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1.
Tuberculosis (Edinb) ; 147: 102503, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38729070

RESUMO

Mycobacterium abscessus, a rapidly growing nontuberculous mycobacterium, is increasingly recognized as an important pathogen of the human lung, disproportionally affecting people with cystic fibrosis (CF) and other susceptible individuals with non-CF bronchiectasis and compromised immune functions. M. abscessus infections are extremely difficult to treat due to intrinsic resistance to many antibiotics, including most anti-tuberculous drugs. Current standard-of-care chemotherapy is long, includes multiple oral and parenteral repurposed drugs, and is associated with significant toxicity. The development of more effective oral antibiotics to treat M. abscessus infections has thus emerged as a high priority. While murine models have proven instrumental in predicting the efficacy of therapeutic treatments for M. tuberculosis infections, the preclinical evaluation of drugs against M. abscessus infections has proven more challenging due to the difficulty of establishing a progressive, sustained, pulmonary infection with this pathogen in mice. To address this issue, a series of three workshops were hosted in 2023 by the Cystic Fibrosis Foundation (CFF) and the National Institute of Allergy and Infectious Diseases (NIAID) to review the current murine models of M. abscessus infections, discuss current challenges and identify priorities toward establishing validated and globally harmonized preclinical models. This paper summarizes the key points from these workshops. The hope is that the recommendations that emerged from this exercise will facilitate the implementation of informative murine models of therapeutic efficacy testing across laboratories, improve reproducibility from lab-to-lab and accelerate preclinical-to-clinical translation.


Assuntos
Modelos Animais de Doenças , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Animais , Mycobacterium abscessus/efeitos dos fármacos , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Camundongos , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Humanos , Avaliação Pré-Clínica de Medicamentos/métodos , Pulmão/microbiologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia
2.
Radiol Case Rep ; 19(8): 3240-3243, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38800075

RESUMO

A paraganglioma is a neuroendocrine tumor that may secrete catecholamines and present with symptoms of sympathetic overload such as hypertension and diaphoresis. It is important that paragangliomas are identified, as they must often be treated by surgical excision. IgG4-related retroperitoneal fibrosis (IgG4-RPF) is a systemic inflammatory disease that results in the infiltration of IgG4-positive plasma cells in the retroperitoneum. Such fibrosis may adversely affect nearby organs and tissues. Here, we describe a case of combined paraganglioma and IgG4-RPF in a 47-year-old female patient. This case demonstrates the deleterious effect of these two conditions when they occur simultaneously.

3.
Clin Gastroenterol Hepatol ; 22(1): 51-61, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37302442

RESUMO

BACKGROUND & AIMS: Gastric intestinal metaplasia (GIM) is associated with a higher risk of noncardia intestinal gastric adenocarcinoma (GA). The aim of this study was to estimate lifetime benefits, complications, and cost-effectiveness of GIM surveillance using esophagogastroduodenoscopy (EGD). METHODS: We developed a semi-Markov microsimulation model of patients with incidentally detected GIM, to compare the effectiveness of EGD surveillance with no surveillance at 10-year, 5-year, 3-year, 2-year, and 1-year intervals. We modeled a simulated cohort of 1,000,000 US individuals aged 50 with incidental GIM. Outcome measures were lifetime GA incidence, mortality, number of EGDs, complications, undiscounted life-years gained, and incremental cost-effectiveness ratio with a willingness-to-pay threshold of $100,000/quality-adjusted life-year (QALY). RESULTS: In the absence of surveillance, the model simulated 32.0 lifetime GA cases and 23.0 lifetime GA deaths per 1000 individuals with GIM, respectively. Among surveilled individuals, simulated lifetime GA incidence (per 1000) decreased with shorter surveillance intervals (10-year to 1-year, 11.2-6.1) as did GA mortality (7.4-3.6). Compared with no surveillance, all modeled surveillance intervals yielded greater life expectancy (87-190 undiscounted life-years gained per 1000); 5-year surveillance provided the greatest number of life-years gained per EGD performed and was the cost-effective strategy ($40,706/QALY). In individuals with risk factors of family history of GA or anatomically extensive, incomplete-type GIM intensified 3-year surveillance was cost-effective (incremental cost-effectiveness ratio $28,156/QALY and $87,020/QALY, respectively). CONCLUSIONS: Using microsimulation modeling, surveillance of incidentally detected GIM every 5 years is associated with reduced GA incidence/mortality and is cost-effective from a health care sector perspective. Real-world studies evaluating the impact of GIM surveillance on GA incidence and mortality in the United States are needed.


Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Estados Unidos/epidemiologia , Análise Custo-Benefício , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/patologia , Fatores de Risco , Metaplasia/epidemiologia , Anos de Vida Ajustados por Qualidade de Vida
4.
Front Immunol ; 14: 1291666, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38077382

RESUMO

Background: Allergens from Fagales trees frequently cause spring allergy in Europe, North America, and some parts of Asia. The definition of the birch homologous group, which includes birch (Bet v), oak (Que a), alder (Aln g), hazel (Cor a), hornbeam (Car b), beech (Fag s), and chestnut (Cas s), is based on high allergen sequence identity and extensive IgE cross-reactivity. Clinical effect was seen during the alder/hazel, birch, and oak pollen seasons after treatment with tree SLIT-tablets containing only birch allergen extract. Here, we characterize T-cell reactivity with respect to epitope specificities and cross-reactivity toward various Bet v 1 family members, (PR-10/group 1 major allergens). This cross-reactivity may be part of the immunological basis of clinical effect or cross-protection when exposed to birch homologous tree species. Method: T-cell lines were generated from 29 birch-allergic individuals through stimulation of peripheral blood mononuclear cells (PBMCs) with birch/Bet v or oak/Que a allergen extracts. T-cell responses to allergen extracts, purified group 1 allergens, and overlapping 20-mer peptides (Bet v 1, Aln g 1, Cor a 1, and Que a 1) were investigated by T-cell proliferation and cytokine production. Cross-reactivity was evaluated based on Pearson's correlations of response strength and further investigated by flow cytometry using tetramer staining for homologous peptide pairs. Results: T-cell reactivity toward extracts and group 1 allergens from across the birch homologous group was observed for birch/Bet v as well as oak/Que a T-cell lines. T-cell lines responded to multiple Bet v 1 homologous peptides from Aln g 1 and Cor a 1 and a subset of Que a 1 peptides. Significant Pearson's correlations between frequently recognized peptides derived from Bet v 1 and the corresponding peptides derived from alder, hazel, and oak strongly supported the T-cell cross-reactivity toward these allergens. Cross-reactivity between birch and birch homologous peptides was confirmed by pMHCII tetramer staining. Conclusion: T cells from birch tree pollen allergic individuals respond to multiple trees within the birch homologous group in accordance with the level of sequence homology between Bet v 1 family members, (PR-10 allergens) from these allergen sources, confirming the basis for clinical cross-protection.


Assuntos
Hipersensibilidade , Árvores , Humanos , Linfócitos T , Leucócitos Mononucleares , Antígenos de Plantas , Pólen , Alérgenos , Peptídeos/análise , Betula
5.
Gastroenterology ; 164(6): 906-920, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36736437

RESUMO

BACKGROUND & AIMS: The use of computer-aided detection (CAD) increases the adenoma detection rates (ADRs) during colorectal cancer (CRC) screening/surveillance. This study aimed to evaluate the requirements for CAD to be cost-effective and the impact of CAD on adenoma detection by endoscopists with different ADRs. METHODS: We developed a semi-Markov microsimulation model to compare the effectiveness of traditional colonoscopy (mean ADR, 26%) to colonoscopy with CAD (mean ADR, 37%). CAD was modeled as having a $75 per-procedure cost. Extensive 1-way sensitivity and threshold analysis were performed to vary cost and ADR of CAD. Multiple scenarios evaluated the potential effect of CAD on endoscopists' ADRs. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay threshold of $100,000/quality-adjusted life year. RESULTS: When modeling CAD improved ADR for all endoscopists, the CAD cohort had 79 and 34 fewer lifetime CRC cases and deaths, respectively, per 10,000 persons. This scenario was dominant with a cost savings of $143 and incremental effectiveness of 0.01 quality-adjusted life years. Threshold analysis demonstrated that CAD would be cost-effective up to an additional cost of $579 per colonoscopy, or if it increases ADR from 26% to at least 30%. CAD reduced CRC incidence and mortality when limited to improving ADRs for low-ADR endoscopists (ADR <25%), with 67 fewer CRC cases and 28 CRC deaths per 10,000 persons compared with traditional colonoscopy. CONCLUSIONS: As CAD is implemented clinically, it needs to improve mean ADR from 26% to at least 30% or cost less than $579 per colonoscopy to be cost-effective when compared with traditional colonoscopy. Further studies are needed to understand the impact of CAD when used in community practice.


Assuntos
Adenoma , Neoplasias Colorretais , Humanos , Análise Custo-Benefício , Colonoscopia , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/epidemiologia , Adenoma/diagnóstico , Detecção Precoce de Câncer , Computadores
6.
ACS Chem Biol ; 18(4): 724-733, 2023 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32083462

RESUMO

Proteolytic complexes in Mycobacterium tuberculosis (Mtb), the deadliest bacterial pathogen, are major foci in tuberculosis drug development programs. The Clp proteases, which are essential for Mtb viability, are high-priority targets. These proteases function through the collaboration of ClpP1P2, a barrel-shaped heteromeric peptidase, with associated ATP-dependent chaperones like ClpX and ClpC1 that recognize and unfold specific substrates in an ATP-dependent fashion. The critical interaction of the peptidase and its unfoldase partners is blocked by the competitive binding of acyldepsipeptide antibiotics (ADEPs) to the interfaces of the ClpP2 subunits. The resulting inhibition of Clp protease activity is lethal to Mtb. Here, we report the surprising discovery that a fragment of the ADEPs retains anti-Mtb activity yet stimulates rather than inhibits the ClpXP1P2-catalyzed degradation of proteins. Our data further suggest that the fragment stabilizes the ClpXP1P2 complex and binds ClpP1P2 in a fashion distinct from that of the intact ADEPs. A structure-activity relationship study of the bioactive fragment defines the pharmacophore and points the way toward the development of new drug leads for the treatment of tuberculosis.


Assuntos
Antibacterianos , Mycobacterium tuberculosis , Tuberculose , Humanos , Trifosfato de Adenosina/metabolismo , Antibacterianos/farmacologia , Antibacterianos/metabolismo , Proteínas de Bactérias/metabolismo , Endopeptidase Clp/química , Chaperonas Moleculares/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Peptídeo Hidrolases/efeitos dos fármacos , Peptídeo Hidrolases/metabolismo , Tuberculose/tratamento farmacológico
7.
J Clin Orthop Trauma ; 46: 102282, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38196965

RESUMO

Introduction: Bone loss is present in all revision total knee arthroplasties. Metaphyseal cones allow surgeons to negotiate loss of femoral and tibial bone stock while obtaining stable bony fixation. This study examines the mid-term functional and radiographic outcomes in patients undergoing revision total knee arthroplasty (rTKA) utilizing a novel metaphyseal cone system. Methods: This multicenter retrospective study examined all patients who received a porous, titanium tibial or femoral cone at four academic urban tertiary care institutions and presented for a minimum two-year follow-up. Patient demographics, indications for revision surgery, knee range-of-motion (ROM), re-revision rates, radiographic measurements, bone defect per AORI classification, and implant osseointegration were evaluated according to the Knee Society total knee arthroplasty (TKA) radiographic evaluation system. Results: One-hundred and four patients received 128 cone implants (84 tibial, 44 femoral cones; 24 patients with simultaneous ipsilateral tibial and femoral cones; 104 rTKA) with mean follow-up of 32.75 ± 6.54 months. The pre-operative main revision indications were aseptic loosening 36 (34.61 %), periprosthetic infection (PJI) 23 (22.11 %) and instability 18 (17.3 %). Thirteen rTKA underwent re-revision surgery: 3 for acute PJI, 4 for chronic PJI, 5 for instability, and 1 for mechanical failure of a hinged system. At most recent radiographic follow-up available, all unrevised cones had evidence of osteointegration and no visible implant migration.All-cause re-operation free survivorship was 87.5 % (91/104), and all-cause cone implant survivorship was 96.09 % (123/128 cones) at 2-year follow-up. Conclusion: This study demonstrates excellent mid-term outcomes of a novel porous, titanium metaphyseal cone in patients with large bone defects undergoing complex revision TKA. Level of evidence: IV, case series.

8.
Indian J Otolaryngol Head Neck Surg ; 74(Suppl 2): 1496-1501, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36452751

RESUMO

The objective of this study was to evaluate the efficacy and outcome using the maxillary swing approach for the management of extensive nasopharyngeal angiofibroma. A retrospective case series analysis in a tertiary care centre revealed eighteen cases with extensive nasal angiofibroma operated using the maxillary swing approach between 2011 and 2017. All patients had tumour extension to the lateral most portions of the infratemporal fossa with complete occupation and destruction of the lateral wall of the sphenoid sinus causing abutment to the cavernous sinus and complete involvement of the pterygopalatine fossa and pterygoid base. One patient displayed full occupancy of the maxillary sinus as a consequence of erosion of the posterior and medial walls of the maxillary sinus. All patients underwent tumour excision using the maxillary swing approach. Patients were followed up for a minimum period of 1 year after surgery. The maxillary swing approach gave optimal exposure of the entire central skull base including the infratemporal fossa and its extreme lateral and superior aspects. Adequate tumour exposure and vascular control could be achieved in all cases resulting in complete tumour excision. The mean operative time was 3 h 15 min. Post-operative healing was satisfactory with palatal fistula formation in four cases and all patients remaining disease-free up to the present time. One had minimal misalignment of the halves of the upper jaw and two had epiphora, of which one required dacryocystorhinostomy. The maxillary swing is an effective approach in the management of extensive nasopharyngeal angiofibroma and leads to optimal anatomical exposure with minimal morbidity.

9.
Antimicrob Agents Chemother ; 66(11): e0053922, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36197094

RESUMO

Mycobacterium abscessus is an emerging nontuberculous mycobacterium (NTM) pathogen infecting susceptible people with cystic fibrosis (CF) and non-CF bronchiectasis. Here, we demonstrated the activity of an FDA-approved drug, disulfiram, against drug-susceptible and drug-resistant M. abscessus strains utilizing in vitro and intracellular macrophage assays and a zebrafish embryo infection model. These data demonstrate effective antimicrobial activity of disulfiram against M. abscessus infection in vivo and strongly support further study of disulfiram in human NTM infections.


Assuntos
Fibrose Cística , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Humanos , Animais , Peixe-Zebra , Dissulfiram/farmacologia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Micobactérias não Tuberculosas , Fibrose Cística/microbiologia
10.
Indian J Ophthalmol ; 69(2): 352-356, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33463590

RESUMO

Purpose: The aim of this study was to present the outcomes of the 2018 and 2020 Vitreo-retinal Society of India (VRSI) biosimilars of anti-vascular endothelial growth factor (VEGF) (VIBE) surveys. Methods: An online survey of members of VRSI was conducted in July 2018 and January 2020 regarding their practice-patterns on anti-VEGF biosimilars pertaining to safety, efficacy, pricing, and need for enhanced clinical trials before regulatory approval. Results: In 2018, 112 VRSI members participated, whereas in 2020, 98 society members participated. In both surveys, majority of respondents were aware of biosimilars (96%, 2018 vs. 100%, 2020; P = 0.9) and felt that approval of biosimilar drugs should be made more stringent with larger clinical trials (89%, 2018 vs. 91%, 2020; P = 0.93). An increase in use of ranibizumab-biosimilar (41%, 2018 to 56%, 2020; P = 0.2) and a simultaneous significant decline in use of bevacizumab-biosimilar (9%, 2018 to 2%, 2020; P = 0.04) was noted from 2018 to 2020. From 2018 to 2020, the proportion of respondents satisfied with safety (61% to 68%; P = 0.59) and efficacy (65% to 81%; P = 0.32) of ranibizumab-biosimilar increased. However, during the same period, we noted in reduction in satisfaction levels with safety of bevacizumab-biosimilar (30% to 25%; P = 0.54), whereas satisfaction with its efficacy was stable (29% vs 30%; P = 0.99). A substantial proportion of retina specialists considered that current cost of ranibizumab-biosimilar ($130) was sufficiently low for it to be used as a substitute for Avastin (37%, 2018 and 40%, 2020; P = 0.82). Conclusion: The VRSI surveys reveal that Indian vitreoretinal specialists are familiar with anti-VEGF biosimilars. There was a progressive trend favoring ranibizumab-biosimilar over bevacizumab-biosimilar. One-third of the participants deem the current price of ranibizumab-biosimilar as appropriate to replace Avastin. Simultaneously, the need for enhanced pharmacovigilance and larger clinical trials are warranted for regulatory approval of these agents.


Assuntos
Medicamentos Biossimilares , Inibidores da Angiogênese , Bevacizumab , Humanos , Índia/epidemiologia , Ranibizumab , Inquéritos e Questionários , Fator A de Crescimento do Endotélio Vascular
12.
Indian J Otolaryngol Head Neck Surg ; 71(1): 38-41, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30906711

RESUMO

Neocord formation after Type III cordectomy is insufficient for complete glottic closure due to scarring and soft tissue deficit. This study evaluates the role of autologous fat injection (AFI) in phonosurgical management of patients who have previously undergone Type III cordectomy for early glottic cancer. Data was collected from hospital records of patients who underwent AFI after previously undergoing Type III cordectomy. A minimum duration of 6 months post-cordectomy was maintained before fat injection. Trans-oral injection was performed at a single site. Pre-operative voice evaluation was done using VHI, GRBAS scale and MDVP software. Post-operative evaluation was done at 6 weeks. 21 out of 62 post-Type III cordectomy patients chose to undergo fat augmentation and were included in the study. A comparison of pre-operative and 6 months post-operative AFI voice analysis showed a significant improvement in VHI, all parameters of GRBAS scale, and improvement in Jitter, Shimmer, SPI and NHR. There was a decrease in fundamental frequency but this was not statistically significant. AFI is an effective procedure for surgical voice rehabilitation of patients who have undergone Type III cordectomy for early laryngeal cancer.

14.
Eur Arch Otorhinolaryngol ; 275(11): 2783-2786, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30267219

RESUMO

PURPOSE: This study aimed at comparing phonatory outcomes between Trans-oral Laser Surgery and Radiotherapy in T1 glottic cancer. INTRODUCTION: Early glottic carcinoma, i.e. T1 stage, can be treated using trans-oral surgery, radiotherapy, or partial open surgery. Trans-oral laser (TOL) surgical techniques and Radiotherapy (RT) have undergone significant advancement in the past few years leading to a decrease in open procedures. Various studies have been published comparing voice quality after TOL surgery and RT. There are few works which consider patients' opinions, i.e. subjective parameters regarding functional voice quality post treatment. This study uses both subjective and objective parameters to evaluate phonatory outcome of both treatment options. METHODS: Phonatory outcomes were measured in patients who underwent RT and CO2 Laser excision for early laryngeal cancer. VHI, GRBAS and MDVP were used to measure the vocal outcome of treatment modality after 1 year of cancer-free survival. A comparison was then made between the outcomes in the two groups. RESULTS: Superior vocal outcomes in G, R and S criteria of the GRBAS scale, a better VHI index, and better jitter, shimmer and NHR were found in patients who underwent CO2 laser excision as compared to patients who underwent RT. Other parameters were comparable between the two groups. CONCLUSIONS: TOL surgery provides excellent vocal outcome as compared to RT in management of early glottic cancer and should be considered as the first line of management for the same.


Assuntos
Glote/cirurgia , Neoplasias Laríngeas/radioterapia , Neoplasias Laríngeas/cirurgia , Terapia a Laser , Lasers de Gás , Fonação , Adulto , Feminino , Humanos , Neoplasias Laríngeas/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Qualidade da Voz
15.
Ophthalmic Genet ; 39(2): 228-235, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29261364

RESUMO

BACKGROUND: The TP53 codon 72 Proline-Arginine polymorphism (TP53 P72R) is the most widely studied candidate among those evaluated for a putative association between impaired apoptosis and glaucoma. Considering the earlier findings about enhanced apoptotic potential by the Arg variant of TP53 P72R and the conflicting results about its association with glaucoma, we initiated a hospital-based case-control association study in a north Indian cohort to investigate the association of TP53 P72R with glaucoma. MATERIALS AND METHODS: We examined the status of TP53 P72R in 139 cases of primary open angle glaucoma (POAG) and in 111 cases of primary angle closure glaucoma (PACG) with respect to 218 controls using the polymerase chain reaction-restriction fragment length polymorphism method. Logistic regression analysis including age and gender as covariates was carried out to test the association of the polymorphism with overall glaucoma, POAG, and PACG cases. RESULTS: We observed significant differences between the genotypic distributions of combined glaucoma cases and controls in the recessive model. POAG cases with respect to controls did not exhibit any significant differences in the genotypic distributions. In contrast, the genotypic distributions as per the additive and recessive models in PACG cases were significantly different from those in controls. The two models suggested an increased risk of PACG in the Arg homozygotes of the investigated cohort. CONCLUSIONS: Ours is the first study demonstrating the association of TP53 P72R with the risk of PACG. It emphasizes that apart from narrow anterior chamber angle, impaired apoptotic mechanisms could also be an important contributor toward PACG.


Assuntos
Códon/genética , Glaucoma de Ângulo Fechado/genética , Glaucoma de Ângulo Aberto/genética , Polimorfismo de Nucleotídeo Único , Proteína Supressora de Tumor p53/genética , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Genotipagem , Glaucoma de Ângulo Fechado/diagnóstico , Glaucoma de Ângulo Aberto/diagnóstico , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Fatores de Risco
16.
J Vis Exp ; (126)2017 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-28829411

RESUMO

Here, we describe a protocol that allows for shape-anisotropic cadmium chalcogenide nanocrystals (NCs), such as nanorods (NRs) and tetrapods (TPs), to be covalently and site-specifically linked via their end facets, resulting in polymer-like linear or branched chains. The linking procedure begins with a cation-exchange process in which the end facets of the cadmium chalcogenide NCs are first converted to silver chalcogenide. This is followed by the selective removal of ligands at their surface. This results in cadmium chalcogenide NCs with highly reactive silver chalcogenide end facets that spontaneously fuse upon contact with each other, thereby establishing an interparticle facet-to-facet attachment. Through the judicious choice of precursor concentrations, an extensive network of linked NCs can be produced. Structural characterization of the linked NCs is carried out via low- and high-resolution transmission electron microscopy (TEM), as well as energy-dispersive X-ray spectroscopy, which confirm the presence of silver chalcogenide domains between chains of cadmium chalcogenide NCs.


Assuntos
Cádmio/química , Nanoestruturas/química , Aminas/química , Anisotropia , Compostos de Cádmio/síntese química , Compostos de Cádmio/química , Cátions/química , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Nanotubos/química , Compostos de Selênio/síntese química , Compostos de Selênio/química , Prata/química , Espectrometria por Raios X
17.
J Pathol ; 242(1): 52-61, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28097645

RESUMO

Antimicrobial peptides such as cathelicidins are important components of innate immune defence against inhaled microorganisms, and have shown antimicrobial activity against Mycobacterium tuberculosis in in vitro models. Despite this, little is known about the regulation and expression of cathelicidin during tuberculosis in vivo. We sought to determine whether the cathelicidin-related antimicrobial peptide gene (Cramp), the murine functional homologue of the human cathelicidin gene (CAMP or LL-37), is required for regulation of protective immunity during M. tuberculosis infection in vivo. We used Cramp-/- mice in a validated model of pulmonary tuberculosis, and conducted cell-based assays with macrophages from these mice. We evaluated the in vivo susceptibility of Cramp-/- mice to infection, and also dissected various pro-inflammatory immune responses against M. tuberculosis. We observed increased susceptibility of Cramp-/- mice to M. tuberculosis as compared with wild-type mice. Macrophages from Cramp-/- mice were unable to control M. tuberculosis growth in an in vitro infection model, were deficient in intracellular calcium influx, and were defective in stimulating T cells. Additionally, CD4+ and CD8+ T cells from Cramp-/- mice produced less interferon-ß upon stimulation. Furthermore, bacterial-derived cAMP modulated cathelicidin expression in macrophages. Our results demonstrate that cathelicidin is required for innate resistance to M. tuberculosis in a relevant animal model and is a key mediator in regulation of the levels of pro-inflammatory cytokines by calcium and cyclic nucleotides. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Catelicidinas/imunologia , AMP Cíclico/fisiologia , Tuberculose Pulmonar/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos , Apoptose/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Cálcio/metabolismo , Catelicidinas/deficiência , Catelicidinas/genética , Células Cultivadas , Citocinas/biossíntese , Células Dendríticas/imunologia , Modelos Animais de Doenças , Feminino , Imunidade Inata , Mediadores da Inflamação/metabolismo , Subunidade p40 da Interleucina-12/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/imunologia , Camundongos Endogâmicos BALB C , Camundongos Knockout , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/patogenicidade , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Baço/microbiologia , Baço/patologia , Tuberculose Pulmonar/patologia
18.
J Invest Dermatol ; 136(1): 225-235, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26763442

RESUMO

Mutations in GJB2 (connexin [Cx]26) cause either deafness or deafness associated with skin diseases. That different disorders can be caused by distinct mutations within the same gene suggests that unique channel activities are influenced by each class of mutation. We have examined the functional characteristics of two human mutations, Cx26-H73R and Cx26-S183F, causing palmoplantar keratoderma (PPK) and deafness. Both failed to form gap junction channels or hemichannels when expressed alone. Coexpression of the mutants with wild-type Cx43 showed a transdominant inhibition of Cx43 gap junction channels, without reductions in Cx43 protein synthesis. In addition, the presence of mutant Cx26 shifted Cx43 channel gating and kinetics toward a more Cx26-like behavior. Coimmunoprecipitation showed Cx43 being pulled down more efficiently with mutant Cx26 than wild-type, confirming the enhanced formation of heteromeric connexons. Finally, the formation of heteromeric connexons resulted in significantly increased Cx43 hemichannel activity in the presence of Cx26 mutants. These findings suggest a common mechanism whereby Cx26 mutations causing PPK and deafness transdominantly influence multiple functions of wild-type Cx43. They also implicate a role for aberrant hemichannel activity in the pathogenesis of PPK and further highlight an emerging role for Cx43 in genetic skin diseases.


Assuntos
Conexinas/genética , Surdez/genética , Junções Comunicantes/genética , Predisposição Genética para Doença , Ceratodermia Palmar e Plantar/genética , Mutação , Western Blotting , Células Cultivadas , Conexina 26 , Conexina 43/genética , Humanos , Imunoprecipitação , Oócitos/citologia , Oócitos/fisiologia , Estudos de Amostragem
19.
PLoS One ; 10(12): e0144090, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26624013

RESUMO

Autoimmune diabetes is a consequence of immune-cell infiltration and destruction of pancreatic ß-cells in the islets of Langerhans. We analyzed the cellular composition of the insulitic lesions in the autoimmune-prone non-obese diabetic (NOD) mouse and observed a peak in recruitment of plasmacytoid dendritic cells (pDCs) to NOD islets around 8-9 weeks of age. This peak coincides with increased spontaneous expression of type-1-IFN response genes and CpG1585 induced production of IFN-α from NOD islets. The transcription factor E2-2 is specifically required for the maturation of pDCs, and we show that knocking out E2-2 conditionally in CD11c+ cells leads to a reduced recruitment of pDCs to pancreatic islets and reduced CpG1585 induced production of IFN-α during insulitis. As a consequence, insulitis has a less aggressive expression profile of the Th1 cytokine IFN-γ and a markedly reduced diabetes incidence. Collectively, these observations demonstrate a disease-promoting role of E2-2 dependent pDCs in the pancreas during autoimmune diabetes in the NOD mouse.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Células Dendríticas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Animais , Feminino , Interferon-alfa/metabolismo , Interferon gama/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Pâncreas/metabolismo , Fator de Transcrição 4 , Fator de Necrose Tumoral alfa/metabolismo
20.
Retin Cases Brief Rep ; 8(3): 178-82, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25372433

RESUMO

PURPOSE: To describe a surgical technique for salvaging recurrent exposure of scleral buckle. METHODS: A patient, treated for rhegmatogenous retinal detachment with scleral buckle, presented with exposed uninfected buckle 3 weeks after the initial surgery. We tried to cover the exposure twice with conjunctivoplasty and once with scleral patch graft with amniotic membrane transplantation, but each one of them failed. After these failed attempts, we harvested autologous periosteal patch graft from the retroauricular area, which was sutured over the exposed buckle along with conjunctivoplasty. RESULTS: Autologous periosteal patch graft was successful in our case and reepithelialization was completed within 4 weeks. A small granuloma was formed at the suture site at the fifth week, which resolved completely with topical steroids. The conjunctiva and periosteal patch have remained stable over a follow-up period of 1 year. The autologous periosteal patch graft permanently covered the defect with complete reepithelialization by 4 weeks after the surgical procedure. CONCLUSION: Autologous periosteal patch graft can be offered as a viable alternative option to the patients with scleral buckle exposure.


Assuntos
Corpos Estranhos no Olho/cirurgia , Migração de Corpo Estranho/cirurgia , Periósteo/transplante , Complicações Pós-Operatórias/cirurgia , Terapia de Salvação/métodos , Recurvamento da Esclera/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Descolamento Retiniano/cirurgia , Transplante Autólogo , Resultado do Tratamento
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