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1.
Lancet ; 395(10237): 1627-1639, 2020 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-32446407

RESUMO

BACKGROUND: Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment. METHODS: The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232. FINDINGS: The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2-18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT. INTERPRETATION: Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression. FUNDING: The 7th EU Framework Programme.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32312777

RESUMO

Tedizolid has demonstrated its efficacy and safety in clinical trials, however, data concerning its tolerability in long-term treatments is scarce. The aim of the study was to assess the indications and to describe the long-term safety profile of tedizolid.A multicentric, retrospective study of patients who received tedizolid for more than 6-days was conducted. Adverse events (AEs) were identified from patients' medical records and laboratory data. The World Health Organization causality categories were used to discern AEs probably associated with tedizolid.Eighty-one patients, treated with tedizolid 200mg once-daily for a median (IQR) duration of 28 (14-59) days, were included, 36 (44.4%) had previously received linezolid. Most common reasons for selecting tedizolid were to avoid linezolid potential toxicities or interactions (53.1%) or due to previous linezolid-related toxicities (27.2%). Most common indications were off-label, including prosthetic joint infections, osteomyelitis and respiratory infections (77.8%). Overall, 9/81 patients (11.1%) experienced a probably associated AE. Two patients (2.5%) developed gastrointestinal disorders, 1 (1.2%) anemia and 6 thrombocytopenia (7.4%) after a median (IQR) duration of treatment of 26.5 (17-58.5) days. Four (5%) patients discontinued tedizolid due to AEs. Among 23 patients with chronic renal failure (CRF) the rate of mielotoxicity was 17.4% and only 8.7% had to stop tedizolid and 20 out of 22 with previous linezolid-associated toxicity had no AE.Long-term tedizolid treatments had good tolerance with rates of gastrointestinal AE and hematological toxicity lower than those reported with linezolid, particularly in patients with CRF and in those with a previous history of linezolid-associated toxicity.

3.
Circ Res ; 126(8): 988-1003, 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32065054

RESUMO

RATIONALE: Despite increasing understanding of the prognostic importance of vascular stiffening linked to perivascular fibrosis in hypertension, the molecular and cellular regulation of this process is poorly understood. OBJECTIVES: To study the functional role of microRNA-214 (miR-214) in the induction of perivascular fibrosis and endothelial dysfunction driving vascular stiffening. METHODS AND RESULTS: Out of 381 miRs screened in the perivascular tissues in response to Ang II (angiotensin II)-mediated hypertension, miR-214 showed the highest induction (8-fold, P=0.0001). MiR-214 induction was pronounced in perivascular and circulating T cells, but not in perivascular adipose tissue adipocytes. Global deletion of miR-214-/- prevented Ang II-induced periaortic fibrosis, Col1a1, Col3a1, Col5a1, and Tgfb1 expression, hydroxyproline accumulation, and vascular stiffening, without difference in blood pressure. Mechanistic studies revealed that miR-214-/- mice were protected against endothelial dysfunction, oxidative stress, and increased Nox2, all of which were induced by Ang II in WT mice. Ang II-induced recruitment of T cells into perivascular adipose tissue was abolished in miR-214-/- mice. Adoptive transfer of miR-214-/- T cells into RAG1-/- mice resulted in reduced perivascular fibrosis compared with the effect of WT T cells. Ang II induced hypertension caused significant change in the expression of 1380 T cell genes in WT, but only 51 in miR-214-/-. T cell activation, proliferation and chemotaxis pathways were differentially affected. MiR-214-/- prevented Ang II-induction of profibrotic T cell cytokines (IL-17, TNF-α, IL-9, and IFN-γ) and chemokine receptors (CCR1, CCR2, CCR4, CCR5, CCR6, and CXCR3). This manifested in reduced in vitro and in vivo T cell chemotaxis resulting in attenuation of profibrotic perivascular inflammation. Translationally, we show that miR-214 is increased in plasma of patients with hypertension and is directly correlated to pulse wave velocity as a measure of vascular stiffness. CONCLUSIONS: T-cell-derived miR-214 controls pathological perivascular fibrosis in hypertension mediated by T cell recruitment and local profibrotic cytokine release.

4.
Cir Esp ; 98(4): 178-186, 2020 Apr.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31987464

RESUMO

Prehabilitation has a multimodal conception based on three fundamental pillars: improvement of the patient's physical condition, nutritional optimization and cognitive intervention to reduce stress and anxiety, as well as other measures such as smoking cessation and correction of anemia. The aim of prehabilitation programs is to optimize the patient from the moment of diagnosis until the surgical intervention in order to reduce postoperative complications. As in the case of multimodal rehabilitation protocols, the actions of prehabilitation programs have synergistic effects, that is, small changes that, by themselves, do not have clinical significance but when added up, they produce a significant improvement in the postoperative evolution of patients. Although more studies are required to evaluate the impact of these programs on patients groups with different pathologies, interventions and risk factors, their progressive implementation is necessary in the daily clinical practice of our patients. The objective of this narrative review is to evaluate the available evidence about prehabilitation in surgery, focusing on current established strategies, knowledge gaps and future research.

5.
J Pediatr Intensive Care ; 8(4): 238-241, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31673460

RESUMO

Neurogenic stunned myocardium is described as sudden and reversible cardiac dysfunction induced by an acute neurological event. This phenomenon has not been thoroughly investigated in infants, and is probably underdiagnosed. Here, we report the cases of two infants with neurogenic stunned myocardium in whom the clinical suspicion was relevant, with a brief discussion of this condition.

6.
Int J Mol Sci ; 20(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597233

RESUMO

When exposed to hostile environments such as radiation, physical injuries, chemicals, pollution, and microorganisms, the skin requires protective chemical molecules and pathways. Melatonin, a highly conserved ancient molecule, plays a crucial role in the maintenance of skin. As human skin has functional melatonin receptors and also acts as a complete system that is capable of producing and regulating melatonin synthesis, melatonin is a promising candidate for its maintenance and protection. Below, we review the studies of new metabolic pathways involved in the protective functions of melatonin in dermal cells. We also discuss the advantages of the topical use of melatonin for therapeutic purposes and skin protection. In our view, endogenous intracutaneous melatonin production, together with topically-applied exogenous melatonin and its metabolites, represent two of the most potent defense systems against external damage to the skin.


Assuntos
Melatonina/metabolismo , Melatonina/farmacologia , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Pele/metabolismo , Administração Tópica , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Humanos , Melatonina/administração & dosagem , Redes e Vias Metabólicas , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Pele/efeitos dos fármacos
7.
Arch Cardiol Mex ; 89(3): 222-232, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588144

RESUMO

Objective: The purpose of this study was to evaluate early changes in myocardial function in overweight and obese children without hypertension. Methods: Cross-sectional study involving 150 participants of both sexes between 6 and 15 years old. Anthropometric and biochemical evaluations were performed. Ventricular function was assessed by conventional echocardiographic methods and myocardial deformation analysis by two-dimensional speckle tracking echocardiography. One-way analysis of variance was employed for the global comparison of study variables between groups (children with normal weight, overweight and obesity), and post hoc analysis with Bonferroni correction was used for multiple comparison, considering normal-weight children as the reference category. Results: Overall, 142 participants were included, 50 (35%) with normal weight, 39 (28%) overweight and 53 (37%) obesity. Diastolic diameter of the left ventricular (LV) and interventricular septum, diameter of the left atrium and LV mass were significantly higher in children with obesity compared to those with normal weight. No significant differences in the conventional indicators of LV systolic and diastolic function were found between groups. Significant differences in the regional myocardial deformation between the three groups were observed. Mean global longitudinal myocardial deformation was smaller in patients with obesity (-20.9% vs. -23.5%, p < 0.05) compared to children with normal weight. Conclusions: The childhood obesity was associated with altered myocardial deformation, even in the presence of normal ejection fraction. Myocardial deformation evaluation is relevant in the assessment of pediatric patients with obesity.

9.
Dig Liver Dis ; 51(12): 1646-1651, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31383457

RESUMO

BACKGROUND: Information on the use of fecal markers in microscopic colitis screening is limited. AIM: To evaluate the risk variables associated with a diagnosis of microscopic colitis including fecal calprotectin. METHODS: Patients submitted for a colonoscopy due to chronic watery diarrhea fulfilling criteria of functional disease were evaluated. Colonic mucosa was normal but mild erythema and edema was allowed. Fecal calprotectin was analyzed. A logistic regression was used to evaluate variables associated with both raised fecal calprotectin and a diagnosis of microscopic colitis. RESULTS: 94 patients were included, 30 were diagnosed with microscopic colitis and 64 made up the control group. Median calprotectin levels were 175 (IQR, 59-325) for the microscopic colitis and 28 (IQR, 16-111) for the control group (p < 0.001). The optimal cut-off for fecal calprotectin was >100 µg/g (AUC, 0.73), with 67% sensitivity and 75% specificity. The number of drugs used ≥3 (OR, 3.9; CI, 1.4-10.4) and microscopic colitis diagnosis (OR, 6; CI, 2.2-16.3) were associated with raised calprotectin levels. Age >60 years (OR, 3.8; CI, 1.4-10.1) and calprotectin levels (OR, 5.3; CI, 2-14.1) were associated with a risk of microscopic colitis. CONCLUSIONS: Elevated fecal calprotectin concentrations are often seen in microscopic colitis, and may be helpful in the diagnosis of women over 60 with chronic watery diarrhea.

10.
Cir Cir ; 87(4): 396-401, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31264983

RESUMO

Background: The use of osteoclast inhibitors in metastatic bone disease, increase bone mineral density and reduce the risk of fracture, patients with osteonecrosis have been reported after the chronic use of these inhibitors. In our country, the use of osteoclast inhibitors is in the context of osteoporosis and bone metastases, so it is important to describe the incidence of this complication in Mexican population. Objective: To describe the incidence of osteonecrosis of the jaws at the Centro Médico Nacional 20 de Noviembre, during the period from January 1st, 2010 to June 1st, 2016. Methods: This is a retrospective cohort study developed at the Centro Medico Nacional 20 Noviembre, ISSSTE, Mexico. We included all patients who received bisphosphonates or denosumab in the context of metastatic bone disease due to solid tumors and who had osteonecrosis of the jaw. Results: A 802 patients who used bisphosphonates or denosumab in metastatic bone disease (699 bisphosphonates and 103 denosumab). Of these, 28 (3.5%) patients presented osteonecrosis. The median use of zoledronic acid for the presence of osteonecrosis was 25 months (15-49 months) and for Denosumab it was 16 months (11-35 months), without finding significant differences between the use of drugs p = 0.511 and the risk of osteonecrosis. Conclusions: Drug-induced osteonecrosis has a low incidence in Mexican population, denosumab does not show a greater number of cases of osteonecrosis compared to bisphosphonates; no association was found between functional status, number of metastatic bone sites, nor use of antigenic or tyrosine kinase inhibitors as factor associated with osteonecrosis of the jaws.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Conservadores da Densidade Óssea/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Denosumab/efeitos adversos , Difosfonatos/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Alendronato/efeitos adversos , Neoplasias Ósseas/secundário , Feminino , Humanos , Incidência , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Osteoclastos/efeitos dos fármacos , Estudos Retrospectivos , Ácido Risedrônico/efeitos adversos , Fatores de Tempo , Ácido Zoledrônico/efeitos adversos
11.
Redox Biol ; 26: 101263, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31299613

RESUMO

Inflammation is typically associated with the development of fibrosis, cirrhosis and hepatocellular carcinoma. The key role of protein tyrosine phosphatase 1B (PTP1B) in inflammatory responses has focused this study in understanding its implication in liver fibrosis. Here we show that hepatic PTP1B mRNA expression increased after bile duct ligation (BDL), while BDL-induced liver fibrosis was markedly reduced in mice lacking Ptpn1 (PTP1B-/-) as assessed by decreased collagen deposition and α-smooth muscle actin (α-SMA) expression. PTP1B-/- mice also showed a significant increase in mRNA levels of key markers of monocytes recruitment (Cd68, Adgre1 and Ccl2) compared to their wild-type (PTP1B+/+) littermates at early stages of injury after BDL. Interestingly, the lack of PTP1B strongly increased the NADPH oxidase (NOX) subunits Nox1/Nox4 ratio and downregulated Cybb expression after BDL, revealing a pro-survival pattern of NADPH oxidase induction in response to liver injury. Chimeric mice generated by transplantation of PTP1B-/- bone marrow (BM) into irradiated PTP1B+/+ mice revealed similar hepatic expression profile of NOX subunits than PTP1B-/- mice while these animals did not show differences in infiltration of myeloid cells at 7 days post-BDL, suggesting that PTP1B deletion in other liver cells is necessary for boosting the early inflammatory response to the BDL. PTP1B-/- BM transplantation into PTP1B+/+ mice also led to a blockade of TGF-ß and α-SMA induction after BDL. In vitro experiments demonstrated that deficiency of PTP1B in hepatocytes protects against bile acid-induced apoptosis and abrogates hepatic stellate cells (HSC) activation, an effect ameliorated by NOX1 inhibition. In conclusion, our results have revealed that the lack of PTP1B switches NOX expression pattern in response to liver injury after BDL and reduces HSC activation and liver fibrosis.


Assuntos
Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , NADPH Oxidases/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/deficiência , Animais , Apoptose/genética , Ácidos e Sais Biliares/metabolismo , Biomarcadores , Linhagem Celular , Meios de Cultivo Condicionados/metabolismo , Meios de Cultivo Condicionados/farmacologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Células Estreladas do Fígado/metabolismo , Hepatócitos/metabolismo , Imuno-Histoquímica , Macrófagos do Fígado/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , NADPH Oxidases/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta/metabolismo
12.
Case Reports Immunol ; 2019: 6357256, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355024

RESUMO

Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency characterized by elevated levels of immunoglobulin E (IgE), eczematous dermatitis, cold abscesses, and recurrent infections of the lung and skin caused by Staphylococcus aureus. The dominant form is characterized by nonimmunologic features including skeletal, connective tissue, and pulmonary abnormalities in addition to recurrent infections and eczema. Omalizumab is a humanized recombinant monoclonal antibody against IgE. Several studies reported clinical improvement with omalizumab in patients with severe atopic eczema with high serum IgE level. We present the case of a 37-year-old male with HIES and cutaneous manifestations, treated with humanized recombinant monoclonal antibodies efalizumab and omalizumab. After therapy for 4 years, we observed diminished eczema and serum IgE levels.

13.
Arch. argent. pediatr ; 117(3): 252-256, jun. 2019. ilus
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-1001197

RESUMO

La incontinencia pigmenti es un trastorno neurocutàneo raro, con una frecuencia de 1 en 40 000 recién nacidos, de etiología genética asociada a mutaciones en el gen IKBKG, localizado en Xq28, con herencia dominante ligada al X. Tiene una presentación clínica de manifestaciones muy variables detectadas desde la etapa neonatal y puede asociar afectación cutànea, dental, ocular y neurológica, y cada una de estas con un diagnóstico diferencial distinto. Se presenta a una paciente pediàtrica con diagnóstico de incontinencia pigmenti a la semana de vida. En la evaluación oftalmológica inicial, se observaron lesiones vasculares retinianas. Se decidió el tratamiento con làser, con buenos resultados, y se consiguió estabilizar la visión.


Incontinentia pigmenti is a rare neurocutaneous disorder with a frequency of 1 in 40,000 newborn; it is associated with mutations in IKBKG gene in Xq28, inherited as an X-linked dominant trait. Clinical manifestations detected since the newborn period are highly variable, with skin, teeth, eyes, and nervous system manifestations, and each with a characteristic differential diagnosis. We present a pediatric patient diagnosed with incontinentia pigmenti at the first week of life. In the initial ophthalmologic evaluation, retinal vascular lesions were observed. The outcomes of laser treatment of the ischemic peripheral retina were good and resulted in stability of vision.


Assuntos
Humanos , Feminino , Recém-Nascido , Pediatria , Incontinência Pigmentar , Manifestações Oculares , Terapia a Laser , Lesões do Sistema Vascular
14.
Arch Argent Pediatr ; 117(3): e252-e256, 2019 06 01.
Artigo em Espanhol | MEDLINE | ID: mdl-31063312

RESUMO

Incontinentia pigmenti is a rare neurocutaneous disorder with a frequency of 1 in 40,000 newborn; it is associated with mutations in IKBKG gene in Xq28, inherited as an X-linked dominant trait. Clinical manifestations detected since the newborn period are highly variable, with skin, teeth, eyes, and nervous system manifestations, and each with a characteristic differential diagnosis. We present a pediatric patient diagnosed with incontinentia pigmenti at the first week of life. In the initial ophthalmologic evaluation, retinal vascular lesions were observed. The outcomes of laser treatment of the ischemic peripheral retina were good and resulted in stability of vision.

15.
J Oral Maxillofac Surg ; 77(9): 1894-1903, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31078560

RESUMO

PURPOSE: The aim of the present in vitro study was to microscopically evaluate and describe the deformation of Lindeman surgical burs and the bone surface roughness after repeated osteotomies and sterilization cycles. MATERIALS AND METHODS: Twenty-one Lindeman surgical burs were analyzed under scanning electron microscopy (SEM) to evaluate the damage of the bur's integrity after 0, 1, 3, 5, 7, or 9 osteotomies on bovine ribs. Eighteen bone specimens were obtained after osteotomy for roughness analysis using profilometry. One-way analysis of variance was used to compare the mean roughness values across the experimental groups, and P ≤ .05 was considered to indicate statistical significance. RESULTS: Representative SEM images illustrated that all analyzed burs presented with some type of deformation at both the tip and the body, even after their first use. The mean roughness values were independent of the number of uses (P > .05); however, the standard deviation increased with the number of uses of the burs. CONCLUSIONS: These results suggest that even after their first use, rotatory surgical burs will have some type of deformation and that their cutting efficiency on the bone will vary and will be difficult to predict.

16.
PLoS Biol ; 17(5): e3000287, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31141500

RESUMO

Atypical chemokine receptor 2 (ACKR2) is a chemokine-scavenging receptor. ACKR2-/-embryos display a reduction in size of a novel, to our knowledge, embryonic skin macrophage population referred to as 'intermediate' cells. CC chemokine receptor 2 (CCR2)-/-embryos display an identical phenotype, indicating that these cells require CCR2 to enable them to populate embryonic skin. Further analysis revealed that ACKR2-/-embryos have higher circulating concentrations of the CCR2 ligand, CC ligand 2 (CCL2); thus, ACKR2 regulates intraembryonic CCL2 levels. We show that ACKR2 is strongly expressed by trophoblasts and that it blocks movement of inflammatory chemokines, such as CCL2, from the maternal decidua into the embryonic circulation. We propose that trophoblastic ACKR2 is responsible for ensuring chemokine compartmentalisation on the maternal decidua, without which chemokines enter the embryonic circulation, disrupting gradients essential for directed intraembryonic cell migration. Overall, therefore, we describe a novel, to our knowledge, molecular mechanism whereby maternal decidual chemokines can function in a compartmentalised fashion without interfering with intraembryonic leukocyte migration. These data suggest similar functions for other atypical chemokine receptors in the placenta and indicate that defects in such receptors may have unanticipated developmental consequences.


Assuntos
Quimiocinas/metabolismo , Mamíferos/metabolismo , Placenta/metabolismo , Animais , Movimento Celular , Decídua/metabolismo , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Feminino , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Gravidez , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/metabolismo , Pele/embriologia , Pele/metabolismo , Transcrição Genética , Saco Vitelino/metabolismo
17.
Oxid Med Cell Longev ; 2019: 7187128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944696

RESUMO

Head and neck cancer is the sixth leading cancer by incidence worldwide. Unfortunately, drug resistance and relapse are the principal limitations of clinical oncology for many patients, and the failure of conventional treatments is an extremely demoralizing experience. It is therefore crucial to find new therapeutic targets and drugs to enhance the cytotoxic effects of conventional treatments without potentiating or offsetting the adverse effects. Melatonin has oncostatic effects, although the mechanisms involved and doses required remain unclear. The purpose of this study is to determine the precise underlying mitochondrial mechanisms of melatonin, which increase the cytotoxicity of oncological treatments, and also to propose new melatonin treatments in order to alleviate and reverse radio- and chemoresistant processes. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 0.1, 0.5, 1, and 1.5 mM melatonin combined with 8 Gy irradiation or 10 µM cisplatin. Clonogenic and MTT assays, as well as autophagy and apoptosis, involving flow cytometry and western blot, were performed in order to determine the cytotoxic effects of the treatments. Mitochondrial function was evaluated by measuring mitochondrial respiration, mtDNA content (RT-PCR), and mitochondrial mass (NAO). ROS production, antioxidant enzyme activity, and GSH/GSSG levels were analyzed using a fluorometric method. We show that high concentrations of melatonin potentiate the cytotoxic effects of radiotherapy and CDDP in HNSCC, which are associated with increased mitochondrial function in these cells. In HNSCC, melatonin induces intracellular ROS, whose accumulation plays an upstream role in mitochondria-mediated apoptosis and autophagy. Our findings indicate that melatonin, at high concentrations, combined with cisplatin and radiotherapy to improve its effectiveness, is a potential adjuvant agent.


Assuntos
Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Cisplatino/uso terapêutico , Melatonina/uso terapêutico , Mitocôndrias/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose , Autofagia , Cisplatino/farmacologia , Humanos , Melatonina/farmacologia , Espécies Reativas de Oxigênio , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
18.
J Ment Health ; : 1-9, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30862212

RESUMO

BACKGROUND: The identification of factors associated with nonadherence to psychotherapy would allow a better prevention of this problem. AIM: To investigate factors associated with nonadherence in psychotherapy, its possible effect on outcomes, and reasons for therapy dropout. METHOD: Prospective analytic observational study of patients who initiated psychotherapy (N = 144). Sociodemographic, general clinical, treatment-related, subjective, psychological, psychopathologic, and outcome variables were evaluated at baseline and 1, 3, 6, and 12 months later. Objective nonadherence (dropout and irregularity), subjective nonadherence (poor patient engagement), and global nonadherence (combination of both) were analyzed. RESULTS: Global nonadherence was 66%. Global nonadherence was associated with substance use or abuse (OR = 2.64) and younger age (OR = 0.97). Objective nonadherence was associated with active working status (OR = 4.11), younger age (OR = 1.04) and substance use or abuse (OR = 2.35). Subjective nonadherence was associated with worse insight in psychotherapy (OR = 0.95) and poor pharmacologic adherence (OR = 0.55). Contextual reasons (25.8%) were the most commonly reported cause of dropout. Time in psychotherapy was associated with outcome variables. CONCLUSIONS: Nonadherence to psychotherapy is frequent. To reduce nonadherence in psychotherapy, specific interventions for reducing substance use and abuse, measures aimed at facilitating access to Community Mental Health Units, and enhancing insight in psychotherapy should be implemented.

19.
Immunity ; 50(2): 378-389.e5, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30784579

RESUMO

Currently, we lack an understanding of the individual and combinatorial roles for chemokine receptors in the inflammatory process. We report studies on mice with a compound deletion of Ccr1, Ccr2, Ccr3, and Ccr5, which together control monocytic and eosinophilic recruitment to resting and inflamed sites. Analysis of resting tissues from these mice, and mice deficient in each individual receptor, provides clear evidence for redundant use of these receptors in establishing tissue-resident monocytic cell populations. In contrast, analysis of cellular recruitment to inflamed sites provides evidence of specificity of receptor use for distinct leukocyte subtypes and no indication of comprehensive redundancy. We find no evidence of involvement of any of these receptors in the recruitment of neutrophils or lymphocytes to resting or acutely inflamed tissues. Our data shed important light on combinatorial inflammatory chemokine receptor function and highlight Ccr2 as the primary driver of myelomonocytic cell recruitment in acutely inflamed contexts.


Assuntos
Eosinófilos/imunologia , Inflamação/imunologia , Monócitos/imunologia , Receptores CCR/imunologia , Animais , Quimiocinas/imunologia , Quimiocinas/metabolismo , Eosinófilos/metabolismo , Perfilação da Expressão Gênica/métodos , Inflamação/genética , Inflamação/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptores CCR/genética , Receptores CCR/metabolismo , Receptores CCR1/imunologia , Receptores CCR1/metabolismo , Receptores CCR2/imunologia , Receptores CCR2/metabolismo , Receptores CCR3/imunologia , Receptores CCR3/metabolismo , Receptores CCR5/imunologia , Receptores CCR5/metabolismo
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