RESUMO
Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) is a mitochondrial protein that plays important roles in cristae structure, oxidative phosphorylation and apoptosis. Multiple mutations in CHCHD2 have been associated with Lewy body disorders (LBDs), such as Parkinson's disease (PD) and dementia with Lewy bodies, with the CHCHD2-T61I mutation being the most widely studied. However, at present, only CHCHD2 knockout or CHCHD2/CHCHD10 double knockout mouse models have been investigated. They do not recapitulate the pathology seen in patients with CHCHD2 mutations. We generated the first transgenic mouse model expressing the human PD-linked CHCHD2-T61I mutation driven by the mPrP promoter. We show that CHCHD2-T61I Tg mice exhibit perinuclear mitochondrial aggregates, neuroinflammation, and have impaired long-term synaptic plasticity associated with synaptic dysfunction. Dopaminergic neurodegeneration, a hallmark of PD, is also observed along with α-synuclein pathology. Significant motor dysfunction is seen with no changes in learning and memory at 1 year of age. A minor proportion of the CHCHD2-T61I Tg mice (~10%) show a severe motor phenotype consistent with human Pisa Syndrome, an atypical PD phenotype. Unbiased proteomics analysis reveals surprising increases in many insoluble proteins predominantly originating from mitochondria and perturbing multiple canonical biological pathways as assessed by ingenuity pathway analysis, including neurodegenerative disease-associated proteins such as tau, cofilin, SOD1 and DJ-1. Overall, CHCHD2-T61I Tg mice exhibit pathological and motor changes associated with LBDs, indicating that this model successfully captures phenotypes seen in human LBD patients with CHCHD2 mutations and demonstrates changes in neurodegenerative disease-associated proteins, which delineates relevant pathological pathways for further investigation.
Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Animais , Camundongos , Doença de Parkinson/metabolismo , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/metabolismo , Doenças Neurodegenerativas/metabolismo , Proteínas Mitocondriais/genética , Mutação , Modelos Animais de DoençasRESUMO
Mendel's Law of Dominance suggests that recessive disease expression requires the inheritance of two mutated alleles as the dominant, wildtype allele suppresses disease presentation leading to the expression of physiological normal phenotypes. However, there is existing evidence that challenges this school of thought. Here, we summarise existing literature evaluating metabolic and health impacts among carriers of autosomal recessive conditions, focusing on phenylketonuria (PKU), classical homocystinuria, galactosemia and Usher syndrome as examples. Our findings suggest that carriers, often described as 'unaffected', may actually display attenuated symptoms for the recessive disease they are carrying. For instance, PKU is an inborn error of metabolism characterised by the build-up of plasma phenylalanine attributed to the deficiency of the phenylalanine hydroxylase (PAH) enzyme. While less severe, PKU carriers also exhibit this impaired enzymatic activity, leading to elevated plasma phenylalanine levels, especially after phenylalanine consumption. Related to these metabolic alterations in the PAH pathway, there is early evidence to suggest that PKU carriers may have compromised cognitive and mental health outcomes. Overall, research on the health and metabolic impacts of PKU carriers is sparse, with most studies conducted several decades ago. However, early evidence suggests that intermediate phenotypes among carriers of autosomal recessive conditions are plausible. The illustrated possible intermediate phenotypes observed among carriers necessitates future research to determine possible clinical implications among this population.
Assuntos
Fenilalanina Hidroxilase , Fenilcetonúrias , Humanos , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/genética , Padrões de Herança , Fenótipo , Fenilalanina/metabolismoRESUMO
Chronic inflammatory diseases are increasing in developed societies, thus new anti-inflammatory approaches are needed in the clinic. Synthetic peptides complexes can be designed to mimic the activity of anti-inflammatory mediators, in order to alleviate inflammation. Here, we evaluated the anti-inflammatory efficacy of tethered peptides mimicking the interleukin-1 receptor antagonist (IL-1Ra) and the heat-shock protein 70 (HSP70). We tested their biocompatibility and anti-inflammatory activity in vitro in primary human monocytes and differentiated macrophages activated with two different stimuli: the TLR agonists (LPS + IFN-γ) or Pam3CSK4. Our results demonstrate that IL-1Ra and HSP70 synthetic peptides present a satisfactory biocompatible profile and significantly inhibit the secretion of several pro-inflammatory cytokines (IL-6, IL-8, IL-1ß and TNFα). We further confirmed their anti-inflammatory activity when peptides were coated on a biocompatible material commonly employed in surgical implants. Overall, our findings support the potential use of IL-1Ra and HSP70 synthetic peptides for the treatment of inflammatory conditions.
Assuntos
Anti-Inflamatórios , Proteína Antagonista do Receptor de Interleucina 1 , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Peptídeos/farmacologia , Peptídeos/uso terapêuticoRESUMO
OBJECTIVE: To assess the impact of secondary intervention (SI) on health-related quality of life (HR-QOL) after fenestrated-branched endovascular aortic repair (FB-EVAR) for complex abdominal aortic aneurysms and thoracoabdominal aortic aneurysms. BACKGROUND: The effect of SI after FB-EVAR on physical and mental HR-QOL has not been described. METHODS: A cohort of 430 consecutive patients enrolled in a prospective, nonrandomized study to evaluate FB-EVAR (2013-2020) was assessed with 1325 short-form 36 HR-QOL questionnaires preoperatively and during follow-up visits. SIs were classified as major or minor procedures. Endpoints included patient survival, freedom from aortic-related mortality (ARM), freedom from SIs, and changes in HR-QOL physical component score (PCS) and mental component score. RESULTS: There were 302 male with mean age 74±8 years treated by FB-EVAR for 133 complex abdominal aortic aneurysms and 297 thoracoabdominal aortic aneurysms. After a mean follow up of 26±20 months, 97 patients (23%) required 137 SIs. At 5 years, freedom from any SI was 64%±4%, including freedom from minor SIs of 77%±4% and major SIs of 87%±3%. There was no difference in patient survival and freedom from ARM at same interval. On adjusted analysis, minor SIs correlated with improved survival. SIs had a negative correlation with PCS ( r =-0.8). There were no significant changes in mental component score with SIs. Predictors for SIs were fluoroscopy time, graft design, and aneurysm sac change. CONCLUSION: SIs were needed in nearly 1 out of 4 patients treated by FB-EVAR with no effect on patient survival or ARM. SI resulted in decline in PCS.
Assuntos
Aneurisma da Aorta Abdominal , Aneurisma da Aorta Torácica , Aneurisma da Aorta Toracoabdominal , Aneurisma Aórtico , Implante de Prótese Vascular , Procedimentos Endovasculares , Humanos , Masculino , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Torácica/cirurgia , Qualidade de Vida , Prótese Vascular , Implante de Prótese Vascular/efeitos adversos , Estudos Prospectivos , Resultado do Tratamento , Fatores de Risco , Procedimentos Endovasculares/métodos , Aneurisma da Aorta Abdominal/cirurgia , Estudos RetrospectivosRESUMO
OBJECTIVE: Aberrant subclavian artery (ASA) and Kommerell's diverticulum (KD) are rare vascular anomalies that may be associated with lifestyle-limiting and life-threatening complications. The aim of this study is to report contemporary outcomes after invasive treatment of ASA/KD using a large international dataset. METHODS: Patients who underwent treatment for ASA/KD (2000-2020) were identified through the Vascular Low Frequency Disease Consortium, a multi-institutional collaboration to investigate uncommon vascular disorders. We report the early and mid-term clinical outcomes including stroke and mortality, technical success, and other operative outcomes including reintervention rates, patency, and endoleak. RESULTS: Overall, 285 patients were identified during the study period. The mean patient age was 57 years; 47% were female and 68% presented with symptoms. A right-sided arch was present in 23%. The mean KD diameter was 47.4 mm (range, 13.0-108.0 mm). The most common indication for treatment was symptoms (59%), followed by aneurysm size (38%). The most common symptom reported was dysphagia (44%). A ruptured KD was treated in 4.2% of cases, with a mean diameter of 43.9 mm (range, 18.0-100.0 mm). An open procedure was performed in 101 cases (36%); the most common approach was ASA ligation with subclavian transposition. An endovascular or hybrid approach was performed in 184 patients (64%); the most common approach was thoracic endograft and carotid-subclavian bypass. A staged operative strategy was employed more often than single setting repair (55% vs 45%). Compared with endovascular or hybrid approach, those in the open procedure group were more likely to be younger (49 years vs 61 years; P < .0001), female (64% vs 36%; P < .0001), and symptomatic (85% vs 59%; P < .0001). Complete or partial symptomatic relief at 1 year after intervention was 82.6%. There was no association between modality of treatment and symptom relief (open 87.2% vs endovascular or hybrid approach 78.9%; P = .13). After the intervention, 11 subclavian occlusions (4.5%) occurred; 3 were successfully thrombectomized resulting in a primary and secondary patency of 95% and 96%, respectively, at a median follow-up of 39 months. Among the 33 reinterventions (12%), the majority were performed for endoleak (36%), and more reinterventions occurred in the endovascular or hybrid approach than open procedure group (15% vs 6%; P = .02). The overall survival rate was 87.3% at a median follow-up of 41 months. The 30-day stroke and death rates were 4.2% and 4.9%, respectively. Urgent or emergent presentation was independently associated with increased risk of 30-day mortality (odds ratio [OR], 19.8; 95% confidence interval [CI], 3.3-116.6), overall mortality (OR, 3.6; 95% CI, 1.2-11.2) and intraoperative complications (OR, 8.3; 95% CI, 2.8-25.1). Females had a higher risk of reintervention (OR, 2.6; 95% CI, 1.0-6.5). At an aneurysm size of 44.4 mm, receiver operator characteristic curve analysis suggested that 60% of patients would have symptoms. CONCLUSIONS: Treatment of ASA/KD can be performed safely with low rates of mortality, stroke and reintervention and high rates of symptomatic relief, regardless of the repair strategy. Symptomatic and urgent operations were associated with worse outcomes in general, and female gender was associated with a higher likelihood of reintervention. Given the worse overall outcomes when symptomatic and the inherent risk of rupture, consideration of repair at 40 mm is reasonable in most patients. ASA/KD can be repaired in asymptomatic patients with excellent outcomes and young healthy patients may be considered better candidates for open approaches versus endovascular or hybrid modalities, given the lower likelihood of reintervention and lower early mortality rate.
Assuntos
Aneurisma , Implante de Prótese Vascular , Divertículo , Procedimentos Endovasculares , Acidente Vascular Cerebral , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Endoleak/etiologia , Aneurisma/diagnóstico por imagem , Aneurisma/cirurgia , Aneurisma/complicações , Artéria Subclávia/diagnóstico por imagem , Artéria Subclávia/cirurgia , Artéria Subclávia/anormalidades , Procedimentos Endovasculares/efeitos adversos , Acidente Vascular Cerebral/etiologia , Divertículo/diagnóstico por imagem , Divertículo/cirurgia , Aorta Torácica/cirurgia , Resultado do Tratamento , Implante de Prótese Vascular/efeitos adversosRESUMO
BACKGROUND: Aberrant subclavian artery (ASA) with or without Kommerell's diverticulum (KD) is a rare anatomic aortic arch anomaly that can cause dysphagia and/or life-threatening rupture. The objective of this study is to compare outcomes of ASA/KD repair in patients with a left versus right aortic arch. METHODS: Using the Vascular Low Frequency Disease Consortium methodology, a retrospective review was performed of patients ≥18 years old with surgical treatment of ASA/KD from 2000 to 2020 at 20 institutions. RESULTS: 288 patients with ASA with or without KD were identified; 222 left-sided aortic arch (LAA), and 66 right-sided aortic arch (RAA). Mean age at repair was younger in LAA 54 vs. 58 years (P = 0.06). Patients in RAA were more likely to undergo repair due to symptoms (72.7% vs. 55.9%, P = 0.01), and more likely to present with dysphagia (57.6% vs. 39.1%, P < 0.01). The hybrid open/endovascular approach was the most common repair type in both groups. Rates of intraoperative complications, death within 30 days, return to the operating room, symptom relief and endoleaks were not significantly different. For patients with symptom status follow-up data, in LAA, 61.7% had complete relief, 34.0% had partial relief and 4.3% had no change. In RAA, 60.7% had complete relief, 34.4% had partial relief and 4.9% had no change. CONCLUSIONS: In patients with ASA/KD, RAA patients were less common than LAA, presented more frequently with dysphagia, had symptoms as an indication for intervention, and underwent treatment at a younger age. Open, endovascular and hybrid repair approaches appear equally effective, regardless of arch laterality.
Assuntos
Transtornos de Deglutição , Divertículo , Cardiopatias Congênitas , Doenças Vasculares , Adolescente , Humanos , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/cirurgia , Aorta Torácica/anormalidades , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/cirurgia , Divertículo/diagnóstico por imagem , Divertículo/cirurgia , Divertículo/complicações , Cardiopatias Congênitas/complicações , Artéria Subclávia/diagnóstico por imagem , Artéria Subclávia/cirurgia , Artéria Subclávia/anormalidades , Resultado do Tratamento , Doenças Vasculares/complicações , Adulto , Pessoa de Meia-IdadeRESUMO
PURPOSE: Common celiomesenteric trunk (CMT) is a rare anatomical variation that occurs in 0.5% to 3.4% of the general population. Its presence may complicate planning and implantation of fenestrated and branched stent-grafts because the wide diameter and short length of the CMT to its bifurcation does not allow sufficient sealing for placement of bridging stents. CASE REPORT: We report a patient with thoracoabdominal aortic aneurysm (TAAA) and CMT treated by fenestrated-branched endovascular aortic repair (FB-EVAR) using double kissing directional branches to incorporate the celiac axis and superior mesenteric artery. Pitfalls of stent design and implantation are outlined. CONCLUSION: Double kissing directional branches should be considered as an alternative to incorporate vessels with early bifurcation such as a CMT.
Assuntos
Aneurisma da Aorta Torácica , Implante de Prótese Vascular , Procedimentos Endovasculares , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/cirurgia , Prótese Vascular , Procedimentos Endovasculares/efeitos adversos , Humanos , Desenho de Prótese , Fatores de Risco , Stents , Fatores de Tempo , Resultado do TratamentoRESUMO
Medullary Thyroid Carcinoma (MTC) is a rare neuroendocrine cancer that accounts for 1-2% of thyroid cancers in the United States (U.S.). While most cases are sporadic, 25% of MTC cases are hereditary. These hereditary cases occur in the setting of Multiple Endocrine Neoplasia Type 2A (MEN2A) or 2B (MEN2B) driven by mutations in the Rearranged during Transfection RET proto-oncogene. This article discusses hereditary MTC in the setting of MEN2 and the treatment options available for it. The first line treatment for this disease is typically a total thyroidectomy and tyrosine kinase inhibitors. Two tyrosine kinase inhibitors, vandetanib and cabozantinib, have been approved for treatment of advanced MTC, but options beyond those are limited. However, several promising treatments are being studied, which are discussed in this review.
Assuntos
Carcinoma Neuroendócrino/terapia , Neoplasia Endócrina Múltipla Tipo 2a/complicações , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia/métodos , Carcinoma Neuroendócrino/etiologia , Carcinoma Neuroendócrino/patologia , Terapia Combinada , Gerenciamento Clínico , Humanos , Mutação , Prognóstico , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/etiologia , Neoplasias da Glândula Tireoide/patologiaRESUMO
OBJECTIVE: Adipose-derived stem cells (ASCs) are a potential adult mesenchymal stem cell source for restoring endothelial function in patients with critical limb ischemia. Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF) play a major role in angiogenesis and wound healing. This study evaluated the effects of FGF and VEGF on the proliferation, migration, and potential endothelial differentiation of human ASCs with regards to their use as endothelial cell substitutes. METHODS: ASCs were isolated from clinical lipoaspirates and cultured in M199 medium with fetal bovine serum (10%), FGF2 (10 ng/mL), VEGF (50 ng/mL), or combinations of FGF2 and VEGF. Cell proliferation rates, viability, and migration were measured by growth curves, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), and scratch assays. For cell attachment determinations, ASCs were seeded onto a scaffold of small intestinal submucosa for 5 days. Endothelial differentiation capabilities of ASCs were confirmed by expression of endothelial cell-specific markers using quantitative polymerase chain reaction, immunofluorescence staining, and cord formation on Matrigel (BD Biosciences, San Jose, Calif). PD173074, a selective inhibitor of FGF receptor, was used to confirm the importance of FGF signaling. RESULTS: ASCs treated with FGF or combinations of FGF and VEGF showed increased proliferation rates and consistent differentiation toward an endothelial cell lineage increase in platelet endothelial cell adhesion molecule (CD31), von Willebrand factor, endothelial nitric oxide synthase, and vascular endothelial cadherin message, and in protein and cord formation on Matrigel. FGF and VEGF stimulated ASC migration and increased the attachment and retention after seeding onto a matrix graft of small intestinal submucosa. Blockade of FGF signaling with PD173074 abrogated ASC endothelial cell differentiation potential. CONCLUSIONS: These results indicate that FGF and VEGF are ASC promoters for proliferation, migration, attachment, and endothelial differentiation. FGF and VEGF have a costimulatory effect on ASC endotheliogenesis. These results further suggest that ASCs with enhanced FGF signaling may potentially be used for tissue engineering and cell-based therapies in patients with critical limb ischemia.
Assuntos
Tecido Adiposo/citologia , Indutores da Angiogênese/farmacologia , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Progenitoras Endoteliais/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/farmacologia , Biomarcadores/metabolismo , Adesão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Progenitoras Endoteliais/metabolismo , Matriz Extracelular/metabolismo , Humanos , Intestino Delgado/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fenótipo , Fatores de Tempo , Alicerces TeciduaisRESUMO
Managing dental caries remains a challenge to cliniciansmore so when treating caries in remote, underserved areas of the world. The purpose of this article is to report preliminary results of an effort to reduce to practice the best features of silver nitrate (SN) anti-caries effect and atraumatic restorative treatment (ART) for lesion preparation and restoration. The modifications made to two approaches have practical applications to school-based outreach programs hoping to respond to the dire need for preventive and conservative restorative methods in parts of the world where access to the dental office is unobtainable.
Assuntos
Tratamento Conservador , Tratamento Dentário Restaurador sem Trauma , Cárie Dentária/terapia , Nitrato de Prata/uso terapêutico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Humanos , Jamaica , Pessoa de Meia-Idade , Saúde da População Rural , Adulto JovemRESUMO
OBJECTIVE: Recent advances in endovascular aneurysm repair have overcome substantial anatomic barriers associated with short and challenging necks. With greater range to treat more difficult anatomy from an endovascular approach, one would assume the need of open surgical repair (OSR) would be diminished. The purpose of our study was to determine the need for OSR for abdominal aortic aneurysms, in a tertiary academic setting, with a moderate volume (10-15 cases/year) of fenestrated endografting being performed. METHODS: An Institutional Review Board approved retrospective review was performed of all patients who underwent elective aortic aneurysm repair between January 2010 and July 2014. Computed tomography scans for patients who underwent OSR were reviewed and anatomic characteristics obtained. Instructions for use of (IFU) a commercially available fenestrated device (Cook Medical, Bloomington, Ind) were used to determine if open repair patients had anatomy amenable to advanced endovascular repair. RESULTS: During the study interval, 415 patients underwent abdominal aortic aneurysm repair. Of those patients who underwent elective aneurysm repair, 105 patients had OSR. The study subsequently excluded 11 patients because they underwent secondary interventions after a failed endovascular repair and thus were not further evaluated. Also excluded were 18 patients who had OSR for an emergency intervention. The remaining 76 patients (35 female, 41 male; average age, 72 ± 8 years) had OSR and were outside the IFU of the fenestrated endovascular aneurysm repair (FEVAR) device. The average diameter of the abdominal aorta was 5.9 cm. Indications for OSR were an aneurysm neck <4 mm (71%), inclusion of at least 1 visceral vessel (69.7%), unilateral iliac artery aneurysms (15.5%), bilateral iliac artery aneurysms (14.3%), iliac artery tortuosity >40° of angulation (37.6%), extensive aortic thrombus (23.2%), and aortic neck angulation >45° (11.8%). Rejected patients had an average of 1.7 ± 0.8 anatomic constraints (range 1-4) that prevented use of the FEVAR device. CONCLUSIONS: With evidence to support the strict adherence to IFU protocols of the FEVAR device in patients, our institution's practice has been to continue to perform open abdominal aortic aneurysm repair for patients with anatomy outside device protocols. Although it was thought that the decreased requirement of aortic neck required to deploy an endograft would lead to an increased patient population amenable to endovascular repair, there is still a clinically significant need for open aortic surgery.
Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Implante de Prótese Vascular/métodos , Procedimentos Endovasculares/métodos , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aortografia/métodos , Prótese Vascular , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/instrumentação , Angiografia por Tomografia Computadorizada , Procedimentos Cirúrgicos Eletivos , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/instrumentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , New Jersey , Seleção de Pacientes , Desenho de Prótese , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção Terciária , Resultado do TratamentoRESUMO
BACKGROUND: Cancer patients with chemotherapy-induced immunosuppression have poor surgical site wound healing. Prior literature supports the use of human adipose-derived stem cell (hASC) lipoinjection to improve wound healing. It has been established that multipotent hASCs facilitate neovascularization, accelerate epithelialization, and quicken wound closure in animal models. Although hASC wound therapy may benefit surgical cancer patients, the chemotherapeutic effects on hASCs are unknown. We hypothesized that paclitaxel, a chemotherapeutic agent, impairs hASC growth, multipotency, and induces apoptosis. METHODS: hASCs were isolated and harvested from consented, chemotherapy and radiation naive patients. Growth curves, MTT (3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide), and EdU (5-ethynyl-2-deoxyguridine) assays measured cytotoxicity and proliferation. Oil Red O stain, Alizarin Red stain, matrigel tube formation assay, and quantitative polymerase chain reaction analyzed hASC differentiation. Annexin V assay measured apoptosis. Immunostaining and Western blot determined tumor necrosis factor α (TNF-α) expression. RESULTS: hASCs were selectively more sensitive to paclitaxel (0.01-30 µM) than fibroblasts (P < 0.05). After 12 d, paclitaxel caused hASC growth arrest, whereas control hASCs proliferated (P = 0.006). Paclitaxel caused an 80.6% reduction in new DNA synthesis (P < 0.001). Paclitaxel severely inhibited endothelial differentiation and capillary-like tube formation. Differentiation markers, lipoprotein lipase (adipogenic), alkaline phosphatase (osteogenic), CD31, and van Willebrand factor (endothelial), were significantly decreased (all P < 0.05) confirming paclitaxel impaired differentiation. Paclitaxel was also found to induce apoptosis and TNF-α was upregulated in paclitaxel-treated hASCs (P < 0.001). CONCLUSIONS: Paclitaxel is more cytotoxic to hASCs than fibroblasts. Paclitaxel inhibits hASC proliferation, differentiation, and induces apoptosis, possibly through the TNF-α pathway. Paclitaxel's severe inhibition of endothelial differentiation indicates neovascularization disruption, possibly causing poor wound healing in cancer patients receiving chemotherapy.
Assuntos
Células-Tronco Adultas/efeitos dos fármacos , Antineoplásicos Fitogênicos/efeitos adversos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Paclitaxel/efeitos adversos , Tecido Adiposo/citologia , Células-Tronco Adultas/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Células Endoteliais/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Osteogênese/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Review the literature on secondary interventions performed for patients who underwent endovascular repair of their type B aortic dissection. Endovascular repair for type B aortic dissection (TBAD) has been proven to be both technically feasible and beneficial in some patients. However, the information regarding secondary interventions is not cohesive. To date, there are little data to help guide physicians on the indications and benefits of secondary interventions in the setting of previous endovascular repair for TBAD. METHODS: PubMed database was queried for publications using the following combination of keywords; "aortic dissection," "type B," "secondary intervention," "false lumen thrombosis," "stent graft," "aortic remodeling," and endovascular repair. Sixteen articles were selected and reviewed for secondary interventions, indications for procedure, and effects on false lumen thrombosis. Data were collected, and a composite database of patients was created. RESULTS: Literature review demonstrated 161 of 862 patients required secondary interventions for entry tears, retrograde type A dissection, false lumen degeneration with aortic expansion, graft malfunction, and various access complications. The complete false lumen thrombosis rate was 33%, and overall mortality was 18.2%. CONCLUSIONS: Secondary interventions provide a useful adjunct to failing endovascular repair of aortic dissections. A variety of treatment options are available for aneurysmal degeneration after thoracic endovascular aneurysm repair. This review also shows that these secondary interventions, in combination with proper surveillance and optimal medical management, are feasible but carry a high all-cause mortality.
Assuntos
Aneurisma da Aorta Torácica/cirurgia , Dissecção Aórtica/cirurgia , Implante de Prótese Vascular , Procedimentos Endovasculares , Complicações Pós-Operatórias/cirurgia , Dissecção Aórtica/diagnóstico , Dissecção Aórtica/mortalidade , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/mortalidade , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/mortalidade , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Humanos , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/mortalidade , Reoperação , Fatores de Risco , Fatores de Tempo , Falha de Tratamento , Remodelação VascularRESUMO
BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive genetic condition that results in reduced enzymatic functioning within the phenylalanine hydroxylase (PAH) pathway, which is involved in the metabolism of Phenylalanine (Phe) into Tyrosine (Tyr). Without dietary intervention, individuals with PKU exhibit significantly elevated levels of Phe, which is presumed to cause severe neurological dysfunction and other associated health risks. Carriers of PKU are heterozygotes for a PAH gene mutation and are typically described in the literature as "unaffected." However, decades of existing research challenges this classical thinking and it is plausible that these individuals currently classified as carriers may present with an intermediate phenotype or may be "moderately affected." SUMMARY: The purpose of this scoping review was to explore this hypothesis further, by searching for and summarizing existing literature on metabolism and health outcomes among PKU carriers. Preliminary research has suggested that some PKU carriers exhibit reduced PAH enzyme function, and related, elevated circulating Phe levels compared to non-carriers. In addition, Phe dosing trials have further demonstrated that carriers have increased Phe levels and decreased Tyr levels compared to non-carriers. Because of these metabolic perturbations, it is biologically plausible for carriers to experience an intermediate phenotype in terms of metabolic consequences and clinical outcomes. While these outcomes have yet to be thoroughly explored, early research has found associations between PKU carrier status and lower IQs as well as decreased executive functioning, memory, processing speed, and inhibitory control. The PAH pathway is also involved in melanogenesis and research has demonstrated increased melanoma risk among PKU carriers. However, there are many limitations to this research and thus whether or not carriers are clinically impacted cannot yet be conclusively determined. KEY MESSAGE: Overall, while preliminary research suggests a possible intermediate phenotype among PKU carriers, the current available research is limited and PKU carriers are still clinically considered "unaffected." This review outlines the current literature while discussing future research endeavours related to the metabolism and health of PKU carriers.
RESUMO
OBJECTIVE: Characterizing access to sudden sensorineural hearing loss (SSNHL) care at private practice otolaryngology clinics of varying ownership models. STUDY DESIGN: Cross-sectional prospective review. SETTING: Private practice otolaryngology clinics. METHODS: We employed a Secret Shopper study design with private equity (PE) owned and non-PE-owned clinics within 15 miles of one another. Using a standardized script, researchers randomly called 50% of each clinic type between October 2021 and January 2022 requesting an appointment on behalf of a family member enrolled in either Medicaid or private insurance (PI) experiencing SSNHL. Access to timely care was assessed between clinic ownership and insurance type. RESULTS: Seventy-eight total PE-owned otolaryngology clinics were identified across the United States. Only 40 non-PE clinics could be matched to the PE clinics; 39 PE and 28 non-PE clinics were called as Medicaid patients; 39 PE and 25 non-PE clinics were called as PI patients; 48.7% of PE and 28.6% of non-PE clinics accepted Medicaid. The mean wait time to new appointment ranged between 9.55 and 13.21 days for all insurance and ownership types but did not vary significantly (P > .480). Telehealth was significantly more likely to be offered for new Medicaid patients at non-PE clinics compared to PE clinics (31.8% vs 0.0%, P = .001). The mean cost for an appointment was significantly greater at PE clinics than at non-PE clinics ($291.18 vs $203.75, P = .004). CONCLUSIONS: Patients seeking SSNHL care at PE-owned otolaryngology clinics are likely to face long wait times prior to obtaining an initial appointment and reduced telehealth options.
Assuntos
Acessibilidade aos Serviços de Saúde , Perda Auditiva Neurossensorial , Otolaringologia , Humanos , Estados Unidos , Perda Auditiva Neurossensorial/terapia , Perda Auditiva Neurossensorial/economia , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Estudos Transversais , Estudos Prospectivos , Otolaringologia/economia , Medicaid , Perda Auditiva Súbita/terapia , Perda Auditiva Súbita/economia , Propriedade , Prática Privada/economia , Prática Privada/estatística & dados numéricos , Seguro Saúde/estatística & dados numéricos , Instituições de Assistência Ambulatorial/economia , Instituições de Assistência Ambulatorial/estatística & dados numéricosRESUMO
Arrestins are multifunctional proteins that regulate G-protein-coupled receptor (GPCR) desensitization, signaling, and internalization. The arrestin family consists of four subtypes: visual arrestin1, ß-arrestin1, ß-arrestin2, and visual arrestin-4. Recent studies have revealed the multifunctional roles of ß-arrestins beyond GPCR signaling, including scaffolding and adapter functions, and physically interacting with non-GPCR receptors. Increasing evidence suggests that ß-arrestins are involved in the pathogenesis of a variety of neurodegenerative diseases, including Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD). ß-arrestins physically interact with γ-secretase, leading to increased production and accumulation of amyloid-beta in AD. Furthermore, ß-arrestin oligomers inhibit the autophagy cargo receptor p62/SQSTM1, resulting in tau accumulation and aggregation in FTD. In PD, ß-arrestins are upregulated in postmortem brain tissue and an MPTP model, and the ß2AR regulates SNCA gene expression. In this review, we aim to provide an overview of ß-arrestin1 and ß-arrestin2, and describe their physiological functions and roles in neurodegenerative diseases. The multifaceted roles of ß-arrestins and their involvement in neurodegenerative diseases suggest that they may serve as promising therapeutic targets.
Assuntos
Doença de Alzheimer , Demência Frontotemporal , Doenças Neurodegenerativas , Humanos , beta-Arrestinas/metabolismo , Arrestina/metabolismo , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/terapia , Receptores Acoplados a Proteínas G/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/etiologiaRESUMO
Background: Transatrial approach is the standard method in repairing ventricular septal defects (VSD) in the pediatric population. However, the tricuspid valve (TV) apparatus might obscure the inferior border of the VSD risking the adequacy of repair by leaving residual VSD or heart block. Detachment of the TV chordae has been described as an alternative technique to TV leaflet detachment. The aim of this study is to investigate the safety of such a technique. Methods: Retrospective review of patients who underwent VSD repair between 2015 and 2018. Group A (n = 25) had VSD repair with TV chordae detachment were matched for age and weight to group B (n = 25) without tricuspid chordal or leaflet detachment. Electrocardiogram (ECG) and echocardiogram at discharge and at 3 years of follow-up were reviewed to identify new ECG changes, residual VSD, and TV regurgitation. Results: Median ages in groups A and B were 6.13 (IQR 4.33-7.91) and 6.33 (4.77-7.2) months. New onset right bundle branch block (RBBB) was diagnosed at discharge in 28% (n = 7) of group A versus 56% (n = 14) in group B (P = .044), while the incidence dropped to 16% (n = 4) in group A versus 40% (n = 10) in group B (P = .059) in the 3 years follow-up ECG. Echocardiogram at discharge showed moderate tricuspid regurgitation in 16% (n = 4) in group A and 12% (n = 3) in group B (P = .867). Three years of follow-up echocardiography revealed no moderate or severe tricuspid regurgitation and no significant residual VSD in either group. Conclusion: No significant difference in operative time was observed between the two techniques. TV chordal detachment technique reduces the incidence of postoperative RBBB without increasing the incidence of TV regurgitation at discharge.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Comunicação Interventricular , Insuficiência da Valva Tricúspide , Humanos , Criança , Lactente , Valva Tricúspide/diagnóstico por imagem , Valva Tricúspide/cirurgia , Estudos Retrospectivos , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Insuficiência da Valva Tricúspide/cirurgia , Insuficiência da Valva Tricúspide/etiologia , Seguimentos , Procedimentos Cirúrgicos Cardíacos/métodos , Comunicação Interventricular/diagnóstico por imagem , Comunicação Interventricular/cirurgia , Comunicação Interventricular/complicações , Resultado do TratamentoRESUMO
OBJECTIVE: To gain an insight into coping strategies that people living with chronic pain use to self-manage their pain. DESIGN: This qualitative Patient-oriented Research study used the Patient and Community Engagement Research approach. It was conducted by people with chronic pain lived experience, ensuring that patient perspective and needs were considered and addressed throughout the research cycle. Purposeful sampling was used for recruiting individuals living with chronic pain. A focus group and one-on-one semi-structured interviews were conducted via videoconference. The data were analysed iteratively using inductive thematic analysis and narrative story analysis. SETTING: Calgary, Alberta, Canada. PARTICIPANTS: Eleven adult participants, between the ages of 18 and 65, who self-identified as living with chronic pain for greater than 2 years. RESULTS: Three main themes emerged from the data: (1) the elements of chronic pain, (2) the chronic pain journey to acceptance and (3) daily coping strategies for chronic pain. Participants thought it was important to discuss these three themes because the daily coping strategies that they employed at any given time (theme 3) depended on the factors discussed in themes 1 and 2. Overlaying all of this is also a grieving process that people living with chronic pain may have to go through more than once. Participants also identified recommendations for healthcare professionals to support people living with chronic pain. CONCLUSIONS: Dealing with chronic pain affects all aspects of a person's life and involves a grieving process. When treating patients with chronic pain, it is important for healthcare professionals to understand the journey that people living with chronic pain go through, not just coping strategies. Diagnosis is critical for a patient's acceptance and in helping them find their new normal where they can employ daily coping strategies to manage their pain.
Assuntos
Dor Crônica , Adulto , Humanos , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Dor Crônica/terapia , Adaptação Psicológica , Pesquisa Qualitativa , AlbertaRESUMO
Native pulmonary tract flow after a cavopulmonary anastomosis may promote pulmonary artery growth but can lead to undesirable consequences. We report the case of a 17-month child with prolonged pleural effusions after cavopulmonary anastomosis in whom a ventricular septal defect occluder device was placed in the native right ventricular outflow tract. (Level of Difficulty: Advanced.).
RESUMO
BACKGROUND: Submassive and massive pulmonary embolism is associated with a high risk of complications. We aimed to evaluate our initial experience with a mechanical thrombectomy device in the management of these patients. METHODS: A single-center, retrospective study was performed in patients with acute submassive and massive pulmonary embolism treated with the FlowTriever device (Inari Medical, Irvine, CA, USA) between June 2019 and November 2020. Clinical and technical parameters were analyzed during the hospitalization and at 30- and 180-days after the procedure. RESULTS: Fourteen patients were evaluated with a median (IQR) age of 60 (50-69) years and 64% were male. All had right heart strain as the main indication for thrombectomy. The procedure duration and fluoroscopic time was 52 (37-89) and 13 (9-24) minutes, respectively. There was 100% technical success, and the pulmonary arterial pressure went from 60 (48-65) mmHg to 40 (34-47) mmHg. Thrombolysis was used in two patients and nine patients required intensive care. 100% experienced improvement in symptoms at the time of discharge. There were no device-related complications, major bleeding events, myocardial infarctions, or deaths. Preprocedural hemoglobin was 13 (12-15) g/dL, and predischarge was 12 (10-13) g/dL. Overall postprocedural length of stay was three (2-6) days. All the patients were discharged with oral anticoagulation. There were no device-related complications or recurrence of embolism at 30 and 180 days. CONCLUSIONS: The mechanical thrombectomy device for submassive and massive pulmonary embolism is promising and appears a safe and effective procedure with 100% technical success, no complications, short intensive care requirement/stay, and good early clinical outcomes.