Conditionally mutant animal model for investigating the invasive trophoblast cell lineage.

Placental development involves coordinated expansion and differentiation of trophoblast cell lineages possessing specialized functions. Among the differentiated trophoblast cell lineages are invasive trophoblast cells, which exit the placenta and invade the uterus, where they restructure the uterine parenchyma and facilitate remodeling of uterine spiral arteries. The rat exhibits deep intrauterine trophoblast cell invasion, a feature shared with human placentation, and is also amenable to gene manipulation using genome-editing techniques. In this investigation, we generated a conditional rat model targeting the invasive trophoblast cell lineage. Prolactin family 7, subfamily b, member 1 (Prl7b1) is uniquely and abundantly expressed in the rat invasive trophoblast cell lineage. Disruption of Prl7b1 did not adversely affect placental development. We demonstrated that the Prl7b1 locus could be effectively used to drive the expression of Cre recombinase in invasive trophoblast cells. Our rat model represents a new tool for investigating candidate genes contributing to the regulation of invasive trophoblast cells and their roles in trophoblast-guided uterine spiral artery remodeling.

TAF7L regulates early stages of male germ cell development in the rat.

Male germ cell development is dependent on the orchestrated regulation of gene networks. TATA-box binding protein associated factors (TAFs) facilitate interactions of TATA-binding protein with the TATA element, which is known to coordinate gene transcription during organogenesis. TAF7 like (Taf7l) is situated on the X chromosome and has been implicated in testis development. We examined the biology of TAF7L in testis development using the rat. Taf7l was prominently expressed in preleptotene to leptotene spermatocytes. To study the impact of TAF7L on the testis we generated a global loss-of-function rat model using CRISPR/Cas9 genome editing. Exon 3 of the Taf7l gene was targeted. A founder was generated possessing a 110 bp deletion within the Taf7l locus, which resulted in a frameshift and the premature appearance of a stop codon. The mutation was effectively transmitted through the germline. Deficits in TAF7L did not adversely affect pregnancy or postnatal survival. However, the Taf7l disruption resulted in male infertility due to compromised testis development and failed sperm production. Mutant germ cells suffer meiotic arrest at late zygotene/early pachynema stages, with defects in sex body formation. This testis phenotype was more pronounced than previously described for the subfertile Taf7l null mouse. We conclude that TAF7L is essential for male germ cell development in the rat.

Osteoporotic vertebral fractures: Natural history and impact. / Fracturas vertebrales osteoporóticas: historia natural e impacto.

Osteoporosis, and the consequences derived from it, such as fragility fractures, constitute a growing public health problem. Suffering from a fracture of this nature is the main risk factor for suffering a new fracture. It is documented that vertebral compression fractures lead to significant morbidity and mortality, in the short and long term, as well as other complications, such as sagittal imbalance and hyperkyphosis of the segment. However, we have not found documentation that analyzes the medium and long-term consequences of these injuries, assessing the type of treatment used, and the economic impact they represent. The purpose of this review is to analyze the main recent literature on the subject and make a breakdown of the consequences of these fractures in various spheres, such as economic, quality of life, sagittal balance and radiographic parameters, pain or mortality; as well as a brief analysis of epidemiology and natural history. CONCLUSION: Osteoporotic fractures constitute an emerging problem, both in the medical and economic fields. The consequences and sequelae on the patient are multiple and although surgical options offer good long-term results, it is necessary to properly select the patient, through multidisciplinary teams, to try to minimize potential complications.

Osteoporotic vertebral fractures: Natural history and impact.

Osteoporosis, and the consequences derived from it, such as fragility fractures, constitute a growing public health problem. Suffering from a fracture of this nature is the main risk factor for suffering a new fracture. It is documented that vertebral compression fractures lead to significant morbidity and mortality, in the short and long term, as well as other complications, such as sagittal imbalance and hyperkyphosis of the segment. However, we have not found documentation that analyzes the medium and long-term consequences of these injuries, assessing the type of treatment used, and the economic impact they represent. The purpose of this review is to analyze the main recent literature on the subject and make a breakdown of the consequences of these fractures in various spheres, such as economic, quality of life, sagittal balance and radiographic parameters, pain or mortality; as well as a brief analysis of epidemiology and natural history. Conclusion Osteoporotic fractures constitute an emerging problem, both in the medical and economic fields. The consequences and sequelae on the patient are multiple and although surgical options offer good long-term results, it is necessary to properly select the patient, through multidisciplinary teams, to try to minimize potential complications.

Recommendations on the treatment of metastatic hormone-sensitive prostate cancer: Patient selection.

The standard treatment for metastatic hormone-sensitive prostate cancer (mHSPC) is now a combination of androgen deprivation therapy plus an androgen receptor-targeted therapy (abiraterone, apalutamide, enzalutamide or darolutamide), with or without chemotherapy (docetaxel). The selection of suitable patients for each therapeutic approach has become a determining factor to ensure efficacy and minimize side effects. This article combines recent clinical evidence with the accumulated experience of experts in medical oncology, radiation oncology and urology, to provide a comprehensive view and therapeutic recommendations for mHSPC.

Uso de albúmina a largo plazo en el paciente cirrótico. Revisión sistemática / Long-term use of albumin in the cirrhotic patient. Systematic review

Introducción. La cirrosis constituye la etapa final de la enfermedad hepática crónica, con una alta mortalidad, y puede deberse a diferentes etiologías. La albúmina tiene tres indicaciones bien establecidas: la prevención de la disfunción circulatoria inducida por paracentesis, la peritonitis bacteriana espontánea y el síndrome hepatorrenal, sin embargo, su uso a largo plazo es controvertido. El objetivo de esta revisión fue identificar si el uso prolongado de la albúmina tiene efectos beneficiosos en el tratamiento de pacientes cirróticos. Metodología. Se realizaron búsquedas en la base de datos de PubMed, empleando los siguientes términos: ("Liver Cirrhosis"[Mesh]) AND ("Serum Albumin"[Mesh] OR "Serum Albumin, Human"[Mesh]). Se excluyeron los artículos que no cumplieron con la temática y aquellos que tenían más de 5 años de antigüedad, a excepción de aquellos relevantes para la revisión. Resultados. Se ha demos-trado en varios estudios realizados en los últimos 4 años, que la administración prolongada de albúmina reduce la mortalidad en el paciente cirrótico. Además, resulta en una disminución en ingresos hospitalarios por complicaciones de la cirrosis, disminución de la necesidad de para-centesis y menor uso de albúmina para otras indicaciones ya establecidas, lo que contrarresta los costos derivados de la terapia. Conclusión. Se concluye con base en la evidencia presenta-da, que el uso de albúmina a largo plazo podría resultar beneficioso en pacientes con cirrosis hepática descompensada. No obstante, es necesario abordar otros aspectos de la terapia en estudios posteriores

Introduction. Cirrhosis is the final stage of chronic liver disease, has a high mortality and can be due to different etiologies. Albumin has three well-established indications: prevention of circulatorydysfunction induced by paracentesis, spontaneous bacterial peritonitis, and hepatorenal syndrome, however, its long-term use is controversial. The objective of this review was to identify if the prolonged use of albumin has beneficial effects in the treatment of cirrhotic patients. Methodology. PubMed database was searched using the following terms: ("Liver Cirrhosis"[Mesh]) AND ("Serum Albumin"[Mesh] OR "Serum Albumin, Human"[Mesh]). Articles that did not meet the topic and those that were more than 5 years old were excluded, except for those relevant to the review. Results.It has been shown in several studies within the previous 4 years, that prolonged administration of albumin reduces mortality in cirrhotic patients. In addition, it results in a decrease in hospital ad-missions due to complications of cirrhosis, a decrease in the need for paracentesis and less use of albumin for other established indications, which offsets the costs derived from therapy. Conclusion. It is concluded based on the evidence presented, that the long-term use of albumin could be beneficial in patients with decompensated liver cirrhosis. However, other aspects of the therapy need to be addressed in further studies

Cardiomiopatía en el paciente con cirrosis hepática: artículo de revisión / Cardiomyopathy in patients with liver cirrhosis: review article

La cardiomiopatía cirrótica se trata de una complicación en el paciente cirrótico, con una pre- valencia superior al 40%. Es una entidad subclínica, pero ante el ejercicio o estrés circulatorio, desencadena su sintomatología. Su fisiopatología se explica por la hipertensión portal que lleva a vasodilatación esplácnica, con posterior liberación de vasodilatadores y factores cardiosupresores, lo cual conduce a una circulación hiperdinámica y disfunción circulatoria, con elevación del gasto cardíaco, disminución de la resistencia vascular y presión arterial baja. Sus características principales son disfunción cardiaca sistólica y diastólica, circulación hiperdinámica y alteraciones electrofisiológicas, especialmente prolongación del intervalo QT. Para su diagnóstico se usa la ecocardiografía y pruebas de estrés físico o farmacológico. No existe un protocolo de tratamiento estandarizado, sin embargo, el trasplante hepático puede ser un procedimiento efectivo para revertir la disfunción cardiaca en algunos pacientes. En el presente artículo se describen tanto las características de la cardiomiopatía cirrótica, como su papel en la morbilidad y mortalidad del paciente con cirrosis.

Cirrhotic cardiomyopathy is a complication in cirrhotic patients, with a prevalence of more than 40%. During the resting state, it is a subclinical entity, which triggers symptoms upon exercise or circulatorystress. Its pathophysiology is explained by portal hypertension leading to splanchnic vasodilatation, with subsequent release of vasodilators and cardio-suppressive factors, which leads to hyperdynamic circulation and circulatory dysfunction, with elevated cardiac output, decreased vascular resistance and low blood pressure. The main characteristics are systolic and diastolic cardiac dysfunction, hyperdynamic circulation and electrophysiological alterations, especially prolongation of the QT interval. Echocardiography and physical or pharmacological stress tests are used in diagnosis. There is not an standardized treatment protocol. Liver transplantation can be an effective procedure to reverse cardiac dysfunction in selected patients. In this review, we describe the characteristics of cirrhotic cardiomyopathy and its role in the morbidity and mortality of the patient with cirrhosis.

Trastornos de la coagulación en cirrosis hepática: artículo de revisión / Coagulation disorders in liver cirrhosis: a review article

Los eventos fisiopatológicos de la cirrosis hepática alteran drásticamente los procesos de hemostasia primaria, secundaria y fibrinólisis. Antiguamente se conceptuaba que dichas alteraciones predisponían exclusivamente a un estado de hipocoagulabilidad, debido a la baja producción hepática de factores procoagulantes y a la trombocitopenia característica. Actualmente existe evidencia de mecanismos de compensación que llevan a un reequilibrio hemostático, que es inestable y fácilmente desregulado ante comorbilidades, complicaciones y progresión de la enfermedad, conduciendo a fenómenos prohemorrágicos o protrombóticos, como trombosis venosa portal, tromboembolismo venoso, etc. Para determinar eficazmente si un paciente cirrótico tiene riesgo de sangrado, no son de utilidad las pruebas de coagulación convencionales. El tratamiento dependerá del estado hipo o hipercoagulable del paciente. Para ello desarrollamos una revisión de los fenómenos hemostáticos en la cirrosis, con el fin de dar a conocer sus características, el método de diagnóstico más eficaz y los tratamientos disponibles.

The pathophysiological events of liver cirrhosis drastically alter the processes of primary and secondary hemostasis and fibrinolysis. Previously, it was conceptualized that these alterations exclusively predisposed to hypocoagulation, due to the low hepatic production of procoagulant factors and the characteristic thrombocytopenia. Currently, there is evidence of compensation mechanisms that lead to a hemostatic rebalancing, which is unstable and easily dysregulated in the presence of comorbidities, complications and progression of the disease, leading to prohemorrhagic or prothrombotic phenomena, such as portal vein thrombosis, venous thromboembolism, etc. To effectively determine whether a cirrhotic patient is at risk for bleeding, conventional coagulation tests are not helpful. Treatment will depend on the hypo or hypercoagulable state of the patient. In this manuscript, we review the hemostatic phenomena in cirrhosis, to reveal its characteristics, effective diagnostic methods and treatment.

Protocolo de inmunosupresión en trasplante hepático: revisión de la literatura / Immunosuppression protocol in liver transplantation: review article

El trasplante de hígado es el último recurso para el tratamiento de hepatopatías. Para evitar el rechazo del injerto se requieren esquemas de inmunosupresión que han ido evolucionando a lo largo de los años. Se realizó una revisión bibliográfica en la base de datos PubMed sobre las terapias inmunosupresoras disponibles para evitar el rechazo del injerto en el trasplante hepático, los esquemas utilizados, efectos adversos, interacciones y sus modificaciones desde la fase de inducción hasta el seguimiento posterior. Se encontró que la inducción habitual es con esteroides o terapia inmunológica clonal. En el mantenimiento, los inhibidores de la calcineurina son los más utilizados, las dosis se deben ajustar según sus niveles séricos y la presencia de efectos adversos como nefrotoxicidad o diabetes. Por otra parte, los inhibidores del mTOR han sido considerados como agentes reductores del riesgo de recidiva de cáncer hepatocelular. Las características del paciente y sus comorbilidades (embarazo, insuficiencia renal, diabetes, sepsis, carcinoma hepatocelular) requieren modificar el tratamiento e individualizarlo

Liver transplantation is the last option for the treatment of liver disease. Immunosuppression schemes are required to avoid graft rejection, which have evolved over the years. A literature review was carried out in PubMed on the immunosuppressive therapies available to avoid graft rejection in liver transplantation, as well as on the schemes used, adverse effects, interactions and their modifications from the induction phase to subsequent follow-up. The usual induction was found to be with steroids or clonal immune therapy. In maintenance, calcineurin inhibitors are the most widely used, and their doses should be adjusted according to their serum levels and the presence of adverse effects such as nephrotoxicity or diabetes. On the other hand, mTOR inhibitors have been considered to reduce the risk of hepatocellular cancer recurrence. The characteristics of the patient and their comorbidities (pregnancy, kidney failure, diabetes, sepsis, hepatocellular carcinoma) require modification and individualization of the treatment.