RESUMEN
Tetracyclines constitute a unique class of antibiotic agents, widely prescribed for both community and hospital infections due to their broad spectrum of activity. Acting by disrupting protein synthesis through tight binding to the 30S ribosomal subunit, their interference is typically reversible, rendering them bacteriostatic in action. Resistance to tetracyclines has primarily been associated with changes in pump efflux or ribosomal protection mechanisms. To address this challenge, tetracycline molecules have been chemically modified, resulting in the development of third-generation tetracyclines. These novel tetracyclines offer significant advantages in treating infections, whether used alone or in combination therapies, especially in hospital settings. Beyond their conventional antimicrobial properties, research has highlighted their potential non-antibiotic properties, including their impact on immunomodulation and malignancy. This review will focus on third-generation tetracyclines, namely tigecycline, eravacycline, and omadacycline. We will delve into their mechanisms of action and resistance, while also evaluating their pros and cons over time. Additionally, we will explore their therapeutic potential, analyzing their primary indications of prescription, potential future uses, and non-antibiotic features. This review aims to provide valuable insights into the clinical applications of third-generation tetracyclines, thereby enhancing understanding and guiding optimal clinical use.
Asunto(s)
Antibacterianos , Tetraciclinas , Tigeciclina , Tetraciclinas/uso terapéutico , Tetraciclinas/química , Tetraciclinas/farmacología , Humanos , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/uso terapéutico , Tigeciclina/uso terapéutico , Tigeciclina/farmacología , AnimalesRESUMEN
Klebsiella pneumoniae is a major human pathogen, because it causes both community- and hospital-acquired infections. Several multidrug-resistant high-risk clones of K. pneumoniae have been reported worldwide, and these are responsible for high numbers of difficult-to-treat infections. In Greece, a K. pneumoniae ST39 high-risk clone was detected in 2019 in a survey of carbapenem- and/or colistin-resistant Enterobacteriacae. The present study included nine carbapenem-resistant K. pneumoniae (CRKP) isolates collected during a retrospective analysis from October 2020 to December 2020. They were isolated from nine different patients hospitalized in the intensive care unit (ICU) of a hospital in Volos, Greece, and they were selected for analysis due to their phenotypic profile. In this study, we analyzed A165 strain K. pneumoniae ST39 isolated from a blood culture in November 2020. Whole-genome sequencing (WGS) was performed using Ion Torrent Platform, and resistance genes, virulence determinants, capsular types, insertion sequences, phage regions, and clustered regularly interspaced palindromic repeats (CRISPR) regions were detected by bioinformatic analysis. The molecular characterization revealed antimicrobial resistance genes, including sul2 for sulfamethoxazole; dfrA1 for trimethoprim; blaVIM-1 and blaKPC-2 for carbapenems; aac(6')-II for aminoglycosides; fosA for fosfomycin and aad1 for streptomycin, blaSHV-40, blaSHV-85, blaSHV-79, blaSHV-56, and blaSHV-89 for beta-lactams. Point mutations were identified in ompK36, and ompK37 and in acrR, gyrA, parC. Several replicons were found, including CoIRNA, IncC, IncFIB(K), IncFIB(pQiL), and IncFII(K). The capsular typing revealed that the strain was KL23, O2afg. The genome sequence of A165 was submitted to NCBI under PRJNA1074377 and have been assigned to Genbank accession number JAZIBV000000000.
Asunto(s)
Infecciones por Klebsiella , Klebsiella pneumoniae , Humanos , Antibacterianos/farmacología , Proteínas Bacterianas/genética , beta-Lactamasas/genética , Carbapenémicos/farmacología , Células Clonales , Grecia , Infecciones por Klebsiella/microbiología , Pruebas de Sensibilidad Microbiana , Tipificación de Secuencias Multilocus , Estudios RetrospectivosRESUMEN
Cutaneous nocardiosis is an infrequent infection which has been increasingly reported in immunocompromised patients. Although trimethoprim-sulfamethoxazole is considered to be the agent of choice for treatment of nocardiosis, newer antimicrobials such as tigecycline have been proven to be effective in vitro, as well. We report the first case of primary cutaneous nocardiosis in a renal transplant recipient having corresponded well to treatment with tigecycline.
Asunto(s)
Antibacterianos/uso terapéutico , Trasplante de Riñón/efectos adversos , Enfermedades Linfáticas/tratamiento farmacológico , Nocardiosis/tratamiento farmacológico , Infecciones Oportunistas/tratamiento farmacológico , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Tigeciclina/uso terapéutico , Humanos , Huésped Inmunocomprometido , Inmunosupresores/efectos adversos , Enfermedades Linfáticas/diagnóstico , Enfermedades Linfáticas/inmunología , Enfermedades Linfáticas/microbiología , Masculino , Persona de Mediana Edad , Nocardiosis/diagnóstico , Nocardiosis/inmunología , Nocardiosis/microbiología , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/microbiología , Enfermedades Cutáneas Bacterianas/diagnóstico , Enfermedades Cutáneas Bacterianas/inmunología , Enfermedades Cutáneas Bacterianas/microbiología , Resultado del TratamientoRESUMEN
PURPOSE: Kisspeptins, which are derived from the gene KISS1, supress tumor progression. We intended to investigate the production of KISS1 and its receptor (KISSR) in gastric cancer. METHODS: The expression of KISS1 and KISS1R in both normal and cancer tissue was examined with immunohistochemistry in tissue specimens of 40 cases of gastric adenocarcinoma. RESULTS: KISS1 expression in normal gastric mucosa was much higher than in malignant mucosa. KISS1 expression was higher in early stages (stage I or II) than in advanced stages (stage III or IV), in tumors with intestinal histological type than in those with diffuse histological type, in tumors without lymphovascular invasion than in those with and in cancers of older patients (≥70 years) than in younger patients. No significant differences were found regarding other clinicopathological parameters. There was no KISS1R expression in cancer tissues, while only low levels of KISS1R were detected in normal gastric epithelium. CONCLUSIONS: KISS1 expression is decreased during carcinogenesis in gastric mucosa. More advanced tumors and more aggressive histological types produce lower KISS1 levels. In addition, no KISS1R is produced in malignant gastric epithelium, while KISS1R is only weakly expressed in normal gastric epithelium.
Asunto(s)
Kisspeptinas , Receptores de Kisspeptina-1 , Anciano , Carcinogénesis , Mucosa Gástrica/metabolismo , Genes Supresores de Tumor , Humanos , Kisspeptinas/metabolismo , Receptores Acoplados a Proteínas G , Receptores de Kisspeptina-1/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMEN
OBJECTIVES: To report a case of intravascular lymphoma (IVL) in a Caucasian patient who presented with anasarca as his sole clinical sign. MATERIAL AND METHODS: A man presented with anasarca-type oedema and fatigue. After excluding heart failure, hepatic cirrhosis, nephrotic syndrome, hypothyroidism, AL-amyloidosis and adverse drug reaction which can all cause oedema, we turned our attention to capillary permeability disorders. RESULTS: Closer review of the bone marrow aspirate demonstrated haemophagocytic histiocytosis, while core, renal and duodenal biopsies showed a B-cell IVL. CONCLUSION: The differential diagnosis of anasarca, a relatively common clinical sign, should include IVL although the diagnosis may still be challenging. LEARNING POINTS: Anasarca-type oedema is an unusual initial presentation of intravascular lymphoma (IVL) and is normally attributed to capillary permeability disorders.Two clinical forms of IVL have been recognized: a Western form and an Asian variant which is characterized by haemophagocytosis.Patients of Caucasian origin who have the clinical features of the Asian variant of IVL make the diagnosis of this condition even more challenging.
Asunto(s)
Fallo Renal Crónico , Lupus Eritematoso Sistémico , Enfermedades Renales Poliquísticas/complicaciones , Prednisolona/administración & dosificación , Anciano , Femenino , Glucocorticoides/administración & dosificación , Humanos , Fallo Renal Crónico/etiología , Fallo Renal Crónico/terapia , Enfermedades de Inicio Tardío/diagnóstico , Enfermedades de Inicio Tardío/tratamiento farmacológico , Enfermedades de Inicio Tardío/fisiopatología , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/fisiopatología , Diálisis Renal/métodos , Resultado del TratamientoRESUMEN
Kisspeptins, the products of the KISS1 gene have tumor suppressing and antimetastatic properties. We aimed to study KISS1 and KISS1R expression in colorectal cancer. We analyzed KISS1 and KISS1R expression using immunohistochemistry and image analysis in normal and malignant tissue samples from 111 patients with colorectal adenocarcinoma. KISS1 expression was much higher in the normal than in the malignant colonic mucosa. Regarding malignant tissues, KISS1 levels were higher in larger tumors, in stage III and IV cancers, in cancers with lymph node metastasis and in tumors located in the distal part of the large intestine. Patients with greater KISS1 levels had worse prognosis. No KISS1R expression was detected in normal or malignant tissues or in liver metastases. KISS1 expression is reduced during the malignant transformation of the colonic mucosa. However, larger and advanced colorectal cancers express more KISS1, without reaching the former normal levels, and increased KISS1 levels are associated with worse prognosis. Finally, neither the normal nor the malignant colonic epithelial cells produce KISS1R.
Asunto(s)
Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Kisspeptinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Transformación Celular Neoplásica/genética , Neoplasias Colorrectales/patología , Femenino , Humanos , Inmunohistoquímica , Mucosa Intestinal/patología , Kisspeptinas/genética , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Metástasis Linfática/diagnóstico , Metástasis Linfática/genética , Metástasis Linfática/patología , Masculino , Pronóstico , Receptores Acoplados a Proteínas G/genética , Receptores de Kisspeptina-1RESUMEN
Our purpose was to investigate the expression pattern of BRCA1 protein in sporadic breast carcinomas, as well as the clinicopathological and prognostic value of its subcellular localizations. Immunohistochemistry was performed on paraffin embedded tissue specimens from 111 sporadic, invasive breast carcinomas to detect the expression of the proteins BRCA1, ER, PR, erbB2, p53 and Ki67. BRCA1 protein was detected in the nuclei and the cytoplasm of the tumor cells. Nuclear BRCA1 immunoreactivity showed no relation with the classic clinicopathological markers and the expression of cerbB2, p53 and Ki67. Reduced expression of nuclear BRCA1 protein was found to exert an independent favorable impact on both the overall and relapse-free (RF) survival of the patients (p=0.019 and p=0.043, respectively). Cytoplasmic BRCA1 was associated with none of the classic histomorphological indices, except from the lymph node metastasis, with which its relation was found to be inverse (p=0.05), prolonging the RF survival of the patients (p=0.05). Our findings suggest that BRCA1 protein depicts different prognostic significance, according to its subcellular distribution. Nuclear detection of the protein was associated with a worse prognosis, while the cytoplasmic one was related to fewer recurrences as a result of fewer lymph node metastases.
Asunto(s)
Proteína BRCA1/metabolismo , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismoRESUMEN
Kisspeptins, the products of the KISS1 gene, are involved in cancer invasion, migration, metastasis and angiogenesis, while they induce apoptosis in various cancers. Herein, we studied KISS1 expression in colorectal cancer. We analyzed KISS1 expression using immunohistochemistry and image analysis in normal and malignant tissue samples from 60 patients with colorectal adenocarcinoma. The results correlated with various clinicopathological parameters. The expression of KISS1 was much higher in normal than in malignant colonic mucosa. However, among malignant tissues, KISS1 expression was higher in larger tumors (>4 cm) than in smaller ones (≤4 cm) and in stages III and IV than in stages I and II. In addition, it was higher in patients with lymph node metastases. Moreover, KISS1 levels in the normal mucosa and their difference from those in the malignant mucosa were higher in the right part of the large intestine than in the left one. KISS1 expression is reduced during the malignant transformation of the colonic mucosa and there is a difference in the expression pattern between the right and the left part of the large intestine. However, larger and advanced colorectal tumors express higher KISS1 levels than smaller and localized ones.
Asunto(s)
Adenocarcinoma/genética , Transformación Celular Neoplásica/genética , Colon/metabolismo , Neoplasias Colorrectales/genética , Mucosa Intestinal/metabolismo , Kisspeptinas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Colon/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Expresión Génica , Humanos , Mucosa Intestinal/patología , Kisspeptinas/metabolismo , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Carga TumoralRESUMEN
AIMS: Our purpose was to investigate, in breast carcinomas, the prognostic importance of the proteins Wnt1 and glycogen synthasekinase (GSK)-3ß, and their associations with classic clinicopathological indices. METHODS AND RESULTS: Immunohistochemistry was performed on paraffin-embedded tissue specimens from 288 invasive breast carcinomas to detect the expression of the proteins Wnt1, GSK3ß, oestrogen receptor (ER), progesterone receptor (PR), erbB2, p53, Ki67, caspase-3 and ß-catenin. Both Wnt1 and GSK3ß were detected predominantly in the cytoplasm of the invasive tumour cells and the in-situ component, while GSK3ß was also detected in the stromal fibroblasts. Wnt1 immunoreactivity in the invasive tumour cells showed an inverse association with histological grade (P = 0.002), Ki67 (P = 0.008) and p53 (P = 0.031), while its relation with ER, erbB2 and caspase-3 was found to be positive (P = 0.007, P = 0.018 and P = 0.03, respectively). Cytoplasmic Wnt1 expression was related to a favourable prognosis within the subgroup of patients with stage II disease (P = 0.032). CONCLUSIONS: Wnt1 expression in the invasive tumour cells seems to promote differentiation and apoptosis, while being related inversely to proliferation. Therefore, this suggests its participation in the primary stages of breast carcinogenesis. The latter is supported further by the immunodetection of Wnt1 in in-situ carcinomas.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Proteína Wnt1/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/patología , Diferenciación Celular , Proliferación Celular , Femenino , Glucógeno Sintasa Quinasa 3 beta , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Pronóstico , Vía de Señalización WntRESUMEN
AIMS: To study the clinicopathological and prognostic value of cyclin D1 overexpression in patients with breast carcinoma. METHODS AND RESULTS: Immunohistochemistry was performed on paraffin-embedded tissue specimens from 290 invasive breast carcinomas to detect the proteins cyclin D1, oestrogen receptor (ER), progesterone receptor (PR), p53, c-erbB2, and topoisomerase IIα (topoIIα). Cyclin D1 staining was quantified using a computerized image analysis method. Cyclin D1 overexpression characterized smaller, ER-positive and PR-positive tumours (P = 0.017, P < 0.0001, and P < 0.0001, respectively), of a lower histological and nuclear grade (P = 0.011 and P < 0.0001, respectively), and with reduced expression of topoIIα (P = 0.001) and p53 (P < 0.001). Cyclin D1 was found to have an independent favourable impact on the overall survival of both the unselected cohort of patients (P = 0.011) and of patients with ER-negative and lymph node-positive tumours (P = 0.034 and P = 0.015, respectively). In triple-negative tumours, cyclin D1 overexpression was found to have independent favourable impacts on both overall and relapse-free survival (P = 0.002 for both). CONCLUSIONS: This is the first immunohistochemical study to dissociate the advantageous prognostic effect of cyclin D1 overexpression from its association with ER expression, and to provide evidence that cyclin D1 overexpression may be a marker of prolonged survival in patient subgroups with aggressive phenotypes.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Ciclina D1/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/patología , Ciclina D1/análisis , Supervivencia sin Enfermedad , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Inmunohistoquímica , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Fenotipo , Pronóstico , Modelos de Riesgos Proporcionales , Receptores de Estrógenos/biosíntesisRESUMEN
INTRODUCTION: Monosodium urate monohydrate (MSU) crystals synergize with various toll-like receptor (TLR) ligands to induce cytokine production via activation of the NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLPR3) inflammasome. This has been demonstrated in vitro using human cell lines or monocytes of healthy volunteers. In the present study, we have investigated the effect of MSU crystals and of their combination with TLR ligands in peripheral blood mononuclear cells (PBMC) of patients with gout. METHODS: PBMCs from 18 patients with primary gout and 12 healthy donors were exposed to MSU crystals in the presence or absence of saturated fatty acid C18:0 (free fatty acid, TLR2 ligand), palmitoyl-3-cystein (Pam3Cys, TLR1/2 ligand) and fibroblast stimulating factor-1 (FSL-1, TLR 2/6 ligand). Production of IL-1ß, IL-6, IL-8, IL-17 and tumor necrosis factor alpha (TNFα) was determined by ELISA. mRNA transcripts of IL-1ß were measured by real-time PCR. RESULTS: MSU crystals alone failed to induce IL-1ß, IL-6 or TNFα in both patients and control groups, but a stronger synergy between MSU/Pam3Cys and MSU/C18:0 for the induction of IL-1ß was found in patients with gout compared to healthy controls. IL-6, but not IL-8, followed the kinetics of IL-1ß. No production of the neutrophil-recruiting IL-17 was detectable after stimulation of the patients' PBMCs with MSU in both the presence or absence of TLR ligands. No change of gene transcripts of IL-1ß after stimulation with MSU and Pam3Cys or with MSU and C18:0 was found. A positive correlation was found between synergy in IL-1ß production from PBMCs of patients between C18:0 and MSU crystals, as well as the annual number of attacks of acute gouty arthritis (rs: +0.649, P: 0.022). CONCLUSIONS: The synergy between MSU crystals and TLR-2 ligands is more prominent in patients with gout than in controls. This is likely mediated by the enhanced maturation of pro-IL-1ß into IL-1ß.
Asunto(s)
Gota/metabolismo , Interleucina-1beta/biosíntesis , Leucocitos Mononucleares/metabolismo , Receptor Toll-Like 2/biosíntesis , Ácido Úrico/farmacología , Adulto , Anciano , Cristalización , Femenino , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Ligandos , Masculino , Persona de Mediana Edad , Receptor Toll-Like 2/agonistasRESUMEN
OBJECTIVES: Despite the experimental research data on antiphospholipid syndrome (APS), the pathogenesis of thrombosis and fetal loss remains unknown. The objective of this study was to analyze the major advances in the field of complement activation as a possible thrombosis mechanism in the APS. METHODS: The authors conducted a systemic analysis of the English literature and summarized both animal and human data that indicate the inappropriate complement activation as a mechanism causing thrombosis in the APS. RESULTS: The important role of complement activation in the pathogenesis of fetal loss was established using mice deficient in a complement regulatory protein. Further studies have shown that the infusion of human IgG antiphospholipid antibodies (aPL) induced fetal loss in pregnant mice, an effect that was abrogated by the concurrent administration of a C3 convertase inhibitor. Further studies suggested that C5a and neutrophils were the key components responsible for fetal injury. Moreover, use of F(ab)'2 fragments of aPL suggested the complement activation occurred mainly via the classical pathway. Other studies using models of induced thrombosis suggested that antibodies against ß2GPI required the presence of terminal complement components to induce thrombus formation, and mice deficient in C3 or C5 were found to be resistant to aPL-induced thrombosis. Based on the aforementioned findings, it has been suggested that heparin prevents fetal loss in patients with APS by inhibiting complement activation rather than by its anticoagulant effect. CONCLUSIONS: The studies on complement are significant because they shift the focus of research in APS from thrombosis to inflammation. However, as human data are limited, more clinical research is necessary before the above findings translate in changes in the management of APS.
Asunto(s)
Síndrome Antifosfolípido/inmunología , Activación de Complemento , Complemento C5a/fisiología , Muerte Fetal/inmunología , Neutrófilos/inmunología , Trombosis/inmunología , Adulto , Animales , Vía Alternativa del Complemento , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Noqueados , Embarazo , Receptor de Anafilatoxina C5a/fisiologíaRESUMEN
Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations (AVMs). Brain abscess is a complication of HHT with AVMs. Literature provides evidence that Enterococcus faecalis can cause endodontic infections. We present the case of an HHT patient who developed brain abscess due to E. faecalis after a dental procedure.
Asunto(s)
Absceso Encefálico/diagnóstico , Absceso Encefálico/microbiología , Enterococcus faecalis/aislamiento & purificación , Infecciones por Bacterias Grampositivas/diagnóstico , Infecciones por Bacterias Grampositivas/microbiología , Pulpitis/complicaciones , Adulto , Encéfalo/diagnóstico por imagen , Absceso Encefálico/patología , Femenino , Infecciones por Bacterias Grampositivas/patología , Humanos , Imagen por Resonancia Magnética , Pulpitis/terapia , Radiografía Torácica , Telangiectasia Hemorrágica Hereditaria/complicacionesRESUMEN
OBJECTIVE: The concept that intraarticular crystals of uric acid by themselves trigger episodes of painful gouty arthritis is inconsistent with the clinical reality. Patients with large deposits of monosodium urate monohydrate (MSU) crystals (tophi) do not necessarily experience gouty attacks. In fact, it is the excessive consumption of food or alcohol that elicits the inflammation of the acute gout attack. The aim of this study was to identify the precise mechanism that initiates flares of gouty arthritis. METHODS: Human peripheral blood mononuclear cells (PBMCs) and murine macrophages were stimulated in vitro with MSU, free fatty acids (FFAs), or both in combination. Thereafter, production of interleukin-1ß (IL-1ß) and activation of caspase 1 were determined. Gouty arthritis was induced in mice with deficiencies in the genes for caspase 1, ASC, NALP3, or IL-1ß, and the lack of inflammasome activity during joint swelling or other joint pathologic features was investigated in these mice. RESULTS: MSU crystals had no biologic effects on PBMCs from healthy subjects, whereas the FFA C18:0 in the presence of MSU crystals induced the release of large amounts of IL-1ß following engagement of Toll-like receptor 2 (TLR-2). Interaction of FFAs, but not alcohol, with TLR-2 synergized with MSU crystals to induce an inflammatory reaction. An important event of MSU/FFA-induced acute joint inflammation is the activation of the inflammasome. MSU/FFA-induced release of IL-1ß was dependent on activation of caspase 1 and ASC, but surprisingly, not NALP3. CONCLUSION: The synergistic effect between FFAs and MSU crystals leads to ASC/caspase 1-driven IL-1ß release. This mechanism could explain how constitutionally derived metabolic events initiate attacks of gout via the induction of IL-1ß-mediated joint inflammation.
Asunto(s)
Artritis Gotosa/metabolismo , Caspasa 1/metabolismo , Proteínas del Citoesqueleto/metabolismo , Ácidos Grasos/metabolismo , Interleucina-1beta/biosíntesis , Receptor Toll-Like 2/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis , Artritis Gotosa/inducido químicamente , Proteínas Adaptadoras de Señalización CARD , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Humanos , Inflamación/metabolismo , Articulación de la Rodilla/metabolismo , Leucocitos Mononucleares/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Estadísticas no Paramétricas , Ácido ÚricoRESUMEN
AIMS: Loss of phosphatase and tensin homologue (PTEN) leads to activation of several kinases, including mammalian target of rapamycin (mTOR), which promotes cell cycle progression. The aim was to study the expression of PTEN and phosphorylated (p)-mTOR in familial and sporadic invasive breast carcinomas and their relation to clinicopathological features, molecular indices (Wnt1) and patients' survival. METHODS AND RESULTS: PTEN and p-mTOR were detected immunohistochemically in 215 sections of invasive breast carcinomas (112 with a familial history of breast cancer). Image analysis was used and univariate and multivariate analyses employed for statistical evaluation of results. PTEN was detected in the nucleus (73.5%) and p-mTOR in the cytoplasm (44.2%) of cancer cells. Loss of PTEN protein was more frequently detected in women with a familial history of breast cancer (72%) (P < 0.0001), while its expression was negatively correlated with Wnt1, in total (P = 0.049). p-mTOR showed a positive association with lymph node status (P = 0.010) and was found to have a negative impact on patients' overall survival (P = 0.016). CONCLUSIONS: Loss of PTEN protein expression appears to occur more frequently in women with a family history of breast cancer, whereas activation of mTOR protein seems to be related to a more aggressive phenotype.
Asunto(s)
Neoplasias de la Mama/metabolismo , Carcinoma/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfohidrolasa PTEN/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Carcinoma/patología , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Fosforilación , Modelos de Riesgos Proporcionales , Serina-Treonina Quinasas TORRESUMEN
The authors conducted a systematic review of the English literature for cases of Gastric Syphilis (GS) in the last 50 years. The 34 studies which met selection criteria included 52 patients with GS. Of the reviewed patients, only 13% had a history of syphilis diagnosis and 46% had prior or concurrent clinical manifestations of the disease. Epigastric pain/fullness was the most common presenting symptom (92%) and epigastric tenderness being the most common sign. Gastric bleeding of variable intensity was documented in 35% of the cases. In the radiologic examinations, fibrotic narrowing and rigidity of the gastric wall was the most common finding (43%), followed by hypertrophic and irregular folds, while in endoscopy the most common lesion types were multiple ulcerations (48%), nodular mucosa, and erosions. The antrum was the most commonly affected area (56%). The majority of the patients received penicillin (83%) with a rapid resolution of their symptoms. Seventeen percent of the patients were treated surgically either due to a complication or due to strong suspicion of infiltrating tumor or lymphoma. The nonspecific clinical, radiologic, and pathologic characteristics of GS can establish it as a great imitator of other gastric diseases. GS should be considered in the differential diagnosis in patients at risk for sexually transmitted diseases who present with abdominal complaints and unusual endoscopic lesions and no other diagnosis is made, irrespective of the presence of H. pylori. The absence of primary or secondary luetic lesions should not deter one from considering GS.
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Gastropatías , Sífilis , Adulto , Anciano , Endoscopía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiografía , Gastropatías/diagnóstico por imagen , Gastropatías/tratamiento farmacológico , Gastropatías/microbiología , Gastropatías/patología , Sífilis/diagnóstico por imagen , Sífilis/tratamiento farmacológico , Sífilis/microbiología , Sífilis/patología , Treponema pallidum/aislamiento & purificación , Adulto JovenRESUMEN
Adult onset Still's disease (AOSD) is a well recognized clinical disorder characterized by a typical rash. However, there have been several atypical cutaneous findings reported in patients with AOSD. Cutaneous polyarteritis nodosa (PAN) is a necrotizing vasculitis of the small and medium sized arteries, distinguishing itself from systemic PAN by its restriction to the skin and to the neurological and osteo-muscular systems. We report the case of a patient with AOSD who is unique in having developed cutaneous polyarteritis nodosa (PAN) during the active phase of her disease. To the best of our knowledge, no previous cases of AOSD associated with a cutaneous variant of PAN have been reported.
Asunto(s)
Poliarteritis Nudosa/complicaciones , Poliarteritis Nudosa/diagnóstico , Enfermedad de Still del Adulto/complicaciones , Enfermedad de Still del Adulto/diagnóstico , Adulto , Antirreumáticos/uso terapéutico , Diagnóstico Diferencial , Quimioterapia Combinada , Femenino , Glucocorticoides/uso terapéutico , Humanos , Poliarteritis Nudosa/tratamiento farmacológico , Enfermedad de Still del Adulto/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Cell migration is a highly integrated process where actin turnover, actomyosin contractility, and adhesion dynamics are all closely linked. In this paper, we propose a computational model investigating the coupling of these fundamental processes within the context of spontaneous (i.e. unstimulated) cell migration. In the unstimulated cell, membrane oscillations originating from the interaction between passive hydrostatic pressure and contractility are sufficient to lead to the formation of adhesion spots. Cell contractility then leads to the maturation of these adhesion spots into focal adhesions. Due to active actin polymerization, which reinforces protrusion at the leading edge, the traction force required for cell translocation can be generated. Computational simulations first show that the model hypotheses allow one to reproduce the main features of fibroblast cell migration and established results on the biphasic aspect of the cell speed as a function of adhesion strength. The model also demonstrates that certain temporal parameters, such as the adhesion proteins recycling time and adhesion lifetimes, influence cell motion patterns, particularly cell speed and persistence of the direction of migration. This study provides some elements, which allow a better understanding of spontaneous cell migration and enables a first glance at how an individual cell would potentially react once exposed to a stimulus.