[Predatory journals in Orthopedics and Traumatology]. / Revistas depredadoras en Ortopedia y Traumatología.

Predatory journals are distinguished from legitimate journals by their lack of adequate reviews and editorial processes, compromising the quality of published content. These journals do not conduct peer reviews or detect plagiarism, and accept manuscripts without requiring substantial modifications. Their near 100% acceptance rate is driven by profit motives, regardless of the content they publish. While they boast a prestigious editorial board composed of renowned researchers, in most cases, it is a facade aimed at impressing and attracting investigators. Furthermore, these journals lack appropriate ethical practices and are non-transparent in their editorial processes. Predatory journals have impacted multiple disciplines, including Orthopedics and Traumatology, and their presence remains unknown to many researchers, making them unwitting victims. Their strategy involves soliciting articles via email from authors who have published in legitimate journals, promising quick, easy, and inexpensive publication. The implications and negative consequences of predatory journals on the scientific community and researchers are numerous. The purpose of this work is to provide general information about these journals, specifically in the field of Orthopedics and Traumatology, offering guidelines to identify and avoid them, so that authors can make informed decisions when publishing their manuscripts and avoid falling into the hands of predatory journals or publishers.

Las revistas depredadoras se diferencian de las revistas legítimas por su falta de adecuadas revisiones y procesos editoriales, lo que compromete la calidad del contenido publicado. Estas revistas no llevan a cabo revisiones por pares ni realizan acciones que detecten y prevengan el plagio y aceptan manuscritos sin exigir modificaciones sustanciales. Su tasa de aceptación cercana al 100% se debe a su enfoque lucrativo, sin importarles el contenido que publican. Aunque presumen tener un comité editorial compuesto por investigadores destacados, en la mayoría de los casos es una simulación destinada a impresionar y atraer a los investigadores. Además, estas revistas carecen de prácticas éticas adecuadas y no son transparentes en sus procesos editoriales. Las revistas depredadoras han afectado a múltiples disciplinas, incluida la Ortopedia y Traumatología y su presencia es aún desconocida para muchos investigadores, lo que los convierte en víctimas sin saberlo. Su estrategia consiste en solicitar artículos por correo electrónico a autores que han publicado en revistas legítimas, prometiendo una publicación rápida, sencilla y económica. Las implicaciones y consecuencias negativas de las revistas depredadoras en la comunidad científica y los investigadores son numerosas. El propósito de este trabajo es proporcionar información general sobre estas revistas y específicamente en el campo de la Ortopedia y Traumatología, brindando pautas para identificarlas y evitarlas, para que los autores puedan tomar decisiones informadas al publicar sus manuscritos y evitar caer en manos de revistas o editoriales depredadoras.

[Interposition hemiarthroplasty using extensor hallucis brevis for the treatment of hallux rigidus with lateral unicompartmental involvement: a case report]. / Hemiartroplastía por interposición utilizando el extensor hallucis brevis para el tratamiento de hallux rigidus con involucro unicompartimental lateral: reporte de un caso.

Hallux rigidus is the degenerative pathology of the metatarsophalangeal joint of the hallux. This pathology causes pain and decreased movement. There are multiple surgical treatments for this pathology, all with their respective indications. We present the case of a 54-year-old patient diagnosed with hallux rigidus who had only the lateral aspect of the metatarsal head affected. This patient was treated with a novel surgical procedure, performing an interposition hemiarthroplasty using the hallucis brevis extender associated with a cheilectomy and exostectomy. The patient had a favorable clinical evolution with improvement evidenced by clinical scales, with resolution of the symptoms and without complications. Interposition hemiarthroplasty using the extensor hallucis brevis is a successful joint and movement preservation treatment for hallux rigidus in young patients with lateral unicompartmental involvement of the metatarsal head, in whom it is important to preserve movement.

Hallux rigidus es la patología degenerativa de la articulación metatarsofalángica del hallux. Esta patología provoca dolor y disminución en el movimiento. Existen múltiples tratamientos quirúrgicos para esta patología, todas con sus respectivas indicaciones. Presentamos el caso de un paciente de 54 años de edad con el diagnóstico de hallux rigidus quien tenía afectación únicamente del aspecto lateral de la cabeza del metatarsiano. Este paciente fue tratado con un procedimiento quirúrgico novedoso, se realizó una hemiartroplastía de interposición utilizando el extensor hallucis brevis asociado a una queilectomía y exostectomía. El paciente tuvo una favorable evolución clínica con mejoría evidenciado por escalas clínicas, con resolución de la sintomatología y sin complicaciones. La hemiartroplastía de interposición utilizando el extensor hallucis brevis es un tratamiento exitoso de preservación articular y del movimiento para el hallux rigidus en pacientes jóvenes en los que hay afectación unicompartimental lateral de la cabeza metatarsiana, en quienes es importante preservar el movimiento.

[Applications of tranexamic acid in Orthopaedics and Traumatology]. / Aplicaciones del ácido tranexámico en cirugía Ortopédica y Traumatología.

INTRODUCTION: Tranexamic acid is an antifibrinolytic drug which has been used in many disciplines of Medicine, as well as in Orthopaedics and Traumatology, with the objective of diminishing and preventing blood loss and the necessity of allogenic blood transfusion. This study has the objective to demonstrate the uses, indications and contraindications of tranexamic acid in the different subspecialties of Orthopaedics and Traumatology. MATERIAL AND METHODS: A through search was performed looking at the most recent evidence regarding the use of tranexamic acid in the different subspecialties of Orthopaedics and Traumatology, as well as its indications, contraindications and adverse effects. RESULTS: Tranexamic acid has a great amount of applications in Orthopaedics and Traumatology, especially in primary and revision knee and hip arthroplasties, spine surgery and trauma. It has been observed that tranexamic acid is effective in diminishing perioperative bleeding, less necessity of blood transfusion, among other benefits. Tranexamic acid is a safe drug, which does not increase the risk of developing thrombotic events in healthy patients. There are a number of administration routes of tranexamic acid as well as many dosage regimens, all being efficient. Therefore, no standardization regarding the best administration route and most effective dose has been established. CONCLUSIONS: Tranexamic acid is a safe and effective drug for diminishing perioperative bleeding and to avoid the necessity of blood transfusion, with many applications in Orthopaedics and Traumatology.

INTRODUCCIÓN: El ácido tranexámico (ATX) es un medicamento antifibrinolítico que se ha utilizado en diversas disciplinas de la medicina, entre ellas en la Ortopedia y Traumatología con el objetivo de prevenir y disminuir el sangrado y evitar la necesidad de transfusiones. El presente trabajo tiene el objetivo de revisar los usos, indicaciones y contraindicaciones del ATX en Ortopedia y Traumatología. MATERIAL Y MÉTODOS: Se realizó una búsqueda de la evidencia más importante y reciente acerca del uso del ATX en Ortopedia y Traumatología, así como sus indicaciones, contraindicaciones y efectos adversos. RESULTADOS: El ATX tiene una gran cantidad de aplicaciones dentro de las que destacan las artroplastías de rodilla, cadera (primarias y de revisión), la cirugía de columna y el trauma, observándose con su uso una disminución en el sangrado perioperatorio y en la necesidad de transfusiones. El ATX es seguro, no aumenta el riesgo de desarrollar efectos trombóticos en pacientes sanos. Existen múltiples vías de administración, así como múltiples regímenes de dosis, todas siendo eficaces, por lo que aún no se ha estandarizado la mejor vía de administración ni la dosis más eficaz. CONCLUSIONES: El ATX es un medicamento seguro y eficaz para la disminución del sangrado perioperatorio.

[The 50 most cited articles in orthopedics and traumatology by Mexican authors]. / Los 50 artículos más citados en ortopedia y traumatología de autores mexicanos.

BACKGROUND: The amount of quotation a scientific article receives is important for the academic impact. In the present study, we analyzed the 50 most cited articles in orthopedics and related areas published by mexican authors, as well as analyzing their main characteristics. MATERIAL AND METHODS: A search was conducted using Web of Science, of the 50 articles with the largest number of quotation on orthopedics and related areas, in which the principal author or corresponding author had an address in Mexico. We analyzed the articles of 66 scientific journals within the category Orthopedics. We examined the quantity and density of citations, Origin institution, subspeciality to which the article corresponds, and level of evidence. RESULTS: The most cited article had 222 cites. The 50 most cited articles accumulated a total of 1,944, with an average of 3.6 cites per year per article. The year with the largest number of publications was the 2011, and the year with the largest number of quotation was 2008. Public institutions had a larger number of publications in relation to private institutions. The subspecialty with the largest number of publications was arthroscopy and sport medicine. Most publications with a large number of citations refer to studies with a low level of evidence. CONCLUSIONS: The present study points out the 50 most cited articles published by mexican authors in orthopedics and related areas. There is a tendency towards publishing articles on some subspecialities, in particular on arthroscopy and sport medicine. Most publications have a low level of evidence.

ANTECEDENTES: La cantidad de veces que un artículo es citado es importante para analizar el impacto académico. En el presente estudio se analizan los 50 artículos más citados en ortopedia y áreas afines publicados por autores mexicanos y sus principales características. MATERIAL Y MÉTODOS: Se realizó una búsqueda utilizando Web of Science de los 50 artículos más citados sobre ortopedia y áreas afines cuyo autor principal o autor correspondiente tuviera una dirección en México. Se analizaron los artículos de 66 revistas científicas dentro de la categoría Orthopedics. Se examinaron la cantidad y densidad de citas, institución de procedencia, subespecialidad a la que corresponde el artículo y nivel de evidencia. RESULTADOS: El artículo más citado tuvo 222 citas. Los 50 artículos más citados acumularon un total de 1,944, con un promedio de 3.6 citas por año por artículo. El año con mayor cantidad de publicaciones fue 2011 y el año con mayor número de citas fue 2008. Las instituciones públicas tuvieron un volumen más alto de publicaciones en comparación con las instituciones privadas. La subespecialidad con mayor volumen de publicaciones fue artroscopía y medicina del deporte. La mayoría de publicaciones con un número considerable de citas hacen referencia a estudios con un nivel bajo de evidencia. CONCLUSIONES: El presente estudio señala los 50 artículos más citados publicados por autores mexicanos en ortopedia y áreas afines. Existe una tendencia a publicar artículos sobre algunas subespecialidades, en particular sobre artroscopía y medicina del deporte. La mayoría de las publicaciones tienen un bajo nivel de evidencia.

TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27(KIP1) protein.

Increasing evidence suggests that tissue inhibitor of metalloproteinases-1 (TIMP-1) can directly regulate cell growth and apoptosis independent of its matrix metalloproteinases (MMPs)-inhibitory activity. While TIMP-1's antiapoptotic activity has been well demonstrated, conflicting data has been reported regarding TIMP-1's role in growth regulation. Here we show that TIMP-1 reduces the growth rate of human breast epithelial (MCF10A) cells by inducing cell cycle arrest at G(1). TIMP-1-mediated cell cycle arrest is associated with its downregulation of cyclin D(1) and upregulation of p27(KIP1), resulting in inhibition of cyclin-dependent kinase activity necessary for phosphorylation of the tumor suppressor retinoblastoma protein. We further show that TIMP-1 modulation of cyclin D(1) and p27(KIP1) is achieved through TIMP-1-mediated differential regulation of protein stability independent of growth factor signaling. We also show that TIMP-1-mediated differential regulation of cyclin D(1) and p27(KIP1) is independent of cell adhesion signaling. Whereas approximately 50% of MCF10A cells with reduced TIMP-1 expression underwent cell death following loss of cell adhesion (anoikis), TIMP-1 overexpressing cells remained viable with prominent cell cycle arrest without detectable cell death. Taken together, we propose that TIMP-1-mediated cell survival independent of cell adhesion is accompanied with cell cycle arrest in human breast epithelial cells, although cell cycle regulation may not be a prerequisite for TIMP-1 regulation of apoptosis in general.

Interferon enhances prostacyclin production by cultured vascular endothelial cells.

The effects of interferon (IFN) on the arachidonate metabolism and physiological functions of cultured endothelial cells and blood platelets have been examined. Cultured bovine aortic endothelial cells were found to be sensitive to the antiviral and antiproliferative activities of human leukocyte (alpha) IFN and to increase their capacity to synthesize prostacyclin (PGI2) upon exposure to IFN. Several observations indicate that IFN stimulates PGI2 synthesis at the level of the enzymes phospholipase A2 and cyclooxygenase: (a) PGI2 production was dependent upon the supply of exogenous arachidonic acid or the liberation of endogenous cellular arachidonate by ionophore A23187, but was not observed when IFN-treated cells were exposed to the endoperoxide prostaglandin H2. (b) IFN had no effect on the spontaneous release of PGI2 into the culture medium during the incubation period (24-72 h). (c) The stimulatory effect of IFN on PGI2 production was inhibited by both glucocorticoids and indomethacin. The effect of IFN on platelet prostaglandin metabolism was also investigated. Incubation of platelet-rich plasma with IFN had no effect on platelet aggregation and thromboxane A2 production. The biological significance of the findings presented in this paper may be considered in view of the protective role of PGI2 in the vessel wall and the fact that infection with certain viruses induces endothelial damage both in man and experimental animal models.

Hemiartroplastía por interposición utilizando el extensor hallucis brevis para el tratamiento de hallux rigidus con involucro unicompartimental lateral: reporte de un caso / Interposition hemiarthroplasty using extensor hallucis brevis for the treatment of hallux rigidus with lateral unicompartmental involvement: a case report

Resumen: Hallux rigidus es la patología degenerativa de la articulación metatarsofalángica del hallux. Esta patología provoca dolor y disminución en el movimiento. Existen múltiples tratamientos quirúrgicos para esta patología, todas con sus respectivas indicaciones. Presentamos el caso de un paciente de 54 años de edad con el diagnóstico de hallux rigidus quien tenía afectación únicamente del aspecto lateral de la cabeza del metatarsiano. Este paciente fue tratado con un procedimiento quirúrgico novedoso, se realizó una hemiartroplastía de interposición utilizando el extensor hallucis brevis asociado a una queilectomía y exostectomía. El paciente tuvo una favorable evolución clínica con mejoría evidenciado por escalas clínicas, con resolución de la sintomatología y sin complicaciones. La hemiartroplastía de interposición utilizando el extensor hallucis brevis es un tratamiento exitoso de preservación articular y del movimiento para el hallux rigidus en pacientes jóvenes en los que hay afectación unicompartimental lateral de la cabeza metatarsiana, en quienes es importante preservar el movimiento.

Abstract: Hallux rigidus is the degenerative pathology of the metatarsophalangeal joint of the hallux. This pathology causes pain and decreased movement. There are multiple surgical treatments for this pathology, all with their respective indications. We present the case of a 54-year-old patient diagnosed with hallux rigidus who had only the lateral aspect of the metatarsal head affected. This patient was treated with a novel surgical procedure, performing an interposition hemiarthroplasty using the hallucis brevis extender associated with a cheilectomy and exostectomy. The patient had a favorable clinical evolution with improvement evidenced by clinical scales, with resolution of the symptoms and without complications. Interposition hemiarthroplasty using the extensor hallucis brevis is a successful joint and movement preservation treatment for hallux rigidus in young patients with lateral unicompartmental involvement of the metatarsal head, in whom it is important to preserve movement.

The neurotoxin 1-methyl-4-phenylpyridinium: a selective cytostatic agent in small-cell lung cancer cell lines with neuroendocrine properties.

BACKGROUND: Small-cell lung cancer (SCLC) is a common malignancy that is usually fatal, since it metastasizes and recurs even after aggressive chemotherapy. While the cellular origin of this cancer is not well established, the cells of certain tumors exhibit neuroendocrine markers, including L-dopa decarboxylase. PURPOSE: We designed in vitro and in vivo studies to investigate whether the neuroendocrine features in classic SCLC cell lines were sufficient to make them sensitive to 1-methyl-4-phenylpyridinium (MPP+), a known neurotoxin that destroys nigrostriatal dopaminergic neurons. METHODS: Both classic SCLC cell lines (NCI-H345, NCI-H510, NCI-H187, and NCI-H146) and variant SCLC cell lines (NCI-H417, NCI-H82, NCI-H446, and NCI-H524) were exposed to MPP+ (0-512 microM) for 3 days. Inhibition of DNA synthesis was determined by [3H]thymidine incorporation assays. In a related experiment, MPP+ was removed from the classic cell line culture, and the incorporation of [3H]thymidine was determined. In the in vivo study, male athymic nude mice received subcutaneous injections of 0.5 mL tumor cells with matrigel for 10 days to enhance tumor growth, followed by MPP+ at doses of 100-400 micrograms/d given intraperitoneally for 2 days. RESULTS: All four classic SCLC cell lines showed great sensitivity to MPP+, with detachment from laminin substrates and inhibition of DNA synthesis. MPP+ interfered with [3H]thymidine incorporation and, thus, with DNA synthesis in classic SCLC cell lines at low doses (median +/- SD, 12 +/- 4 microM), whereas much higher doses (median, > 512 microM) were required to inhibit [3H]thymidine incorporation in the variant lines. Treated cells excluded trypan blue dye, showing that inhibition of DNA synthesis was not due to cytotoxicity, and the cells incorporated [3H]thymidine when MPP+ was removed from the culture medium, demonstrating that the inhibition was reversible. MPP+ inhibited the growth of the classic NCI-H187 and variant NCI-H417 cell lines implanted in nude mice. CONCLUSIONS: These results suggest that MPP+ differentially interferes with DNA synthesis in SCLC cell lines in vitro; the selective inhibitory effect on classic cell lines suggests that the neuroendocrine properties expressed by classic SCLC cells may be responsible for the differential effect. IMPLICATIONS: MPP+ exerts a cytostatic effect on these cell lines, and the differential sensitivity observed in vitro is maintained in vivo, suggesting that MPP+ or other pyridinium compounds may be of therapeutic value in SCLC.

Enhanced tumor growth of both primary and established human and murine tumor cells in athymic mice after coinjection with Matrigel.

Previously we found that the reconstituted basement membrane matrix Matrigel, when premixed with human small-cell lung carcinoma cells and injected subcutaneously into athymic mice, permitted tumor growth, whereas cells injected in the absence of Matrigel did not form tumors. In the present study, we examined additional cell types and determined some of the underlying mechanisms involved in the promotion of tumor formation by Matrigel. The tumor cell lines that we studied included transformed mouse Englebreth-Holm-Swarm tumor cells (T-EHS), human submandibular carcinoma A253 cells, mouse melanoma B16F10 cells, human epidermoid carcinoma KB cells, and human primary renal cell carcinoma cells. When coinjected subcutaneously with Matrigel, these cell lines formed rapidly proliferating tumors. Primary biopsy specimens of human colon carcinoma, when dispersed and coinjected with Matrigel, also formed tumors. Only A253, KB, and B16F10 cells formed small tumors in the absence of Martrigel, but a fivefold to tenfold increase in tumor size was observed in the presence of Matrigel. These data demonstrate a useful method for improving the growth of human tumors in athymic mice.

Invasive and metastatic potential of a v-Ha-ras-transformed human bronchial epithelial cell line.

The in vivo growth behavior and invasive potential of normal and "immortalized" human bronchial epithelial cells were studied by xenotransplantation procedures, an in vitro assay of invasiveness, and determinations of type IV collagenase activity and mRNA expression. BEAS-2B cells, immortalized after hybrid virus infection (adenovirus 12-simian virus 40), reconstituted a columnar epithelium when xenotransplanted into de-epithelialized rat tracheas transplanted sc into athymic BALB/c mice. A few adenomatous growths could be seen 16 weeks after transplantation. BZR cells, obtained by transfer of the v-Ha-ras oncogene into BEAS-2B cells, were tumorigenic in this xenotransplantation model. BZR-T33 cells, obtained from a tumor produced after injection of BZR cells, were also tumorigenic; however, they exhibited a shorter latent period. When these same cell lines were injected sc and iv into athymic BALB/c mice, BEAS-2B cells were not tumorigenic, and the BZR-T33 cells were more tumorigenic than the BZR cells. The incidence of spontaneous metastases after sc inoculation was zero for BEAS-2B cells, 33% for BZR cells, and 100% for BZR-T33 cells. Similar increasing values that correlated well with the data on in vivo growth were noted in the in vitro invasion assay, the collagenolytic ability, and the mRNA expression of type IV collagenase. Normal human bronchial epithelial cells showed the lowest values in all the assays. These progressive changes occurring in cells derived from the same parental line indicate that the presence of the v-Ha-ras oncogene in immortalized bronchial cells is associated with a full-fledged malignant phenotype, which is further enhanced by in vivo passaging.

Activation of progelatinase B (MMP-9) by gelatinase A (MMP-2).

The M(r) 72,000 (MMP-2; gelatinase A) and M(r) 92,000 (MMP-9; gelatinase B) gelatinases are two members of the family of matrix metalloproteinases (MMPs). These proteinases are thought to play a critical role in tumor cell invasion and are frequently coexpressed in human cancers. Gelatinases are secreted in a latent inactive form, and their conversion to the active species can be accomplished by other proteolytic enzymes, including other MMPs. We report herein that organomercurial or plasma membrane-activated M(r) 72,000 gelatinase A activates progelatinase B to an M(r) 82,000 active form in a process inhibited by tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Progelatinase B activation was accomplished by the two active species of gelatinase A, the M(r) 62,000 and M(r) 45,000 forms, generated after plasma membrane or organomercurial activation of TIMP-2-free progelatinase A. The M(r) 45,000 species of gelatinase A lacks both the NH2-terminal profragment and the COOH-terminal domain known to play a role in plasma membrane activation and the regulation of TIMP-2 inhibition. These results suggest a novel mechanism of activation of progelatinase B mediated by gelatinase A species that may be localized in the surface of tumor cells and enhance matrix degradation during cancer metastasis.

Phorbol ester-induced cell surface association of matrix metalloproteinase-9 in human MCF10A breast epithelial cells.

Cell surface association of extracellular matrix (ECM)-degrading enzymes has been suggested to facilitate proteolysis of ECM in areas of cell-matrix contacts and to be crucial for the process of tumor cell invasion. Matrix metalloproteinase-9 (MMP-9) is a member of the MMP family of endopeptidases that has been shown to play a critical role in hydrolysis of ECM components and has been localized on the surface of tumor cells. However, the nature of the cell surface association of MMP-9 is unknown. Here, we report the cell surface association of MMP-9 in human breast epithelial MCF10A cells treated with 12-O-tetradecanoylphorbol-13-acetate (TPA). Surface biotinylation and immunoprecipitation with anti-MMP-9 antibodies revealed the presence of two MMP-9 forms (M(r) 92,000 and 85,000) on the surface of TPA-treated MCF10A cells, whereas in the media, only the M(r) 92,000 form was detected, mostly in complex with TIMP-1, a specific MMP-9 inhibitor. The MMP-9 forms were also found in purified plasma membranes of TPA-treated cells. In contrast, the plasma membranes contained little or no TIMP-1. The surface-bound MMP-9 forms were recognized by an antibody to the NH2-terminal prodomain, indicating that both represent latent enzymes. Pulse-chase analysis and endoglycosidase H digestion of surface-biotinylated MMP-9 forms demonstrated that the M(r) 85,000 species was endoglycosidase H sensitive, suggesting targeting of the precursor form of MMP-9 to the cell surface. These studies demonstrate a specific cell surface association of MMP-9 in response to TPA that may help to localize TIMP-1-free enzyme on the surface of breast epithelial cells.

Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells.

The signaling pathways critical for cell survival are mediated in part by the composition and integrity of the extracellular matrix and the action of its components on specific cell adhesion receptors. Withdrawal of anchorage-dependent epithelial cells from their association with ECM results in apoptotic cell death. Consistently, the matrix metalloproteinases (MMPs) or their inhibitors (TIMPs) have been suggested to regulate apoptosis. In this report, we investigated whether bcl-2 inhibition of apoptosis involves regulation of TIMP expression. We have found that bcl-2 overexpression induces TIMP-1 expression in breast epithelial cell lines (MCF10A, MCF10AneoT.TG3B, and MCF-7), whereas it has no effect on TIMP-2 expression. We demonstrated that TIMP-1 inhibits cell death induced by hydrogen peroxide, Adriamycin, or X-ray irradiation. In addition, TIMP-1 overexpression inhibits apoptosis after the loss of cell adhesion (anoikis) in MCF10A cells, suggesting that the antiapoptotic activity of TIMP-1 does not depend on its ability to stabilize cell-matrix interactions. We also showed that TIMP-1 overexpression is associated with constitutive activation of focal adhesion kinase, a signaling molecule known to be critical for the cell survival pathway.

High levels of tissue inhibitor of metalloproteinase-2 (TIMP-2) expression are associated with poor outcome in invasive bladder cancer.

The matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) have been associated with tumor invasion and metastasis in many human cancers. Immunohistochemical studies were performed on frozen tumor samples from 42 patients with invasive bladder cancer treated by cystectomy with monoclonal antibodies against the Mr 72,000 gelatinase A (MMP-2), Mr 92,000 gelatinase B (MMP-9), and TIMP-2 to evaluate their significance in bladder cancer. Immunoreactivity for the gelatinases was predominantly tumor cell-associated, whereas strong TIMP-2 staining was mostly detected in the stroma. Tumor cells demonstrated moderate to strong reactivity for MMP-2 and MMP-9 in 71 and 71% of cases, respectively, which did not correlate with stage, grade, or outcome. Tumor cells were positive for TIMP-2 in 26 (62%) of 42 cases, and this correlated with a worse outcome (69 versus 25% died of disease; P < 0.05). In 31 (74%) of 42, there was moderate to strong stromal staining for TIMP-2; this also was associated with a poor outcome (65 versus 25% died of cancer; P < 0.05). Tumor basement membrane (BM) status was investigated using an antibody to type IV collagen. In 9 cases, the invasive tumor nests were surrounded by an intact BM; in 7 of these, stromal staining for TIMP-2 was absent. None of these 9 patients (0%) died of tumors compared with 7 (100%) of 7 with complete loss of BM staining (P < 0.001). These results suggest a potential role for TIMP-2 and BM staining as prognostic indicators in invasive bladder cancer.

Aplicaciones del ácido tranexámico en cirugía Ortopédica y Traumatología / Applications of tranexamic acid in Orthopaedics and Traumatology

Resumen: Introducción: El ácido tranexámico (ATX) es un medicamento antifibrinolítico que se ha utilizado en diversas disciplinas de la medicina, entre ellas en la Ortopedia y Traumatología con el objetivo de prevenir y disminuir el sangrado y evitar la necesidad de transfusiones. El presente trabajo tiene el objetivo de revisar los usos, indicaciones y contraindicaciones del ATX en Ortopedia y Traumatología. Material y métodos: Se realizó una búsqueda de la evidencia más importante y reciente acerca del uso del ATX en Ortopedia y Traumatología, así como sus indicaciones, contraindicaciones y efectos adversos. Resultados: El ATX tiene una gran cantidad de aplicaciones dentro de las que destacan las artroplastías de rodilla, cadera (primarias y de revisión), la cirugía de columna y el trauma, observándose con su uso una disminución en el sangrado perioperatorio y en la necesidad de transfusiones. El ATX es seguro, no aumenta el riesgo de desarrollar efectos trombóticos en pacientes sanos. Existen múltiples vías de administración, así como múltiples regímenes de dosis, todas siendo eficaces, por lo que aún no se ha estandarizado la mejor vía de administración ni la dosis más eficaz. Conclusiones: El ATX es un medicamento seguro y eficaz para la disminución del sangrado perioperatorio.

Abstract: Introduction: Tranexamic acid is an antifibrinolytic drug which has been used in many disciplines of Medicine, as well as in Orthopaedics and Traumatology, with the objective of diminishing and preventing blood loss and the necessity of allogenic blood transfusion. This study has the objective to demonstrate the uses, indications and contraindications of tranexamic acid in the different subspecialties of Orthopaedics and Traumatology. Material and methods: A through search was performed looking at the most recent evidence regarding the use of tranexamic acid in the different subspecialties of Orthopaedics and Traumatology, as well as its indications, contraindications and adverse effects. Results: Tranexamic acid has a great amount of applications in Orthopaedics and Traumatology, especially in primary and revision knee and hip arthroplasties, spine surgery and trauma. It has been observed that tranexamic acid is effective in diminishing perioperative bleeding, less necessity of blood transfusion, among other benefits. Tranexamic acid is a safe drug, which does not increase the risk of developing thrombotic events in healthy patients. There are a number of administration routes of tranexamic acid as well as many dosage regimens, all being efficient. Therefore, no standardization regarding the best administration route and most effective dose has been established. Conclusions: Tranexamic acid is a safe and effective drug for diminishing perioperative bleeding and to avoid the necessity of blood transfusion, with many applications in Orthopaedics and Traumatology.

Matrix metalloproteinase-9 expression in bladder washes from bladder cancer patients predicts pathological stage and grade.

The matrix metalloproteinases (MMPs), in particular the gelatinases (MMP-2 and MMP-9) have been associated with tumor cell invasion and metastasis in many human cancers. Here we examined the expression of proMMP-2 (gelatinase A) and proMMP-9 (gelatinase B) proteins in the cellular component of bladder washes obtained from 65 patients. Twenty-six patients had active bladder cancer, 24 had a history of bladder cancer but no evidence of active disease at the time of cystoscopy (recurrence-free), and 15 patients had lesions other than bladder cancer (controls). The results were correlated with the cytological findings of the bladder wash and the histopathological results of the tumor resection when performed. In patients with active transitional cell carcinoma of the bladder, 71 and 38% had expression and overexpression of the latent form of MMP-9 (proMMP-9), respectively. In contrast, neither latent nor active MMP-2 could be detected in any of the samples examined, regardless of tumor status. Overexpression of proMMP-9 correlated with higher grade (P = 0.003) and pathological stage (P = 0.04) of disease in the active bladder cancer group. No significant gelatinase expression was detected in the recurrence-free and control cases. Compared with urine cytology, proMMP-9 expression had an overall higher sensitivity for bladder cancer identification (71 versus 54%, P = 0.11). Detection of proMMP-9 in bladder washes may be a novel approach for the identification of patients with more aggressive forms of bladder cancer.

Membrane type 1-matrix metalloproteinase (MT1-MMP) and MMP-2 immunolocalization in human prostate: change in cellular localization associated with high-grade prostatic intraepithelial neoplasia.

Membrane type 1-matrix metalloproteinase (MT1-MMP) is a known activator of latent MMP-2 (pro-MMP-2), and increased MMP-2 expression has been associated with tumor aggressiveness in prostate cancer. However, expression of MT1-MMP in human prostate tissue has not been described. We investigated the expression and immunolocalization of MT1-MMP and MMP-2 in the epithelial components of benign prostate epithelium, high-grade prostatic intraepithelial neoplasia (HGPIN), and prostate cancer. Tissue sections from the peripheral zone of 50 prostates (radical prostatectomy specimens) were chosen based on their containing benign glands, HGPIN, and prostate cancer glands. All 50 sections were immunostained for MT1-MMP and MMP-2 and were evaluated for staining pattern, uniformity, and intensity. Western blotting and gelatin zymography were done to confirm expression of MT1-MMP and activity of MMP-2, respectively. Comparisons were made between benign epithelium, HGPIN, and cancer. In benign glands, basal cells (BCs) uniformly stained intensely for MT1-MMP, whereas secretory cells (SCs) were rarely positive (P < 0.0001). Conversely in HGPIN, SCs showed consistent cytoplasmic staining (P < 0.0001). In cancer cells, staining was heterogeneous and varied from no staining to very intense staining in select glands. MMP-2 in normal tissue stained both BCs and the apical region of SCs, whereas in HGPIN, staining was observed in the SC in a predominantly cytoplasmic pattern. Similar to MT1-MMP, staining in cancer tissue for MMP-2 was heterogeneous; however, there was a significant association between the pattern of MMP-2 and MT1-MMP staining within the epithelial components of the cancer glands in individual specimens (P < 0.001). Finally, MMP-2 and MT1-MMP were confirmed to be expressed in the prostate tissues by gelatin zymography and Western blotting. In conclusion, we found that consistent changes in localization and intracellular distribution of MMP-2 and MT1-MMP were associated with the transition from benign prostate epithelium to HGPIN, suggesting that regulation of these enzymes is altered during the earliest stages of prostate cancer.

Increased expression of matrix metalloproteinases (MMP)-2, MMP-9, and the urokinase-type plasminogen activator is associated with progression from benign to advanced ovarian cancer.

Proteases are linked to the malignant phenotype of different solid tumors. Therefore, the expression of the matrix metalloproteinase (MMP)-2 and MMP-9 and of the serine protease urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor type 1 (PAI-1) in the progression of ovarian cancer was investigated. Gelatinolytic activity and protein expression of MMP-2 and MMP-9 were analyzed in tissue extracts of 19 cystadenomas and 18 low malignant potential (LMP) tumors, as well as 41 primary tumors of advanced ovarian cancer stage International Federation of Gynecology and Obstetrics IIIc/IV and their corresponding omentum metastases by quantitative gelatin zymography and Western blot. In the same tissue extracts, antigen levels of uPA and its inhibitor PAI-1 were determined by ELISA. Protein expression of pro-MMP-2 (72 kDa) and pro-MMP-9 (92 kDa as well as antigen levels of uPA and PAI-1 were low in benign ovarian tumors but increased significantly from LMP tumors to advanced ovarian cancers. The highest values of all of the proteolytic factors were detected in omentum metastases. Active MMP-2 enzyme (62 kDa) was detected only in ovarian cancer (66%) and corresponding metastases (93%) but never in benign or LMP tumors. The activation rate of MMP-2 to its active isoform was higher in the metastases. Comparing both proteolytic systems, higher PAI-1 concentrations were consistently found in cancers with high pro-MMP-9 expression. These data indicate that members of the plasminogen activator system, as well as the metalloproteinases MMP-2/9, increase with growing malignant potential of ovarian tumors. These findings are of particular relevance to the development of protease inhibitors as new therapeutic approaches in ovarian cancer.

Correlation in the expression of type IV collagenase and the invasive and chemotactic abilities of myelomonocytic cells during differentiation into macrophages.

Monomyelocytic phagocytes originate in the bone marrow and while differentiating into macrophages migrate to inflammatory foci and target tissues by egress from the capillary blood vessels. During such diapedesis, the cells must traverse tissue barriers such as basement membrane, which has type IV collagen as its principal structural element. We studied whether the expression of type IV collagenase activity, invasion through basement membrane, and the response to inflammatory chemoattractants are related to each other and to the process of differentiation of murine M1 myeloid leukemia cells into macrophages. M1 cells stimulated with mouse lung-conditioned medium (MLCM) or interleukin 6 (IL6) differentiate into macrophages by 72 h, as determined by expression of Fc receptors, induction of lysozyme, and morphological changes from blast cells to mature macrophages. During this process of differentiation the invasive ability of the cells and the amount of type IV collagenase in the supernatants from the invading cells continuously increased up to 72 h. Zymographic analysis of supernatants of the invading cells revealed a single 100-kd metalloproteinase with gelatinolytic activity. Chemotaxis towards arachidonic acid metabolites, which are present in inflamed tissues, was detected only in differentiated cells. Studies with thioglycolate (TG)-elicited peritoneal macrophages gave results similar to those obtained with differentiated M1 cells, showing that the ability to invade basement membrane, the expression of type IV collagenase, and the chemotactic response to inflammatory chemoattractants all increased with the differentiation of myeloid cells and reached their highest expression in fully differentiated cells.

Long-term benzodiazepine users 3 years after participation in a discontinuation program.

OBJECTIVE: Clinical status and use of benzodiazepines and other psychotropic drugs at follow-up were assessed in patients who had been chronically dependent on benzodiazepines and had been referred for participation in a discontinuation study. METHOD: Of 123 benzodiazepine-dependent patients screened for entry into a tapered discontinuation program, 48 had completed the program, 38 had not, and 37 had not undergone drug tapering. Follow-up information was obtained through a structured telephone interview and a mail questionnaire that included a global severity scale assessing anxiety and depression and the Hopkins Symptom Checklist. The time to follow-up was 2.7-5.0 years, and the mean +/- SD interval between screening and follow-up was 2.9 +/- 0.9 years. RESULTS: Outcome at follow-up significantly favored the patients who had completed the discontinuation program; 73% were not using benzodiazepines, compared to 39% in the unsuccessful taper group and 14% in the no-taper group. Moderate or marked anxiety was still reported by 35% of the patients who were taking benzodiazepines and 25% of those who were not. At follow-up, 22% of the patients were being treated with nonbenzodiazepine psychotropic agents, primarily antidepressants. CONCLUSIONS: The high percentage of patients who were benzodiazepine-free at follow-up and the continued anxiety and depression present in many patients suggest that some patients may have been taking benzodiazepines because of chronic or recurrent anxiety or depression, not physical dependence.