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1.
BMC Psychiatry ; 20(1): 307, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546136

RESUMO

BACKGROUND: The Binge Eating Genetics Initiative (BEGIN) is a multipronged investigation examining the interplay of genomic, gut microbiota, and behavioral factors in bulimia nervosa and binge-eating disorder. METHODS: 1000 individuals who meet current diagnostic criteria for bulimia nervosa or binge-eating disorder are being recruited to collect saliva samples for genotyping, fecal sampling for microbiota characterization, and recording of 30 days of passive data and behavioral phenotyping related to eating disorders using the app Recovery Record adapted for the Apple Watch. DISCUSSION: BEGIN examines the interplay of genomic, gut microbiota, and behavioral factors to explore etiology and develop predictors of risk, course of illness, and response to treatment in bulimia nervosa and binge-eating disorder. We will optimize the richness and longitudinal structure of deep passive and active phenotypic data to lay the foundation for a personalized precision medicine approach enabling just-in-time interventions that will allow individuals to disrupt eating disorder behaviors in real time before they occur. TRIAL REGISTRATION: The ClinicalTrials.gov identifier is NCT04162574. November 14, 2019, Retrospectively Registered.

2.
FASEB J ; 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32579292

RESUMO

Eicosapentaenoic acid (EPA) has garnered attention after the success of the REDUCE-IT trial, which contradicted previous conclusions on EPA for cardiovascular disease risk. Here we first investigated EPA's preventative role on hyperglycemia and hyperinsulinemia. EPA ethyl esters prevented obesity-induced glucose intolerance, hyperinsulinemia, and hyperglycemia in C57BL/6J mice. Supporting NHANES analyses showed that fasting glucose levels of obese adults were inversely related to EPA intake. We next investigated how EPA improved murine hyperinsulinemia and hyperglycemia. EPA overturned the obesity-driven decrement in the concentration of 18-hydroxyeicosapentaenoic acid (18-HEPE) in white adipose tissue and liver. Treatment of obese inbred mice with RvE1, the downstream immunoresolvant metabolite of 18-HEPE, but not 18-HEPE itself, reversed hyperinsulinemia and hyperglycemia through the G-protein coupled receptor ERV1/ChemR23. To translate the findings, we determined if the effects of RvE1 were dependent on host genetics. RvE1's effects on hyperinsulinemia and hyperglycemia were divergent in diversity outbred mice that model human genetic variation. Secondary SNP analyses further confirmed extensive genetic variation in human RvE1/EPA-metabolizing genes. Collectively, the data suggest EPA prevents hyperinsulinemia and hyperglycemia, in part, through RvE1's activation of ERV1/ChemR23 in a host genetic manner. The studies underscore the need for personalized administration of RvE1 based on genetic/metabolic enzyme profiles.

3.
BMC Neurol ; 20(1): 162, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32349710

RESUMO

BACKGROUND: Spinal cerebrospinal fluid (CSF) leak can lead to intracranial hypotension and is an important differential diagnosis to consider in patients with sudden-onset chronic daily headaches. Pars interarticularis (PI) fracture is a potential rare cause of suspected spinal CSF leak. METHODS: This is a retrospective case series of 6 patients with suspected spinal CSF leak evaluated between January 2016 and September 2019. All patients received a magnetic resonance imaging (MRI) of the brain with and without gadolinium, MRI whole spine and full spine computed tomography (CT) myelogram. Targeted epidural patches with fibrin sealant were performed. Treatment response at return visit (3 months post-patch) was documented. RESULTS: Six patients (4 females, 2 males) were diagnosed with a suspected spinal CSF leak and PI fracture. Mean age at the time of headache onset was 39 years old, and a range from 32 to 50 years old. Mean time to targeted epidural patches with fibrin sealant was 4.5 years. All 6 patients had PI fractures identified on CT myelogram and received targeted epidural patches with fibrin sealant at the site of the PI fracture. All patients had significant improvement in their headache intensity. CONCLUSION: Our study highlights: 1) the importance of PI fracture as a possible culprit of suspected spinal CSF leak in patients with intracranial hypotension; 2) the added benefit of CT imaging for detecting bony abnormalities such as fractures in patients with intracranial hypotension; and 3) the successful treatment of suspected spinal CSF leak when targeting the fracture site.

4.
ISME J ; 14(7): 1809-1820, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32313261

RESUMO

Transplanting human gut microbiotas into germ-free (GF) mice is a popular approach to disentangle cause-and-effect relationships between enteric microbes and disease. Algorithm development has enabled sequence variant (SV) identification from 16S rRNA gene sequence data. SV analyses can identify which donor taxa colonize recipient GF mice, and how SV abundance in humans is replicated in these mice. Fecal microbiotas from 8 human subjects were used to generate 77 slurries, which were transplanted into 153 GF mice. Strong correlations between fecal and slurry microbial communities were observed; however, only 42.15 ± 9.95% of SVs successfully transferred from the donor to the corresponding recipient mouse. Firmicutes had a particularly low transfer rate and SV abundance was poorly correlated between donor and recipient pairs. Our study confirms human fecal microbiotas colonize formerly GF mice, but the engrafted community only partially resembles the input human communities. Our findings emphasize the importance of reporting a standardized transfer rate and merit the exploration of other animal models or in silico tools to understand the relationships between human gut microbiotas and disease.

5.
Clin J Sport Med ; 30(1): e11-e14, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30908328

RESUMO

A 61-year-old man presented with chronic dorsal foot pain of 9 years that worsened with ambulation. Conventional diagnostic imaging and medical workup were unrevealing, and ankle arthrodesis had been recommended by an orthopedic surgeon for pain relief. Instead, the patient participated in a clinical imaging trial designed for identifying pain generators using whole-body fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI). The scan revealed not only high 18F-FDG uptake at the site of pain, but also a hematoma and an inflamed, fibrotic, ruptured plantaris muscle. The fibrotic plantaris likely altered biomechanics with walking, explaining why symptoms worsened with activity. A simple tenotomy of the plantaris tendon was performed to decouple ankle movement from the plantaris injury, resulting in pain relief. This case illustrates the potential of whole-body 18F-FDG PET/MRI to better localize pain generators.

6.
Gut Microbes ; 11(1): 32-50, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31179826

RESUMO

Iron deficiency, a common comorbidity of gastrointestinal inflammatory disorders such as inflammatory bowel diseases (IBD), is often treated with oral iron supplementation. However, the safety of oral iron supplementation remains controversial because of its association with exacerbated disease activity in a subset of IBD patients. Because iron modulates bacterial growth and function, one possible mechanism by which iron may exacerbate inflammation in susceptible hosts is by modulating the intestinal microbiota. We, therefore, investigated the impact of dietary iron on the intestinal microbiota, utilizing the conventionalization of germ-free mice as a model of a microbial community in compositional flux to recapitulate the instability of the IBD-associated intestinal microbiota. Our findings demonstrate that altering intestinal iron availability during community assembly modulated the microbiota in non-inflamed wild type (WT) and colitis-susceptible interleukin-10-deficient (Il10-/-) mice. Depletion of luminal iron availability promoted luminal compositional changes associated with dysbiotic states irrespective of host genotype, including an expansion of Enterobacteriaceae such as Escherichia coli. Mechanistic in vitro growth competitions confirmed that high-affinity iron acquisition systems in E. coli enhance its abundance over other bacteria in iron-restricted conditions, thereby enabling pathobiont iron scavenging during dietary iron restriction. In contrast, distinct luminal community assembly was observed with dietary iron supplementation in WT versus Il10-/- mice, suggesting that the effects of increased iron on the microbiota differ with host inflammation status. Taken together, shifts in dietary iron intake during community assembly modulate the ecological structure of the intestinal microbiota and is dependent on host genotype and inflammation status.

7.
Pain Med ; 21(1): 161-170, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30933284

RESUMO

BACKGROUND: Opioid-sparing postoperative pain management therapies are important considering the opioid epidemic. Total knee arthroplasty (TKA) is a common and painful procedure accounting for a large number of opioid prescriptions. Adjuvant analgesics, nonopioid drugs with primary indications other than pain, have shown beneficial pain management and opioid-sparing effects following TKA in clinical trials. We evaluated the adjuvant analgesic gabapentin for its usage patterns and its effects on opioid use, pain, and readmissions. METHODS: This retrospective, observational study included 4,046 patients who received primary TKA between 2009 and 2017 using electronic health records from an academic tertiary care medical institute. Descriptive statistics and multivariate modeling were used to estimate associations between inpatient gabapentin use and adverse pain outcomes as well as inpatient oral morphine equivalents per day (OME). RESULTS: Overall, there was an 8.72% annual increase in gabapentin use (P < 0.001). Modeled estimates suggest that gabapentin is associated with a significant decrease in opioid consumption (estimate = 0.63, 95% confidence interval = 0.49-0.82, P < 0.001) when controlling for patient characteristics. Patients receiving gabapentin had similar discharge pain scores, follow-up pain scores, and 30-day unplanned readmission rates compared with patients receiving no adjuvant analgesics (P > 0.05). CONCLUSIONS: When assessed in a real-world setting over a large cohort of TKA patients, gabapentin is an effective pain management therapy that is associated with reduced opioid consumption-a national priority in this time of opioid crisis-while maintaining the same quality of pain management.

9.
Health Informatics J ; : 1460458219881339, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31621460

RESUMO

Postoperative pain scores are widely monitored and collected in the electronic health record, yet current methods fail to fully leverage the data with fast implementation. A robust linear regression was fitted to describe the association between the log-scaled pain score and time from discharge after total knee replacement. The estimated trajectories were used for a subsequent K-medians cluster analysis to categorize the longitudinal pain score patterns into distinct clusters. For each cluster, a mixture regression model estimated the association between pain score and time to discharge adjusting for confounding. The fitted regression model generated the pain trajectory pattern for given cluster. Finally, regression analyses examined the association between pain trajectories and patient outcomes. A total of 3442 surgeries were identified with a median of 22 pain scores at an academic hospital during 2009-2016. Four pain trajectory patterns were identified and one was associated with higher rates of outcomes. In conclusion, we described a novel approach with fast implementation to model patients' pain experience using electronic health records. In the era of big data science, clinical research should be learning from all available data regarding a patient's episode of care instead of focusing on the "average" patient outcomes.

11.
Twin Res Hum Genet ; 22(4): 233-239, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31498059

RESUMO

The Wisconsin Twin Project comprises multiple longitudinal studies that span infancy to early adulthood. We summarize recent papers that show how twin designs with deep phenotyping, including biological measures, can inform questions about phenotypic structure, etiology, comorbidity, heterogeneity, and gene-environment interplay of temperamental constructs and mental and physical health conditions of children and adolescents. The general framework for investigations begins with rich characterization of early temperament and follows with study of experiences and exposures across childhood and adolescence. Many studies incorporate neuroimaging and hormone assays.


Assuntos
Sintomas Afetivos/genética , Doenças em Gêmeos/genética , Transtornos do Humor/genética , Gêmeos/genética , Adolescente , Adulto , Sintomas Afetivos/fisiopatologia , Sintomas Afetivos/psicologia , Criança , Doenças em Gêmeos/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Transtornos do Humor/fisiopatologia , Transtornos do Humor/psicologia , Neurociências/tendências , Fenótipo , Psicologia do Desenvolvimento/tendências , Psicopatologia/tendências , Temperamento/fisiologia , Wisconsin
13.
Gastroenterol Clin North Am ; 48(3): 343-356, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31383275

RESUMO

Anorexia nervosa has poor prognosis and treatment outcomes and is influenced by genetic, metabolic, and psychological factors. Gut microbes interact with gut physiology to influence metabolism and neurobiology, although potential therapeutic benefits remain unknown. Type 1 diabetes is linked to anorexia nervosa through energy dysregulation, which in both disease states is related to the gut microbiota, disordered eating, and genetics.


Assuntos
Anorexia Nervosa/etiologia , Anorexia Nervosa/terapia , Encéfalo/fisiologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/terapia , Microbioma Gastrointestinal/fisiologia , Humanos , Prognóstico
14.
PLoS One ; 14(8): e0221519, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31469842

RESUMO

OBJECTIVES: To investigate the biologic relevance of cross-platform concordant changes in gene expression in intact human failing/hypertrophied ventricular myocardium undergoing reverse remodeling. BACKGROUND: Information is lacking on genes and networks involved in remodeled human LVs, and in the associated investigative best practices. METHODS: We measured mRNA expression in ventricular septal endomyocardial biopsies from 47 idiopathic dilated cardiomyopathy patients, at baseline and after 3-12 months of ß-blocker treatment to effect left ventricular (LV) reverse remodeling as measured by ejection fraction (LVEF). Cross-platform gene expression change concordance was investigated in reverse remodeling Responders (R) and Nonresponders (NR) using 3 platforms (RT-qPCR, microarray, and RNA-Seq) and two cohorts (All 47 subjects (A-S) and a 12 patient "Super-Responder" (S-R) subset of A-S). RESULTS: For 50 prespecified candidate genes, in A-S mRNA expression 2 platform concordance (CcpT), but not single platform change, was directly related to reverse remodeling, indicating CcpT has biologic significance. Candidate genes yielded a CcpT (PCR/microarray) of 62% for Responder vs. Nonresponder (R/NR) change from baseline analysis in A-S, and ranged from 38% to 100% in S-R for PCR/microarray/RNA-Seq 2 platform comparisons. Global gene CcpT measured by microarray/RNA-Seq was less than for candidate genes, in S-R R/NR 17.5% vs. 38% (P = 0.036). For S-R global gene expression changes, both cross-cohort concordance (CccT) and CcpT yielded markedly greater values for an R/NR vs. an R-only analysis (by 22 fold for CccT and 7 fold for CcpT). Pathway analysis of concordant global changes for R/NR in S-R revealed signals for downregulation of multiple phosphoinositide canonical pathways, plus expected evidence of a ß1-adrenergic receptor gene network including enhanced Ca2+ signaling. CONCLUSIONS: Two-platform concordant change in candidate gene expression is associated with LV biologic effects, and global expression concordant changes are best identified in an R/NR design that can yield novel information.

15.
Am J Surg ; 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31280840

RESUMO

Understanding variation in perioperative opioid exposure and its effect on patients' outcomes is critical for pain management. This study characterized perioperative exposure to morphine and its association with postoperative pain and 30-day readmissions. We utilized nationwide Veterans Healthcare Administration (VHA) data on four high-volume surgical procedures, 2007-2014. We identified 235,239 Veterans undergoing orthopedic, general, or vascular surgery; 5.4% high trajectories (116.1 OME/Day), 53.2% medium trajectories (39.7 OME/Day), and 41.4% low trajectories (19.1 OME/Day). Modeled estimates suggest that patients in the high OME group had higher risk of a pain-related readmission (OR: 1.59; CI: 1.39, 1.83) compared to the low OME trajectory. Yet when stratified by pain trajectory, patients with high pain and high OME had lower risk of a pain-related readmission compared to patients in the high pain low OME group (OR: 0.76, CI: 0.62, 0.94). In conclusion, patients receiving high perioperative OME are more likely to return to care for pain-related problems. This study highlights opportunities to reduce the amount of prescriptions opioids in the communities.

16.
J Clin Invest ; 130: 3702-3716, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31211700

RESUMO

Resident microbiota activate regulatory cells that modulate intestinal inflammation and promote and maintain intestinal homeostasis. IL-10 is a key mediator of immune regulatory function. Our studies described the functional importance and mechanisms by which gut microbiota and specific microbial components influenced the development of intestinal IL-10-producing B cells. We used fecal transplant to germ-free (GF) Il10+/EGFP reporter and Il10-/- mice to demonstrate that microbiota from specific pathogen-free mice primarily stimulated IL-10-producing colon-specific B cells and T regulatory-1 cells in ex-GF mice. IL-10 in turn down-regulated microbiota-activated mucosal inflammatory cytokines. TLR2/9 ligands and enteric bacterial lysates preferentially induced IL-10 production and regulatory capacity of intestinal B cells. Analysis of Il10+/EGFP mice crossed with additional gene-deficient strains and B cell co-transfer studies demonstrated that microbiota-induced IL-10-producing intestinal B cells ameliorated chronic T cell-mediated colitis in a TLR2, MyD88 and PI3K-dependent fashion. In vitro studies implicated PI3Kp110δ and AKT downstream signaling. These studies demonstrated that resident enteric bacteria activated intestinal IL-10-producing B cells through TLR2, MyD88 and PI3K pathways. These B cells reduced colonic T cell activation and maintained mucosal homeostasis in response to intestinal microbiota.

17.
J Crohns Colitis ; 13(12): 1558-1568, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31056700

RESUMO

BACKGROUND AND AIMS: The pathogenesis of pouch inflammation may involve epithelial barrier disruption. We investigated whether faecal proteolytic activity is increased during pouchitis and results in epithelial barrier dysfunction through protease activating receptor [PAR] activation, and assessed whether the intestinal microbiome may be the source of the proteases. METHODS: Faecal samples were measured for protease activity using a fluorescein isothiocyanate [FITC]-casein florescence assay. Caco-2 cell monolayers were exposed to faecal supernatants to assess permeability to FITC-dextran. Tight junction protein integrity and PAR activation were assessed by immunoblot and immunofluorescence. A truncated PAR2 protein in Caco-2 cells was achieved by stable transfection using CRISPR/Cas9 plasmid. PAR2 activation in pouch biopsies was examined using antibodies directed to the N-terminus of the protein. Microbial composition was analysed based on 16S rRNA gene sequence analysis. RESULTS: Ten pouchitis patients, six normal pouch [NP] patients and nine healthy controls [HC] were recruited. The pouchitis patients exhibited a 5.19- and 5.35-fold higher faecal protease [FP] activity [p ≤ 0.05] compared to the NP and HC participants, respectively. The genus Haemophilus was positively associated with FP activity [R = 0.718, false discovery rate < 0.1]. Faecal supernatants from pouchitis patients activated PAR2 on Caco-2 monolayers, disrupted tight junction proteins and increased epithelial permeability. PAR2 truncation in Caco-2 abrogated faecal protease-mediated permeability. Pouch biopsies obtained from pouchitis patients, but not from NP patients, displayed PAR2 activation. CONCLUSIONS: Protease-producing bacteria may increase faecal proteolytic activity that results in pouch inflammation through disruption of tight junction proteins and increased epithelial permeability in a PAR2-dependent manner. This mechanism may initiate or propagate pouch inflammation.

18.
Psychiatry Clin Neurosci ; 73(9): 518-525, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31056797

RESUMO

Anorexia nervosa (AN) has one of the highest mortality rates of any psychiatric disorder. Treatments are often ineffective and relapse is common. Most research attempting to understand the underlying causes and maintenance factors of AN has focused on environmental contributions, yet there is much to be explored in terms of biological risk and maintenance factors. In this paper, we focus primarily on AN research related to genetics and the complex microbial community in the gut (intestinal microbiota), and how these impact our conceptualization of this disorder. Emerging research identifying significant negative genetic correlations between AN and obesity suggests that the conditions may represent 'metabolic bookends'. The identification of underlying biological mechanisms may provide both insight into extreme weight dysregulation on both ends of the spectrum and new possible points of entry for AN treatment. Additionally, the reported microbial imbalance (dysbiosis) in the gut microbiota in AN patients, potentially due to a nutrient- and energy-deprived gut environment, implies alterations in functional and metabolic capacity of the gut microbiome. The extent to which AN and obesity can also be considered to be 'microbiome bookends' requires further investigation. Finally, we discuss ongoing and future AN projects exploring the interplay between host genomics, the environment, and cumulative microbial genomes (microbiome) as well as interventions at the microbial and gut level.


Assuntos
Anorexia Nervosa/genética , Anorexia Nervosa/microbiologia , Disbiose/microbiologia , Microbioma Gastrointestinal , Anorexia Nervosa/metabolismo , Disbiose/metabolismo , Interação Gene-Ambiente , Humanos , Obesidade/genética , Resposta de Saciedade
19.
JACC Heart Fail ; 7(7): 586-598, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31042551

RESUMO

OBJECTIVES: The purpose of this study was to compare the effectiveness of bucindolol with that of metoprolol succinate for the maintenance of sinus rhythm in a genetically defined heart failure (HF) population with atrial fibrillation (AF). BACKGROUND: Bucindolol is a beta-blocker whose unique pharmacologic properties provide greater benefit in HF patients with reduced ejection fraction (HFrEF) who have the beta1-adrenergic receptor (ADRB1) Arg389Arg genotype. METHODS: A total of 267 HFrEF patients with a left ventricular ejection fraction (LVEF) <0.50, symptomatic AF, and the ADRB1 Arg389Arg genotype were randomized 1:1 to receive bucindolol or metoprolol therapy and were up-titrated to target doses. The primary endpoint of AF or atrial flutter (AFL) or all-cause mortality (ACM) was evaluated by electrocardiogram (ECG) during a 24-week period. RESULTS: The hazard ratio (HR) for the primary endpoint was 1.01 (95% confidence interval [CI]: 0.71 to 1.42), but trends for bucindolol benefit were observed in several subgroups. Precision therapeutic phenotyping revealed that a differential response to bucindolol was associated with the interval of time from the initial diagnoses of AF and HF to randomization and with the onset of AF relative to that of the initial HF diagnosis. In a cohort whose first AF and HF diagnoses were <12 years prior to randomization, in which AF onset did not precede HF by more than 2 years (n = 196), the HR was 0.54 (95% CI: 0.33 to 0.87; p = 0.011). CONCLUSIONS: Pharmacogenetically guided bucindolol therapy did not reduce the recurrence of AF/AFL or ACM compared to that of metoprolol therapy in HFrEF patients, but populations were identified who merited further investigation in future phase 3 trials.

20.
J Am Coll Cardiol ; 73(10): 1173-1184, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30871701

RESUMO

BACKGROUND: The phosphodiesterase 3A (PDE3A) gene encodes a PDE that regulates cardiac myocyte cyclic adenosine monophosphate (cAMP) levels and myocardial contractile function. PDE3 inhibitors (PDE3i) are used for short-term treatment of refractory heart failure (HF), but do not produce uniform long-term benefit. OBJECTIVES: The authors tested the hypothesis that drug target genetic variation could explain clinical response heterogeneity to PDE3i in HF. METHODS: PDE3A promoter studies were performed in a cloned luciferase construct. In human left ventricular (LV) preparations, mRNA expression was measured by reverse transcription polymerase chain reaction, and PDE3 enzyme activity by cAMP-hydrolysis. RESULTS: The authors identified a 29-nucleotide (nt) insertion (INS)/deletion (DEL) polymorphism in the human PDE3A gene promoter beginning 2,214 nt upstream from the PDE3A1 translation start site. Transcription factor ATF3 binds to the INS and represses cAMP-dependent promoter activity. In explanted failing LVs that were homozygous for PDE3A DEL and had been treated with PDE3i pre-cardiac transplantation, PDE3A1 mRNA abundance and microsomal PDE3 enzyme activity were increased by 1.7-fold to 1.8-fold (p < 0.05) compared with DEL homozygotes not receiving PDE3i. The basis for the selective up-regulation in PDE3A gene expression in DEL homozygotes treated with PDE3i was a cAMP response element enhancer 61 nt downstream from the INS, which was repressed by INS. The DEL homozygous genotype frequency was also enriched in patients with HF. CONCLUSIONS: A 29-nt INS/DEL polymorphism in the PDE3A promoter regulates cAMP-induced PDE3A gene expression in patients treated with PDE3i. This molecular mechanism may explain response heterogeneity to this drug class, and may inform a pharmacogenetic strategy for a more effective use of PDE3i in HF.


Assuntos
Insuficiência Cardíaca , Inibidores da Fosfodiesterase 3/farmacologia , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/genética , Miócitos Cardíacos/metabolismo , Testes Farmacogenômicos , Polimorfismo Genético , Transdução de Sinais
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