Experiencia en práctica clínica de optimización de tiopurinas mediante determinación de sus metabolitos en la enfermedad inflamatoria intestinal

Introduction

Thiopurine therapy can be optimised by determining the concentration of the drug's metabolites.

Musashi2 sustains the mixed-lineage leukemia–driven stem cell regulatory program

Leukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Leukemia cells exhibit a dysregulated developmental program as the result of genetic and epigenetic alterations. Overexpression of the RNA-binding protein Musashi2 (MSI2) has been previously shown to predict poor survival in leukemia. Here, we demonstrated that conditional deletion of Msi2 in the hematopoietic compartment results in delayed leukemogenesis, reduced disease burden, and a loss of LSC function in a murine leukemia model. Gene expression profiling of these Msi2-deficient animals revealed a loss of the hematopoietic/leukemic stem cell self-renewal program and an increase in the differentiation program. In acute myeloid leukemia patients, the presence of a gene signature that was similar to that observed in Msi2-deficent murine LSCs correlated with improved survival. We determined that MSI2 directly maintains the mixed-lineage leukemia (MLL) self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc, and Ikzf2 mRNAs. Moreover, depletion of MLL target Ikzf2 in LSCs reduced colony formation, decreased proliferation, and increased apoptosis. Our data provide evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and suggest MSI2 as a potential therapeutic target for myeloid leukemia.     

Pain and Bloody Ear Discharge in a Returning Traveler

Cochliomyia hominivorax, the New World screwworm, was a serious livestock pest in the southern United States until the 1960s, when it was successfully eradicated by the release of sterile male flies. It remains endemic in parts of the Caribbean and South America, and there is concern that climate change may extend its geographic distribution. Cochliomyia hominivorax is voracious and can cause extensive damage to soft tissue and bone. We describe the case of a 26-year-old traveler who presented with otalgia and bloody otorrhea after returning from a vacation in the Dominican Republic, where exposure to screwworm flies most likely occurred during a nap on the beach. The causative agent was recognized by its characteristic larval anatomy, which includes pigmented dorsal tracheal trunks and posterior spiracles with an open peritreme.A 26-year-old female presented with a 2-day history of otalgia and bloody otorrhea after returning from a week of vacation in the Dominican Republic, where she stayed in a beachside resort with screened windows, swam in the ocean, hiked near an estuary, and sunbathed on the beach. She admitted to falling asleep on the beach one evening after drinking alcohol. The next day she had right ear discomfort with the sensation of movement, and removed a fly from her ear. One day later during the flight home, she had acute onset of ear pain, which she initially attributed to pressure changes associated with her flight, until she began noting discharge from the ear. The discharge was initially clear but became bloody within 1–2 hours. She sought medical care the next day, when an otoscopic examination revealed multiple motile larvae (Figure 1, Panel A). She was immediately referred to an otolaryngologist who performed excision and debridement of her external auditory canal with atticotomy.Open in a separate windowFigure 1.Panel A: Excised tissue displaying multiple motile larvae that were removed from the external auditory canal of a returning traveler vacationing in the Dominican Republic with auricular myiasis. Panel B: The characteristic pigmented dorsal tracheal trunks (white open arrow) and posterior spiracles with an open peritreme (gray closed arrow and inset) of Cochliomyia hominivorax.Intraoperative findings revealed soft tissue larval infiltration extending to the temporal bone and tympanic membrane perforation without middle ear involvement. The patient tolerated the debridement well and was prescribed amoxicillin-clavulanic acid for potential secondary soft-tissue infection. She subsequently underwent tympanoplasty with a split-thickness skin graft. The removed larvae were preliminarily identified as Cochliomyia hominivorax by the University of Washington Microbiology Laboratory on the basis of characteristic anatomic findings. Definitive identification was confirmed by the U.S. Department of Agriculture Screwworm Research Unit.Cochliomyia hominivorax (“human eater”), the New World screwworm, has smooth larvae with pigmented dorsal tracheal trunks (white open arrow) and posterior spiracles with an open peritreme (gray closed arrow, and inset) (Figure 1, Panel B).¹ The larvae feed on the living tissue of warm-blooded mammals using sharp hook-like mandibles (Supplemental Video). Spines found in concentric rings along the larvae resemble a screw and aid in anchoring the larvae within tissue, hence the name “screwworm.”² A female adult can lay hundreds of eggs at one time, often within existing open wounds.³ The voracious larvae emerge within 24 hours and can cause extensive soft tissue damage, and in some cases, destruction of bone. After 5–7 days the pupae mature and attempt to leave the wound to eventually burrow into the ground to pupate.² Adult flies can live for 2–3 weeks. Female flies are attracted to the scent of normal secretions of the orifices of mammals, with case reports describing infestation of the ears, eyes, nose, mouth, vagina, and rectum,⁴ and are able to fly great distances (∼50 km/week) to find a suitable host in which to deposit their eggs.² The scent of tissue infested with C. hominivorax can attract additional adult female flies that deposit their eggs within the same site. Individuals who are immobile, developmentally delayed, mentally ill, or alcoholic are at a higher risk of infestation.³ Orbital myiasis can be particularly devastating, requiring extensive debridement and sometimes enucleation.⁴ Several case reports have described secondary myiasis of ulcerative cutaneous malignancies.⁵ Auricular myiasis, as observed in our patient, is extremely rare and primarily occurs in children.³ Treatment of New World screwworm infestation consists of debridement, antibiotics if evidence of secondary infection is present, and adjunctive ivermectin in severe cases.⁴Cochliomyia hominivorax was formerly endemic in the southern United States where it was responsible for a serious economic burden caused by livestock destruction, until the 1960s when it became the first pest to be successfully eradicated by the release of sterile male flies.⁶ The New World screwworm remains endemic in parts of the Caribbean and South America, and there is concern that climate change may extend its geographic distribution.⁷ Since the New World screwworm has been eradicated from the United States for decades, clinicians may be unaware of this potentially devastating infestation resulting from foreign travel to endemic areas. As a result of the risk for significant tissue destruction, particularly if diagnosis is delayed, it is important for clinicians to be able to promptly recognize and appropriately treat this form of myiasis.     

Evaluación prospectiva del desarrollo de nefropatía inducida por contraste en pacientes con síndrome coronario agudo tratados con angiografía coronaria rotacional vs. angiografía coronaria convencional: Estudio CINERAMA

Introduction and objectives

Rotational coronary angiography (RCA) requires less contrast to be administered and can prevent the onset of contrast-induced nephropathy (CIN) during invasive coronary procedures. The aim of the study is to evaluate the impact of RCA on CIN (increase in serum creatinine ≥0.5 mg/dl or ≥25%) after an acute coronary syndrome.

Nogo receptor antagonizes p75NTR-dependent motor neuron death

The Nogo-66 receptor (NgR) plays a critical role in restricting axon regeneration in the central nervous system. This inhibitory action is in part mediated by a neuronal receptor complex containing p75NTR, a multifunctional receptor also well known to trigger cell death upon binding to neurotrophins such as NGF. In the present study, we show that Pep4 and NEP1-40, which are two peptides derived from the Nogo-66 sequence that modulate NgR-mediated neurite outgrowth inhibition, prevent NGF-stimulated p75NTR-dependent death of cultured embryonic motor neurons. They also confer protection on spinal cord motor neurons after neonatal sciatic nerve axotomy. These findings demonstrate an as-yet-unknown function of NgR in maintaining neuronal survival that may be relevant for motor neuron development and degeneration.     

Phylogeny and Comparative Genomics Unveil Independent Diversification Trajectories of qnrB and Genetic Platforms within Particular Citrobacter Species

To gain insights into the diversification trajectories of qnrB genes, a phylogenetic and comparative genomics analysis of these genes and their surrounding genetic sequences was performed. For this purpose, Citrobacter sp. isolates (n = 21) and genome or plasmid sequences (n = 56) available in public databases harboring complete or truncated qnrB genes were analyzed. Citrobacter species identification was performed by phylogenetic analysis of different genotypic markers. The clonal relatedness among isolates, the location of qnrB genes, and the genetic surroundings of qnrB genes were investigated by pulsed-field gel electrophoresis (PFGE), S1-/I-CeuI-PFGE and hybridization, and PCR mapping and sequencing, respectively. Identification of Citrobacter isolates was achieved using leuS and recN gene sequences, and isolates characterized in this study were diverse and harbored chromosomal qnrB genes. Phylogenetic analysis of all known qnrB genes revealed seven main clusters and two branches, with most of them included in two clusters. Specific platforms (comprising pspF and sapA and varying in synteny and/or identity of other genes and intergenic regions) were associated with each one of these qnrB clusters, and the reliable identification of all Citrobacter isolates revealed that each platform evolved in different recognizable (Citrobacter freundii, C. braakii, C. werkmanii, and C. pasteurii) and putatively new species. A high identity was observed between some of the platforms identified in the chromosome of Citrobacter spp. and in different plasmids of Enterobacteriaceae. Our data corroborate Citrobacter as the origin of qnrB and further suggest divergent evolution of closely related qnrB genes/platforms in particular Citrobacter spp., which were delineated using particular genotypic markers.