Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis.

The coincident downregulation of NR4A1 and NR4A3 has been implicated in myeloid leukemogenesis, but it remains unknown how these two genes function in myeloid cells and how their combined downregulation promotes myeloid leukemogenesis. Since NR4A1 abrogation is thought to confer a survival and proliferation advantage to myeloid cells, we hypothesized that downregulation of NR4A3 may have a complementary effect on myeloid cell differentiation. First, we tested the association between differentiation status of leukemic cells and NR4A3 expression using two large clinical datasets from patients with different acute myeloid leukemia (AML) subtypes. The analysis revealed a close association between differentiation status and different subtypes of AML Then, we probed the effects of differentiation-inducing treatments on NR4A3 expression and NR4A3 knockdown on cell differentiation using two myeloid leukemia cell lines. Differentiation-inducing treatments caused upregulation of NR4A3, while NR4A3 knockdown prevented differentiation in both cell lines. The cell culture findings were validated using samples from chronic myeloid leukemia (CML) patients at chronic, accelerated and blastic phases, and in acute promyelocytic leukemia (APL) patients before and after all trans-retinoic acid (ATRA)-based differentiation therapy. Progressive NR4A3 downregulation was coincident with impairments in differentiation in patients during progression to blastic phase of CML, and NR4A3 expression was increased in APL patients treated with ATRA-based differentiating therapy. Together, our findings demonstrate a tight association between impaired differentiation status and NR4A3 downregulation in myeloid leukemias, providing a plausible mechanistic explanation of how myeloid leukemogenesis might occur upon concurrent downregulation of NR4A1 and NR4A3.

Guidelines for the diagnosis and management of critical illness-related corticosteroid insufciency (CIRCI) in critically ill patients (Part II): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017

Tis part II of the guidelines for the diagnosis and management of critical illness-related corticosteroid insufciency (CIRCI) in critically ill patients is related to acute illnesses that may be complicated by CIRCI. We followed strictly the same methodology as for part I (see Appendix 1 in Supplementary material), which summarized the guidelines related to CIRCI and sepsis/septic shock, acute respiratory distress syndrome (ARDS), and major trauma. PICOM questions were developed a priori for community-acquired pneumonia, infuenza, meningitis, and non-septic systemic infammatory response syndrome (SIRS) that may be associated with shock, namely burns, cardiac arrest and cardiopulmonary bypass surgery. For all these conditions, we formulated statements for or against the use of exogenous corticosteroids. Recommendations and their strength required the agreement of at least 80% of the task force members. During the editorial process, discussions about the burn condition resulted in the compromise of this question being left out and reconsidered in the next update of these guidelines.

Polymorphism of PXR gene associated with the increased risk of drug-induced liver injury in Indonesian pulmonary tuberculosis patients.

WHAT IS KNOWN AND OBJECTIVE: Tuberculosis is still a major infectious disease in Indonesia. Patients are treated mostly using fixed-dose combination treatment in primary public health facilities. The incidence of antituberculosis drug-induced liver injury (AT-DILI) is approximately 10% among Indonesian tuberculosis patients who used standard fixed combination regimens during the intensive phase of treatment. However, information regarding genetic polymorphism associated with the increase risk of drug-induced liver injury is still limited. The aim of this study was to investigate pregnane X receptor (PXR) gene polymorphisms as one of the risk factors of AT-DILI. METHODS: In this prospective cohort study, we recruited 106 adult patients diagnosed with pulmonary tuberculosis and treated with category I FDC (fixed-dose combination). The identification of SNP -25385C>T (rs3814055) was conducted by ARMS (amplification refractory mutation system). Hepatotoxicity was defined as ALT and/or AST levels above the normal threshold on the second, fourth and sixth months of monitoring during tuberculosis treatment. RESULTS AND DISCUSSION: The logistic regression analysis showed that patients with the TT genotype of PXR gene (rs3814055) significantly had a greater risk of AT-DILI (OR 8·89; 95% CI 1·36-57·93, P < 0·05), compared with those of wild-type CC genotype. WHAT IS NEW AND CONCLUSION: The result suggests that in Indonesian patients with tuberculosis, the risk of having AT-DILI was associated with TT genotype of the PXR gene.

Lupus eritematoso sistémico en el anciano / Systemic lupus erythematosus in the elderly

El lupus eritematoso sistémico (LES) del anciano se refiere, en general, a la enfermedad que aparece después de los 65 años y presenta unas características diferenciales respecto al LES clásico de pacientes más jóvenes. Así, es aceptado que el LES de inicio tardío, responsable del 10-20% de los casos de lupus entre la población general, tiene un curso clínico diferente y unas primeras manifestaciones clínicas inespecíficas. En general, se ha descrito que el curso clínico del LES de inicio tardío es más indolente que el del LES clásico. Por otra parte, la incidencia significativamente mayor de varones con LES de inicio tardío y el curso más benigno de la enfermedad en mujeres postmenopáusicas sugieren que el estatus estrogénico puede influir de forma significativa en la actividad de la enfermedad. Debido al inicio insidioso y la poca especificidad de las manifestaciones al inicio de la enfermedad, se produce a menudo un diagnóstico tardío de la enfermedad. En el anciano, la presencia de comorbilidades y terapias concomitantes limita a menudo las opciones terapéuticas del LES. El tratamiento de elección para las manifestaciones articulares y la serositis son los antiinflamatorios no esteroideos o dosis bajas de corticosteroides durante un corto período de tiempo. Además de la necesidad de adoptar un enfoque multidisciplinar, obtener información sobre la capacidad funcional, el estado cognitivo y la situación social son elementos importantes que ayudarán en la toma de decisiones asistenciales en estos pacientes(AU)

Late-onset systemic lupus erythematosus (SLE) usually appears in patients older than 65 years and has clinical features different from the classical form observed in younger patients. In the elderly, SLE represents 10-20% of all SLE cases, shows a different and less aggressive clinical evolution and the first manifestations are non-specific. A significantly higher incidence of late-onset SLE in males, and the fact that postmenopausal women have a more benign disease, suggests that the estrogenic status may influence the activity of the disease. Owing to the insidious onset and the non-specific clinical manifestations on presentation, there is commonly a delayed diagnosis of late-onset SLE. Furthermore, the presence of comorbidities and concomitant therapies in elderly patients may limit the therapeutic options for SLE. The treatment of choice of joint symptoms and serositis includes non-steroidal anti-inflammatory drugs and low-dose steroids for short periods. In addition to the need for adopting a multidisciplinary approach, it is fundamental to obtain information about the functional, cognitive and social status of these patients in order to make appropriate healthcare decisions(AU)

Síndrome de movilidad articular limitada (queiroartropatía) en niña diabética / Limited joint mobility syndrome (cheiroarthropathy) in the diabetic child

El término queiroartropatía diabética o síndrome de limitación de la movilidad articular se emplea para describir la limitación de la movilidad articular de la mano asociada a diabetes. Se caracteriza por contracturas de una o más articulaciones de los dedos, afectando principalmente a la extensión de las articulaciones metacarpofalángicas e interfalángicas. El objetivo ha sido revisar la bibliografía, en relación con las opciones terapéuticas y exponer un caso clínico con los resultados de la opción elegida. Niña de 12 años diabética con flexo indoloro de articulación interfalángica proximal del quinto dedo de ambas manos. Tratada con cinesiterapia y ortesis correctoras. A los 2 años de evolución se consiguió la reducción completa del flexo en la mano derecha y corrección parcial en la izquierda. El uso precoz y prolongado del tratamiento rehabilitador parece favorecer la ganancia articular (AU)

The term diabetic cheiroarthropathy or limited joint mobility syndrome is used to describe joint mobility limitation of the hand associated to diabetes. It is characterized by contractures of one or more joints of the fingers, particularly affecting extension of the metacarpophalangeal and interphalangeal joints. This study has aimed to review the bibliography related to the therapeutic options and to present a clinical case with the results of the chosen option. The case of a 12-year old girl with diabetes with painless contracture of proximal interphalangeal joint of the 5th finger in both hands is presented. She was treated with kinesitherapy and orthotic braces. At 2 years of evolution, complete reduction of the right hand contracture and partial correction in the left one was achieved. Early and prolonged use of rehabilitation treatment seems to help the joint improvement (AU)

Is there an association between wheezing and pneumonia?

Objective The aim of this study was to investigate whether there is a relationship in school aged children between wheezing and pneumonia prior, during, or following the pneumonia episode. Patients-Methods One hundred and three children with community acquired pneumonia who were hospitalised were recruited along with 55 controls. Results During hospitalisation wheezing was audible in 11/103 (10.6%) patients with pneumonia and in none of the controls (p=0.009). Wheezing ever or asthma was elicited in 29/103(28%) patients with pneumonia and in 8/55 (14.5%) of the controls and this difference was not significant. Two years after the hospitalisation with pneumonia, wheezing episodes occurred in 12/103 with pneumonia and 1/55 of the controls (p=0.034). Among those who developed asthma following pneumonia 11/12 also had wheezing prior to pneumonia. Conclusion There is an excess of wheezing prior, during, and after an episode of pneumonia in school aged children and therefore children with pneumonia should be followed up carefully

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A mechanism for the anti-fibrogenic effects of the pregnane X receptor (PXR) in the liver: inhibition of NF-kappaB?

The liver is susceptible to chronic damage through exposure to a variety of toxins (e.g. alcohol) and viruses (e.g. hepatitis C). Obesity, autoimmune diseases (e.g. autoimmune hepatitis) and a variety of genetic diseases (e.g. Wilson's disease) also lead to chronic liver damage. This damage results in scarring fibrogenesis, structural disruption and functional impairment of the organ. Recent work suggests that there is cross-talk between the PXR and NF-kappaB pathways. This cross-talk may explain the observation that PXR activators inhibit liver fibrosis in in vitro and in vivo animal models of the disease. This reveiw will focus on the two transcription factors and their potential interaction.

Adaptive and maladaptive psychobiological responses to severe psychological stress: implications for the discovery of novel pharmacotherapy.

Post-traumatic stress disorder (PTSD) is one of the few DSM-IV diagnoses contingent upon a psychosocial stressor. In this context, there is an urgent need to acquire a better understanding of both the adaptive and maladaptive psychobiological responses to traumatic stress. Preclinical investigators have utilized a variety of animal models to identify the behavioral and neurobiological features of the organism's response to stress. However, given the complexity of the healthy and pathological human response to physiological and psychological stress, the extent to which the animal data is immediately transferable to human remains to be fully determined. This review draws upon preclinical and clinical literature to examine the transformation of an adaptive human stress response into a maladaptive and debilitating mental disorder. An integrative psychobiological model for PTSD is presented, linking psychological processes and behavioral patterns with current findings in neurocircuitry, neurochemistry and psychophysiology. The implications of this model for the discovery of novel pharmacological approaches to the treatment of severe psychological distress are discussed.