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1.
J Tissue Viability ; 29(2): 91-99, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32249090

RESUMO

Manuka honey, a wound treatment used to eradicate bacteria, resolve inflammation, and promote wound healing, is a current focus in the tissue engineering community as a tissue template additive. However, Manuka honey's effect on neutrophils during the inflammation-resolving phase has yet to be examined. This study investigates the effect of 0.5% and 3% Manuka honey on the release of cytokines, chemokines, and matrix-degrading enzymes from a dHL-60 neutrophil model in the presence of anti-inflammatory stimuli (TGF-ß, IL-4, IL-4 +IL-13). We hypothesized that Manuka honey would reduce the output of pro-inflammatory signals and increase the release of anti-inflammatory signals. The results of this study indicate that 0.5% honey significantly increases the release of CXCL8/IL-8, CCL2/MCP-1, CCL4/MIP-1ß, CCL20/MIP-3α, IL-4, IL-1ra, and FGF-13 while reducing Proteinase 3 release in the anti-inflammatory-stimulated models. However, 3% honey significantly increased the release of TNF-α and CXCL8/IL-8 while reducing the release of all other analytes. We replicated a subset of the most notable findings in primary human neutrophils, and the consistent results indicate that the HL-60 data are relevant to the performance of primary cells. These findings demonstrate the variable effects of Manuka honey on the release of cytokines, chemokines, and matrix-degrading enzymes of this model of neutrophil anti-inflammatory activity. This study reinforces the importance of tailoring the concentration of Manuka honey in a wound or tissue template to elicit the desired effects during the inflammation-resolving phase of wound healing. Future in vivo investigation should be undertaken to translate these results to a physiologically-relevant wound environment.

2.
Orthop Clin North Am ; 51(2): 235-239, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32138861

RESUMO

To determine if orthopedic surgeons are more efficient than nonsurgical providers at care of operative injuries in walk-in clinics, patients in a walk-in clinic for evaluation of acute injury who subsequently had surgical treatment of isolated distal radial fracture were compared based on whether the initial visit was with a surgical or nonsurgical provider. Initial evaluation in a walk-in orthopedic clinic setting versus a conventional hand surgeon's clinic was associated with longer delay between initial evaluation and surgical treatment, but this difference may not be significant. Evaluation by a nonsurgical provider was not associated with increased duration to definitive treatment.


Assuntos
Fraturas do Rádio/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial , Instituições de Assistência Ambulatorial , Feminino , Fixação Interna de Fraturas , Consolidação da Fratura , Humanos , Masculino , Pessoa de Meia-Idade , Fraturas do Rádio/terapia , Tempo para o Tratamento , Adulto Jovem
3.
BJU Int ; 125(1): 89-102, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31392791

RESUMO

OBJECTIVES: To identify cytokines that can activate and expand NK cells in the presence of prostate cancer cells in order to determine whether these agents may be useful in future intra-tumoural administration in pre-clinical and clinical prostate cancer trials. MATERIALS AND METHODS: Lymphocytes isolated from normal donor blood were set up in co-cultures with either cancer or non-cancerous prostate cell lines, together with each of the cytokines interleukin (IL)-2, IL-12, IL-15, interferon (IFN)-γ or IL-21 for a period of 7 days. Then, expansion of NK cells, NKT cells and CD8 T cells was measured by flow cytometry and compared with the expansion of the same cells in the absence of prostate cells. The cytotoxic activity of NK cells, as measured by perforin and tumour cell killing, was also assessed. NK cell receptors and their corresponding ligands on prostate tumour cells were analysed to determine whether any of these were modulated by co-culture. The role of the tumour-secreted heat shock proteins HSP90 and HSP70 in the expansion of NK cells in the co-cultures was also investigated because of their effects on NK and CD8 T-cell activation. RESULTS: We showed that, among a panel of cytokines known to cause NK cell activation and expansion, only IL-15 could actively induce expansion of NK, NKT and CD8 T cells in the presence of prostate cancer cell lines. Furthermore, the expansion of NK cells was far greater (up to 50% greater) in the presence of the cancer cells (LNCaP, PC3) than when lymphocytes were incubated alone. In contrast, non-cancerous cell lines (PNT2 and WPMY-1) did not exert any expansion of NK cells. The cytolytic activity of the NK cells, as measured by perforin, CD107a and killing of tumour cells, was also greatest in co-cultures with IL-15. Examination of NK cell receptors shows that NKG2D is upregulated to a greater degree in the presence of prostate cancer cells, compared with the upregulation with IL-15 in lymphocytes alone. However, blocking of NKG2D does not inhibit the enhanced expansion of NK cells in the presence of tumour cells. CONCLUSIONS: Among a panel of NK cell-activating cytokines, IL-15 was the only cytokine that could stimulate expansion of NK cells in the presence of prostate cancer cells; therefore IL-15 may be a good candidate for novel future intra-tumoural therapy of the disease.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31834035

RESUMO

INTRODUCTION: Bundling of services, typically into a 90-day episode of care, is intended to facilitate cost reduction. The purpose of this study was to determine the impact of a private insurance bundling program on the costs of outpatient total shoulder arthroplasty (TSA) at a freestanding ambulatory surgery center. METHODS: A cost minimization analysis was done of patients who had anatomic TSA by a single surgeon at a single freestanding ambulatory surgery center, including line-by-line comparisons of demographic and comorbidity factors for all patients treated within the 90-day episode of care. RESULTS: Seventy-six primary anatomic TSAs were included, 39 in the bundled group and 37 outside of the program. The bundled group was on average older (58 years) than the unbundled group (54 years, P = 0.021), but the groups were otherwise similar in demographics. The average total implant charges were significantly less for the bundled group ($24,822.43 versus $28,405.51, P = 0.014). Average total surgery supply charges and anesthesia supply charges were similar (P > 0.05). Mean total outpatient surgical day charges (implants, surgical, and anesthesia equipment) were significantly less for the bundled group ($29,782.43 versus $33,238.68, P = 0.022), as were average operating room staffing costs ($135.37 versus $162.55, P = 0.015). During the 90-day postoperative period, charges were similar. CONCLUSIONS: Primary anatomic TSA using a bundled care program in an outpatient setting coincides with markedly lower charges. The primary driver of this reduction is implant pricing, which is negotiated as part of the bundle. Surgeons must carefully analyze their unique practices in the changing economic health care environment when creating an outpatient TSA and/or bundling program. LEVEL OF EVIDENCE: Level III economic analysis.

5.
Bioengineering (Basel) ; 6(3)2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31480458

RESUMO

Neutrophils, the first cells that interact with surface-adsorbed proteins on biomaterials, have been increasingly recognized as critical maestros in the foreign body response for guided tissue regeneration. Recent research has shown that small diameter (SD) fibers of electrospun tissue regeneration templates, which have a high surface area to volume ratio (SAVR), enhance the release of neutrophil extracellular traps (NETs) compared to large diameter (LD) fibers, resulting in impaired tissue regeneration. In this study, we evaluated the adsorption of eight human serum proteins on the surface of electrospun templates to investigate how protein adsorption may regulate the release of NETs. Electrospun polydioxanone templates made from SD fibers with high SAVR and LD fibers with low SAVR, were incubated with 0.2% human serum and in situ protein adsorption was quantified with infrared-based immunodetection. Of the detected proteins, IgM and vitronectin adsorbed at low levels, suggesting that they do not play a central role in the release of NETs. Contrastingly, albumin and IgG adsorbed rapidly to the surface of the templates. One-hundred to 200 times more IgG adsorbed on the templates compared to albumin, with significantly greater adsorption occurring on the SD templates with high SAVR. Given that neutrophils express receptors that interact with IgG during phagocytosis and NET release, these results suggest that SAVR-dependent adsorption of IgG on the SD electrospun templates may contribute to the up-regulated release of NETs. Overall, this study may aid in the design of immunomodulatory biomaterials that regulate NET release and thus the potential for neutrophil-driven tissue regeneration.

6.
Med One ; 4(2)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31245627

RESUMO

A large body of in vivo and in vitro evidence indicates that Manuka honey resolves inflammation and promotes healing when applied topically to a wound. In this study, the effect of two different concentrations (0.5% and 3% v/v) of Manuka honey on the release of cytokines, chemokines, and matrix-degrading enzymes from neutrophils was examined using a differentiated HL-60 cell line model in the presence of inflammatory stimuli. The results indicate that 0.5% honey decreased TNF-α, IL-1ß, MIP-1α, MIP-1ß, IL-12 p70, MMP-9, MMP-1, FGF-13, IL-1ra, and IL-4 release, but increased MIP-3α, Proteinase 3, VEGF, and IL-8 levels. In contrast, 3% honey reduced the release of all analytes except TNF-α, whose release was increased. Together, these results demonstrate a dose-dependent ability of Manuka honey to modify the release of cytokines, chemokines, and matrix-degrading enzymes that promote or inhibit inflammation and/or healing within a wound. The findings of this study provide further guidance for the future use of Manuka honey in wounds or tissue engineering templates. Future in vivo investigation is warranted to validate the in vitro results and translate these results to physiologically relevant environments.

7.
Int J Biomater ; 2019: 6132581, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30936919

RESUMO

Recent work has shown that Manuka honey, an increasingly popular wound additive with potent antibacterial properties, also has anti-inflammatory properties. However, little research has been done examining its effect on neutrophils. This study investigates the hypothesis that Manuka honey reduces neutrophil superoxide release and chemotaxis and reduces the activation of the inflammatory nuclear factor-κB (NF-κB) signaling pathway under honey's cytotoxic limit. A differentiated HL-60 cell line was used as a neutrophil model and cultured in various concentrations of Manuka honey for 3 and 24 hours to measure cytotoxicity via mitochondrial activity and visual trypan-exclusion count. Cytochrome C and Boyden chamber assays were used to measure the effect of Manuka honey on superoxide release and chemotaxis toward fMLP, respectively. Additionally, a Western blot for NF-κB inhibitor α (IκBα) was performed to measure Manuka honey's effect on the NF-κB pathway via IκBα phosphorylation. The results indicate a cytotoxic limit of 3-5% v/v. The presence of 1% honey decreased superoxide release at 24 hours. The 0.5, 1, and 3% honey concentrations reduced chemotaxis and IκBα phosphorylation in a dose-dependent fashion. These results suggest that Manuka honey significantly reduces neutrophil recruitment and inflammatory behavior in the wound site in a dose-dependent fashion under the cytotoxic limit.

8.
Muscle Nerve ; 59(5): 531-536, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30620104

RESUMO

INTRODUCTION: Universally established comprehensive clinical bulbar scales objectively assessing disease progression in amyotrophic lateral sclerosis (ALS) are currently lacking. The goal of this working group project is to design a best practice set of provisional bulbar ALS guidelines, available for immediate implementation within all ALS clinics. METHODS: ALS specialists across multiple related disciplines participated in a series of clinical bulbar symposia, intending to identify and summarize the currently accepted best practices for the assessment and management of bulbar dysfunction in ALS Results: Summary group recommendations for individual speech, Augmentative and Alternative Communication (AAC), and swallowing sections were achieved, focusing on the optimal proposed level of care within each domain. DISCUSSION: We have identified specific clinical recommendations for each of the 3 domains of bulbar functioning, available for incorporation within all ALS clinics. Future directions will be to establish a formal set of bulbar guidelines through a methodological and evidence-based approach. Muscle Nerve 59:531-531, 2019.


Assuntos
Esclerose Amiotrófica Lateral/reabilitação , Transtornos de Deglutição/reabilitação , Distúrbios da Fala/reabilitação , Esclerose Amiotrófica Lateral/complicações , Auxiliares de Comunicação para Pessoas com Deficiência , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/etiologia , Gerenciamento Clínico , Humanos , Encaminhamento e Consulta , Distúrbios da Fala/diagnóstico , Distúrbios da Fala/etiologia , Fonoterapia
9.
J Am Acad Orthop Surg ; 27(5): 177-182, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30192247

RESUMO

INTRODUCTION: Our purpose was to determine whether the chronic use of preoperative narcotics adversely affected clinical and/or radiographic outcomes. METHODS: Seventy-three patients (79 shoulders) with primary total shoulder arthroplasty for osteoarthritis were evaluated clinically and radiographically at preoperative visits and postoperatively at a minimum follow-up of 2 years: 26 patients (28 shoulders) taking chronic narcotic pain medication for at least 3 months before surgery and 47 patients (51 shoulders) who were not taking narcotics preoperatively. RESULTS: Postoperatively, significant differences were noted between the narcotic and nonnarcotic groups regarding American Shoulder and Elbow Surgeons scores and visual analog scale scores, as well as forward elevation, external rotation, and all strength measurements (P < 0.01). The nonnarcotic group had markedly higher American Shoulder and Elbow Surgeons scores, better overall range of motion and strength, and markedly lower visual analog scale scores than the narcotic group. CONCLUSION: Chronic preoperative narcotic use seems to be a notable indicator of poor outcomes of anatomic total shoulder arthroplasty for glenohumeral osteoarthritis.


Assuntos
Analgésicos Opioides/efeitos adversos , Artroplastia do Ombro , Osteoartrite/cirurgia , Articulação do Ombro/cirurgia , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/diagnóstico por imagem , Osteoartrite/fisiopatologia , Período Pré-Operatório , Amplitude de Movimento Articular , Articulação do Ombro/diagnóstico por imagem , Articulação do Ombro/fisiopatologia , Resultado do Tratamento
10.
J Shoulder Elbow Surg ; 27(12): 2257-2261, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30340926

RESUMO

BACKGROUND: Postoperative pain control, short-term and long-term narcotic consumption, complication rates, and costs of indwelling interscalene catheter (ISC) were compared with a liposomal bupivacaine (LBC) mixture in patients undergoing primary total elbow arthroplasty. METHODS: Forty-four consecutive patients were identified, the first 28 with an ISC and the later 16 with intraoperative LBC injection that also included ketorolac and 0.5% bupivacaine. Medical records were reviewed for visual analog scale scores for pain, oral morphine equivalent (OME) use, complications, and facility charges. RESULTS: Average visual analog scale scores at 24 hours, 2 weeks, 6 weeks, and 12 weeks were not significantly different. Mean OME use was significantly greater in the LBC group at 24 hours but less at 12 weeks, although this difference was not statistically significant. Twelve anesthetic-related complications occurred in the ISC group (1 major and 11 minor); 10 patients (36%) had at least 1 complication. The major complication was respiratory failure requiring emergent tracheostomy. Minor complications included leaking pump/catheters, catheters inadvertently pulled out early, global hand paresthesias, forearm paresthesias, and pain at the catheter site. There were no anesthetic-related complications in the LBC group. The average charge for the LBC mixture was $327.10; charges for ISC, including equipment and anesthesia fees, were $1472.42. CONCLUSIONS: An LBC mixture provides similar pain relief with fewer complications at a lower cost than indwelling ISC after total elbow arthroplasty. Although the OME use in the LBC group was almost double that of the ISC group at 24 hours, there was no difference at later time points.


Assuntos
Analgésicos não Entorpecentes/administração & dosagem , Anestésicos Locais/administração & dosagem , Artroplastia de Substituição do Cotovelo , Bupivacaína/administração & dosagem , Cetorolaco/administração & dosagem , Idoso , Analgésicos não Entorpecentes/efeitos adversos , Analgésicos não Entorpecentes/economia , Analgésicos Opioides/uso terapêutico , Anestésicos Locais/efeitos adversos , Anestésicos Locais/economia , Bupivacaína/efeitos adversos , Bupivacaína/economia , Cateteres de Demora , Combinação de Medicamentos , Uso de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Injeções , Cetorolaco/efeitos adversos , Cetorolaco/economia , Masculino , Morfina/uso terapêutico , Dor Pós-Operatória/prevenção & controle , Estudos Retrospectivos , Escala Visual Analógica
11.
Br J Clin Pharmacol ; 84(12): 2849-2856, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30152872

RESUMO

AIMS: A recent double-blind placebo-controlled crossover 70-day trial demonstrated that a fixed combination of dextromethorphan and quinidine (DM/Q) improves speech and swallowing function in most patients with amyotrophic lateral sclerosis. In this study, a subset of participants, many of whom did not substantially improve while on DM/Q, were re-evaluated using computer-based speech analyses and expert clinician ratings of the overall severity of speech impairment. METHODS: Speech samples were recorded from the subset of 10 patients at four visits made at approximately 30-day intervals. The recordings were analysed by automated computer-based analysis of speech pausing patterns. Severity of speech impairment was rated by three experienced speech-language pathologists using direct magnitude estimation. Scores on patient-reported and clinician-administered scales of bulbar motor involvement were obtained at each visit. RESULTS: The effects of DM/Q were detected on several of the objective speech measures, including total pause duration (s) (Cohen's d = 0.73, 95% confidence interval (CI) -1.70, 0.24), pause time (%) (d = 0.77, 95% CI -1.75, 0.21), and mean speech event duration (s) (d = 0.52, 95% CI -0.44, 1.47), but not on clinician ratings of speech or the speech components of the self-report or clinician-administered scales. CONCLUSIONS: These findings suggest that even patients with modest improvement while on DM/Q may experience quantifiable improvements in speech when assessed using sensitive and objective measures. This study provides additional evidence of the positive impact of DM/Q on one or more of the neural systems that control bulbar motor function and production of speech.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Dextrometorfano/uso terapêutico , Quinidina/uso terapêutico , Fala/efeitos dos fármacos , Adulto , Idoso , Esclerose Amiotrófica Lateral/fisiopatologia , Esclerose Amiotrófica Lateral/psicologia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
12.
Sci Rep ; 8(1): 4687, 2018 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-29535322

RESUMO

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

13.
J Shoulder Elbow Surg ; 27(8): 1462-1467, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29526600

RESUMO

BACKGROUND: To determine the effectiveness of hybrid glenoid components in reducing the frequency of glenoid component loosening, we evaluated clinical and radiographic outcomes at a minimum 5-year follow-up in 45 shoulders that underwent total shoulder arthroplasty (TSA) using a system with a central porous titanium post to augment the cemented peripheral pegs. METHODS: Function and pain were evaluated with the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment score, visual analog scale, active shoulder range of motion, and strength. Postoperative radiographs were analyzed for radiolucent lines, progressive loosening, and at-risk signs. RESULTS: The mean American Shoulder and Elbow Surgeons score improved from 40.4 to 83.7 (P < .0001) and the mean visual analog scale from 5.9 to 0.8 (P < .0001). Forward elevation improved from 113° to 151° (P < .001), internal rotation from 49° to 60° (P = .035), and mean external rotation from 36° to 50° (P = .0006). Radiographs showed glenoid component radiolucency in 29 shoulders. Radiolucencies were confined to the area under the glenoid faceplate in 6 and were only around the central post in 13. Nine TSAs (20%) demonstrated 2 or more columns of involvement but were not judged to be at-risk. One implant (2.2%) had glenoid component failure and was revised to a hemiarthroplasty. CONCLUSION: Anatomic TSA using a hybrid glenoid component with a central porous titanium post demonstrated a low rate of mechanical failure and a rate of radiolucent lines comparable to reports of all polyethylene implants. Further evaluations are needed to demonstrate the long-term durability of these implants and to determine the significance and fate of the radiolucent lines, particularly relative to the central post.


Assuntos
Artroplastia do Ombro/instrumentação , Articulação do Ombro/diagnóstico por imagem , Articulação do Ombro/cirurgia , Prótese de Ombro , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Osseointegração , Osteoartrite/cirurgia , Desenho de Prótese , Amplitude de Movimento Articular , Titânio , Escala Visual Analógica
14.
Nat Commun ; 9(1): 22, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29295973

RESUMO

The public health threat posed by a looming 'post-antibiotic' era necessitates new approaches to antibiotic discovery. Drug development has typically avoided exploitation of membrane-binding properties, in contrast to nature's control of biological pathways via modulation of membrane-associated proteins and membrane lipid composition. Here, we describe the rejuvenation of the glycopeptide antibiotic vancomycin via selective targeting of bacterial membranes. Peptide libraries based on positively charged electrostatic effector sequences are ligated to N-terminal lipophilic membrane-insertive elements and then conjugated to vancomycin. These modified lipoglycopeptides, the 'vancapticins', possess enhanced membrane affinity and activity against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria, and retain activity against glycopeptide-resistant strains. Optimised antibiotics show in vivo efficacy in multiple models of bacterial infection. This membrane-targeting strategy has potential to 'revitalise' antibiotics that have lost effectiveness against recalcitrant bacteria, or enhance the activity of other intravenous-administered drugs that target membrane-associated receptors.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Daptomicina/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Vancomicina/farmacologia , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacocinética , Bactérias/classificação , Sobrevivência Celular/efeitos dos fármacos , Glicopeptídeos/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos
15.
J Shoulder Elbow Surg ; 27(1): 23-28, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28747276

RESUMO

BACKGROUND: In the current health care environment, it is becoming increasingly important to recognize risks factors that may affect a patient's postoperative outcome. To determine the potential impact of tobacco as a risk factor, we evaluated postoperative pain, narcotic use, length of stay, reoperations, and complications in the global 90-day episode of care for patients undergoing anatomic total shoulder arthroplasty (TSA) who were current tobacco users, former users, or nonusers. METHODS: Database search identified 163 patients with primary anatomic TSA done for glenohumeral arthritis; these were divided into 3 groups: current tobacco users (28), nonusers (88), and former users (47). All surgeries were done with the same technique and implants. RESULTS: Patients in the current tobacco use group had significantly higher visual analog scale scores preoperatively and at 12 weeks postoperatively than nonusers and former users. Mean improvement in visual analog scale scores was significantly less in current tobacco users. Cumulative oral morphine equivalent use at 12 weeks was significantly higher in current tobacco users than in nonusers and former users. The average oral morphine equivalent per day was also significantly higher in the current tobacco users than in nonusers and former users. There were no significant differences in length of stay or complications. CONCLUSIONS: Although length of stay, complication rates, hospital readmissions, and reoperation rates were not significantly different, tobacco users reported increased postoperative pain and narcotic use in the global period after TSA. Former tobacco users were found to have a postoperative course similar to that of nonusers, suggesting that discontinuation of tobacco use can improve a patient's episode of care performance after TSA.


Assuntos
Analgésicos Opioides/uso terapêutico , Artroplastia do Ombro , Dor Pós-Operatória/etiologia , Uso de Tabaco , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite/cirurgia , Artroplastia do Ombro/efeitos adversos , Cuidado Periódico , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Medição da Dor , Reoperação , Estudos Retrospectivos , Fatores de Risco , Articulação do Ombro/cirurgia , Uso de Tabaco/efeitos adversos , Resultado do Tratamento
16.
Sci Rep ; 7(1): 16090, 2017 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-29170426

RESUMO

Complement activation is a recognised mediator of myocardial ischaemia-reperfusion-injury (IRI) and cardiomyocytes are a known source of complement proteins including the central component C3, whose activation products can mediate tissue inflammation, cell death and profibrotic signalling. We investigated the potential to detect and quantify the stable covalently bound product C3d by external body imaging, as a marker of complement activation in heart muscle in a murine model of myocardial IRI. We used single-photon-emission-computed-tomography (SPECT) in conjunction with 99mTechnecium-labelled recombinant complement receptor 2 (99mTc-rCR2), which specifically detects C3d at the site of complement activation. Compared to control imaging with an inactive CR2 mutant (99mTc-K41E CR2) or an irrelevant protein (99mTc-PSMA) or using 99mTc-rCR2 in C3-deficient mice, the use of 99mTc-rCR2 in complement-intact mice gave specific uptake in the reperfused myocardium. The heart to skeletal muscle ratio of 99mTc-rCR2 was significantly higher than in the three control groups. Histological analysis confirmed specific uptake of 99mTc-rCR2. Following therapeutic inhibition of complement C3 activation, we found reduced myocardial uptake of 99mTc-rCR2. We conclude, therefore that 99mTc-rCR2 imaging can be used for non-invasive detection of activated complement and in future could be exploited to quantify the severity of myocardial damage due to complement activation.


Assuntos
Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Cintilografia/métodos , Animais , Modelos Animais de Doenças , Feminino , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/metabolismo , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único
17.
Trials ; 18(1): 255, 2017 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-28587616

RESUMO

BACKGROUND: Delayed graft function (DGF) is traditionally defined as the requirement for dialysis during the first week after transplantation. DGF is a common complication of renal transplantation, and it negatively affects short- and long-term graft outcomes. Ischaemia reperfusion injury (IRI) is a prime contributor to the development of DGF. It is well established that complement system activation plays a pivotal role in the pathogenesis of IRI. Mirococept is a highly effective complement inhibitor that can be administered ex vivo to the donor kidney just before transplantation. Preclinical and clinical evidence suggests that Mirococept inhibits inflammatory responses that follow IRI. The EMPIRIKAL trial (REC 12/LO/1334) aims to evaluate the efficacy of Mirococept in reducing the incidence of DGF in cadaveric renal transplantation. METHODS/DESIGN: EMPIRIKAL is a multicentre double-blind randomised case-control trial designed to test the superiority of Mirococept in the prevention of DGF in cadaveric renal allografts, as compared to standard cold perfusion fluid (Soltran®). Patients will be randomised to Mirococept or placebo (Pbo) and will be enrolled in cohorts of N = 80 with a maximum number of 7 cohorts. The first cohort will be randomised to 10 mg of Mirococept or Pbo. After the completion of each cohort, an interim analysis will be carried out in order to evaluate the dose allocation for the next cohort (possible doses: 5-25 mg). Immunosuppression therapy, antibiotic and antiviral prophylaxis will be administered as per local centre protocols. The enrolment will take approximately 24 months, and patients will be followed for 12 months. The primary endpoint is DGF, defined as the requirement for dialysis during the first week after transplantation. Secondary endpoints include duration of DGF, functional DGF, renal function at 12 months, acute rejection episodes at 6 and 12 months, primary non-function and time of hospital stay on first admission and in the first year following transplant. Safety evaluation will include the monitoring of laboratory data and the recording of all adverse events. DISCUSSION: The EMPIRIKAL trial is the first study to evaluate the efficacy of an ex vivo administered complement inhibitor (Mirococept) in preventing DGF in cadaveric human renal transplantation. Mirococept has a unique 'cytotopic' property that permits its retention in the organ microvasculature. TRIAL REGISTRATION: ISRCTN registry, ISRCTN49958194 . Registered on 3 August 2012.


Assuntos
Inativadores do Complemento/administração & dosagem , Função Retardada do Enxerto/prevenção & controle , Transplante de Rim/efeitos adversos , Fragmentos de Peptídeos/administração & dosagem , Receptores de Complemento 3b/química , Traumatismo por Reperfusão/prevenção & controle , Aloenxertos , Protocolos Clínicos , Inativadores do Complemento/efeitos adversos , Função Retardada do Enxerto/diagnóstico , Função Retardada do Enxerto/imunologia , Método Duplo-Cego , Esquema de Medicação , Humanos , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/química , Traumatismo por Reperfusão/diagnóstico , Traumatismo por Reperfusão/imunologia , Projetos de Pesquisa , Fatores de Tempo , Resultado do Tratamento , Reino Unido
18.
J Arthroplasty ; 32(11): 3557-3562, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28390888

RESUMO

BACKGROUND: The efficacy and costs of indwelling interscalene catheter (ISC) and liposomal bupivacaine (LBC), with and without adjunctive medications, in patients with primary shoulder arthroplasty are a source of current debate. METHODS: In 214 arthroplasties, 156 patients had ISC and 58 had LBC injections that were mixed with morphine, ketorolac, and 0.5% bupivacaine with epinephrine. Charts were reviewed for visual analog scale pain scores, oral morphine equivalent (OME) usage, major complications, and costs. RESULTS: Visual analog scale scores were not significantly different at 24 hours or at 2, 6, and 12 weeks. Average OME consumption at 24 hours was significantly more with LBC, but was not significantly different at 12 weeks. Relative risk of a major complication was nearly 4 times higher with ISC than with LBC. The average cost for the LBC mixture was $289.04, and for ISC, including equipment and anesthesia fees, was $1559.42. CONCLUSION: The intraoperative LBC mixture provided equivalent pain relief with significantly fewer major complications and at markedly lower cost than ISC. LBC required almost twice as much OME to attain the same level of pain relief at 24 hours, but there was no significant difference in the cumulative amount of outpatient narcotic use.


Assuntos
Anestésicos Locais/administração & dosagem , Artroplastia do Ombro/efeitos adversos , Bupivacaína/administração & dosagem , Cateteres de Demora/efeitos adversos , Dor Pós-Operatória/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos/administração & dosagem , Anestésicos Locais/economia , Bupivacaína/economia , Cateterismo , Cateteres de Demora/economia , Epinefrina/administração & dosagem , Feminino , Humanos , Cetorolaco/administração & dosagem , Tempo de Internação , Lipossomos , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Manejo da Dor , Medição da Dor , Dor Pós-Operatória/etiologia , Estudos Retrospectivos , Ombro
19.
J Shoulder Elbow Surg ; 26(1): 140-143, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27727050

RESUMO

BACKGROUND: Two popular systems for classifying rheumatoid arthritis affecting the elbow are the Larsen and Sharp schemes. To our knowledge, no study has investigated the reliability of these 2 systems. We compared the intraobserver and interobserver agreement of the 2 systems to determine whether one is more reliable than the other. METHODS: The radiographs of 45 patients diagnosed with rheumatoid arthritis affecting the elbow were evaluated. Anteroposterior and lateral radiographs were deidentified and distributed to 6 evaluators (4 fellowship-trained upper extremity surgeons and 2 orthopedic trainees). Each evaluator graded all 45 radiographs according to the Larsen and Sharp scoring methods on 2 occasions, at least 2 weeks apart. RESULTS: Overall intraobserver reliability was 0.93 (95% confidence interval [CI], 0.90-0.95) for the Larsen system and 0.92 (95% CI, 0.86-0.96) for the Sharp classification, both indicating substantial agreement. Overall interobserver reliability was 0.70 (95% CI, 0.60-0.80) for the Larsen classification and 0.68 (95% CI, 0.54-0.81) for the Sharp system, both indicating good agreement. There were no significant differences in the intraobserver or interobserver reliability of the systems overall and no significant differences in reliability between attending surgeons and trainees for either classification system. CONCLUSION: The Larsen and Sharp systems both show substantial intraobserver reliability and good interobserver agreement for the radiographic classification of rheumatoid arthritis affecting the elbow. Differences in training level did not result in substantial variances in reliability for either system. We conclude that both systems can be reliably used to evaluate rheumatoid arthritis of the elbow by observers of varying training levels.


Assuntos
Artrite Reumatoide/classificação , Articulação do Cotovelo , Artrite Reumatoide/diagnóstico por imagem , Humanos , Variações Dependentes do Observador , Radiografia , Reprodutibilidade dos Testes
20.
Sci Rep ; 6: 38446, 2016 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-27910935

RESUMO

The plasma membrane provides an essential barrier, shielding a cell from the pressures of its external environment. Pore-forming proteins, deployed by both hosts and pathogens alike, breach this barrier to lyse target cells. Intermedilysin is a cholesterol-dependent cytolysin that requires the human immune receptor CD59, in addition to cholesterol, to form giant ß-barrel pores in host membranes. Here we integrate biochemical assays with electron microscopy and atomic force microscopy to distinguish the roles of these two receptors in mediating structural transitions of pore formation. CD59 is required for the specific coordination of intermedilysin (ILY) monomers and for triggering collapse of an oligomeric prepore. Movement of Domain 2 with respect to Domain 3 of ILY is essential for forming a late prepore intermediate that releases CD59, while the role of cholesterol may be limited to insertion of the transmembrane segments. Together these data define a structural timeline for ILY pore formation and suggest a mechanism that is relevant to understanding other pore-forming toxins that also require CD59.


Assuntos
Bacteriocinas/metabolismo , Antígenos CD59/metabolismo , Colesterol/metabolismo , Interações Hospedeiro-Patógeno , Bacteriocinas/química , Bacteriocinas/genética , Sítios de Ligação , Antígenos CD59/química , Antígenos CD59/genética , Membrana Celular/química , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Colesterol/química , Humanos , Microscopia de Força Atômica , Porinas/química , Porinas/genética , Porinas/metabolismo , Domínios Proteicos/genética
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