos
Artrite/genética , Doenças Inflamatórias Intestinais/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Imunodeficiência Combinada Severa/genética , Alelos , Artrite/imunologia , Citocinas/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Linfopenia/genética , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Linhagem , Imunodeficiência Combinada Severa/imunologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-29939941

RESUMO

X-linked severe combined immunodeficiency disease (SCID) is caused by mutations in the interleukin (IL)-2 receptor γ (IL2RG) gene and patients usually present with a TBNK SCID phenotype. Nevertheless, a minority of these patients present with a TBNK phenotype, similar to the IL-7R-deficient patients. We report a patient with a novel missense p.Glu297Gly mutation in the IL2RG gene presenting with a leaky TBNK SCID with delayed onset, moderate susceptibility to infections, and nodular regenerative hyperplasia. He presents with preserved STAT5 tyrosine phosphorylation in response to IL-15 stimulation but not in response to IL-2 and IL-7, resulting in the NK phenotype.

10.
Int J Crit Illn Inj Sci ; 8(1): 36-40, 2018 Jan-Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29619338

RESUMO

Objective: The objective of this study was to evaluate the effectiveness of 3-factor prothrombin complex concentrate (3F-PCC) compared to 4-factor PCC (4F-PCC) in warfarin-associated bleeding. Methods: This multicenter, retrospective, cohort study analyzed data from patients admitted between May 2011 and October 2014 who received PCC for warfarin-associated bleeding. The primary outcome was the rate of international normalized ratio (INR) normalization, defined as an INR ≤1.3, after administration of 3F-PCC compared to 4F-PCC. Other variables of interest included the incidence of additional reversal agents, new thromboembolic events, and mortality. Results: A total of 134 patients were included in the analysis. The average dose of PCC administered was 24.6 ± 9.3 units/kg versus 36.3 ± 12.8 units/kg in the 3F-PCC and 4F-PCC groups, respectively, P < 0.001. Baseline INR in the 3F-PCC and 4F-PCC groups was 3.61 ± 2.3 and 6.87 ± 2.3, respectively P < 0.001. 4F-PCC had a higher rate of INR normalization at first INR check post-PCC administration compared to 3F-PCC (84.2% vs. 51.9%, P = 0.0001). Thromboembolic events, intensive care unit and hospital length of stay, and mortality were similar among both groups. Conclusion: The use of 4F-PCC leads to a more significant reduction in INR compared to 3F-PCC though no difference in mortality or length of stay was observed. Thromboembolism rates were similar among both groups.

11.
Dysphagia ; 33(5): 602-609, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29445857

RESUMO

The Dynamic Swallow Study (DSS) is a methodology used to objectively and quantitatively assess swallowing kinematics during Videofluoroscopic Swallow Studies (VFSS). No DSS normative data exist delineating superior and anterior hyoid displacement (Hsup and Hant, respectively), nor the ratio between Hsup and Hant (SAratio). The aims of this study were to (1) establish normative data for Hsup, Hant, and SAratio and (2) assess the effects of age, sex, and bolus size on these measures in non-dysphagic patients, within the context of DSS. VFSSs were reviewed for consecutive elderly (≥ 65 years) and non-elderly (< 65 years) male and female non-dysphagic patients. Measurements of Hsup, Hant, and SAratio were made using a novel measurement methodology within the context of the Dynamic Swallow Study (DSS) protocol. Statistical analysis was performed to establish interaction effects and main effects of age, sex, and bolus size on Hsup, Hant, and SAratio. Descriptive statistics (mean ± standard deviations) are outlined for Hsup, Hant, and SAratio. Hsup was significantly effected by bolus size and age. Additionally, a significant three-way interaction of age, sex, and bolus size was observed. Hant was significantly effected by bolus size and sex, but no two- or three-way interactions were present. Neither bolus size, age, nor sex significantly effected SAratio. Age, sex, and bolus size normative data were established for Hsup, Hant, and SAratio for VFSS kinematic analysis. By outlining these measures, one can more thoroughly evaluate the areas of specific swallowing impairment, better determine the therapy targets, and track changes over time.

12.
Sci Rep ; 8(1): 1276, 2018 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-29352140

RESUMO

The design, fabrication, and characterization of ultra-high responsivity photodetectors based on mesoscopic multilayer MoS2 is presented, which is a less explored system compared to direct band gap monolayer MoS2 that has received increasing attention in recent years. The device architecture is comprised of a metal-semiconductor-metal (MSM) photodetector, where Mo was used as the contact metal to suspended MoS2 membranes. The photoresponsivity [Formula: see text] was measured to be ~1.4 × 104 A/W, which is > 104 times higher compared to prior reports, while the detectivity D* was computed to be ~2.3 × 1011 Jones at 300 K at an optical power P of ~14.5 pW and wavelength λ of ~700 nm. In addition, the dominant photocurrent mechanism was determined to be the photoconductive effect (PCE), while a contribution from the photogating effect was also noted from trap-states that yielded a wide spectral photoresponse from UV-to-IR (400 nm to 1100 nm) with an external quantum efficiency (EQE) ~104. From time-resolved photocurrent measurements, a decay time τ d ~ 2.5 ms at 300 K was measured from the falling edge of the photogenerated waveform after irradiating the device with a stream of incoming ON/OFF white light pulses.

13.
Front Immunol ; 9: 2863, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619256

RESUMO

Background: The auto-inflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome is a rare primary immunodeficiency caused by a gain-of-function mutation S707Y in the PLCG2 gene previously described in two patients from one family. The APLAID patients presented with early-onset blistering skin lesions, posterior uveitis, inflammatory bowel disease (IBD) and recurrent sinopulmonary infections caused by a humoral defect, but lacked circulating autoantibodies and had no cold-induced urticaria, contrary to the patients with the related PLAID syndrome. Case: We describe a new APLAID patient who presented with vesiculopustular rash in the 1st weeks of life, followed by IBD, posterior uveitis, recurrent chest infections, interstitial pneumonitis, and also had sensorineural deafness and cutis laxa. Her disease has been refractory to most treatments, including IL1 blockers and a trial with ruxolitinib has been attempted. Results: In this patient, we found a unique de novo heterozygous missense L848P mutation in the PLCG2 gene, predicted to affect the PLCγ2 structure. Similarly to S707Y, the L848P mutation led to the increased basal and EGF-stimulated PLCγ2 activity in vitro. Whole blood assays showed reduced production of IFN-γ and IL-17 in response to polyclonal T-cell stimulation and reduced production of IL-10 and IL-1ß after LPS stimulation. Reduced IL-1ß levels and the lack of clinical response to treatment with IL-1 blockers argue against NLRP3 inflammasome hyperactivation being the main mechanism mediating the APLAID pathogenesis. Conclusion: Our findings indicate that L848P is novel a gain-of-function mutation that leads to PLCγ2 activation and suggest cutis laxa as a possible clinical manifestations of the APLAID syndrome.


Assuntos
Cútis Laxa/genética , Doenças Hereditárias Autoinflamatórias/genética , Síndromes de Imunodeficiência/genética , Mutação de Sentido Incorreto , Fosfolipase C gama/genética , Sequência de Aminoácidos , Sequência de Bases , Cútis Laxa/complicações , Cútis Laxa/enzimologia , Análise Mutacional de DNA , Feminino , Doenças Hereditárias Autoinflamatórias/complicações , Doenças Hereditárias Autoinflamatórias/enzimologia , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/enzimologia , Recém-Nascido , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/genética , Masculino , Linhagem , Fosfolipase C gama/química , Fosfolipase C gama/metabolismo , Homologia de Sequência de Aminoácidos
14.
Laryngoscope ; 127(11): 2591-2595, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28699172

RESUMO

OBJECTIVES/HYPOTHESIS: To evaluate the effect of medialization laryngoplasty (ML) performed alone compared to ML with arytenoid adduction (AA) on glottic gap and voice quality in unilateral vocal fold paralysis (UVFP) patients. STUDY DESIGN: Retrospective case series. METHODS: UVFP patients treated with ML alone and ML with AA at the University of California San Francisco Voice and Swallowing Center were identified. Demographic information and history of laryngeal procedures were collected. Preoperative and postoperative examinations were digitally analyzed using ImageJ for normalized anterior and posterior glottic gap and voice samples graded with CAPE-V scores. RESULTS: Forty-seven patients underwent ML and 27 patients underwent ML with AA. Normalized anterior gap (AG) improved in both ML (preop: 4.4 pixel units (u), postop: 0.8 u; P < 0.001) and ML with AA groups (preop: 3.3 u, postop 0.6 u; P < 0.001). There was no statistically significant difference in normalized AG values between treatment groups. Postoperative normalized posterior gap (PG) improved in the ML with AA group only (preop: 1.8 u, postop: 0.5 u; P = 0.01). Overall severity, roughness, and strain voice parameters had acceptable reliability for analysis. Overall severity improved in ML (preop: 54, postop: 27; P < 0.001) and ML with AA (preop: 44, postop: 24; P = 0.005). There was no statistically significant difference in any voice parameter between treatment groups. CONCLUSION: UVFP patients undergoing ML may benefit from addition of AA when a large posterior glottic gap is present. In this study, ML with AA but not ML alone resulted in statistically significant improvement in PG. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2591-2595, 2017.


Assuntos
Cartilagem Aritenoide/cirurgia , Laringoplastia/métodos , Paralisia das Pregas Vocais/cirurgia , Feminino , Humanos , Laringoscopia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Qualidade da Voz
15.
J Allergy Clin Immunol ; 139(2): 597-606.e4, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27555459

RESUMO

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Síndromes de Imunodeficiência/genética , Transtornos Linfoproliferativos/genética , Mutação/genética , Infecções Respiratórias/genética , Adolescente , Adulto , Animais , Antibioticoprofilaxia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Estudos de Coortes , Inibidores Enzimáticos/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/mortalidade , Infecções por Herpesviridae/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/terapia , Lactente , Cooperação Internacional , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/terapia , Masculino , Camundongos , Pessoa de Meia-Idade , Recidiva , Infecções Respiratórias/mortalidade , Infecções Respiratórias/terapia , Inquéritos e Questionários , Análise de Sobrevida , Adulto Jovem
16.
Nat Commun ; 7: 13992, 2016 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-28008925

RESUMO

Mutations in genes encoding components of the immune system cause primary immunodeficiencies. Here, we study a patient with recurrent atypical mycobacterial infection and early-onset metastatic bladder carcinoma. Exome sequencing identified two homozygous missense germline mutations, P733L and P832S, in the JAK1 protein that mediates signalling from multiple cytokine receptors. Cells from this patient exhibit reduced JAK1 and STAT phosphorylation following cytokine stimulations, reduced induction of expression of interferon-regulated genes and dysregulated cytokine production; which are indicative of signalling defects in multiple immune response pathways including Interferon-γ production. Reconstitution experiments in the JAK1-deficient cells demonstrate that the impaired JAK1 function is mainly attributable to the effect of the P733L mutation. Further analyses of the mutant protein reveal a phosphorylation-independent role of JAK1 in signal transduction. These findings clarify JAK1 signalling mechanisms and demonstrate a critical function of JAK1 in protection against mycobacterial infection and possibly the immunological surveillance of cancer.


Assuntos
Alelos , Janus Quinase 1/genética , Mutação/genética , Infecções por Mycobacterium/enzimologia , Infecções por Mycobacterium/genética , Sequência de Aminoácidos , Sequência de Bases , Células Sanguíneas/metabolismo , Criança , Pré-Escolar , Citocinas/sangue , Suscetibilidade a Doenças , Feminino , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interferon-alfa/farmacologia , Interferon gama/farmacologia , Janus Quinase 1/química , Masculino , Linhagem , Fosforilação/efeitos dos fármacos , Domínios Proteicos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/genética , TYK2 Quinase/metabolismo , Adulto Jovem
17.
J Allergy Clin Immunol ; 138(1): 210-218.e9, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27221134

RESUMO

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]-R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α, and p50α) of class IA phosphoinositide 3-kinases. OBJECTIVES: We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort. METHODS: The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed. RESULTS: Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2-related complications. CONCLUSION: APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase δ inhibitors are possible treatment options.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/etiologia , Fenótipo , Adolescente , Adulto , Alelos , Biópsia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Frequência do Gene , Genótipo , Humanos , Síndromes de Imunodeficiência/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Sítios de Splice de RNA , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem
18.
Laryngoscope ; 126(10): 2291-4, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26691853

RESUMO

OBJECTIVES/HYPOTHESIS: To determine the sensitivity and specificity for assessing pharyngeal residue, laryngeal penetration, and tracheal aspiration when comparing findings from the Static Endoscopic Evaluation of Swallowing (SEES) with findings from the Videofluoroscopic Swallow Study (VFSS). METHODS: Retrospective study at a tertiary academic medical center. Records were reviewed consecutive outpatients who underwent both SEES and VFSS evaluations. Video segments from SEES and VFSS examinations were blindly judged by experienced clinicians on a categorical/ordinal rating form for the absence, quantitative presence, and location of postswallow residue, penetration, and aspiration. Statistical analysis was performed to identify intra- and interrater reliability and correlation between SEES and VFSS findings. RESULTS: Thirty-nine patients were identified who met the above inclusion criteria, for a total of 206 video segments. Inter- and intrarater reliability was judged by Cronbach's alpha to be good to excellent. SEES findings revealed statistically significant correlations with VFSS findings (P < 0.001) with the absence, quantitative presence, and location of thin liquid and solid swallow residue, penetration, and aspiration. In addition, SEES was more sensitive to the presence of liquid residue, penetration, and aspiration than VFSS. CONCLUSION: SEES is an endoscopic screening procedure that strengthens the clinical swallowing evaluation by documenting the presence or absence of postswallow residue, penetration, and aspiration. Accurate identification of a patient's risk for aspiration helps to direct further workup. It is an expedient, repeatable, and clinical relevant procedure that can be easily incorporated into a clinician's practice. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2291-2294, 2016.


Assuntos
Transtornos de Deglutição/diagnóstico , Esofagoscopia/estatística & dados numéricos , Fluoroscopia/estatística & dados numéricos , Deglutição/fisiologia , Esofagoscopia/métodos , Fluoroscopia/métodos , Humanos , Boca/cirurgia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Gravação em Vídeo
19.
Blood ; 126(13): 1527-35, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-26224645

RESUMO

Megakaryoblastic leukemia 1 (MKL1), also known as MAL or myocardin-related transcription factor A (MRTF-A), is a coactivator of serum response factor, which regulates transcription of actin and actin cytoskeleton-related genes. MKL1 is known to be important for megakaryocyte differentiation and function in mice, but its role in immune cells is unexplored. Here we report a patient with a homozygous nonsense mutation in the MKL1 gene resulting in immunodeficiency characterized predominantly by susceptibility to severe bacterial infection. We show that loss of MKL1 protein expression causes a dramatic loss of filamentous actin (F-actin) content in lymphoid and myeloid lineage immune cells and widespread cytoskeletal dysfunction. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro. Similarly, primary dendritic cells were unable to spread normally or to form podosomes. Silencing of MKL1 in myeloid cell lines revealed that F-actin assembly was abrogated through reduction of globular actin (G-actin) levels and disturbed expression of multiple actin-regulating genes. Impaired migration of these cells was associated with failure of uropod retraction likely due to altered contractility and adhesion, evidenced by reduced expression of the myosin light chain 9 (MYL9) component of myosin II complex and overexpression of CD11b integrin. Together, our results show that MKL1 is a nonredundant regulator of cytoskeleton-associated functions in immune cells and fibroblasts and that its depletion underlies a novel human primary immunodeficiency.


Assuntos
Códon sem Sentido , Síndromes de Imunodeficiência/genética , Infecções por Pseudomonas/genética , Transativadores/genética , Actinas/metabolismo , Actinas/ultraestrutura , Linhagem Celular , Movimento Celular , Células Cultivadas , Citoesqueleto/metabolismo , Citoesqueleto/ultraestrutura , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Homozigoto , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/metabolismo , Neutrófilos/citologia , Neutrófilos/metabolismo , Pseudomonas/isolamento & purificação , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/diagnóstico , Infecções por Pseudomonas/metabolismo
20.
Nat Genet ; 47(5): 523-527, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25774636

RESUMO

Human genetic factors predispose to tuberculosis (TB). We studied 7.6 million genetic variants in 5,530 people with pulmonary TB and in 5,607 healthy controls. In the combined analysis of these subjects and the follow-up cohort (15,087 TB patients and controls altogether), we found an association between TB and variants located in introns of the ASAP1 gene on chromosome 8q24 (P = 2.6 × 10(-11) for rs4733781; P = 1.0 × 10(-10) for rs10956514). Dendritic cells (DCs) showed high ASAP1 expression that was reduced after Mycobacterium tuberculosis infection, and rs10956514 was associated with the level of reduction of ASAP1 expression. The ASAP1 protein is involved in actin and membrane remodeling and has been associated with podosomes. The ASAP1-depleted DCs showed impaired matrix degradation and migration. Therefore, genetically determined excessive reduction of ASAP1 expression in M. tuberculosis-infected DCs may lead to their impaired migration, suggesting a potential mechanism of predisposition to TB.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Células Dendríticas/fisiologia , Tuberculose Pulmonar/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Estudos de Casos e Controles , Movimento Celular , Células Cultivadas , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Transporte Proteico
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