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1.
Crit Care ; 26(1): 384, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36514110

RESUMO

BACKGROUND: In the context of COVID-19 pandemic, antifungal overuse may have occurred in our hospitals as it has been previously reported for antibacterials. METHODS: To investigate the impact of COVID-19 on antifungal consumption, a multicenter retrospective study including four medical sites and 14 intensive care units (ICU) was performed. Antifungal consumption and incidences of invasive fungal diseases before and during COVID-19 pandemic, for non-COVID-19 patients and COVID-19 patients, were described. RESULTS: An increase in voriconazole consumption was observed in 2020 compared with 2019 for both the whole hospital and the ICU (+ 40.3% and + 63.7%, respectively), whereas the incidence of invasive aspergillosis significantly increased in slightly lower proportions in the ICU (+ 46%). Caspofungin consumption also increased in 2020 compared to 2019 for both the whole hospital and the ICU (+ 34.9% and + 17.0%, respectively) with an increased incidence of invasive candidiasis in the whole hospital and the ICU but in lower proportions (+ 20.0% and + 10.9%, respectively). CONCLUSIONS: We observed an increased consumption of antifungals including voriconazole and caspofungin in our hospital during the COVID-19 pandemic and explained in part by an increased incidence of invasive fungal diseases in COVID-19 patients. These results are of utmost importance as it raises concern about the urgent need for appropriate antifungal stewardship activities to control antifungal consumption.


Assuntos
COVID-19 , Candidíase , Humanos , Antifúngicos/uso terapêutico , Caspofungina/uso terapêutico , Voriconazol/uso terapêutico , Estudos Retrospectivos , Pandemias , COVID-19/epidemiologia , Candidíase/tratamento farmacológico , Unidades de Terapia Intensiva
2.
J Antimicrob Chemother ; 77(9): 2532-2535, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-35696322

RESUMO

BACKGROUND: Necrotizing external otitis (NEO) is a severe infection of the skull base that occurs generally in the elderly and/or in diabetic recipients. There are few data in the literature about the therapeutic management of this complex bone infection. OBJECTIVES: To analyse relapses after NEO treatment completion, and to describe the clinical features of NEO. METHODS: We performed a retrospective cohort study in the Lyon regional reference centre for the management of complex bone and joint infections. Consecutive cases of NEO from 1 January 2006 to 31 December 2018 were included. The primary outcome was the relapse of NEO. Variables were analysed using Cox regression survival analysis with adjusted hazard ratio (aHR) and Kaplan-Meier curve. RESULTS: Sixty-six patients were included. Median age was 75 (IQR 69-81) years and 46 (70%) patients were diabetic. Eleven patients (17%) had temporomandibular arthritis, 10 (15%) cranial nerve paralysis, 2 (3%) cerebral thrombophlebitis, and 2 (3%) contiguous abscess. Microbiological documentation was obtained in 56 patients and revealed Pseudomonas aeruginosa in 44/56 patients (79%). Nine (14%) cases had no microbiological documentation. Antibiotic therapy was dual for 63 (95%) patients. During a median follow-up of 27 (IQR 12-40) months, 16 out of 63 (25%) patients experienced a relapse. Fungal infection was significantly associated with relapse [aHR 4.1 (95% CI 1.1-15); P = 0.03]. CONCLUSIONS: NEO is a severe bone infection, mainly (but not exclusively) caused by P. aeruginosa, which occurs in elderly and diabetic recipients. Fungal infections at baseline significantly impact the outcome.


Assuntos
Diabetes Mellitus , Osteomielite , Otite Externa , Infecções por Pseudomonas , Idoso , Humanos , Osteomielite/tratamento farmacológico , Osteomielite/microbiologia , Otite Externa/tratamento farmacológico , Otite Externa/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa , Recidiva , Estudos Retrospectivos , Fatores de Risco
3.
J Med Microbiol ; 71(6)2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35771615

RESUMO

Introduction. Antifungal stewardship programmes are needed in healthcare facilities to limit the overuse or misuse of antifungals, which are responsible for an increase in antifungal resistance.Hypothesis/Gap Statement. Core recommendations for antifungal stewardship were published by the Mycoses Study Group Education and Research Consortium, while the Centers for Disease Control and Prevention (CDC) provided a Core Elements of Hospital Antibiotic Stewardship Programs checklist. The recommendations offer global core elements for best practices in antifungal stewardship, but do not provide a framework for the implementation of antifungal stewardship programmes in healthcare facilities.Aim. In line with the recommendations, it is of the utmost importance to establish a practical checklist that may be used to implement antifungal stewardship programmes.Methodology. The practical checklist was established by a national consensus panel of experts involved in antifungal stewardship activities. A preliminary checklist was sent to all experts. The final document was approved by the panel after discussion and the resolution of any disagreements by consensus.Results. The final checklist includes the following items: leadership support; actions to support optimal antifungal use; actions to monitor antifungal prescribing, use and resistance; and an education programme.Conclusion. This antifungal stewardship checklist offers opportunities for antifungal resistance containment, given that antifungal stewardship activities promote the optimal use of antifungals.


Assuntos
Gestão de Antimicrobianos , Micoses , Antibacterianos/farmacologia , Antifúngicos/uso terapêutico , Lista de Checagem , Farmacorresistência Fúngica , Humanos , Micoses/tratamento farmacológico
4.
Pharmaceutics ; 14(1)2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-35057009

RESUMO

Daptomycin is a candidate for therapeutic drug monitoring (TDM). The objectives of this work were to implement and compare two pharmacometric tools for daptomycin TDM and precision dosing. A nonparametric population PK model developed from patients with bone and joint infection was implemented into the BestDose software. A published parametric model was imported into Tucuxi. We compared the performance of the two models in a validation dataset based on mean error (ME) and mean absolute percent error (MAPE) of individual predictions, estimated exposure and predicted doses necessary to achieve daptomycin efficacy and safety PK/PD targets. The BestDose model described the data very well in the learning dataset. In the validation dataset (94 patients, 264 concentrations), 21.3% of patients were underexposed (AUC24h < 666 mg.h/L) and 31.9% of patients were overexposed (Cmin > 24.3 mg/L) on the first TDM occasion. The BestDose model performed slightly better than the model in Tucuxi (ME = -0.13 ± 5.16 vs. -1.90 ± 6.99 mg/L, p < 0.001), but overall results were in agreement between the two models. A significant proportion of patients exhibited underexposure or overexposure to daptomycin after the initial dosage, which supports TDM. The two models may be useful for model-informed precision dosing.

5.
Open Forum Infect Dis ; 8(7): ofab351, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34337099

RESUMO

A prospective cohort study was conducted to evaluate long-term safety of tedizolid as suppressive antimicrobial treatment in patients with implant-associated bone and joint infection caused by multidrug-resistant gram-positive pathogens. Seventeen patients received tedizolid with a median duration of treatment of 6 months. No patients developed a serious adverse event.

7.
J Antimicrob Chemother ; 76(5): 1250-1257, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33550409

RESUMO

BACKGROUND: Daptomycin is increasingly used in the treatment of bone and joint infection (BJI), but its pharmacokinetics (PK) and dosage requirements have not been thoroughly investigated in this indication. Daptomycin may be co-administered with rifampicin, which raises questions about a potential drug interaction. OBJECTIVES: To investigate the population PK and dosage requirements of daptomycin in patients with BJI, and examine the influence of rifampicin co-administration. METHODS: A population approach was used to analyse PK data from patients who received daptomycin in our regional reference for BJI. We examined the influence of available covariates, including rifampicin co-administration on daptomycin PK. Simulations performed with the final model investigated the influence of dosages and covariates on PTA for both efficacy and safety. RESULTS: A total of 1303 daptomycin concentrations from 183 patients were analysed. A two-compartment model best described the data. Significant intra-individual variability was observed. Daptomycin clearance was influenced by renal function and sex, with females having a 26% lower typical clearance than males. Central volume of distribution (V1) was influenced by body weight, age, sex and rifampicin co-administration. Typical V1 was 11% lower in patients who were co-administered rifampicin. In PK/PD simulations, sex influenced the probability of AUC24/MIC target attainment, while rifampicin had a marginal effect. CONCLUSIONS: A daptomycin dosage of 8 mg/kg/24 h in women and 10 mg/kg/24 h in men should optimize efficacy but may lead to excessive trough concentrations in many patients, especially in women. Therapeutic drug monitoring appears necessary for precision dosing of daptomycin.


Assuntos
Daptomicina , Antibacterianos , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Rifampina , Caracteres Sexuais
8.
Front Med (Lausanne) ; 7: 513242, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33195289

RESUMO

Background: P. aeruginosa implant-associated bone and joint infections (BJI) is considered to be one of the most difficult to treat BJI. The data focusing specifically on this pathogen are sparse, and it seems difficult to extrapolate the results obtained with Enterobacteriaceae. Methods: We performed a retrospective observation study of all P. aeruginosa implant-associated BJI diagnosed at our institution from 2011 to 2018. We defined failure as any type of relapse, including persistence of the same P. aeruginosa, superinfection by another organism(s) or any other cause of relapse such as the need for a subsequent surgery. Nonparametric statistical methods were used to compare the study groups and Kaplan-Meier curves and multivariate Cox analysis and were used to detect determinants associated with treatment failure. Results: A total of 90 patients (62% men, median age 60 years IQR 47-72) including 30 (33%) prosthetic-joint infections and 60 (66%) other implant-associated BJIs were studied. Most of them were acute (62%). During the prolonged follow-up, (median 20 months; IQR 9-37), 23 patients (26%) experienced treatment failure. Optimal surgical treatment (DAIR for acute forms, explantation, 1-stage or 2-stage exchange for others) was significantly associated with a higher success rate in the univariate analysis (p = 0.003). Sixty-four (71%) patients received effective initial treatment against P. aeruginosa administered and 81 of them (90%) did for at least 3 weeks: both these parameters correlated with a higher success rate. In the multivariate Cox-analysis optimal surgical treatment, IV effective treatment of at least 3 weeks and treatment with ciprofloxacin for at least 3 months proved to be independently associated to a better outcome in patients with P. aeruginosa implant-associated BJI. Conclusion: P. aeruginosa implant-associated BJI is one of the most difficult-to-treat BJI, with a strong impact on the prognosis of the surgical strategy. An effective initial IV antibiotic treatment for at least 3 weeks seems to be required, followed by oral ciprofloxacin for a total duration of 3 months.

11.
J Antimicrob Chemother ; 74(4): 1012-1020, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30629193

RESUMO

BACKGROUND: Daptomycin has been recognized as a therapeutic option for the treatment of bone and joint infection (BJI). Gene polymorphism of ABCB1, the gene encoding P-glycoprotein (P-gp), may influence daptomycin pharmacokinetics (PK). OBJECTIVES: We aimed to examine population PK of daptomycin and its determinants, including genetic factors, in patients with BJI. PATIENTS AND METHODS: We analysed data from patients who received daptomycin for BJI between 2012 and 2016 in our regional reference centre and who had measured daptomycin concentrations and P-gp genotyping. A population approach was used to analyse PK data. In covariate analysis, we examined the influence of three single nucleotide variations (SNVs) of ABCB1 (3435C > T, 2677G > T/A and 1236C > T) and that of the corresponding haplotype on daptomycin PK parameters. Simulations performed with the final model examined the influence of covariates on the probability to achieve pharmacodynamic (PD) targets. RESULTS: Data from 81 patients were analysed. Daptomycin body CL (CLDAP) correlated with CLCR and was 23% greater in males than in females. Daptomycin central V (V1) was allometrically scaled to body weight and was 25% lower in patients with homozygous CGC ABCB1 haplotype than in patients with any other genotype. Simulations performed with the model showed that sex and P-gp haplotype may influence the PTA for high MIC values and that a dosage of 10 mg/kg/24 h would optimize efficacy. CONCLUSIONS: Daptomycin dosages higher than currently recommended should be evaluated in patients with BJI. Gender and P-gp gene polymorphism should be further examined as determinants of dosage requirements.


Assuntos
Antibacterianos/farmacocinética , Daptomicina/farmacocinética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Alelos , Área Sob a Curva , Artrite Infecciosa/tratamento farmacológico , Artrite Infecciosa/epidemiologia , Artrite Infecciosa/genética , Doenças Ósseas Infecciosas/tratamento farmacológico , Doenças Ósseas Infecciosas/epidemiologia , Doenças Ósseas Infecciosas/genética , Monitoramento de Medicamentos , Feminino , Genótipo , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética/métodos , Vigilância da População
12.
BMC Infect Dis ; 18(1): 659, 2018 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-30547753

RESUMO

BACKGROUND: Nontuberculous mycobacteria (NTM) lung diseases are increasingly recognized as chronic opportunistic infections, occurring in individuals with a wide variety of underlying conditions. In the absence of systemic immunodeficiency, decision of NTM lung disease treatment must relies on a careful risk/benefit assessment, given the requirement of long-term administration of multidrug therapies supported by limited evidence. The primary objective was to identify the factors associated with anti-NTM treatment initiation. Clinical and radiological outcome upon treatment were studied. METHODS: This retrospective, single center study (2013-2016, 45 months) addressed the criteria supporting treatment decision among adults with NTM lung disease without systemic immunodeficiency at our institution, with the assigned goal to harmonize the practice. All patients matched the current international definitions of NTM lung disease according to the American Thoracic Society criteria. Factors associated with anti-NTM treatment were investigated by conditional logistic regression. Clinical and radiological outcomes of treated and untreated NTM-disease cases were examined. Mortality rate was assessed. An expert radiologist conducted a blinded computed tomography (CT)-scan review of the treated and untreated patients. RESULTS: Among 51 cases of NTM lung diseases, 25 (49%) received anti-NTM treatment. In univariate analysis, a body mass index (BMI) < 18 kg/m2 (odds ratio (OR), 4.2 [95% confidence interval (CI) 1.2-15.2]; p = 0.042), hemoptysis (OR, 11.8 [95% CI 1.35-12.9]; p = 0.026), excavation(s) (OR, 4.8 [95% CI 1.4-16.4], p = 0.012), prior anti-NTM treatment (OR, 5.65 [95% CI 1.06-29.9]; p = 0.042), Aspergillus spp. co-infection (OR, 6.3 [95% CI 1.8-22.2]; p = 0.004) were associated with treatment initiation. In multivariate analysis, Aspergillus spp. co-infection was the only independent determinant of treatment initiation (OR, 5.3 [95% CI 1.1-25.4]; p = 0.036). Twenty-one (81%) patients received ≥3 anti-NTM drugs. Median treatment duration and follow-up were 36.3 (interquartile range [IQR], 13.1-64.4) weeks and 17.1 (IQR, 8.7-27.1) months, respectively. Regarding radiological outcome, 85 CT-scans were reviewed, showing similar rates of regression or stabilization in treated and untreated patients. Overall mortality rate was not different in treated and untreated patients. CONCLUSION: The most relevant variable associated with anti-NTM treatment initiation was Aspergillus spp. co-infection. Radiological regression or stabilization of pulmonary lesions was not different between the treated and untreated patients.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Adulto , Tomada de Decisão Clínica , Humanos , Modelos Logísticos , Infecções por Mycobacterium não Tuberculosas/diagnóstico por imagem , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Infecções por Mycobacterium não Tuberculosas/terapia , Estudos Retrospectivos
14.
BMC Musculoskelet Disord ; 18(1): 218, 2017 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-28545490

RESUMO

BACKGROUND: A body of evidence demonstrating changes to the glutaminergic system in tendinopathy has recently emerged. This hypothesis was further tested by studying the effects of glutamate on the tenocyte phenotype, and the impact of loading and exposure to glucocorticoids on the glutamate signaling machinery. METHODS: Plantaris tendon tissue and cultured plantaris tendon derived cells were immunohisto-/cytochemically stained for glutamate, N-Methyl-D-Aspartate receptor 1 (NMDAR1) and vesicular glutamate transporter 2 (VGluT2). Primary cells were exposed to glutamate or receptor agonist NMDA. Cell death/viability was measured via LDH/MTS assays, and Western blot for cleaved caspase 3 (c-caspase 3) and cleaved poly (ADP-ribose) polymerase (c-PARP). Scleraxis mRNA (Scx)/protein(SCX) were analyzed by qPCR and Western blot, respectively. A FlexCell system was used to apply cyclic strain. The effect of glucocorticoids was studies by adding dexamethasone (Dex). The mRNA of the glutamate synthesizing enzymes Got1 and Gls, and NMDAR1 protein were measured. Levels of free glutamate were determined by a colorimetric assay. RESULTS: Immunoreactions for glutamate, VGluT2, and NMDAR1 were found in tenocytes and peritendinous cells in tissue sections and in cultured cells. Cell death was induced by high concentrations of glutamate but not by NMDA. Scleraxis mRNA/protein was down-regulated in response to NMDA/glutamate stimulation. Cyclic strain increased, and Dex decreased, Gls and Got1 mRNA expression. Free glutamate levels were lower after Dex exposure. CONCLUSIONS: In conclusion, NMDA receptor stimulation leads to a reduction of scleraxis expression that may be involved in a change of phenotype in tendon cells. Glutamate synthesis is increased in tendon cells in response to strain and decreased by glucocorticoid stimulation. This implies that locally produced glutamate could be involved in the tissue changes observed in tendinopathy.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Ácido Glutâmico/farmacologia , Músculo Esquelético/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Receptores de N-Metil-D-Aspartato/biossíntese , Tendões/metabolismo , Adulto , Idoso , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Proteínas do Tecido Nervoso/agonistas , Receptores de N-Metil-D-Aspartato/agonistas , Tendões/citologia , Tendões/efeitos dos fármacos , Proteína Vesicular 2 de Transporte de Glutamato/biossíntese , Adulto Jovem
15.
BMC Infect Dis ; 16: 83, 2016 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-26888539

RESUMO

BACKGROUND: Even if daptomycin does not have approval for the treatment of bone and joint infections (BJI), the Infectious Diseases Society of America guidelines propose this antibiotic as alternative therapy for prosthetic joint infection. The recommended dose is 6 mg/kg/d, whereas recent data support the use of higher doses in these patients. METHODS: We performed a cohort study including consecutive patients that have received daptomycin >6 mg/kg/d for complex BJI between 2011 and 2013 in a French regional reference center. Factors associated with treatment failure were determined on univariate Cox analysis and Kaplan-Meier curves. RESULTS: Forty-three patients (age, 61 ± 17 years) received a mean dose of 8 ± 0.9 mg/kg/d daptomycin, for a mean 81 ± 59 days (range, 6-303 days). Most had chronic (n = 37, 86 %) implant-associated (n = 37, 86 %) BJI caused by coagulase-negative staphylococci (n = 32, 74 %). A severe adverse event (SAE) occurred in 6 patients (14 %), including 2 cases of eosinophilic pneumonia, concomitant with daptomycin Cmin >24 mg/L. Outcome was favorable in 30 (77 %) of the 39 clinically assessable patients. Predictors for treatment failure were age, non-optimal surgery and daptomycin withdrawal for SAE. CONCLUSIONS: Prolonged high-dose daptomycin therapy was effective in patients with complex BJI. However, optimal surgery remains the cornerstone of medico-surgical strategy; and a higher incidence of eosinophilic pneumonia than expected was recorded.


Assuntos
Antibacterianos/uso terapêutico , Daptomicina/uso terapêutico , Prótese Articular/efeitos adversos , Infecções Relacionadas à Prótese/tratamento farmacológico , Terapia de Salvação/métodos , Infecções Estafilocócicas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Falha de Tratamento , Resultado do Tratamento , Adulto Jovem
16.
Antimicrob Agents Chemother ; 60(5): 3148-51, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26902764

RESUMO

The interindividual and intraindividual variabilities in daptomycin pharmacokinetics were investigated in 23 patients (69 pharmacokinetic profiles) who were treated for several months for bone and joint infections. Population daptomycin clearance was significantly influenced by renal function and was significantly higher in male than in female patients. We observed significant intraindividual changes in daptomycin clearance, which were uncorrelated with changes in renal function, suggesting that therapeutic drug monitoring is important in patients receiving prolonged daptomycin therapy.


Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Artrite Infecciosa/tratamento farmacológico , Daptomicina/farmacocinética , Daptomicina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Adulto Jovem
17.
J Infect ; 72(2): 214-22, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26518057

RESUMO

OBJECTIVES: Human herpes virus 6 (HHV-6) can reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with significant clinical manifestations. METHODS: Case control study of HHV-6 infections after allo-HSCT. Chromosomal integration (ciHHV-6) for viral loads ≥ 5.5-log10 copies/mL was investigated. Viral co-infections, T-cell recovery, risk factors and outcome were compared in HHV-6- and non-HHV-6-infected patients. Antiviral treatment strategies were reviewed. RESULTS: Among 366 adult allo-HSCT recipients, 75 HHV-6 infections occurred. Three (4%) recipients were ciHHV-6. HHV-6 infections were associated with CMV (p = 0.05; sdHR 1.73, CI 0.99-3.02) and/or BKV infections (p < 0.0001; sdHR 4.63, CI 2.04-10.53) but not EBV reactivation (p = 0.34). A slower CD8+ T-cells recovery was observed until 6 months after allo-HSCT in the HHV-6-infected group (p < 0.001), independently of acute and/or chronic graft-versus-host disease. The overall probability of survival after allo-HSCT was diminished for active HHV-6-infected patients (p = 0.0326). Cord blood unit recipients had a higher risk of developing HHV-6 infection compared to bone marrow recipients (p = 0.0007; sdHR 3.82, CI 1.76-8.27). Anti-HHV-6 treatment achieved complete response in only 2/3 of the cases. CONCLUSIONS: In this series of allo-HSCT recipients, 4% were ciHHV-6, active HHV-6 infection was likely associated with CMV and BKV co-reactivations, delayed CD8+ T-cell recovery and poorer outcome.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 6/fisiologia , Infecções por Roseolovirus/epidemiologia , Infecções por Roseolovirus/patologia , Transplante Homólogo/efeitos adversos , Integração Viral , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Coinfecção/epidemiologia , Coinfecção/patologia , Coinfecção/virologia , Feminino , Herpesvirus Humano 6/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Roseolovirus/virologia , Ativação Viral , Adulto Jovem
18.
Mol Pharmacol ; 89(2): 215-25, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26646648

RESUMO

Keratocytes, the resident cells of the corneal stroma, are responsible for maintaining turnover of this tissue by synthesizing extracellular matrix components. When the cornea is injured, the keratocytes migrate to the wounded site and participate in the stromal wound healing. The neuropeptide substance P (SP), which is also known to be produced by non-neuronal cells, has previously been implicated in epithelial wound healing after corneal injury. Corneal scarring, which occurs in the stroma when the process of wound healing has malfunctioned, is one of the major causes of preventable blindness. This study aimed to elucidate the potential role of SP in keratocyte migration and therefore in stromal wound healing. We report that the expression and secretion of SP in human keratocytes are increased in response to injury in vitro. Moreover, SP enhances the migration of keratocytes by inducing the actin cytoskeleton reorganization and focal adhesion formation through the activation of the phosphatidylinositide 3-kinase and Ras-related C3 botulinum toxin substrate 1/Ras homolog gene family, member A pathway. Furthermore, SP stimulation leads to upregulated expression of the proinflammatory and chemotactic cytokine interleukin-8 (IL-8), which also contributes significantly to SP-enhanced keratocyte migration and is able to attract neutrophils. In addition, the preferred SP receptor, the neurokinin-1 receptor, is necessary to induce keratocyte migration and IL-8 secretion. In conclusion, we describe new mechanisms by which SP enhances migration of keratocytes and recruits neutrophils, two necessary steps in the corneal wound-healing process, which are also likely to occur in other tissue injuries.


Assuntos
Movimento Celular/fisiologia , Ceratócitos da Córnea/metabolismo , Interleucina-8/biossíntese , Infiltração de Neutrófilos/fisiologia , Substância P/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Ceratócitos da Córnea/efeitos dos fármacos , Humanos , Infiltração de Neutrófilos/efeitos dos fármacos , Substância P/farmacologia , Cicatrização/efeitos dos fármacos , Cicatrização/fisiologia
19.
Curr Eye Res ; 41(8): 1035-1043, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26673553

RESUMO

PURPOSE: Transforming growth factor beta 1 (TGF-ß1) is a cytokine involved in a variety of processes, such as differentiation of fibroblasts into myofibroblasts. TGF-ß1 has also been shown to delay the internalization of the neurokinin-1 receptor (NK-1 R) after its activation by its ligand, the neuropeptide substance P (SP). NK-1 R comprises two naturally occurring variants, a full-length and a truncated form, triggering different cellular responses. SP has been shown to affect important events in the cornea - such as stimulating epithelial cell proliferation - processes that are involved in corneal wound healing and thus in maintaining the transparency of the corneal stroma. An impaired signaling through NK-1 R could thus impact the visual quality. We hypothesize that TGF-ß1 modulates the expression pattern of NK-1 R in human corneal stroma cells, keratocytes. The purpose of this study was to test that hypothesis. METHODS: Cultures of primary keratocytes were set up with cells derived from healthy human corneas, obtained from donated transplantation graft leftovers, and characterized by immunocytochemistry and Western blot. Immunocytochemistry for TGF-ß receptors and NK-1 R was performed. Gene expression was assessed with real-time polymerase chain reaction (qPCR). RESULTS: Expression of TGF-ß receptors was confirmed in keratocytes in vitro. Treating the cells with TGF-ß1 significantly reduced the gene expression of NK-1 R. Furthermore, immunocytochemistry for NK-1 R demonstrated that it is specifically the expression of the full-length isotype of the receptor that is reduced after treatment with TGF-ß1, which was also confirmed with qPCR using a specific probe for the full-length receptor. CONCLUSIONS: TGF-ß1 down-regulates the gene expression of the full-length variant of NK-1 R in human keratocytes, which might impact its signaling pathway and thus explain the known delay in internalization after activation by SP seen with TGF-ß1 treatment.


Assuntos
Ceratócitos da Córnea/metabolismo , Regulação da Expressão Gênica , RNA/genética , Receptores da Neurocinina-1/genética , Fator de Crescimento Transformador beta1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Ceratócitos da Córnea/citologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Receptores da Neurocinina-1/biossíntese , Transdução de Sinais , Fator de Crescimento Transformador beta1/biossíntese
20.
PLoS One ; 10(7): e0134157, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26214847

RESUMO

Keratocytes, the quiescent cells of the corneal stroma, play a crucial role in corneal wound healing. Neuropeptides and neurotransmitters are usually associated with neuronal signaling, but have recently been shown to be produced also by non-neuronal cells and to be involved in many cellular processes. The aim of this study was to assess the endogenous intracellular and secreted levels of the neuropeptides substance P (SP) and neurokinin A (NKA), and of the neurotransmitters acetylcholine (ACh), catecholamines (adrenaline, noradrenaline and dopamine), and glutamate, as well as the expression profiles of their receptors, in human primary keratocytes in vitro and in keratocytes of human corneal tissue sections in situ. Cultured keratocytes expressed genes encoding for SP and NKA, and for catecholamine and glutamate synthesizing enzymes, as well as genes for neuropeptide, adrenergic and ACh (muscarinic) receptors. Keratocytes in culture produced SP, NKA, catecholamines, ACh, and glutamate, and expressed neurokinin-1 and -2 receptors (NK-1R and NK-2R), dopamine receptor D2, muscarinic ACh receptors, and NDMAR1 glutamate receptor. Human corneal sections expressed SP, NKA, NK-1R, NK-2R, receptor D2, choline acetyl transferase (ChAT), M3, M4 and M5 muscarinic ACh receptors, glutamate, and NMDAR1, but not catecholamine synthesizing enzyme or the α1 and ß2 adrenoreceptors, nor M1 receptor. In addition, expression profiles assumed significant differences between keratocytes from the peripheral cornea as compared to those from the central cornea, as well as differences between keratocytes cultured under various serum concentrations. In conclusion, human keratocytes express an array of neuropeptides and neurotransmitters. The cells furthermore express receptors for neuropeptides/neurotransmitters, which suggests that they are susceptible to stimulation by these substances in the cornea, whether of neuronal or non-neuronal origin. As it has been shown that neuropeptides/neurotransmitters are involved in cell proliferation, migration, and angiogenesis, it is possible that they play a role in corneal wound healing.


Assuntos
Regulação da Expressão Gênica , Queratinócitos/metabolismo , Neuropeptídeos/metabolismo , Neurotransmissores/metabolismo , Receptores de Neuropeptídeos/biossíntese , Receptores de Neurotransmissores/biossíntese , Movimento Celular , Proliferação de Células , Células Cultivadas , Lesões da Córnea/metabolismo , Lesões da Córnea/patologia , Feminino , Humanos , Queratinócitos/citologia , Masculino
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