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Hospital readmission is a common occurrence following kidney transplantation, but less is known about the predictors of early and recurrent hospitalization. We analyzed a cohort of adult kidney transplant recipients in Nova Scotia, Canada, from January 2010 to December 2015. Readmission rates for 30 days, 6 months, and 1 year were calculated as a proportion of total transplants. Factors independently associated with early readmission were investigated using multivariable Cox hazards models with multivariable Anderson-Gill Cox models being used for factors independently associated with recurrent readmission. Of the 213 patients included, 41 (19.2%), 78 (36.6%), and 88 (41.3%) were readmitted to hospital within 30 days, 6 months, and 1 year, respectively. On multivariable analyses, a history of congestive heart failure (HR 1.741, 95% CI 1.039-2.918), peptic ulcer disease (HR 2.290, 95% CI 1.054-4.973), and liver disease (HR 2.492, 95% CI 1.162-5.344) was associated with higher risk of first rehospitalization. Recurrent hospital admission was associated with initial hospital duration ≥ 8 days (HR 2.140, 95% CI 1.265-3.618), congestive heart failure (HR 1.366, 95% CI 1.044-1.787), and liver disease (HR 1.785, 95% CI 1.257-2.534). Increasing duration of initial hospitalization, congestive heart failure, and liver disease are important to consider when evaluating a patient's risk for recurrent readmission following kidney transplant.
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Trasplante de Riñón , Adulto , Canadá/epidemiología , Estudios de Cohortes , Hospitalización , Humanos , Trasplante de Riñón/efectos adversos , Readmisión del Paciente , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Dasatinib is a tyrosine kinase inhibitor indicated for the treatment of chronic myeloid leukemia (CML). Skin rashes are common, occurring in about a quarter of patients treated, and are generally mild. The commonest rash is a keratosis pilaris-like eruption. A neutrophilic dermatosis has rarely been reported. OBJECTIVE: We report a patient whose CML was successfully treated with dasatinib and who several years later developed episodes of a neutrophilic dermatosis recurring at the same sites. CONCLUSION: This report extends the clinical spectrum of neutrophilic dermatoses to include dasatinib-induced recurrent and fixed erythematous plaques.
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Dasatinib/efectos adversos , Erupciones por Medicamentos , Diagnóstico Diferencial , Erupciones por Medicamentos/diagnóstico , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/patología , Humanos , Masculino , Persona de Mediana Edad , Infiltración Neutrófila , Recurrencia , Piel/patología , Síndrome de Sweet , Tórax/patologíaRESUMEN
Inhibition of isoprenylcysteine carboxyl methyltransferase (Icmt) offers a promising strategy for K-Ras driven cancers. We describe the synthesis and inhibitory activity of substrate-based analogs derived from several novel scaffolds. Modifications of both the prenyl group and thioether of N-acetyl-S-farnesyl-L-cysteine (AFC), a substrate for human Icmt (hIcmt), have resulted in low micromolar inhibitors of Icmt and have given insights into the nature of the prenyl binding site of hIcmt.
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Cisteína/análogos & derivados , Inhibidores Enzimáticos/farmacología , Lípidos/química , Proteína Metiltransferasas/antagonistas & inhibidores , Azufre/química , Cisteína/síntesis química , Cisteína/química , Cisteína/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Proteína Metiltransferasas/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
RATIONALE: Primary hyperoxaluria (PH) is a rare autosomal recessive disorder more commonly diagnosed in children or adolescents. Owing to its rarity and heterogeneous phenotype, it is often underrecognized, resulting in delayed diagnosis, including diagnosis after end-stage kidney disease (ESKD) has occurred or recurrence after kidney-only transplantation. CASE PRESENTATION: A 40-year-old Caucasian Canadian woman with a history of recurrent nephrolithiasis since age 19 presented with ESKD and cutaneous symptoms. She had no known prior kidney disease and no family history of kidney disease or nephrolithiasis. DIAGNOSIS: A diagnosis of primary hyperoxaluria type 1 (PH1) due to homozygous splice donor mutation (AGXT c.680+1G>A) was made with kidney and cutaneous pathology demonstrating calcium oxalate deposition and ultrasound suggestive of nephrocalcinosis. INTERVENTIONS: She was initiated on frequent, high-efficiency, high-flux conventional hemodialysis and oral pyridoxine. Lumasiran was added 11 months later, after she developed bilateral swan-neck deformities. OUTCOMES: After 14 months of high-intensity dialysis and 3 months of lumasiran, there have been no signs of renal recovery, and extra-renal involvement has increased with progressive swan-neck deformities, reduced cardiac systolic function, and pulmonary hypertension. The patient has been waitlisted for kidney-liver transplantation. TEACHING POINTS: This case report describes an adult presentation of PH1. The case highlights the importance of timely workup of metabolic causes of recurrent nephrolithiasis or nephrocalcinosis in adults which can be a presenting sign of PH and genetic testing for PH to facilitate early diagnosis and treatment especially in the era of novel therapeutics that may alter disease course and outcomes. The case also demonstrates the value of testing for PH in adults presenting with unexplained ESKD and a history of recurrent nephrolithiasis or nephrocalcinosis due to implications for organ transplantation strategy and presymptomatic family screening.
JUSTIFICATION: L'hyperoxalurie primaire (HP) est un trouble récessif autosomique rare plus souvent rencontré chez les enfants ou les adolescents. En raison de sa rareté et de son phénotype hétérogène, cette affection est fréquemment sous-reconnue, ce qui entraîne un retard dans le diagnostic, et ce, même après l'apparition d'une insuffisance rénale terminale (IRT) ou une récidive suivant une greffe simple de rein. PRÉSENTATION DU CAS: Nous présentons le cas d'une Canadienne de race blanche âgée de 40 ans avec des antécédents de néphrolithiase récurrente depuis l'âge de 19 ans. La patiente était atteinte d'IRT et présentait des symptômes cutanés. Elle n'avait aucun antécédent connu de maladie rénale ou antécédent familial de maladie rénale ou de néphrolithiase. DIAGNOSTIC: Une pathologie rénale et cutanée montrant des dépôts d'oxalate de calcium et une échographie suggérant une néphrocalcinose ont permis de poser un diagnostic d'hyperoxalurie primaire de type 1 (HP1) due à une mutation de donneur d'épissage homozygote (AGXT c.680+1G>A). INTERVENTIONS: La patiente a amorcé des traitements d'hémodialyse conventionnelle à grande fréquence, à haut rendement et à flux élevé, et a reçu de la pyridoxine par voie orale. Un traitement par lumasiran a été ajouté 11 mois plus tard, après le développement de déformations bilatérales en col de cygne. RÉSULTATS: Après quatorze mois de dialyze à haute intensité et trois mois de lumasiran, aucun signe de récupération rénale n'a été observé. L'intervention d'épuration extra-rénale a été augmentée en raison de déformations progressives en col de cygne, d'une réduction de la fonction cardiaque systolique et d'une hypertension pulmonaire. La patiente a été placée sur la liste d'attente pour une transplantation rénale et hépatique. ENSEIGNEMENTS TIRÉS: Ce rapport de cas décrit une présentation adulte d'HP1. Ce cas souligne l'importance de traiter rapidement les causes métaboliques de la néphrolithiase ou de la néphrocalcinose récidivante chez les adultes, car celles-ci peuvent être des signes d'hyperoxalurie primaire (HP). Ce cas souligne en outre l'importance de procéder à des tests génétiques pour l'HP afin de permettre le diagnostic et le traitement précoces, en particulier à l'ère de nouveaux traitements susceptibles d'infléchir l'évolution et les résultats de la maladie. Enfin, il démontre la valeur du dépistage de l'HP chez les adultes présentant une IRT inexpliquée et des antécédents de néphrolithiase ou de néphrocalcinose récidivante, en raison de ses implications sur la stratégie de transplantation d'organes et sur le dépistage pré-symptomatique de la famille.
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Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models. Global HDAC11 deletion had no effect on health or development, and compared to WT controls, Foxp3+ Tregs lacking HDAC11 showed increased suppressive function, and increased expression of Foxp3 and TGF-ß. Likewise, compared to WT recipients, conditional deletion of HDAC11 within Tregs led to long-term survival of fully MHC-mismatched cardiac allografts, and prevented development of transplant arteriosclerosis in an MHC class II-mismatched allograft model. The translational significance of HDAC11 targeting was shown by the ability of an HDAC11i to promote long-term allograft allografts in fully MHC-disparate strains. These data are powerful stimuli for the further development and testing of HDAC11-selective pharmacologic inhibitors, and may ultimately provide new therapies for transplantation and autoimmune diseases.
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Factores de Transcripción Forkhead/inmunología , Histona Desacetilasas/inmunología , Histonas/inmunología , Linfocitos T Reguladores/inmunología , Aloinjertos , Animales , Factores de Transcripción Forkhead/metabolismo , Perfilación de la Expresión Génica/métodos , Supervivencia de Injerto/efectos de los fármacos , Supervivencia de Injerto/genética , Supervivencia de Injerto/inmunología , Células HEK293 , Trasplante de Corazón/métodos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Linfocitos T Reguladores/metabolismoRESUMEN
Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressive degeneration of motor and sensory nerves leads to motor problems and sensory loss and for which no pharmacological treatment is available. Recently, it has been shown in a model for the axonal form of CMT that histone deacetylase 6 (HDAC6) can serve as a target for the development of a pharmacological therapy. Therefore, we aimed at developing new selective and activity-specific HDAC6 inhibitors with improved biochemical properties. By utilizing a bicyclic cap as the structural scaffold from which to build upon, we developed several analogues that showed improved potency compared to tubastatin A while maintaining excellent selectivity compared to HDAC1. Further screening in N2a cells examining both the acetylation of α-tubulin and histones narrowed down the library of compounds to three potent and selective HDAC6 inhibitors. In mutant HSPB1-expressing DRG neurons, serving as an in vitro model for CMT2, these inhibitors were able to restore the mitochondrial axonal transport deficits. Combining structure-based development of HDAC6 inhibitors, screening in N2a cells and in a neuronal model for CMT2F, and preliminary ADMET and pharmacokinetic profiles, resulted in the selection of compound 23d that possesses improved biochemical, functional, and druglike properties compared to tubastatin A.
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Enfermedad de Charcot-Marie-Tooth/tratamiento farmacológico , Enfermedad de Charcot-Marie-Tooth/enzimología , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/metabolismo , Acetilación/efectos de los fármacos , Animales , Línea Celular Tumoral , Células Cultivadas , Modelos Animales de Enfermedad , Ganglios Espinales/citología , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/genética , Humanos , Interleucina-2/genética , Ratones , Ratones Transgénicos , Mutación/genética , Neuroblastoma/patología , Neuronas/efectos de los fármacos , Neuronas/enzimología , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismoRESUMEN
Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as α-tubulin. HDAC6 dysfunction is associated with several pathological conditions in the central nervous system. This study investigated the beneficial effects of tubastatin A (TubA), a novel specific HDAC6 inhibitor, in a rat model of transient middle cerebral artery occlusion (MCAO) and an in vitro model of excitotoxicity. Post-ischemic TubA treatment robustly improved functional outcomes, reduced brain infarction, and ameliorated neuronal cell death in MCAO rats. These beneficial effects lasted at least three days after MCAO. Notably, when given at 24 hours after MCAO, TubA still exhibited significant protection. Levels of acetylated α-tubulin were decreased in the ischemic hemisphere on Days 1 and 3 after MCAO, and were significantly restored by TubA. MCAO markedly downregulated fibroblast growth factor-21 (FGF-21) and TubA significantly reversed this downregulation. TubA also mitigated impaired FGF-21 signaling in the ischemic hemisphere, including up-regulating ß-Klotho, and activating ERK and Akt/GSK-3ß signaling pathways. In addition, both TubA and exogenous FGF-21 conferred neuroprotection and restored mitochondrial trafficking in rat cortical neurons against glutamate-induced excitotoxicity. Our findings suggest that the neuroprotective effects of TubA likely involve HDAC6 inhibition and the subsequent up-regulation of acetylated α-tubulin and FGF-21.
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Infarto Encefálico/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Indoles/farmacología , Fármacos Neuroprotectores/farmacología , Tubulina (Proteína)/metabolismo , Acetilación , Animales , Infarto Encefálico/tratamiento farmacológico , Infarto Encefálico/genética , Infarto Encefálico/fisiopatología , Muerte Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Factores de Crecimiento de Fibroblastos/genética , Regulación de la Expresión Génica , Ácido Glutámico/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neuritas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Recuperación de la Función/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Long-term sedative use is prevalent and associated with significant morbidity, including adverse events such as falls, cognitive impairment, and sedation. The development of dependence can pose significant challenges when discontinuation is attempted as withdrawal symptoms often develop. We conducted a scoping review to map and characterize the literature and determine opportunities for future research regarding deprescribing strategies for long-term benzodiazepine and Z-drug (zopiclone, zolpidem, and zaleplon) use in community-dwelling adults. METHODS: We searched PubMed, Cochrane Central Register of Controlled Trials, EMBASE, PsycINFO, CINAHL, TRIP, and JBI Ovid databases and conducted a grey literature search. Articles discussing methods for deprescribing benzodiazepines or Z-drugs in community-dwelling adults were selected. RESULTS: Following removal of duplicates, 2797 articles were reviewed for eligibility. Of these, 367 were retrieved for full-text assessment and 139 were subsequently included for review. Seventy-four (53%) articles were original research, predominantly randomized controlled trials (n = 52 [37%]), whereas 58 (42%) were narrative reviews and seven (5%) were guidelines. Amongst original studies, pharmacologic strategies were the most commonly studied intervention (n = 42 [57%]). Additional deprescribing strategies included psychological therapies (n = 10 [14%]), mixed interventions (n = 12 [16%]), and others (n = 10 [14%]). Behaviour change interventions were commonly combined and included enablement (n = 56 [76%]), education (n = 36 [47%]), and training (n = 29 [39%]). Gradual dose reduction was frequently a component of studies, reviews, and guidelines, but methods varied widely. CONCLUSIONS: Approaches proposed for deprescribing benzodiazepines and Z-drugs are numerous and heterogeneous. Current research in this area using methods such as randomized trials and meta-analyses may too narrowly encompass potential strategies available to target this phenomenon. Realist synthesis methods would be well suited to understand the mechanisms by which deprescribing interventions work and why they fail.
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Acetamidas/uso terapéutico , Compuestos de Azabiciclo/uso terapéutico , Benzodiazepinas/uso terapéutico , Deprescripciones , Piperazinas/uso terapéutico , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Humanos , ZolpidemRESUMEN
The anti-inflammatory cytokine IL-10 is a key modulator of immune responses. A better understanding of the regulation of this cytokine offers the possibility of tipping the balance of the immune response toward either tolerance, or enhanced immune responses. Histone deacetylases (HDACs) have been widely described as negative regulators of transcriptional regulation, and in this context, the primarily nuclear protein HDAC11 was shown to repress il-10 gene transcriptional activity in antigen-presenting cells (APCs). Here we report that another HDAC, HDAC6, primarily a cytoplasmic protein, associates with HDAC11 and modulates the expression of IL-10 as a transcriptional activator. To our knowledge, this is the first demonstration of two different HDACs being recruited to the same gene promoter to dictate divergent transcriptional responses. This dynamic interaction results in dynamic changes in the expression of IL-10 and might help to explain the intrinsic plasticity of the APC to determine T-cell activation versus T-cell tolerance.
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Células Presentadoras de Antígenos/inmunología , Histona Desacetilasas/inmunología , Interleucina-10/genética , Animales , Línea Celular , Regulación de la Expresión Génica , Histona Desacetilasa 6 , Histona Desacetilasas/genética , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Regiones Promotoras Genéticas , Interferencia de ARN , ARN Interferente Pequeño , Linfocitos T/inmunología , Transcripción Genética , Activación Transcripcional/inmunologíaRESUMEN
INTRODUCTION: Tau pathology is associated with a number of age-related neurodegenerative disorders. Few treatments have been demonstrated to diminish the impact of tau pathology in mouse models and none are yet effective in humans. Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from cytoplasmic proteins, rather than nuclear histones. Its substrates include tubulin, heat shock protein 90 and cortactin. Tubastatin A is a selective inhibitor of HDAC6. Modification of tau pathology by specific inhibition of HDAC6 presents a potential therapeutic approach in tauopathy. METHODS: We treated rTg4510 mouse models of tau deposition and non-transgenic mice with tubastatin (25 mg/kg) or saline (0.9%) from 5 to 7 months of age. Cognitive behavior analysis, histology and biochemical analysis were applied to access the effect of tubastatin on memory, tau pathology and neurodegeneration (hippocampal volume). RESULTS: We present data showing that tubastatin restored memory function in rTg4510 mice and reversed a hyperactivity phenotype. We further found that tubastatin reduced the levels of total tau, both histologically and by western analysis. Reduction in total tau levels was positively correlated with memory improvement in these mice. However, there was no impact on phosphorylated forms of tau, either by histology or western analysis, nor was there an impact on silver positive inclusions histologically. CONCLUSION: Potential mechanisms by which HDAC6 inhibitors might benefit the rTg4510 mouse include stabilization of microtubules secondary to increased tubulin acetylation, increased degradation of tau secondary to increased acetylation of HSP90 or both. These data support the use of HDAC6 inhibitors as potential therapeutic agents against tau pathology.
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This Perspective provides an in depth look at the numerous disease states in which histone deacetylase 6 (HDAC6) has been implicated. The physiological pathways, protein-protein interactions, and non-histone substrates relating to different pathological conditions are discussed with regard to HDAC6. Furthermore, the compounds and methods used to modulate HDAC6 activity are profiled. The latter half of this Perspective analyzes reported HDAC6 selective inhibitors in terms of structure, potency, and selectivity over the other HDAC isoforms with the intent of providing a comprehensive overview of the molecular tools available. Potential obstacles and future directions of HDAC6 research are also presented.
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Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/efectos de los fármacos , Enfermedad/clasificación , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas/uso terapéutico , HumanosRESUMEN
We report the design and synthesis of novel FTPA-triazole compounds as potent inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt), through a focus on thioether and isoprenoid mimetics. These mimetics were coupled utilizing a copper-assisted cycloaddition to assemble the potential inhibitors. Using the resulting triazole from the coupling as an isoprenyl mimetic resulted in the biphenyl substituted FTPA triazole 10n. This lipid-modified analog is a potent inhibitor of Icmt (IC(50) = 0.8 ± 0.1 µM; calculated K(i) = 0.4 µM).
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The incidence of malignant melanoma has dramatically increased in recent years thus requiring the need for improved therapeutic strategies. In our efforts to design selective histone deactylase inhibitors (HDACI), we discovered that the aryl urea 1 is a modestly potent yet nonselective inhibitor. Structure-activity relationship studies revealed that adding substituents to the nitrogen atom of the urea so as to generate compounds bearing a branched linker group results in increased potency and selectivity for HDAC6. Compound 5 g shows low nanomolar inhibitory potency against HDAC6 and a selectivity of â¼600-fold relative to the inhibition of HDAC1. These HDACIs were evaluated for their ability to inhibit the growth of B16 melanoma cells with the most potent and selective HDAC6I being found to decrease tumor cell growth. To the best of our knowledge, this work constitutes the first report of HDAC6-selective inhibitors that possess antiproliferative effects against melanoma cells.