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Somatic mosaic states in telomere biology disorders are characterized by somatic variants in the spliceosome and DNA damage response and repair pathways. A likely maladaptive response to short telomeres that may lead to increased hematological cancer.
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Telomerase , Telômero , Humanos , Fator de Processamento U2AF/genética , Telômero/genética , Telômero/metabolismo , Biologia , Telomerase/genética , Telomerase/metabolismoRESUMO
BACKGROUND: Lung transplant recipients are prone to invasive fungal infections prompting many transplant centers to use prolonged triazole antifungal prophylaxis. From a practical standpoint, it is unclear if lung transplant recipients are able to continue prolonged or lifelong prophylaxis without premature discontinuation from side effects, drug interactions, development of fungal disease, or medication cost. We examined the number of patients that are able to reach a prophylactic endpoint and understand the reasons for early termination. METHODS: We conducted a retrospective chart review of all lung and heart-lung transplant patients at Mayo Clinic Rochester from May 1, 2002 to December 31, 2017. Type, duration, and reason for discontinuation of triazole prophylaxis were examined. RESULTS: During the study period, 193 patients underwent lung or heart-lung transplantation. Itraconazole, voriconazole, and posaconazole were given to 180, 73, and 60 post-transplant patients, respectively. Providers switched itraconazole to another prophylactic antifungal medication for reasons other than prophylactic completion in 61.8% (126 out of 204) of exposure episodes; this was similar with voriconazole (68.8%, 53 out of 77, P = 0.41). Posaconazole was actively discontinued significantly less often (18.3%, 11 out of 60, P < 0.05). The most common reasons for discontinuing itraconazole were malabsorption (15.5% of exposure episodes) and concern for breakthrough fungal infection (10.2%). In comparison, the most common reason for voriconazole discontinuation was side effect or intolerance (54.5% of VR exposure episodes vs 9.8% of IT exposure episodes, P < 0.05). CONCLUSIONS: Itraconazole and posaconazole appeared to have fewer side effects prompting discontinuation than voriconazole, but itraconazole was discontinued more often because of malabsorption and clinical suspicion of fungal infections.
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Antifúngicos/efeitos adversos , Transplante de Pulmão/efeitos adversos , Adesão à Medicação/estatística & dados numéricos , Micoses/prevenção & controle , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Adulto , Idoso , Antifúngicos/uso terapêutico , Interações Medicamentosas , Feminino , Humanos , Infecções Fúngicas Invasivas/prevenção & controle , Itraconazol/efeitos adversos , Itraconazol/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Voriconazol/efeitos adversos , Voriconazol/uso terapêuticoRESUMO
OBJECTIVE: The objective of this retrospective review was to evaluate the perioperative and procedural management of patients with pulmonary alveolar proteinosis (PAP) who presented for whole-lung lavage (WLL). DESIGN: The records of all adult patients with PAP who underwent WLL between January 1, 1988 and August 20, 2017 were reviewed and pertinent demographic, preoperative, anesthetic, procedural, and postoperative data were recorded. SETTING: Large academic tertiary referral center. PARTICIPANTS: Forty patients with PAP underwent 79 WLL procedures. INTERVENTIONS: Patients with PAP undergoing WLL. MEASUREMENTS: Successful WLL, defined by visual clearing of lavage fluid, was completed in 91% of cases. Whole-lung lavage was terminated prematurely in 9% of cases (refractory hypoxia most common), while 8% of cases were found to have 30-day complications. There were no cases of intraoperative death, hemodynamic collapse, pneumothorax or hydrothorax, or need for emergent reintubation. Postoperative clinical follow-up at the authors' institution within 6 months of WLL showed 68% of patients reported improvement in symptoms and/or functional status. CONCLUSION: The authors here present a retrospective study describing the perioperative and procedural management of PAP patients undergoing WLL to help familiarize providers with the management of this population (Fig 1). The findings of this study outline a successful and consistent approach to WLL using a multidisciplinary team experienced in this procedure. Even in experienced hands, procedural complications and 30-day postoperative complications emphasize the risk in this complex patient population.
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Lavagem Broncoalveolar/métodos , Avaliação de Resultados da Assistência ao Paciente , Proteinose Alveolar Pulmonar/diagnóstico por imagem , Proteinose Alveolar Pulmonar/cirurgia , Adulto , Lavagem Broncoalveolar/instrumentação , Líquido da Lavagem Broncoalveolar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
We carried out the first matched retrospective cohort study aimed at studying the safety and efficacy of extracorporeal photopheresis (ECP) for bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT). Medical records of 1325 consecutive adult patients who underwent HCT between 2005 and 2015 were reviewed. Seventy-four patients (median age, 51 years) with a diagnosis of BOS were included in the study. After propensity-score matching for BOS severity, 26 patients who underwent ≥3 months of ECP were matched to 26 non-ECP-treated patients, who were assigned an index date corresponding to the ECP start date for their matched pairs. The rate of decline in FEV1 percentage predicted (FEV1PP) decreased after ECP initiation (and after index date in the non-ECP group), with no significant difference between the 2 groups (P = .33). On a multivariable analysis that included baseline transplant and pulmonary function test variables, matched related donor HCT (HR, .1; 95% CI, .03 to .5; P = .002), ECP (HR, .1; 95% CI, .01 to .3; P = .001), and slower rate of decline in FEV1PP before the ECP/index date (HR, .7; 95% CI, .6 to .8; P = .001) were associated with a better overall survival. At last follow-up, non-ECP-treated patients were more likely to be on >5 mg daily dose of prednisone (54% versus 23%; P = .04) and had a greater decline in their Karnofsky performance score (mean difference, -9.5 versus -1.6; P = .06) compared with ECP-treated-patients. In conclusion, compared with other BOS-directed therapies, ECP was found to improve survival in HCT patients with BOS, without significantly impacting measured pulmonary functions. These findings need prospective validation in a larger patient cohort.
Assuntos
Bronquiolite Obliterante/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fotoferese/métodos , Testes de Função Respiratória/métodos , Condicionamento Pré-Transplante/efeitos adversos , Adulto , Idoso , Bronquiolite Obliterante/patologia , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/mortalidade , Adulto JovemRESUMO
During deployment, a 52-year-old male developed acute behavioral changes. Though initially considered to have PTSD and related agitation and confusional state, his evaluation was consistent with acute encephalopathy. Magnetic resonance imaging of the brain showed T2 hyperintensities, and CSF analysis was positive for anti-N-methyl-D-aspartate receptor antibody. A nuclear protein in testis carcinoma midline carcinoma was discovered in the lung. Immunotherapy and surgical resection led to steady improvement prior to adjuvant chemotherapy. Autoimmune encephalitis due to anti-N-methyl-D-aspartate receptor antibodies is increasingly being recognized as causal of acute behavioral change.
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Encefalite , Neoplasias Pulmonares , Imageamento por Ressonância Magnética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico , Encefalite/diagnóstico , Encefalite/complicações , Imageamento por Ressonância Magnética/métodos , Transtornos Psicóticos/etiologia , Transtornos Psicóticos/diagnóstico , Doença de Hashimoto/complicações , Doença de Hashimoto/diagnósticoRESUMO
BACKGROUND: Airway stenting may be needed to manage anastomotic complications in lung transplant recipients. Conventional stenting strategies may be inadequate due to anatomic variations between the recipient and donor or involvement of both the anastomosis and lobar bronchi. METHODS: We investigated the efficacy of 3D-designed patient-specific silicone Y-stents in managing this scenario. 9 patients with complex airway stenosis underwent custom stent insertion after either failing traditional management strategies or having anatomy not suitable for conventional stents. CT images were uploaded to stent design software to make a virtual stent model. 3D printing technology was then used to make a mold for the final silicone stent which was implanted via rigid bronchoscopy. Forced expiratory volume in 1 s (FEV1) was measured pre- and post-stent placement. RESULTS: 78 % of patients experienced an increase in their FEV1 after stent insertion, (p = 0.001, 0.02 at 30 and 90 days respectively). Unplanned bronchoscopies primarily occurred due to mucous plugging. 2 patients had sufficient airway remodeling allowing for stent removal. CONCLUSIONS: Personalized 3D-designed Y-stents demonstrate promising results for managing complicated airway stenosis, offering improved lung function and potential long-term benefits for lung transplant recipients.
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Broncoscopia , Transplante de Pulmão , Silicones , Stents , Humanos , Transplante de Pulmão/efeitos adversos , Masculino , Feminino , Constrição Patológica/cirurgia , Constrição Patológica/etiologia , Pessoa de Meia-Idade , Broncoscopia/métodos , Adulto , Impressão Tridimensional , Anastomose Cirúrgica/efeitos adversos , Volume Expiratório Forçado , Complicações Pós-Operatórias/etiologia , Tomografia Computadorizada por Raios X , Idoso , TransplantadosAssuntos
Fibrose Cística/microbiologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Pulmão/fisiopatologia , Infecções por Mycobacterium/tratamento farmacológico , Adulto , Criança , Fibrose Cística/fisiopatologia , Feminino , Humanos , Masculino , Infecções por Mycobacterium/complicações , Mycobacterium abscessus , Testes de Função RespiratóriaRESUMO
Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a recently approved cystic fibrosis (CF) transmembrane conductance regulator modulator therapy that has shown promising clinical and laboratory improvements on multiple organ systems in people with CF (pwCF). While original clinical trials found little to no effect on depression and anxiety, many post-marketing reports have suggested that ETI may be associated with adverse mental health effects. Here we report on two pwCF with adverse mental health effects shortly after starting ETI. Although many factors such as the burden of living with a chronic disease or widespread effects of the Covid-19 pandemic may have contributed to these events, similar reports have led to mounting concern that ETI may be the cause of such events. Regular mental health screening before the initiation of ETI and monitoring for signs and symptoms of mental diseases afterward should be a routine part of care, given the gravity of possible outcomes.
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COVID-19 , Fibrose Cística , Humanos , Adolescente , Fibrose Cística/tratamento farmacológico , Tentativa de Suicídio , Pandemias , COVID-19/epidemiologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , MutaçãoRESUMO
BACKGROUND: MT-RNR1 variants are a well-known cause of aminoglycoside-induced hearing loss (AIHL). Individuals with cystic fibrosis (CF) routinely receive aminoglycosides and are at high risk of AIHL. However, genetic testing before treatment is not routinely performed due to perceived rarity of risk, and cost ineffectiveness with traditional technologies. AIM: Assess the utility of large-scale screening for AIHL risk in the CF population, using digital droplet polymerase chain reaction (ddPCR), a novel and scalable low-cost molecular technique. METHODS: Using a clinically validated ddPCR assay, we performed retrospective testing on 122 and prospective testing on 32 individuals with CF for the two most common pathogenic variants associated with AIHL, MT-RNR1 m.1555 A > G and m.1494 C > T. Our study screened the largest known cohort of pediatric cases of CF (94/154) for these specific alterations. RESULTS: We identified two individuals positive for MT-RNR1 m.1555 A > G and no positives for m.1494 C > T. Of 32 prospective cases, 17 had aminoglycoside exposure. The positive case in our prospective group recently began inhaled tobramycin and denied hearing issues. The clinician adjusted to care for both the patient and sibling with CF (not included in cohort) who is presumed positive for m.1555 A > G due to the nature of mitochondrial inheritance. CONCLUSION: Our findings demonstrate the utility of pretreatment screening in the cystic fibrosis population for AIHL risk using ddPCR, a scalable and robust testing methodology at a fraction of the cost as compared to other sequencing-based methods. Therefore, the use of large-scale screening for AIHL risk in the cystic fibrosis community should be re-visited.
Assuntos
Fibrose Cística , Perda Auditiva , Ototoxicidade , Humanos , Criança , Aminoglicosídeos/efeitos adversos , Estudos Retrospectivos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Antibacterianos/efeitos adversos , Perda Auditiva/induzido quimicamente , Perda Auditiva/diagnóstico , Perda Auditiva/epidemiologiaRESUMO
Background: Mycoplasma hominis, Ureaplasma urealyticum, and Ureaplasma parvum may cause post-transplant infections in lung transplant recipients. We evaluated routine pretransplant screening for these Mollicutes. Methods: We retrospectively reviewed records of lung transplant recipients at our tri-site institution from 01/01/2015 to 11/15/2019. M. hominis and/or Ureaplasma polymerase chain reaction (PCR) was performed on pretransplant recipient urine specimens and donor bronchial swabs at the time of transplantation. Development of Mollicute infection and hyperammonemia syndrome (HS) was recorded. Results: A total of 268 patients underwent lung transplantation during the study period, of whom 105 were screened with at least 1 Mollicute PCR. Twelve (11%) screened positive; 10 donors, 1 recipient, and 1 both. Among positive donors, 3 were positive for M. hominis, 5 for U. urealyticum, and 4 for U. parvum. Preemptive therapy included doxycycline, levofloxacin, and/or azithromycin administered for 1-12 weeks. Despite therapy, 1 case of M. hominis mediastinitis and 1 case of HS associated with Ureaplasma infection occurred, both donor-derived. Of those screened before transplant, cases with positive screening were more likely (P < 0.05) to develop Mollicute infection despite treatment (2/12, 17%) than those who screened negative (1/93, 1%). Conclusions: Pretransplant recipient urine screening had a low yield and was not correlated with post-transplant Mollicute infection, likely because most M. hominis and U. parvum/urealyticum infections in lung transplant recipients are donor-derived. Routine donor bronchus swab PCR for M. hominis, U. urealyticum, and U. parvum followed by preemptive therapy did not obviously impact the overall incidence of Mollicute infection or HS in this cohort.
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BACKGROUND: Continuous positive airway pressure (CPAP) is a common mode of respiratory support used in neonatal intensive care units. In preterm infants, nasal CPAP (nCPAP) therapy is often delivered via soft, biocompatible nasal mask suitable for long-term direct skin contact and held firmly against the face. Limited sizes of nCPAP mask contribute to mal-fitting related complications and adverse outcomes in this fragile population. We hypothesized that custom-fit nCPAP masks will improve the fit with less skin pressure and strap tension improving efficacy and reducing complications associated with nCPAP therapy in neonates. METHODS: After IRB approval and informed consent, we evaluated several methods to develop 3D facial models to test custom 3D nCPAP masks. These methods included camera-based photogrammetry, laser scanning and structured light scanning using a Bellus3D Face Camera Pro and iPhone X running either Bellus3D FaceApp for iPhone, or Heges application. This data was used to provide accurate 3D neonatal facial models. Using CAD software nCPAP inserts were designed to be placed between proprietary nCPAP mask and the model infant's face. The resulted 3D designed nCPAP mask was form fitted to the model face. Subsequently, nCPAP masks were connected to a ventilator to provide CPAP and calibrated pressure sensors and co-linear tension sensors were placed to measures skin pressure and nCPAP mask strap tension. RESULTS: Photogrammetry and laser scanning were not suited to the neonatal face. However, structured light scanning techniques produced accurate 3D neonatal facial models. Individualized nCPAP mask inserts manufactured using 3D printed molds and silicon injection were effective at decreasing surface pressure and mask strap pressure in some cases by more than 50% compared to CPAP masks without inserts. CONCLUSIONS: We found that readily available structured light scanning devices such as the iPhone X are a low cost, safe, rapid, and accurate tool to develop accurate models of preterm infant facial topography. Structured light scanning developed 3D nCPAP inserts applied to commercially available CPAP masks significantly reduced skin pressure and strap tension at clinically relevant CPAP pressures when utilized on model neonatal faces. This workflow maybe useful at producing individualized nCPAP masks for neonates reducing complications due to misfit.
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Acute eosinophilic pneumonia (AEP) is an infrequently seen interstitial lung disease secondary to medications. We report a series of 3 case of severe AEP which developed as a result of sulfa medication. 2 patients had received treatment with sulfamethoxazole for acne and 1 was treated with sulfasalazine for colitis. Patients were on sulfa medication for 1-3 weeks prior to presentation. All patients presented with fever, acute onset bilateral pulmonary infiltrates as well as marked peripheral eosinophilia. Mean eosinophil count was 2.21 × 109/L. There was a lack of response to steroids. One patient required extracorporeal membrane oxygenation and prolonged mechanical ventilation via tracheostomy. 2 patients underwent successful lung transplantation (1 bilateral living-related lobar lung transplant and 1 orthotropic cardiopulmonary allotransplantation). In all cases lung biopsy and explants showed acute and organizing diffuse alveolar damage with increased interstitial and airspace eosinophils. To our knowledge, our series is the first to show the clinical features of sulfa induced AEP in an adolescent population.
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The colonization of Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), has a detrimental effect on the respiratory care of pediatric patients with cystic fibrosis (CF). In addition to being resistant to multiple antibiotics, S. aureus also has the ability to form biofilms, which makes the infection more difficult to treat and eradicate. In this study, we examined the ability of S. aureus strains isolated from pediatric patients with CF to form biofilms. We screened a transposon mutant library of MRSA and identified a putative cobalt transporter ATP binding domain (cbiO) that is required for biofilm formation. We discovered that deleting cbiO creating a cbiO null mutant in CFSa36 (an MRSA strain isolated from a patient with cystic fibrosis) significantly hinders the ability of CFSa36 to form biofilm. The complementation of cbiO restored the ability of the cbiO deletion mutant to generate biofilm. Interestingly, we revealed that incorporating extra copper ions to the chemically defined medium (CDM) complemented the function of cbiO for biofilm formation in a dose-dependent manner, while the addition of extra iron ions in CDM enhanced the effect of cbiO null mutation on biofilm formation. In addition, neither the addition of certain extra amounts of copper ions nor iron ions in CDM had an impact on bacterial growth. Taken together, our findings suggest that cbiO mediates biofilm formation by affecting the transportation of copper ions in the MRSA CFSa36 strain. This study provides new insights into the molecular basis of biofilm formation by S. aureus.
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Interstitial lung diseases (ILDs) in patients with shortened telomeres have not been well characterized. We describe demographic, radiologic, histopathologic, and molecular features, and p16 expression in patients with telomeres ≤10th percentile (shortened telomeres) and compare them to patients with telomere length >10th percentile. Lung explants, wedge biopsies, and autopsy specimens of patients with telomere testing were reviewed independently by 3 pathologists using defined parameters. High-resolution computed tomography scans were reviewed by 3 radiologists. p16-positive fibroblast foci were quantified. A multidisciplinary diagnosis was recorded. Patients with shortened telomeres (N=26) were morphologically diagnosed as usual interstitial pneumonia (UIP) (N=11, 42.3%), chronic hypersensitivity pneumonitis (N=6, 23.1%), pleuroparenchymal fibroelastosis, fibrotic nonspecific interstitial pneumonia, desquamative interstitial pneumonia (N=1, 3.8%, each), and fibrotic interstitial lung disease (fILD), not otherwise specified (N=6, 23.1%). Patients with telomeres >10th percentile (N=18) showed morphologic features of UIP (N=9, 50%), chronic hypersensitivity pneumonitis (N=3, 16.7%), fibrotic nonspecific interstitial pneumonia (N=2, 11.1%), or fILD, not otherwise specified (N=4, 22.2%). Patients with shortened telomeres had more p16-positive foci (P=0.04). The number of p16-positive foci correlated with outcome (P=0.0067). Thirty-nine percent of patients with shortened telomeres harbored telomere-related gene variants. Among 17 patients with shortened telomeres and high-resolution computed tomography features consistent with or probable UIP, 8 (47.1%) patients showed morphologic features compatible with UIP; multidisciplinary diagnosis most commonly was idiopathic pulmonary fibrosis (N=7, 41.2%) and familial pulmonary fibrosis (N=5, 29%) in these patients. In conclusion, patients with shortened telomeres have a spectrum of fILDs. They often demonstrate atypical and discordant features on pathology and radiology leading to diagnostic challenges.
Assuntos
Doenças Pulmonares Intersticiais , Pulmão , Técnicas de Diagnóstico Molecular , Encurtamento do Telômero , Telômero/patologia , Tomografia Computadorizada por Raios X , Adulto , Idoso , Biomarcadores/análise , Biópsia , Inibidor p16 de Quinase Dependente de Ciclina/análise , Diagnóstico Diferencial , Feminino , Fibroblastos/química , Fibroblastos/patologia , Humanos , Imuno-Histoquímica , Pulmão/química , Pulmão/diagnóstico por imagem , Pulmão/patologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Telômero/genéticaRESUMO
BACKGROUND: Respiratory failure secondary to alveolar inflammation during Pneumocystis pneumonia is a major cause of death in immunocompromised patients. Neutrophil infiltration in the lung of patients with Pneumocystis infection predicts severity of the infection and death. Several previous studies indicate that airway epithelial cells release the neutrophil chemoattractant proteins, MIP-2 (rodents) and IL-8 (humans), in response to Pneumocystis and purified Pneumocystis cell wall beta-glucans (PCBG) through the NF-kappaB-dependent pathway. However, little is known about the molecular mechanisms that are involved in the activation of airway epithelium cells by PCBG resulting in the secretion of IL-8. METHOD: To address this, we have studied the activation of different calcium-dependent mitogen-activated protein kinases (MAPKs) in 1HAEo- cells, a human airway epithelial cell line. RESULTS: Our data provide evidence that PCBG induces phosphorylation of the MAPKs, ERK, and p38, the activation of NF-kappaB and the subsequently secretion of IL-8 in a calcium-dependent manner. Further, we evaluated the role of glycosphingolipids as possible receptors for beta-glucans in human airway epithelial cells. Preincubation of the cells with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) a potent inhibitor of the glycosphingolipids synthesis, prior to PCBG stimulation, significantly decreased IL-8 production. CONCLUSION: These data indicate that PCBG activates calcium dependent MAPK signaling resulting in the release of IL-8 in a process that requires glycosphingolipid for optimal signaling.
Assuntos
Sinalização do Cálcio , Parede Celular/metabolismo , Células Epiteliais/metabolismo , Interleucina-8/metabolismo , Pneumocystis carinii/metabolismo , Mucosa Respiratória/metabolismo , beta-Glucanas/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glicoesfingolipídeos/metabolismo , Humanos , Interleucina-8/genética , NF-kappa B/metabolismo , Fosforilação , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Fatores de Tempo , Fator de Transcrição AP-1/metabolismo , Transfecção , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Major basic protein (MBP) released from activated eosinophils may influence airway hyperresponsiveness (AHR) by either direct effects on airway myocytes or by an indirect effect. In this study, human bronchi, freshly isolated human eosinophils, or MBP purified from human eosinophil granules were incubated for studying eosinophil infiltration and MBP localization. Eosinophils immediately adhered to intact human airway as well as to cultured human airway myocytes and epithelium. Following incubation 18-24 h, eosinophils migrated into the airway media, including the smooth muscle layer, but had no specific recruitment to airway neurons. Eosinophils released significant amounts of MBP within the airway media, including areas comprising the smooth muscle layer. Most deposits of MBP were focally discrete and restricted by immunologic detection to a maximum volume of approximately 300 microm(3) about the eosinophil. Native MBP applied exogenously was immediately deposited on the surface of the airway, but required at least 1 h to become detected within the media of the airway wall. Tissue MBP infiltration and deposition increased in a time- and concentration-dependent manner. Taken together, these findings suggest that eosinophil-derived cationic proteins may alter airway hyperresponsiveness (AHR) in vivo by an effect that is not limited to the bronchial epithelium.
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Brônquios/fisiologia , Proteína Básica Maior de Eosinófilos/fisiologia , Eosinófilos/fisiologia , Mediadores da Inflamação/fisiologia , Asma/patologia , Asma/fisiopatologia , Hiper-Reatividade Brônquica/etiologia , Hiper-Reatividade Brônquica/fisiopatologia , Adesão Celular , Degranulação Celular , Movimento Celular , Células Epiteliais/fisiologia , Humanos , Técnicas In Vitro , Miócitos de Músculo Liso/fisiologia , Distribuição Tecidual , Ubiquitina Tiolesterase/fisiologiaRESUMO
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of infection worldwide, including a wide array of both hospital- and community-acquired infections-most commonly bacteremia, upper and lower respiratory tract infection, skin and soft-tissue infection, osteomyelitis, and septic arthritis. This chapter describes the epidemiology of MRSA infection, its ability to confer antibiotic resistance and produce a wide array of virulence factors, and its pivotal role in human infection, especially cystic fibrosis. It also provides an introduction to the strategies for treatment of both chronic and acute MRSA infections.
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Infecções Comunitárias Adquiridas , Fibrose Cística , Staphylococcus aureus Resistente à Meticilina , Infecções Respiratórias , Infecções dos Tecidos Moles , Infecções Estafilocócicas , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/metabolismo , Infecções Comunitárias Adquiridas/terapia , Fibrose Cística/epidemiologia , Fibrose Cística/metabolismo , Humanos , Staphylococcus aureus Resistente à Meticilina/metabolismo , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/metabolismo , Infecções Respiratórias/terapia , Infecções dos Tecidos Moles/epidemiologia , Infecções dos Tecidos Moles/metabolismo , Infecções dos Tecidos Moles/terapia , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/terapia , Fatores de Virulência/metabolismoRESUMO
CASE PRESENTATION: A 48-year-old woman sought a second opinion for dyspnea and chronic productive cough; she was a never smoker. Mild respiratory symptoms persisted since childhood and had progressively worsened over the previous decade. In addition, an unintentional 30-pound weight loss had occurred over several years. Six years previously, a diagnosis of hypersensitivity pneumonitis was made following right upper lobe wedge resection that revealed chronic bronchiolitis with interstitial pneumonia and non-necrotizing granulomatous inflammation. Subsequent use of prednisone elicited mild intermittent improvement. She had used feather pillows in the past without any other significant exposures. There were no reports of sinus or GI symptoms.
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Alveolite Alérgica Extrínseca/diagnóstico , Aminofenóis/administração & dosagem , Broncoscopia/métodos , Cefazolina/administração & dosagem , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística , Quinolonas/administração & dosagem , Infecções Estafilocócicas , Antibacterianos/administração & dosagem , Bronquiectasia/diagnóstico , Bronquiectasia/etiologia , Agonistas dos Canais de Cloreto/administração & dosagem , Fibrose Cística/diagnóstico , Fibrose Cística/fisiopatologia , Fibrose Cística/terapia , Diagnóstico Diferencial , Feminino , Testes Genéticos , Humanos , Transtornos de Início Tardio/diagnóstico , Transtornos de Início Tardio/fisiopatologia , Transtornos de Início Tardio/terapia , Pessoa de Meia-Idade , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/isolamento & purificação , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
Current guidelines suggest screening all patients with idiopathic pulmonary arterial hypertension for genetic aberrations, particularly mutations in Bone Morphogenic Protein Receptor Type II (BMPR2), the gene most commonly implicated in the pathogenesis of PAH. Herein, we present a novel technique used to identify a pathogenic germline BMPR2 alteration in a 36-year-old female and family members with hereditary pulmonary arterial hypertension who each screened negative by standard cytogenetics and molecular genetics testing.