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Transcriptional and epigenetic alterations occur early in Huntington's disease (HD), and treatment with epigenetic modulators is beneficial in several HD animal models. The drug JQ1, which inhibits histone acetyl-lysine reader bromodomains, has shown promise for multiple cancers and neurodegenerative disease. We tested whether JQ1 could improve behavioral phenotypes in the R6/2 mouse model of HD and modulate HD-associated changes in transcription and epigenomics. R6/2 and non-transgenic (NT) mice were treated with JQ1 daily from 5 to 11 weeks of age and behavioral phenotypes evaluated over this period. Following the trial, cortex and striatum were isolated and subjected to mRNA-seq and ChIP-seq for the histone marks H3K4me3 and H3K27ac. Initially, JQ1 enhanced motor performance in NT mice. In R6/2 mice, however, JQ1 had no effect on rotarod or grip strength but exacerbated weight loss and worsened performance on the pole test. JQ1-induced gene expression changes in NT mice were distinct from those in R6/2 and primarily involved protein translation and bioenergetics pathways. Dysregulation of HD-related pathways in striatum was exacerbated by JQ1 in R6/2 mice, but not in NTs, and JQ1 caused a corresponding increase in the formation of a mutant huntingtin protein-dependent high molecular weight species associated with pathogenesis. This study suggests that drugs predicted to be beneficial based on their mode of action and effects in wild-type or in other neurodegenerative disease models may have an altered impact in the HD context. These observations have important implications in the development of epigenetic modulators as therapies for HD.
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Azepinas/farmacología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/metabolismo , Triazoles/farmacología , Acetilación , Animales , Escala de Evaluación de la Conducta , Síntomas Conductuales/tratamiento farmacológico , Corteza Cerebral/patología , Secuenciación de Inmunoprecipitación de Cromatina , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Ontología de Genes , Histonas/metabolismo , Proteína Huntingtina/genética , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/genética , Enfermedad de Huntington/patología , Masculino , Ratones , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Biosíntesis de Proteínas/efectos de los fármacos , RNA-Seq , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
Myeloproliferative neoplasms (MPNs) driver mutations are usually found in JAK2, MPL, and CALR genes; however, 10%-15% of cases are triple negative (TN). A previous study showed lower rate of JAK2 V617F in primary myelofibrosis patients exposed to low doses of ionizing radiation (IR) from Chernobyl accident. To examine distinct driver mutations, we enrolled 281 Ukrainian IR-exposed and unexposed MPN patients. Genomic DNA was obtained from peripheral blood leukocytes. JAK2 V617F, MPL W515, types 1- and 2-like CALR mutations were identified by Sanger Sequencing and real time polymerase chain reaction. Chromosomal alterations were assessed by oligo-SNP microarray platform. Additional genetic variants were identified by whole exome and targeted sequencing. Statistical significance was evaluated by Fisher's exact test and Wilcoxon's rank sum test (R, version 3.4.2). IR-exposed MPN patients exhibited a different genetic profile vs unexposed: lower rate of JAK2 V617F (58.4% vs 75.4%, P = .0077), higher rate of type 1-like CALR mutation (12.2% vs 3.1%, P = .0056), higher rate of TN cases (27.8% vs 16.2%, P = .0366), higher rate of potentially pathogenic sequence variants (mean numbers: 4.8 vs 3.1, P = .0242). Furthermore, we identified several potential drivers specific to IR-exposed TN MPN patients: ATM p.S1691R with copy-neutral loss of heterozygosity at 11q; EZH2 p.D659G at 7q and SUZ12 p.V71 M at 17q with copy number loss. Thus, IR-exposed MPN patients represent a group with distinct genomic characteristics worthy of further study.
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Accidente Nuclear de Chernóbil , Trastornos Mieloproliferativos/etiología , Neoplasias Inducidas por Radiación/etiología , Contaminantes Radiactivos/efectos adversos , Adulto , Anciano , Calreticulina/genética , Aberraciones Cromosómicas , ADN/genética , Femenino , Dosificación de Gen , Humanos , Janus Quinasa 2/genética , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Mutación Missense , Trastornos Mieloproliferativos/epidemiología , Trastornos Mieloproliferativos/genética , Neoplasias Inducidas por Radiación/epidemiología , Neoplasias Inducidas por Radiación/genética , Receptores de Trombopoyetina/genética , Ucrania/epidemiología , Secuenciación del Exoma , Adulto JovenRESUMEN
The orchestrated action of genes controls complex biological phenotypes, yet the systematic discovery of gene and drug combinations that modulate these phenotypes in human cells is labor intensive and challenging to scale. Here, we created a platform for the massively parallel screening of barcoded combinatorial gene perturbations in human cells and translated these hits into effective drug combinations. This technology leverages the simplicity of the CRISPR-Cas9 system for multiplexed targeting of specific genomic loci and the versatility of combinatorial genetics en masse (CombiGEM) to rapidly assemble barcoded combinatorial genetic libraries that can be tracked with high-throughput sequencing. We applied CombiGEM-CRISPR to create a library of 23,409 barcoded dual guide-RNA (gRNA) combinations and then perform a high-throughput pooled screen to identify gene pairs that inhibited ovarian cancer cell growth when they were targeted. We validated the growth-inhibiting effects of specific gene sets, including epigenetic regulators KDM4C/BRD4 and KDM6B/BRD4, via individual assays with CRISPR-Cas-based knockouts and RNA-interference-based knockdowns. We also tested small-molecule drug pairs directed against our pairwise hits and showed that they exerted synergistic antiproliferative effects against ovarian cancer cells. We envision that the CombiGEM-CRISPR platform will be applicable to a broad range of biological settings and will accelerate the systematic identification of genetic combinations and their translation into novel drug combinations that modulate complex human disease phenotypes.
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Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Código de Barras del ADN Taxonómico , HumanosRESUMEN
Strict iron regulation is essential for normal brain function. The iron homeostasis, determined by the milieu of available iron compounds, is impaired in aging, neurodegenerative diseases and cancer. However, non-invasive assessment of different molecular iron environments implicating brain tissue's iron homeostasis remains a challenge. We present a magnetic resonance imaging (MRI) technology sensitive to the iron homeostasis of the living brain (the r1-r2* relaxivity). In vitro, our MRI approach reveals the distinct paramagnetic properties of ferritin, transferrin and ferrous iron ions. In the in vivo human brain, we validate our approach against ex vivo iron compounds quantification and gene expression. Our approach varies with the iron mobilization capacity across brain regions and in aging. It reveals brain tumors' iron homeostasis, and enhances the distinction between tumor tissue and non-pathological tissue without contrast agents. Therefore, our approach may allow for non-invasive research and diagnosis of iron homeostasis in living human brains.
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Neoplasias Encefálicas , Encéfalo , Humanos , Encéfalo/diagnóstico por imagen , Hierro , Neoplasias Encefálicas/diagnóstico por imagen , Ferritinas , EnvejecimientoRESUMEN
Systemic immunity supports lifelong brain function. Obesity posits a chronic burden on systemic immunity. Independently, obesity was shown as a risk factor for Alzheimer's disease (AD). Here we show that high-fat obesogenic diet accelerated recognition-memory impairment in an AD mouse model (5xFAD). In obese 5xFAD mice, hippocampal cells displayed only minor diet-related transcriptional changes, whereas the splenic immune landscape exhibited aging-like CD4+ T-cell deregulation. Following plasma metabolite profiling, we identified free N-acetylneuraminic acid (NANA), the predominant sialic acid, as the metabolite linking recognition-memory impairment to increased splenic immune-suppressive cells in mice. Single-nucleus RNA-sequencing revealed mouse visceral adipose macrophages as a potential source of NANA. In vitro, NANA reduced CD4+ T-cell proliferation, tested in both mouse and human. In vivo, NANA administration to standard diet-fed mice recapitulated high-fat diet effects on CD4+ T cells and accelerated recognition-memory impairment in 5xFAD mice. We suggest that obesity accelerates disease manifestation in a mouse model of AD via systemic immune exhaustion.
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Enfermedad de Alzheimer , Ratones , Humanos , Animales , Enfermedad de Alzheimer/metabolismo , Ácido N-Acetilneuramínico , Ratones Transgénicos , Trastornos de la Memoria/etiología , Obesidad/complicaciones , Dieta Alta en Grasa/efectos adversos , Modelos Animales de EnfermedadRESUMEN
Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. A subset of tumors harbored multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative 'enhancer rewiring' events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA.
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Neoplasias Cerebelosas , Meduloblastoma , Neoplasias , Humanos , ADN Circular , Meduloblastoma/genética , Estudios Retrospectivos , Neoplasias/genética , Oncogenes , Neoplasias Cerebelosas/genéticaRESUMEN
The complexity of affected brain regions and cell types is a challenge for Huntington's disease (HD) treatment. Here we use single nucleus RNA sequencing to investigate molecular pathology in the cortex and striatum from R6/2 mice and human HD post-mortem tissue. We identify cell type-specific and -agnostic signatures suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) are arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 are negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells shows decreased accessibility regulated by OL maturation genes. The data implicates glucose and lipid metabolism in abnormal cell maturation and identify PRKCE and Thiamine Pyrophosphokinase 1 (TPK1) as central genes. Thiamine/biotin treatment of R6/1 HD mice to compensate for TPK1 dysregulation restores OL maturation and rescues neuronal pathology. Our insights into HD OL pathology spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.
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Biotina , Enfermedad de Huntington , Oligodendroglía , Tiamina , Animales , Humanos , Ratones , Biotina/metabolismo , Biotina/farmacología , Suplementos Dietéticos , Modelos Animales de Enfermedad , Enfermedad de Huntington/metabolismo , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/metabolismo , Núcleo Solitario/metabolismo , Tiamina/metabolismo , Tiamina/farmacologíaRESUMEN
Answer ALS is a biological and clinical resource of patient-derived, induced pluripotent stem (iPS) cell lines, multi-omic data derived from iPS neurons and longitudinal clinical and smartphone data from over 1,000 patients with ALS. This resource provides population-level biological and clinical data that may be employed to identify clinical-molecular-biochemical subtypes of amyotrophic lateral sclerosis (ALS). A unique smartphone-based system was employed to collect deep clinical data, including fine motor activity, speech, breathing and linguistics/cognition. The iPS spinal neurons were blood derived from each patient and these cells underwent multi-omic analytics including whole-genome sequencing, RNA transcriptomics, ATAC-sequencing and proteomics. The intent of these data is for the generation of integrated clinical and biological signatures using bioinformatics, statistics and computational biology to establish patterns that may lead to a better understanding of the underlying mechanisms of disease, including subgroup identification. A web portal for open-source sharing of all data was developed for widespread community-based data analytics.
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Esclerosis Amiotrófica Lateral , Células Madre Pluripotentes Inducidas , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Línea Celular , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas Motoras/fisiologíaRESUMEN
The phenotype of a cell and its underlying molecular state is strongly influenced by extracellular signals, including growth factors, hormones, and extracellular matrix proteins. While these signals are normally tightly controlled, their dysregulation leads to phenotypic and molecular states associated with diverse diseases. To develop a detailed understanding of the linkage between molecular and phenotypic changes, we generated a comprehensive dataset that catalogs the transcriptional, proteomic, epigenomic and phenotypic responses of MCF10A mammary epithelial cells after exposure to the ligands EGF, HGF, OSM, IFNG, TGFB and BMP2. Systematic assessment of the molecular and cellular phenotypes induced by these ligands comprise the LINCS Microenvironment (ME) perturbation dataset, which has been curated and made publicly available for community-wide analysis and development of novel computational methods ( synapse.org/LINCS_MCF10A ). In illustrative analyses, we demonstrate how this dataset can be used to discover functionally related molecular features linked to specific cellular phenotypes. Beyond these analyses, this dataset will serve as a resource for the broader scientific community to mine for biological insights, to compare signals carried across distinct molecular modalities, and to develop new computational methods for integrative data analysis.
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Factor de Crecimiento Epidérmico , Proteómica , Factor de Crecimiento Epidérmico/farmacología , Proteínas de la Matriz Extracelular , Ligandos , FenotipoRESUMEN
Most severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic tests have relied on RNA extraction followed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) assays. Whereas automation improved logistics and different pooling strategies increased testing capacity, highly multiplexed next-generation sequencing (NGS) diagnostics remain a largely untapped resource. NGS tests have the potential to markedly increase throughput while providing crucial SARS-CoV-2 variant information. Current NGS-based detection and genotyping assays for SARS-CoV-2 are costly, mostly due to parallel sample processing through multiple steps. Here, we have established ApharSeq, in which samples are barcoded in the lysis buffer and pooled before reverse transcription. We validated this assay by applying ApharSeq to more than 500 clinical samples from the Clinical Virology Laboratory at Hadassah hospital in a robotic workflow. The assay was linear across five orders of magnitude, and the limit of detection was Ct 33 (~1000 copies/ml, 95% sensitivity) with >99.5% specificity. ApharSeq provided targeted high-confidence genotype information due to unique molecular identifiers incorporated into this method. Because of early pooling, we were able to estimate a 10- to 100-fold reduction in labor, automated liquid handling, and reagent requirements in high-throughput settings compared to current testing methods. The protocol can be tailored to assay other host or pathogen RNA targets simultaneously. These results suggest that ApharSeq can be a promising tool for current and future mass diagnostic challenges.
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COVID-19 , SARS-CoV-2 , Prueba de Ácido Nucleico para COVID-19 , Prueba de COVID-19 , Humanos , Manejo de EspecímenesRESUMEN
Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.
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High-throughput screening and gene signature analyses frequently identify lead therapeutic compounds with unknown modes of action (MoAs), and the resulting uncertainties can lead to the failure of clinical trials. We developed an approach for uncovering MoAs through an interpretable machine learning model of transcriptomics, epigenomics, metabolomics, and proteomics. Examining compounds with beneficial effects in models of Huntington's Disease, we found common MoAs for compounds with unrelated structures, connectivity scores, and binding targets. The approach also predicted highly divergent MoAs for two FDA-approved antihistamines. We experimentally validated these effects, demonstrating that one antihistamine activates autophagy, while the other targets bioenergetics. The use of multiple omics was essential, as some MoAs were virtually undetectable in specific assays. Our approach does not require reference compounds or large databases of experimental data in related systems and thus can be applied to the study of agents with uncharacterized MoAs and to rare or understudied diseases.
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Biología Computacional/métodos , Genómica/métodos , Aprendizaje Automático , Metabolómica/métodos , Proteómica/métodos , Adenosina Trifosfato/metabolismo , Animales , Autofagia/fisiología , Línea Celular , Supervivencia Celular/fisiología , Redes Reguladoras de Genes , Humanos , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , RatonesRESUMEN
Aberrant neuronal development and the persistence of mitotic cellular populations have been implicated in a multitude of neurological disorders, including Huntington's disease (HD). However, the mechanism underlying this potential pathology remains unclear. We used a modified protocol to differentiate induced pluripotent stem cells (iPSCs) from HD patients and unaffected controls into neuronal cultures enriched for medium spiny neurons, the cell type most affected in HD. We performed single-cell and bulk transcriptomic and epigenomic analyses and demonstrated that a persistent cyclin D1+ neural stem cell (NSC) population is observed selectively in adult-onset HD iPSCs during differentiation. Treatment with a WNT inhibitor abrogates this NSC population while preserving neurons. Taken together, our findings identify a mechanism that may promote aberrant neurodevelopment and adult neurogenesis in adult-onset HD striatal neurons with the potential for therapeutic compensation.
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Enfermedad de Huntington/patología , Células Madre Pluripotentes Inducidas/patología , Neuronas/patología , Vía de Señalización Wnt , Adulto , Edad de Inicio , Ciclo Celular/genética , Diferenciación Celular/genética , Células Cultivadas , Epigénesis Genética , Humanos , Enfermedad de Huntington/genética , Mitosis , Neostriado/patología , Células-Madre Neurales/metabolismo , Factores de Transcripción/metabolismo , Transcriptoma/genética , Regulación hacia Arriba/genéticaRESUMEN
The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program that catalogs how human cells globally respond to chemical, genetic, and disease perturbations. Resources generated by LINCS include experimental and computational methods, visualization tools, molecular and imaging data, and signatures. By assembling an integrated picture of the range of responses of human cells exposed to many perturbations, the LINCS program aims to better understand human disease and to advance the development of new therapies. Perturbations under study include drugs, genetic perturbations, tissue micro-environments, antibodies, and disease-causing mutations. Responses to perturbations are measured by transcript profiling, mass spectrometry, cell imaging, and biochemical methods, among other assays. The LINCS program focuses on cellular physiology shared among tissues and cell types relevant to an array of diseases, including cancer, heart disease, and neurodegenerative disorders. This Perspective describes LINCS technologies, datasets, tools, and approaches to data accessibility and reusability.
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Catalogación/métodos , Biología de Sistemas/métodos , Biología Computacional/métodos , Bases de Datos de Compuestos Químicos/normas , Perfilación de la Expresión Génica/métodos , Biblioteca de Genes , Humanos , Almacenamiento y Recuperación de la Información/métodos , Programas Nacionales de Salud , National Institutes of Health (U.S.)/normas , Transcriptoma , Estados UnidosRESUMEN
In recent years, the assay for transposase-accessible chromatin using sequencing (ATAC-Seq) has become a fundamental tool of epigenomic research. However, it is difficult to perform this technique on frozen samples because freezing cells before extracting nuclei can impair nuclear integrity and alter chromatin structure, especially in fragile cells such as neurons. Our aim was to develop a protocol for freezing neuronal cells that is compatible with ATAC-Seq; we focused on a disease-relevant cell type, namely motor neurons differentiated from induced pluripotent stem cells (iMNs) from a patient affected by spinal muscular atrophy. We found that while flash-frozen iMNs are not suitable for ATAC-Seq, the assay is successful with slow-cooled cryopreserved cells. Using this method, we were able to isolate high quality, intact nuclei, and we verified that epigenetic results from fresh and cryopreserved iMNs quantitatively agree.
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Núcleo Celular/efectos de los fármacos , Cromatina/efectos de los fármacos , Criopreservación/métodos , Crioprotectores/farmacología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Neuronas Motoras/efectos de los fármacos , Diferenciación Celular , Núcleo Celular/metabolismo , Núcleo Celular/ultraestructura , Supervivencia Celular/efectos de los fármacos , Cromatina/metabolismo , Cromatina/ultraestructura , Epigénesis Genética , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patología , Cultivo Primario de Células , Análisis de Secuencia de ADN , Transposasas/químicaRESUMEN
Intractable hypotension due to septic shock is associated with high mortality rates in critically ill children worldwide. The use of terlipressin (triglycyl-lysine-vasopressin), an analog of vasopressin with a longer duration of action, recently emerged as a treatment of hypotension not responsive to vasopressors and inotropes. This was a retrospective study set in an 18-bed pediatric critical care department in a tertiary care children's hospital. We reviewed the files of all children with septic shock who were treated with terlipressin between January 2003 and February 2004. Fourteen children (mean age, 5.6 years; range, 4 days to 17.7 years) were treated with terlipressin in 16 septic shock episodes. Significant improvements in respiratory and hemodynamic indices were noted shortly after treatment. Mean arterial blood pressure increased significantly from 54 +/- 3 to 72 +/- 5 mmHg 10 min after terlipressin administration (P = 0.001). Heart rate decreased from 153.0 +/- 6.5 beats/min to 138.0 +/- 7.5 beats/min 12 h after treatment onset (P = 0.003). Epinephrine infusion was decreased or stopped in eight patients after terlipressin administration. Urine output increased from 1.6 +/- 0.5 mL/kg/h to 4.3 +/- 1.2 mL/kg/h 1 h after treatment onset (P = 0.011). PaO2 increased from 95.1 +/- 12.3 mmHg to 110.1 +/- 20.5 mmHg, and the oxygenation index decreased from 10.2 +/- 2.2 to 9.2 +/- 1.7. Terlipressin treatment of hypotension due to septic shock was successful in eight out of 16 episodes. Six of the 14 patients with poor prognosis for survival recovered. We conclude that terlipressin improves hemodynamic indices and renal function in critically ill children. Terlipressin should be considered as a rescue therapy in intractable shock not responsive to catecholamines in children.
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Antihipertensivos/uso terapéutico , Hipotensión/tratamiento farmacológico , Lipresina/análogos & derivados , Lipresina/uso terapéutico , Choque Séptico/complicaciones , Choque Séptico/tratamiento farmacológico , Adolescente , Presión Sanguínea/efectos de los fármacos , Catecolaminas/metabolismo , Niño , Preescolar , Creatinina/sangre , Epinefrina/farmacología , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Lactante , Recién Nacido , Masculino , Oxígeno/química , Oxígeno/metabolismo , Pronóstico , Terlipresina , Factores de TiempoRESUMEN
OBJECTIVE: To report the successful use of terlipressin in an 8-day-old infant for treatment of intractable hypotension caused by septic shock. DESIGN: Descriptive case report. SETTING: An 18-bed pediatric intensive care unit at a tertiary care children's hospital. PATIENT: An 8-day-old child with intractable hypotension due to septic shock after heart surgery. INTERVENTIONS: General supportive intensive care including mechanical ventilatory support, volume replacement, and inotropic support with dopamine 20 microg.kg(-1).min(-1), milrinone 0.75 microg.kg(-1).min(-1), and epinephrine 0.8 microg.kg(-1).min(-1). MEASUREMENTS AND MAIN RESULTS: Terlipressin (7 microg/kg per dose twice daily) was added as rescue therapy because of profound intractable hypotension. Shortly after the beginning of treatment, blood pressure and perfusion dramatically improved. CONCLUSIONS: There is circumstantial evidence that the administration of terlipressin caused the increase in blood pressure. We suggest that terlipressin should be considered as rescue therapy when high-dose catecholamine therapy does not result in sufficient perfusion pressure. Further investigation is needed to prove terlipressin's effectiveness and safety in infants and children.
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Hipotensión/tratamiento farmacológico , Lipresina/análogos & derivados , Lipresina/uso terapéutico , Choque Séptico/tratamiento farmacológico , Vasoconstrictores/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Catecolaminas/uso terapéutico , Humanos , Hipotensión/etiología , Recién Nacido , Inyecciones Intravenosas , Infecciones por Klebsiella/complicaciones , Lipresina/administración & dosificación , Masculino , Choque Séptico/etiología , Terlipresina , Vasoconstrictores/administración & dosificaciónRESUMEN
Several case reports indicate that carbapenem antibiotics, especially meropenem, may decrease the plasma concentrations of valproic acid (VPA), thus decreasing its therapeutic activity. To investigate the onset, severity, and dose dependency of the interaction between meropenem and VPA, the authors carried out a retrospective evaluation of data collected during 24 months from patients hospitalized in a tertiary medical center. The analysis included 36 patients. VPA mean +/- SEM plasma concentration decreased from of 50.8 +/- 4.5 microg/mL to 9.9 +/- 2.1 microg/mL (P < .001) following meropenem administration. After discontinuation of meropenem, VPA plasma concentrations remained low for 7 days and then gradually increased after 8 to 14 days, reaching values comparable to those before meropenem initiation. Different daily VPA doses showed a similar pattern of decreased VPA concentrations. The mean decrease in individual plasma VPA concentration was 82.1% +/- 2.7%. The mean VPA plasma concentration of patients in whom samples were drawn within 24 hours of meropenem initiation was 9.9 +/- 3.2 microg/mL. In conclusion, the interaction between meropenem and VPA causes a significant decrease in VPA plasma concentration, apparently within 24 hours. As the therapeutic effects of VPA are plasma concentration dependent, the data suggest that these drugs should not be administered concomitantly.
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Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Carbapenémicos/administración & dosificación , Tienamicinas/administración & dosificación , Ácido Valproico/administración & dosificación , Ácido Valproico/sangre , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Meropenem , Persona de Mediana Edad , Estudios Retrospectivos , Factores de TiempoRESUMEN
AIMS: To determine laboratory and clinical benefit of oral acetylcysteine, as an adjunct to saline hydration, in chronic renal insufficiency patients undergoing coronary angiography. METHODS AND RESULTS: We prospectively studied 80 patients with chronic renal insufficiency (mean [+/-SD] serum creatinine concentration 2.0+/-0.39mg/dl), who underwent coronary angiography with or without intervention. Patients were randomly assigned to receive either acetylcysteine (600mg orally t.i.d.) or placebo, in addition to intravenous 0.45% saline (1ml/kg of body weight per hour), 12h prior to and after coronary angiography. There was an increase of >/=0.5mg/dl in the serum creatinine concentration 48h after coronary angiography in seven of the 80 patients (9%): in four of the 41 patients (10%) in the acetylcysteine group and in three of the 39 patients (8%) in the placebo group (P=0.52). The incidence of in-hospital adverse clinical events (acetylcysteine, 5% vs placebo, 8%, P=0.47) and the length of hospital stay [acetylcysteine, median (interquartile range) 4 (2-4) days vs placebo, 2 (2-4) days, P=0.44] did not differ significantly between the two treatment groups. CONCLUSION: Our findings do not support routine prophylactic administration of oral acetylcysteine as an adjunct to saline hydration for the prevention of contrast-induced nephropathy in chronic renal insufficiency patients undergoing coronary angiography.