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The solute carrier family 16 (SLC16) is comprised of 14 members of the monocarboxylate transporter (MCT) family that play an essential role in the transport of important cell nutrients and for cellular metabolism and pH regulation. MCTs 1-4 have been extensively studied and are involved in the proton-dependent transport of L-lactate, pyruvate, short-chain fatty acids, and monocarboxylate drugs in a wide variety of tissues. MCTs 1 and 4 are overexpressed in a number of cancers, and current investigations have focused on transporter inhibition as a novel therapeutic strategy in cancers. MCT1 has also been used in strategies aimed at enhancing drug absorption due to its high expression in the intestine. Other MCT isoforms are less well characterized, but ongoing studies indicate that MCT6 transports xenobiotics such as bumetanide, nateglinide, and probenecid, whereas MCT7 has been characterized as a transporter of ketone bodies. MCT8 and MCT10 transport thyroid hormones, and recently, MCT9 has been characterized as a carnitine efflux transporter and MCT12 as a creatine transporter. Expressed at the blood brain barrier, MCT8 mutations have been associated with an X-linked intellectual disability, known as Allan-Herndon-Dudley syndrome. Many MCT isoforms are associated with hormone, lipid, and glucose homeostasis, and recent research has focused on their potential roles in disease, with MCTs representing promising novel therapeutic targets. This review will provide a summary of the current literature focusing on the characterization, function, and regulation of the MCT family isoforms and on their roles in drug disposition and in health and disease. SIGNIFICANCE STATEMENT: The 14-member solute carrier family 16 of monocarboxylate transporters (MCTs) plays a fundamental role in maintaining intracellular concentrations of a broad range of important endogenous molecules in health and disease. MCTs 1, 2, and 4 (L-lactate transporters) are overexpressed in cancers and represent a novel therapeutic target in cancer. Recent studies have highlighted the importance of MCTs in glucose, lipid, and hormone homeostasis, including MCT8 in thyroid hormone brain uptake, MCT12 in carnitine transport, and MCT11 in type 2 diabetes.
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Transportadores de Ácidos Monocarboxílicos/metabolismo , Animales , Humanos , Enfermedades Metabólicas/metabolismo , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Transportadores de Ácidos Monocarboxílicos/química , Transportadores de Ácidos Monocarboxílicos/genética , Relación Estructura-Actividad , Distribución Tisular , Transcripción GenéticaRESUMEN
The drug of abuse, γ-hydroxybutyric acid (GHB), is commonly co-ingested with ethanol, resulting in a high incidence of toxicity and death. Our laboratory has previously reported that GHB is a substrate for the monocarboxylate transporters (MCTs), necessary for its absorption, renal clearance, and tissue distribution, including across the blood-brain barrier. Our goal was to investigate the drug-drug interaction (DDI) between GHB and ethanol and to evaluate MCT1 inhibition as a strategy to reverse toxicity. The toxicokinetics of this DDI were investigated, including brain-to-plasma concentration ratios, in the presence and absence of ethanol. The toxicodynamic parameters examined were respiratory depression (breathing frequency, tidal volume) and sedation (time of return-of-righting reflex). Ethanol was administered (2 g/kg i.v.) 5 minutes before the intravenous or oral administration of GHB, and MCT1 inhibitors AZD-3965 and AR-C155858 (5 mg/kg i.v.) were administered 60 minutes after GHB administration. Ethanol administration did not alter the toxicokinetics or respiratory depression caused by GHB after intravenous or oral administration; however, it significantly increased the sedation effect, measured by return-to-righting time. AZD-3965 or AR-C155858 significantly decreased the effects of the co-administration of GHB and ethanol on respiratory depression and sedation of this DDI and decreased brain concentrations and the brain-to-plasma concentration ratio of GHB. The results indicate that ethanol co-administered with GHB increases toxicity and that MCT1 inhibition is effective in reversing toxicity by inhibiting GHB brain uptake when given after GHB-ethanol administration. SIGNIFICANCE STATEMENT: These studies investigated the enhanced toxicity observed clinically when γ-hydroxybutyric acid (GHB) is co-ingested with alcohol and evaluated strategies to reverse this toxicity. The effects of the novel monocarboxylate transporter 1 (MCT1) inhibitors AR-C155858 and AZD-3965 on this drug-drug interaction have not been studied before, and these preclinical studies indicate that MCT1 inhibitors can decrease brain concentrations of GHB by inhibiting brain uptake, even when administered at times after GHB-ethanol. AZD-3965 represents a potential treatment strategy for GHB-ethanol overdoses.
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Etanol/toxicidad , Hidroxibutiratos/toxicidad , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Pirimidinonas/farmacología , Simportadores/antagonistas & inhibidores , Tiofenos/farmacología , Uracilo/análogos & derivados , Animales , Interacciones Farmacológicas/fisiología , Etanol/metabolismo , Hidroxibutiratos/metabolismo , Masculino , Transportadores de Ácidos Monocarboxílicos/metabolismo , Pirimidinonas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/tratamiento farmacológico , Insuficiencia Respiratoria/metabolismo , Simportadores/metabolismo , Tiofenos/uso terapéutico , Uracilo/farmacología , Uracilo/uso terapéuticoRESUMEN
Gamma hydroxybutyric acid (GHB) has been approved clinically to treat excessive daytime sleepiness and cataplexy in patients with narcolepsy, alcohol and opioid withdrawal, and as an anesthetic. The use of GHB clinically is limited due to its high abuse potential. The absorption, clearance and tissue uptake of GHB is mediated by proton-dependent and sodium-coupled monocarboxylate transporters (MCTs and SMCTs) and inhibition of these transporters may result in a change in GHB pharmacokinetics and pharmacodynamics. Previous studies have reported that non-steroidal anti-inflammatory drugs (NSAIDs) may inhibit these monocarboxylate transporters. Therefore, the purpose of this work was to analyze the interaction between GHB (at a dose of 600 mg/kg i. v.) and the NSAID, diclofenac, by examining the effects of this drug on the in vivo pharmacokinetics and pharmacodynamics in rat studies. The pharmacodynamic effect evaluated was respiratory depression, a measure of toxicity observed by GHB at this dose. There was an improvement in the respiratory rate with diclofenac administration suggesting an effect of diclofenac on GHB toxicity. In vitro studies with rat blood brain endothelial cells (RBE4) that express MCT1 indicated that diclofenac can inhibit GHB transport with an IC50 of 10.6 µM at pH 7.4. In vivo studies found a decrease in brain GHB concentrations and a decrease in the brain-to-plasma concentration ratio following diclofenac treatment. With this study we can conclude that diclofenac and potentially other NSAIDs can inhibit the transport of GHB into the brain, therefore decreasing GHB's pharmacodynamic effects and toxicity.
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Encéfalo , Diclofenaco/farmacocinética , Interacciones Farmacológicas , Hidroxibutiratos/farmacocinética , Transportadores de Ácidos Monocarboxílicos , Insuficiencia Respiratoria , Simportadores , Anestésicos/farmacocinética , Anestésicos/toxicidad , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Transporte Biológico Activo/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Células Endoteliales/metabolismo , Hidroxibutiratos/toxicidad , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Transportadores de Ácidos Monocarboxílicos/metabolismo , Ratas , Ratas Sprague-Dawley , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/tratamiento farmacológico , Oxibato de Sodio/farmacocinética , Simportadores/antagonistas & inhibidores , Simportadores/metabolismoRESUMEN
Peptidyl-tRNA hydrolase 2 (PTRH2) regulates integrin-mediated pro-survival and apoptotic signaling. PTRH2 is critical in muscle development and regulates myogenic differentiation. In humans a biallelic mutation in the PTRH2 gene causes infantile-onset multisystem disease with progressive muscle weakness. We report here that the Ptrh2 knockout mouse model recapitulates the progressive congenital muscle pathology observed in patients. Ptrh2 null mice demonstrate multiple degenerating and regenerating muscle fibers, increased central nuclei, elevated creatine kinase activity and endomysial fibrosis. This progressive muscle pathology resembles the muscular dystrophy phenotype in humans and mice lacking the α7 integrin. We demonstrate that in normal muscle Ptrh2 associates in a complex with the α7ß1 integrin at the sarcolemma and Ptrh2 expression is decreased in α7 integrin null muscle. Furthermore, Ptrh2 expression is altered in skeletal muscle of classical congenital muscular dystrophy mouse models. Ptrh2 levels were up-regulated in dystrophin deficient mdx muscle, which correlates with the elevated levels of the α7ß1 integrin observed in mdx muscle and Duchenne muscular dystrophy patients. Similar to the α7 integrin, Ptrh2 expression was decreased in laminin-α2 dyW null gastrocnemius muscle. Our data establishes a PTRH2 mutation as a novel driver of congenital muscle degeneration and identifies a potential novel target to treat muscle myopathies.
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Hidrolasas de Éster Carboxílico/genética , Integrinas/genética , Proteínas Mitocondriales/genética , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/genética , Animales , Hidrolasas de Éster Carboxílico/biosíntesis , Distrofina/genética , Distrofina/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Integrinas/biosíntesis , Ratones , Ratones Endogámicos mdx , Ratones Noqueados , Proteínas Mitocondriales/biosíntesis , Desarrollo de Músculos/genética , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/patología , Sarcolema/genética , Sarcolema/patologíaRESUMEN
Likely pathogenic variants in CD320 cause transcobalamin receptor defect, a recently discovered inborn errors of cobalamin metabolism. Only 12 cases have been reported to date. There are no long-term clinical and biochemical outcome reports since its first description. In this report, we present two new cases and report their long-term treatment outcome. Two asymptomatic cases were identified through a positive newborn screening for propionic/methylmalonic aciduria. Biochemical abnormalities were normalized on a short course of oral cyanocobalamin (1 mg/day). Direct sequencing of CD320 identified a known pathogenic variant (c.262_264GAG; p.Glu88del) confirming the diagnosis of transcobalamin receptor defect. To date, both patients remain asymptomatic with normal neurodevelopment more than 6 years. Our two new cases with transcobalamin receptor defect due to pathogenic variants in CD320 further expand our knowledge and provide a reassuring long-term good neurodevelopmental outcome. Identification of additional cases requires the consideration of transcobalamin receptor defect in the differential diagnosis of newborns with confirmed positive newborn screening for methylmalonic acidurias.
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Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Antígenos CD/genética , Mutación , Administración Oral , Errores Innatos del Metabolismo de los Aminoácidos/tratamiento farmacológico , Errores Innatos del Metabolismo de los Aminoácidos/genética , Niño , Humanos , Recién Nacido , Masculino , Ácido Metilmalónico/sangre , Tamizaje Neonatal , Receptores de Superficie Celular , Vitamina B 12/administración & dosificación , Vitamina B 12/uso terapéuticoRESUMEN
Muscle differentiation requires a complex signaling cascade that leads to the production of multinucleated myofibers. Genes regulating the intrinsic mitochondrial apoptotic pathway also function in controlling cell differentiation. How such signaling pathways are regulated during differentiation is not fully understood. Bit-1 (also known as PTRH2) mutations in humans cause infantile-onset multisystem disease with muscle weakness. We demonstrate here that Bit-1 controls skeletal myogenesis through a caspase-mediated signaling pathway. Bit-1-null mice exhibit a myopathy with hypotrophic myofibers. Bit-1-null myoblasts prematurely express muscle-specific proteins. Similarly, knockdown of Bit-1 expression in C2C12 myoblasts promotes early differentiation, whereas overexpression delays differentiation. In wild-type mice, Bit-1 levels increase during differentiation. Bit-1-null myoblasts exhibited increased levels of caspase 9 and caspase 3 without increased apoptosis. Bit-1 re-expression partially rescued differentiation. In Bit-1-null muscle, Bcl-2 levels are reduced, suggesting that Bcl-2-mediated inhibition of caspase 9 and caspase 3 is decreased. Bcl-2 re-expression rescued Bit-1-mediated early differentiation in Bit-1-null myoblasts and C2C12 cells with knockdown of Bit-1 expression. These results support an unanticipated yet essential role for Bit-1 in controlling myogenesis through regulation of Bcl-2.
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Hidrolasas de Éster Carboxílico/metabolismo , Diferenciación Celular , Desarrollo de Músculos , Animales , Apoptosis , Hidrolasas de Éster Carboxílico/deficiencia , Caspasa 3/metabolismo , Línea Celular , Técnicas de Silenciamiento del Gen , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Fibras Musculares Esqueléticas/patología , Mioblastos/enzimología , Mioblastos/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Interferente Pequeño/metabolismo , TransfecciónRESUMEN
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare genetic condition affecting the mitochondrial beta-oxidation of long-chain fatty acids. This study reports on the clinical outcomes of patients diagnosed by newborn screening with VLCAD deficiency comparing metabolic parameters, enzyme activities, molecular results, and clinical management. It is a single-center retrospective chart review of VLCAD deficiency patients who met the inclusion criteria between January 2002 and February 2020. The study included 12 patients, 7 of whom had an enzyme activity of more than 10%, and 5 patients had an enzyme activity of less than 10%. The Pearson correlation between enzyme activity and the C14:1 level at newborn screening showed a p-value of 0.0003, and the correlation between enzyme activity and the C14:1 level at diagnosis had a p-value of 0.0295. There was no clear correlation between the number of documented admissions and the enzyme activity level. Patients who had a high C14:1 value at diagnosis were started on a diet with a lower percentage of energy from long-chain triglycerides. The C14:1 result at diagnosis is the value that has been guiding our initial clinical management in asymptomatic diagnosed newborns. However, the newborn screening C14:1 value is the most sensitive predictor of low enzyme activity and may help guide dietary management.
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Biallelic variants in MMACHC results in the combined methylmalonic aciduria and homocystinuria, called cobalamin (cbl) C (cblC) deficiency. We report 26 patients with cblC deficiency with their phenotypes, genotypes, biochemical parameters, and treatment outcomes, who were diagnosed and treated at our center. We divided all cblC patients into two groups: group 1: SX group: identified after manifestations of symptoms (n = 11) and group 2: NB group: identified during the asymptomatic period via newborn screening (NBS) or positive family history of cblC deficiency (n = 15). All patients in the SX group had global developmental delay and/or cognitive dysfunction at the time of the diagnosis and at the last assessment. Seizure, stroke, retinopathy, anemia, cerebral atrophy, and thin corpus callosum in brain magnetic resonance imaging (MRI) were common in patients in the SX group. Global developmental delay and cognitive dysfunction was present in nine patients in the NB group at the last assessment. Retinopathy, anemia, and cerebral atrophy and thin corpus callosum in brain MRI were less frequent. We report favorable outcomes in patients identified in the neonatal period and treated pre-symptomatically. Identification of cblC deficiency by NBS is crucial to improve neurodevelopmental outcomes.
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Combined methylmalonic aciduria and homocystinuria (cobalamin C deficiency, cblC) is a well-described disorder of vitamin B12 metabolism caused by mutations in the MMACHC gene with multisystemic manifestations. While there is no cure, combined treatment with intramuscular hydroxycobalamin and oral betaine may reduce the severity of symptoms and improve clinical outcome. We report a female patient diagnosed with late-onset cobalamin C deficiency at the age of 8 months who presented with developmental regression and severe dermatitis. She developed a movement disorder after initiation of hydroxycobalamin treatment. Similar movement disorders have been described in patients with nutritional vitamin B12 deficiencies following cobalamin supplementation but have not previously been reported in patients with cobalamin C disorder. The movement disorder in our patient gradually resolved with clonazepam treatment, despite no seizure activity detected on EEG. She was eventually weaned off the clonazepam and the abnormal movements have not recurred. The patient remains developmentally delayed but is showing no other symptoms related to cobalamin C deficiency. The patient has a younger affected sibling who was treated from birth and who is physically and developmentally entirely normal; she did not have abnormal movements after treatment with hydroxycobalamin was initiated. There is no clear consensus on the cause of movement disorders that develop following initiation of intramuscular vitamin B12 treatment.
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Duchenne muscular dystrophy (DMD) is a devastating disease caused by mutations in the dystrophin gene that result in the complete absence of dystrophin protein. We have shown previously that recombinant mouse Galectin-1 treatment improves physiological and histological outcome measures in the mdx mouse model of DMD. Because recombinant human Galectin-1 (rHsGal1) will be used to treat DMD patients, we performed a dose-ranging study and intraperitoneal or intravenous delivery to determine the efficacy of rHsGal1 to improve preclinical outcome measures in mdx mice. Our studies showed that the optimal dose of rHsGal1 delivered intraperitoneally was 20 mg/kg and that this treatment improved muscle strength, sarcolemma stability, and capillary density in skeletal muscle. We next examined the efficacy of intravenous delivery and found that a dose of 2.5 mg/kg rHsGal1 was well tolerated and improved outcome measures in the mdx mouse model. Our studies identified that intravenous doses of rHsGal1 exceeding 2.5 mg/kg resulted in toxicity, indicating that dosing using this delivery mechanism will need to be carefully monitored. Our results support the idea that rHsGal1 treatment can improve outcome measures in the mdx mouse model and support further development as a potential therapeutic agent for DMD.
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AR-C155858 and AZD3965, pyrrole pyrimidine derivatives, represent potent monocarboxylate transporter 1 (MCT1) inhibitors, with potential immunomodulatory and chemotherapeutic properties. Currently, there is limited information on the inhibitory properties of this new class of MCT1 inhibitors. The purpose of this study was to characterize the concentration- and time-dependent inhibition of L-lactate transport and the membrane permeability properties of AR-C155858 and AZD3965 in the murine 4T1 breast tumor cells that express MCT1. Our results demonstrated time-dependent inhibition of L-lactate uptake by AR-C155858 and AZD3965 with maximal inhibition occurring after a 5-min pre-incubation period and prolonged inhibition. Following removal of AR-C155858 or AZD3965 from the incubation buffer, inhibition of L-lactate uptake was only fully reversed after 3 and 12 h, respectively, indicating that these inhibitors are slowly reversible. The uptake of AR-C155858 was concentration-dependent in 4T1 cells, whereas the uptake of AZD3965 exhibited no concentration dependence over the range of concentrations examined. The uptake kinetics of AR-C155858 was best fitted to a Michaelis-Menten equation with a diffusional clearance component, P (Km = 0.399 ± 0.067 µM, Vmax = 4.79 ± 0.58 pmol/mg/min, and P = 0.330 ± 0.088 µL/mg/min). AR-C155858 uptake, but not AZD3965 uptake, was significantly inhibited by alpha-cyano-4-hydroxycinnamic acid, a known nonspecific inhibitor of MCTs 1, 2, and 4. AR-C155858 demonstrated a trend toward higher uptake at lower pH, a characteristic of proton-dependent MCT1. These findings provide evidence that AR-C155858 and AZD3965 exert slowly reversible inhibition of MCT1-mediated L-lactate uptake in 4T1 cells, with AR-C155858 representing a potential substrate of MCT1.
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Neoplasias de la Mama/tratamiento farmacológico , Ácido Láctico/metabolismo , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Pirimidinonas/farmacología , Simportadores/antagonistas & inhibidores , Tiofenos/farmacología , Uracilo/análogos & derivados , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Ácidos Cumáricos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Concentración de Iones de Hidrógeno , Ratones , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/metabolismo , Uracilo/farmacologíaRESUMEN
The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) separate the brain and cerebrospinal fluid (CSF) from the systemic circulation and represent a barrier to the uptake of both endogenous compounds and xenobiotics into the brain. For compounds whose passive diffusion is limited due to their ionization or hydrophilicity, membrane transporters can facilitate their uptake across the BBB or BCSFB. Members of the solute carrier (SLC) and ATP-binding case (ABC) families are present on these barriers. Differences exist in the localization and expression of transport proteins between the BBB and BCSFB, resulting in functional differences in transport properties. This review focuses on the expression, membrane localization, and different isoforms present at each barrier. Diseases that affect the central nervous system including brain tumors, HIV, Alzheimer's disease, Parkinson's disease, and stroke affect the integrity and expression of transporters at the BBB and BCSFB and will be briefly reviewed.
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Transportadoras de Casetes de Unión a ATP/análisis , Barrera Hematoencefálica , Proteínas Transportadoras de Solutos/análisis , Transportadoras de Casetes de Unión a ATP/líquido cefalorraquídeo , Membrana Celular/química , Humanos , Isoformas de Proteínas , Proteínas Transportadoras de Solutos/líquido cefalorraquídeoRESUMEN
Laminin-α2 related Congenital Muscular Dystrophy (LAMA2-CMD) is a progressive muscle disease caused by partial or complete deficiency of laminin-211, a skeletal muscle extracellular matrix protein. In the last decade, basic science research has queried underlying disease mechanisms in existing LAMA2-CMD murine models and identified possible clinical targets and pharmacological interventions. Experimental rigor in preclinical studies is critical to efficiently and accurately quantify both negative and positive results, degree of efficiency of potential therapeutics and determine whether to move a compound forward for additional preclinical testing. In this review, we compare published available data measured to assess three common parameters in the widely used mouse model DyW, that mimics LAMA2-CMD, we quantify variability and analyse its possible sources. Finally, on the basis of this analysis, we suggest standard set of assessments and the use of available standardized protocols, to reduce variability of outcomes in the future and to improve the value of preclinical research.
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Modelos Animales de Enfermedad , Laminina/deficiencia , Distrofias Musculares/diagnóstico , Animales , Laminina/genética , Ratones , Distrofias Musculares/metabolismo , Distrofias Musculares/terapia , Fenotipo , Reproducibilidad de los ResultadosRESUMEN
Se trata de un paciente masculino de 31 años con diagnóstico de fibroma condromixoide del ilíaco derecho manejado en el Hospital Universitario San Ignacio en febrero del 2018. El paciente fue llevado inicialmente a biopsia abierta para confirmación histológica, posteriormente fue llevado a embolización preoperatoria, manejo intralesional con curetaje, fresado extendido, manejo adyuvante local y aplicación de cemento óseo. Se realiza seguimiento postoperatorio por 18 meses sin evidencia clínica ni radiográfica de recidiva tumoral. El objetivo de este trabajo es hacer una revisión de la literatura sobre el fibroma condromixoide con énfasis en su localización pélvica y su tratamiento.
We report a case of a 31-year-old male patient with diagnosis of chondromyxoid fibroma (CMF) of the iliac bone diagnosed at Hospital Universitario San Ignacio in february 2018; an open biopsy allowed recognizement and description of cytologic features, forward diagnosis and treatment with combination of pre-operative embolization, local and extended curettage, local adyuvance and bone cement as described. At 18 months follow-up have found the patient remains without clinical or radiologic recurrence of CMF. We made a review of literature on chondromixoid fibroma emphasizing on pelvic bones compromise regarding diagnosis and management options.
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Humanos , Fibroma , Pelvis , IlionRESUMEN
RESUMEN Fundamento La COVID-19 implica retos específicos para los trabajadores de la salud, los cuales representan una mayor carga de estrés. Ello confiere interés y relevancia al estudio de la esfera afectiva en este sector, protagonista en la atención a pacientes positivos de COVID-19. Objetivo caracterizar síntomas afectivos en profesionales que laboran en la atención a casos positivos de COVID-19. Métodos se realizó un estudio descriptivo transversal, en profesionales de la salud que laboran en la atención a pacientes positivos a la COVID-19; enmarcado entre los meses de abril y julio del 2020, en el hospital Manuel Fajardo Rivero de Santa Clara. La población de estudio fueron 82 trabajadores (enfermeros y tecnólogos de la Salud). Las variables estudiadas fueron sexo, categoría profesional y rango de severidad de los síntomas afectivos (depresión y ansiedad). Resultados la totalidad de los profesionales presentó algún grado de ansiedad, con predominio de la forma moderada (64,6 %). El 63,4 % no manifestó depresión, sin embargo, el 43,47 % de los que tuvieron este síntoma fueron mujeres, y el 52,63 % enfermeros de profesión. La ansiedad en forma moderada afectó al 72,22 % de los hombres, 58,69 % de las mujeres, y el 68,42 % de los enfermeros. Conclusión Entre los síntomas afectivos en profesionales que laboran en la atención de casos positivos a la COVID 19 se observó un predominio de la ansiedad. Este estudio explora aspectos de la salud mental que avizoran sobre la importancia de intervenciones futuras.
ABSTRACT Background COVID-19 involves specific challenges for healthcare workers, which represent a greater burden of stress. This confers interest and relevance to the study of the affective sphere in this sector, a protagonist in the positive COVID-19 patient's care. Objective to characterize affective symptoms in professionals who work in the positive COVID-19 cases care. Methods a cross-sectional descriptive study was carried out in health professionals who work in the positive COVID-19 patient's care; between April and July 2020, at the Manuel Fajardo Rivero hospital in Santa Clara. 82 workers (nurses and health technologists) were the study population. The variables studied were sex, professional category and range of severity of affective symptoms (depression and anxiety). Results all the professionals presented some degree of anxiety, with a predominance of the moderate form (64.6%). The 63.4% did not show depression, however, 43.47% of those who had this symptom were women, and 52.63% were professional nurses. Anxiety moderately affected 72.22% of men, 58.69% of women, and 68.42% of nurses. Conclusion Among the affective symptoms in professionals who work in the positive COVID 19 cases care, a predominance of anxiety was observed. This study explores aspects of mental health that foresee the importance of future interventions.
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RESUMEN Fundamento: los neurolépticos con efecto antipsicótico, son eficaces para controlar los síntomas de la esquizofrenia, delirios y alucinaciones. El síndrome neuroléptico maligno es el efecto adverso más grave ocasionado por los antipsicóticos. Objetivo: presentar un caso inusual de un paciente con diagnóstico de cuadro psicótico que presentó un síndrome neuroléptico maligno ocasionado por los antipsicóticos. Presentación del caso: se ingresa un paciente que escucha voces dentro de su cabeza y el médico lo nota hiperconcentrado además realizaba movimientos estereotipados con dificultades para deambular. Al septimo día de hospitalización comienza con rigidez generalizada, temblor, trastornos del lenguaje y disfagia que se interpreta como un síndrome extrapiramidal de causa medicamentosa, con cifras de creatininfosfoquinasa aumentadas. Se emplea la bromocriptina 2,5 mg cada 12 horas, además de hidratación enérgica, anticoagulación profiláctica con heparina de bajo peso molecular y evaluación periódica de la función respiratoria y renal. Conclusiones: el síndrome neurológico maligno corresponde a una reacción de tipo idiosincrático, producida por cualquier fármaco bloqueador del receptor de la dopamina asociada clásicamente a los fármacos antipsicóticos de alta potencia como haloperidol y flufenazina, como se observó en el caso, por lo que fue necesario identificar los signos prodrómicos de forma precoz y realizar las modificaciones terapéuticas de forma oportuna a fin de prevenir el cuadro grave y restablecer la salud del enfermo con mínimo riesgo.
ABSTRACT Background: neuroleptics with an antipsychotic effect are effective in controlling the symptoms of schizophrenia, delusions and hallucinations. Neuroleptic malignant syndrome is the most serious adverse effect caused by antipsychotics. Objective: to present an unusual case of a patient with a diagnosis of psychotic symptoms who presented a neuroleptic malignant syndrome caused by antipsychotics. Case report: a patient who listens to voices inside his head is admitted and the doctor notes that he was hyperconcentrated and performed stereotyped movements with difficulties in wandering. At the 7th day of hospitalization he begins with generalized rigidity, tremor, language disorders and dysphagia that is interpreted as an extrapyramidal syndrome of drug cause, with increased creatinine phosphokinase (CK) levels. Bromocriptine 2.5 mg every 12 hours is used, in addition to vigorous hydration, prophylactic anticoagulation with low molecular weight heparin and periodic assessment of respiratory and renal function. Conclusions: the malignant neurological syndrome corresponds to an idiosyncratic reaction, produced by any dopamine receptor blocker drug classically associated with high potency antipsychotic drugs such as haloperidol and fluphenazine, as observed in the case presented in the article, so it was necessary to identify the prodromal signs early and make the therapeutic changes in a timely manner in order to prevent the serious condition and restore the health of the patient with minimal risk.
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Glioblastoma Multiforme (GBM), a uniformly lethal stage IV astrocytoma, is currently treated with a combination of surgical and radiation therapy as well as Temozolomide (TMZ) chemotherapy. Resistance to TMZ is rapidly acquired by GBM cells and overcoming this resistance has been an area of signi?cant research. GBM 'cancer stem cells' (CSC) also known as 'cancer initiating cells' are often positively selected by CD133 expression and TMZ resistance. In this project, we selected GBM CSC from two cell lines based on CD133 expression. CD133+ and CD133- GBM cells showed comparable cell cycle status. The expression of genes within the Sonic Hedgehog Signaling pathway, PTCH1 (SHH receptor/basal signaling repressor) and Gli1 (effector transcription factor) were increased. The recent literature indicated a decreased in PTCH expression by miRNA and this was independent of SHH expression. We analyzed 5 potential PTCH-targeting miRNA and identi?ed an increase in miRNA-9-2. The CD133+ cells showed an increase in the Multiple Drug Resistance 1 gene (MDR1). Knockdown of Gli1 and MDR1 with siRNA enhanced TMZ induced cell death. Taken together, these studies show CD133+ GBM CSCs expressed greater levels of miR-9 and activation of the SHH/PTCH1/MDR1 axis. This axis has been shown to impart TMZ resistance. In the case of the CD133+ cells, the resistance is not acquires but seems to be inherent. Identi?cation of this pathway as well as the identi?cation of miR-9 may allow for the development of miRNA-targeted approach to Cancer Stem Cell therapy in GBM.
RESUMEN
Chemotherapy with Temozolomide (TMZ), radiation and surgery are the primary methods to treat Glioblastoma Multiforme (GBM), the most common adult intracranial tumor with dismal outcome. GBM resistance to therapy is the main reason of poor patient outcomes. Thus, methods to overcome the resistance are an area of extensive research. This highlight focuses on three recently published articles on the mechanism of resistance and possible therapeutic intervention, including RNA treatment with stem cells. We showed a crucial role of the developmental Sonic Hedgehog (SHH) pathway in the acquisition and maintenance of TMZ resistance. SHH signaling caused TMZ resistance in GBM cells through an increase in the multiple drug resistance gene (MDR1). The SHH receptor, Patched-1 (PTCH1), negatively regulate SHH signaling. In GBM, miR-9 suppressed PTCH1 levels, resulting in the activation of SHH pathway. Thus, SHH signaling is independent of the ligand in resistant GBM cells. MiR-9 was also increased in chemoresistance CD133+ GBM cells. A potential method to reverse resistance was tested by delivering the anti-miR in bone marrow-derived Mesenchymal Stem Cells (MSCs). The anti-miR-9 was transferred into the resistant GBM cells through exosomes and gap junctional intercellular communication. We also review on-going clinical trials with inhibitor of SHH signaling, and also discuss drug delivery by cell therapy for GBM. While GBM treatment has proven to be a challenge, there are a number of novel approaches we are currently developing to manage this malignancy.
RESUMEN
Lack of adherence is a frequent cause of hospitalizations, but its effects on dosing patterns have not been extensively investigated. The purpose of this work was to critically evaluate a novel pharmacometric model for deriving the relationships of adherence to dosing patterns and the dosing interval distribution. The hybrid, stochastic model combines a Markov chain process with the von Mises distribution. The model was challenged with electronic medication monitoring data from 207 hypertension patients and against 5-year persistence data. The model estimates distributions of dosing runs, drug holidays, and dosing intervals. Drug holidays, which can vary between individuals with the same adherence, were characterized by the patient cooperativity index parameter. The drug holiday and dosing run distributions deviate markedly from normality. The dosing interval distribution exhibits complex patterns of multimodality and can be long-tailed. Dosing patterns are an important but under recognized covariate for explaining within-individual variance in drug concentrations.
Asunto(s)
Antihipertensivos/administración & dosificación , Hipertensión/tratamiento farmacológico , Cumplimiento de la Medicación , Modelos Estadísticos , Esquema de Medicación , Humanos , Cadenas de Markov , Procesos Estocásticos , Factores de TiempoRESUMEN
Glioblastoma Multiforme (GBM), the most common and lethal adult primary tumor of the brain, showed a link between Sonic Hedgehog (SHH) pathway in the resistance to temozolomide (TMZ). PTCH1, the SHH receptor, can tonically represses signaling by endocytosis. We asked how the decrease in PTCH1 in GBM cells could lead to TMZ-resistance. TMZ resistant GBM cells have increased PTCH1 mRNA and reduced protein. Knockdown of Dicer, a Type III RNAase, indicated that miRNAs can explain the decreased PTCH1 in TMZ resistant cells. Computational studies, real-time PCR, reporter gene studies, western blots, target protector oligos and ectopic expression identified miR-9 as the target of PTCH1 in resistant GBM cells with concomitant activation of SHH signaling. MiR-9 mediated increases in the drug efflux transporters, MDR1 and ABCG2. MiR-9 was increased in the tissues from GBM patients and in an early passage GBM cell line from a patient with recurrent GBM but not from a naïve patient. Pharmacological inhibition of SHH signaling sensitized the GBM cells to TMZ. Taken together, miR-9 targets PTCH1 in GBM cells by a SHH-independent method in GBM cells for TMZ resistance. The identified pathways could lead to new strategies to target GBM with combinations of drugs.