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BACKGROUND: To assess whether 24-hr urine oxalate (UOx) excretion is a risk factor for incident chronic kidney disease (CKD). METHODS: This longitudinal observational US-based study included 426,896 individuals age ≥ 18 years with no CKD at baseline and with at least one UOx and at least 6 months of baseline and 6 months of follow-up data. Of these, 11,239 (2.6%) had an underlying malabsorptive condition. Incident CKD, defined by relevant ICD codes, was identified from a multi-source data cloud containing individual-level healthcare claims and electronic medical records data. The association between categories of UOx and incident CKD was modeled using logistic regression adjusting for age, sex, race, BMI, baseline urine calcium, urine citrate, urine volume, tobacco use, hypertension, diabetes, malabsorption, and cardiovascular disease. RESULTS: Mean follow-up time was 38.9 months (SD 21.7). Compared with individuals with UOx <20 mg/24-hr, the odds of developing incident CKD increased for UOx 20-29 mg/24-hr (multivariate-adjusted (MV) OR: 1.14, 95% CI: 1.07, 1.21) through 80+ mg/24-hr (MVOR: 1.35 [1.21, 1.50] and was statistically significant for each UOx category. A similar pattern was seen in the subgroup with a malabsorptive condition though the magnitudes of association were larger, with the odds of developing incident CKD increased for UOx 20-29 mg/24-hr (MVOR: 1.50 [1.03, 2.20] through 80+ mg/24-hr (MVOR: 2.34 [1.50, 3.63] as compared with UOx <20 mg/24-hr. CONCLUSIONS: The risk of incident CKD increases with increasing 24-hr urine oxalate excretion. Future studies should examine whether reducing urine oxalate diminishes the risk of developing CKD.
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Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.
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Predisposición Genética a la Enfermedad/genética , Tromboembolia Venosa/genética , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.
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Exoma/genética , Estudio de Asociación del Genoma Completo/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Análisis por Micromatrices/métodos , Tromboembolia Venosa/genética , Negro o Afroamericano/genética , Alelos , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/estadística & datos numéricos , Humanos , Masculino , Análisis por Micromatrices/estadística & datos numéricos , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Tamaño de la Muestra , Tromboembolia Venosa/etnologíaRESUMEN
INTRODUCTION: Ammonia levels are used to assess hepatic encephalopathy, but their levels are highly variable in clinical practice. METHODS: We studied factors associated with variation in ammonia values in cirrhotic patients without previous hepatic encephalopathy and healthy volunteers (HVs). RESULTS: Ammonia increased by 12% and 18% at 1 and 2 hour, respectively, after a protein meal in 64 cirrhotic patients (P < 0.001). In 237 HVs, ammonia levels varied significantly between sites (P < 0.0001). New site-specific ammonia upper limits based on HV levels using a strict analysis protocol differed from routinely used values. Correlation between paired fresh samples was high (r = 0.83) but modest between fresh and frozen samples (r = 0.62). DISCUSSION: Sample handling, processing, and protein intake impact ammonia levels across sites.
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Amoníaco/sangre , Ensayos Clínicos como Asunto , Encefalopatía Hepática/sangre , Cirrosis Hepática/sangre , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Progresión de la Enfermedad , Femenino , Voluntarios Sanos , Encefalopatía Hepática/diagnóstico , Encefalopatía Hepática/etiología , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: Much controversy surrounds the association of traditional cardiovascular disease risk factors with venous thromboembolism (VTE). METHODS: We performed an individual level random-effect meta-analysis including 9 prospective studies with measured baseline cardiovascular disease risk factors and validated VTE events. Definitions were harmonized across studies. Traditional cardiovascular disease risk factors were modeled categorically and continuously using restricted cubic splines. Estimates were obtained for overall VTE, provoked VTE (ie, VTE occurring in the presence of 1 or more established VTE risk factors), and unprovoked VTE, pulmonary embolism, and deep-vein thrombosis. RESULTS: The studies included 244 865 participants with 4910 VTE events occurring during a mean follow-up of 4.7 to 19.7 years per study. Age, sex, and body mass index-adjusted hazard ratios for overall VTE were 0.98 (95% confidence interval [CI]: 0.89-1.07) for hypertension, 0.97 (95% CI: 0.88-1.08) for hyperlipidemia, 1.01 (95% CI: 0.89-1.15) for diabetes mellitus, and 1.19 (95% CI: 1.08-1.32) for current smoking. After full adjustment, these estimates were numerically similar. When modeled continuously, an inverse association was observed for systolic blood pressure (hazard ratio=0.79 [95% CI: 0.68-0.92] at systolic blood pressure 160 vs 110 mm Hg) but not for diastolic blood pressure or lipid measures with VTE. An important finding from VTE subtype analyses was that cigarette smoking was associated with provoked but not unprovoked VTE. Fully adjusted hazard ratios for the associations of current smoking with provoked and unprovoked VTE were 1.36 (95% CI: 1.22-1.52) and 1.08 (95% CI: 0.90-1.29), respectively. CONCLUSIONS: Except for the association between cigarette smoking and provoked VTE, which is potentially mediated through comorbid conditions such as cancer, the modifiable traditional cardiovascular disease risk factors are not associated with increased VTE risk. Higher systolic blood pressure showed an inverse association with VTE.
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Tromboembolia Venosa/etiología , Factores de Edad , Presión Sanguínea , Índice de Masa Corporal , Complicaciones de la Diabetes , Humanos , Hiperlipidemias/complicaciones , Hipertensión/complicaciones , Lípidos/sangre , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Embolia Pulmonar/etiología , Factores de Riesgo , Factores Sexuales , Fumar , Trombosis de la Vena/etiologíaRESUMEN
BACKGROUND: We explored 12-month clinical outcomes of 929 patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) with bare-metal stents (BMS) vs. drug-eluting stents (DES) from the prospective multicenter AFCAS (Atrial Fibrillation undergoing Coronary Artery Stenting) registry. METHODSâANDâRESULTS: Endpoints included the first occurrence of major adverse cardiac and cerebrovascular events (MACCE), defined as a composite of all-cause death, myocardial infarction (MI), target vessel revascularization, definite/probable stent thrombosis (ST), transient ischemic attack or stroke. Bleeding events were defined according to the Bleeding Academic Research Consortium criteria. Altogether, 673 (72.4%) patients received BMS and 220 (23.7%) at least one DES. Patients treated with DES more often had diabetes and prior ischemic events, and a longer stent length (P<0.05 for all), whereas patients treated with BMS more often had heart failure and were more likely to present with acute ST-elevation MI (P<0.05 for both). At 12-month follow-up, rates and risks of MACCE and total bleeding events were comparable between the groups (22.0% with BMS vs. 19.5% with DES, P=0.51, hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.63-1.25 for DES) and (19.5% vs. 15.0%, respectively, P=0.16, HR 0.75, 95% CI 0.51-1.09 for DES). Definite/probable ST was more frequent in the BMS group (1.9% vs. 0%, respectively, P=0.046). CONCLUSIONS: In real-world patients with AF undergoing PCI, DES use was associated with outcomes comparable to those with BMS without excess bleeding complications. More ST was seen in BMS-treated patients.
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Fibrilación Atrial/mortalidad , Fibrilación Atrial/terapia , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Sistema de Registros , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
The prevalence and incidence of atrial fibrillation (AF) are increasing rapidly. Key recommendations in management of AF include prompt administration of oral anticoagulation to all patients with elevated risk of thromboembolic complications, proper use of antiarrhythmic drugs and invasive therapies in highly symptomatic patients and adequate rate control in patients with permanent AF. The selection between warfarin and the novel oral anticoagulants (apixaban, dabigatran, rivaroxaban) is based on careful evaluation of the benefits and disadvantages of the drugs in a given patient.
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Antiarrítmicos/uso terapéutico , Anticoagulantes/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Administración Oral , Antitrombinas/uso terapéutico , Bencimidazoles/uso terapéutico , Dabigatrán , Humanos , Incidencia , Morfolinas/uso terapéutico , Guías de Práctica Clínica como Asunto , Prevalencia , Pirazoles/uso terapéutico , Piridonas/uso terapéutico , Rivaroxabán , Tiofenos/uso terapéutico , Warfarina/uso terapéutico , beta-Alanina/análogos & derivados , beta-Alanina/uso terapéuticoRESUMEN
Asthma is an inflammatory disease of the lower airways. The typical symptoms of asthma are cough, wheezing and shortness of breath. Asthma is diagnosed based on measures of pulmonary function showing variable or reversible airways obstruction. The basic pharmacological treatment consists of alleviating the asthmatic inflammation with regular inhaled glucocorticoids and relieving sudden obstructions with as-needed inhaled beta2-agonists. The treatment is adjusted based on asthma control. If good control of asthma is not achieved with low to medium doses of inhaled glucocorticoids, additional control medication (inhaled long acting beta2-agonists, antileukotrienes, in adults also theophylline or tiotrohium) should be introduced.
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Antiasmáticos/uso terapéutico , Asma/diagnóstico , Asma/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Agonistas Adrenérgicos beta/uso terapéutico , Asma/fisiopatología , Broncodilatadores/uso terapéutico , Glucocorticoides/uso terapéutico , Humanos , Antagonistas de Leucotrieno/uso terapéutico , Pruebas de Función Respiratoria , Derivados de Escopolamina/uso terapéutico , Teofilina/uso terapéutico , Bromuro de TiotropioRESUMEN
Background: Polymorphisms in the CYP2C9, VKORC1, MDR1 and APOE genes may impact warfarin dose. Aim: To investigate the influence of sociodemographic, clinical factors and polymorphisms *1, *2 and *3 for CYP2C9, -1639G>A for VKORC1, 3435C>T for MDR1, and ϵ2, ϵ3 and ϵ4 for APOE genes on the mean weekly warfarin maintenance dose in adults. Methods: This cross-sectional study recruited a calculated sample of 315 patients in three anticoagulation clinics in Brazil. A model containing the variables significantly associated with warfarin dose was estimated. Results: The mean age of patients was 64.1 ± 13.1 years, with 173 (54.9%) women. Age, use of amiodarone, genotype VKORC1 GA, genotype VKORC1 AA, genotypes CYP2C9*1/*2 or *1/*3 and genotypes CYP2C9*2/*2 or *2/*3 or *3/*3 were associated with a reduced warfarin dose. Conclusion: This study pointed out factors that could impact the management of oral anticoagulation.
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Despite available treatment options, many patients with phenylketonuria (PKU) cannot achieve target plasma phenylalanine (Phe) levels1. We previously modified Escherichia coli Nissle 1917 to metabolize Phe in the gut after oral administration (SYNB1618) and designed a second strain (SYNB1934) with enhanced activity of phenylalanine ammonia lyase2,3. In a 14-day open-label dose-escalation study (Synpheny-1, NCT04534842 ), we test a primary endpoint of change from baseline in labeled Phe (D5-Phe AUC0-24; D5-Phe area under the curve (AUC) over 24 hours after D5-Phe administration) in plasma after D5-Phe challenge in adult participants with screening Phe of greater than 600 µM. Secondary endpoints were the change from baseline in fasting plasma Phe and the incidence of treatment-emergent adverse events. A total of 20 participants (ten male and ten female) were enrolled and 15 completed the study treatment. Here, we show that both strains lower Phe levels in participants with PKU: D5-Phe AUC0-24 was reduced by 43% from baseline with SYNB1934 and by 34% from baseline with SYNB1618. SYNB1934 led to a decrease in fasting plasma Phe of 40% (95% CI, -52, -24). There were no serious adverse events or infections. Four participants discontinued because of adverse events, and one withdrew during the baseline period. We show that synthetic biotics can metabolize Phe in the gut, lower post-prandial plasma Phe levels and lower fasting plasma Phe in patients with PKU.
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Fenilalanina , Fenilcetonurias , Adulto , Humanos , Masculino , Femenino , Fenilalanina/uso terapéutico , Fenilcetonurias/tratamiento farmacológico , Fenilanina Amoníaco-Liasa/uso terapéutico , Administración Oral , Escherichia coliRESUMEN
BACKGROUND: The anti-thrombotic strategy during coronary stenting is challenging in patients on long-term oral anticoagulation (OAC) because of atrial fibrillation (AF). Uninterrupted OAC (UAC) is increasingly used, but bridging therapy (BT) is still in common use. METHODS AND RESULTS: Management of patients with Atrial Fibrillation undergoing Coronary Artery Stenting (AFCAS) is a prospective multicenter European registry that recruited 963 patients with AF undergoing coronary stenting. To compare the safety of UAC and BT, bleeding complications and major adverse cardiac and cerebrovascular events (MACCE; death, myocardial infarction, target vessel revascularization, stent thrombosis and stroke) were assessed in 290 patients treated with UAC and 161 patients with BT during a 30-day follow-up period. In the BT group, OAC was interrupted for a median of 5 days. Overall bleeding complications tended to be more common in the BT group (18.6% vs. 12.1%, P=0.07), with no significant difference in the rate of major bleeding (2.5% vs. 1.4%) or MACCE (6.2% vs. 3.8%). After adjustment for propensity score, BT was not associated with bleeding complications (odds ratio [OR], 1.38; 95% confidence interval [CI]: 0.77-2.48, P=0.28) or MACCE (OR, 1.16; 95%CI: 0.44-3.05, P=0.76). Periprocedural international normalized ratio was not associated with bleeding or MACCE. CONCLUSIONS: UAC does not increase perioperative complications during coronary stenting and is a simple and cost-effective alternative to conventional heparin bridging.
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Angioplastia Coronaria con Balón/instrumentación , Anticoagulantes/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/terapia , Heparina/administración & dosificación , Stents , Administración Oral , Anciano , Anciano de 80 o más Años , Angioplastia Coronaria con Balón/efectos adversos , Angioplastia Coronaria con Balón/mortalidad , Anticoagulantes/efectos adversos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/mortalidad , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/mortalidad , Trombosis Coronaria/etiología , Esquema de Medicación , Sustitución de Medicamentos , Europa (Continente) , Femenino , Hemorragia/inducido químicamente , Heparina/efectos adversos , Humanos , Modelos Logísticos , Masculino , Infarto del Miocardio/etiología , Oportunidad Relativa , Puntaje de Propensión , Estudios Prospectivos , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Platelet inhibitors and anticoagulants are called antithrombotic drugs. New platelet inhibitors prasugrel and ticagrelor are more effective than the traditional clopidogrel, but their use is also accompanied by more frequent bleeding complications. Varfarin has gained true competitors; new oral anticoagulants include dabigatran, rivaroxaban and apixaban. New anticoagulants are easier to use but clearly more expensive. The use of new anticoagulants is also accompanied by several potential problems that the clinician should be aware of.
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Anticoagulantes/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Adenosina/análogos & derivados , Adenosina/uso terapéutico , Bencimidazoles/uso terapéutico , Clopidogrel , Dabigatrán , Hemorragia/inducido químicamente , Humanos , Morfolinas/uso terapéutico , Piperazinas/uso terapéutico , Clorhidrato de Prasugrel , Pirazoles/uso terapéutico , Piridonas/uso terapéutico , Rivaroxabán , Tiofenos/uso terapéutico , Ticagrelor , Ticlopidina/análogos & derivados , Ticlopidina/uso terapéutico , Warfarina/uso terapéutico , beta-Alanina/análogos & derivados , beta-Alanina/uso terapéuticoRESUMEN
Phenylketonuria (PKU) is an inherited disorder in which phenylalanine (Phe) is not correctly metabolized leading to an abnormally high plasma Phe concentration that causes profound neurologic damage if left untreated. The mainstay of treatment for PKU has centered around limiting natural protein in the diet while supplementing with medical foods in order to prevent neurologic injury while promoting growth. This review discusses several deleterious effects of the low Phe diet along with benefits that have been reported for patients with increased natural protein intake while maintaining plasma Phe levels within treatment guidelines.
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Fenilcetonurias , Humanos , Fenilalanina , DietaRESUMEN
The identification of inherited antithrombin deficiency (ATD) is critical to prevent potentially life-threatening thrombotic events. Causal variants in SERPINC1 are identified for up to 70% of cases, the majority being single-nucleotide variants and indels. The detection and characterization of structural variants (SVs) in ATD remain challenging due to the high number of repetitive elements in SERPINC1. Here, we performed long-read whole-genome sequencing on 10 familial and 9 singleton cases with type I ATD proven by functional and antigen assays, who were selected from a cohort of 340 patients with this rare disorder because genetic analyses were either negative, ambiguous, or not fully characterized. We developed an analysis workflow to identify disease-associated SVs. This approach resolved, independently of its size or type, all eight SVs detected by multiple ligation-dependent probe amplification, and identified for the first time a complex rearrangement previously misclassified as a deletion. Remarkably, we identified the mechanism explaining ATD in 2 out of 11 cases with previous unknown defect: the insertion of a novel 2.4 kb SINE-VNTR-Alu retroelement, which was characterized by de novo assembly and verified by specific polymerase chain reaction amplification and sequencing in the probands and affected relatives. The nucleotide-level resolution achieved for all SVs allowed breakpoint analysis, which revealed repetitive elements and microhomologies supporting a common replication-based mechanism for all the SVs. Our study underscores the utility of long-read sequencing technology as a complementary method to identify, characterize, and unveil the molecular mechanism of disease-causing SVs involved in ATD, and enlarges the catalogue of genetic disorders caused by retrotransposon insertions.
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Deficiencia de Antitrombina III , Retroelementos , Deficiencia de Antitrombina III/diagnóstico , Deficiencia de Antitrombina III/genética , Antitrombinas , Humanos , Nucleótidos , Retroelementos/genéticaRESUMEN
The development of therapeutics depends on predictions of clinical activity from pre-clinical data. We have previously described SYNB1618, an engineered bacterial therapeutic (synthetic biotic) for the treatment of Phenylketonuria (PKU), a rare genetic disease that leads to accumulation of plasma phenylalanine (Phe) and severe neurological complications. SYNB1618 consumes Phe in preclinical models, healthy human volunteers, and PKU patients. However, it remains unclear to what extent Phe consumption by SYNB1618 in the gastrointestinal tract lowers plasma Phe levels in PKU patients. Here, we construct a mechanistic model that predicts SYNB1618 function in non-human primates and healthy subjects by combining in vitro simulations and prior knowledge of human physiology. In addition, we extend a model of plasma Phe kinetics in PKU patients, in order to estimate plasma Phe lowering by SYNB1618. This approach provides a framework that can be used more broadly to define the therapeutic potential of synthetic biotics.
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Voluntarios Sanos , Fenilcetonurias/genética , Primates/fisiología , Animales , Humanos , Fenilcetonurias/metabolismo , Primates/genéticaRESUMEN
Phenylketonuria (PKU) is a rare disease caused by biallelic mutations in the PAH gene that result in an inability to convert phenylalanine (Phe) to tyrosine, elevated blood Phe levels and severe neurological complications if untreated. Most patients are unable to adhere to the protein-restricted diet, and thus do not achieve target blood Phe levels. We engineered a strain of E. coli Nissle 1917, designated SYNB1618, through insertion of the genes encoding phenylalanine ammonia lyase and L-amino acid deaminase into the genome, which allow for bacterial consumption of Phe within the gastrointestinal tract. SYNB1618 was studied in a phase 1/2a randomized, placebo-controlled, double-blind, multi-centre, in-patient study ( NCT03516487 ) in adult healthy volunteers (n = 56) and patients with PKU and blood Phe level ≥600 mmol l-1 (n = 14). Participants were randomized to receive a single dose of SYNB1618 or placebo (part 1) or up to three times per day for up to 7 days (part 2). The primary outcome of this study was safety and tolerability, and the secondary outcome was microbial kinetics. A D5-Phe tracer (15 mg kg-1) was used to study exploratory pharmacodynamic effects. SYNB1618 was safe and well tolerated with a maximum tolerated dose of 2 × 1011 colony-forming units. Adverse events were mostly gastrointestinal and of mild to moderate severity. All participants cleared the bacteria within 4 days of the last dose. Dose-responsive increases in strain-specific Phe metabolites in plasma (trans-cinnamic acid) and urine (hippuric acid) were observed, providing a proof of mechanism for the potential to use engineered bacteria in the treatment of rare metabolic disorders.
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Terapia Biológica/métodos , Escherichia coli , Fenilcetonurias/terapia , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Terapia Biológica/efectos adversos , Escherichia coli/enzimología , Escherichia coli/genética , Ingeniería Genética , Humanos , Fenilanina Amoníaco-Liasa/genética , Fenilanina Amoníaco-Liasa/metabolismo , Fenilcetonurias/sangre , Fenilcetonurias/genética , Resultado del TratamientoRESUMEN
Clopidogrel inhibits platelet action through the P2Y12-ADP receptor in an irreversible manner. Plasma levels of the active drug and thus the drug effect exhibit large individual variation. Part of the variation is explained by genetic reasons, but drug interactions may also have an effect on the response. The obtained efficacy is lower than anticipated in as many as 30% of the patients. The poor drug response is associated with an increased risk of cardiovascular events. Measurement of clopidogrel resistance with laboratory studies is challenging. Several methods have been developed and are becoming available for clinical use.
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Resistencia a Medicamentos , Inhibidores de Agregación Plaquetaria/farmacología , Ticlopidina/análogos & derivados , Clopidogrel , Interacciones Farmacológicas , Humanos , Factores de Riesgo , Ticlopidina/farmacologíaRESUMEN
Any complaints from a patient about their memory should be examined. Diagnosis is based on international criteria. The basic evaluation consists of the medical history, clinical evaluation, cognitive tests and brain imaging, especially using MRI. When a diagnosis of Alzheimer's disease, AD with cerebrovascular disease or with Lewy Body disease, or Dementia associated with Parkinson's disease or LBD is made, evidence based medical therapy is indicated as part of comprehensive care. An acetylcholinesterase inhibitor or memantine can be used. These drugs are ineffective in the case of frontotemporal degenerations. For severe behavioural disorders, other psychoactive medications can be applied.
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Trastornos de la Memoria/diagnóstico , Trastornos de la Memoria/tratamiento farmacológico , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/tratamiento farmacológico , Demencia/diagnóstico , Demencia/tratamiento farmacológico , Diagnóstico por Imagen , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico , Enfermedad por Cuerpos de Lewy/tratamiento farmacológico , Anamnesis , Pruebas Neuropsicológicas , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Guías de Práctica Clínica como AsuntoRESUMEN
A major proportion of cardiac patients use long-time antithromobitic medication. It is not uncommon that these patients require surgery and operations. Discontinuation of antithrombotic therapy may be used to decrease risk of hemorrhage, but on the other hand the medication break will make the patient susceptible to thrombotic and thromboembolic complications. The attending physician must decide which is safer: to break the medication or to continue it. Often the best choice is a compromise of the above, i.e. application of a somewhat reduced compensatory antithrombotic therapy.
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Fibrinolíticos/uso terapéutico , Cardiopatías/tratamiento farmacológico , Fibrinolíticos/administración & dosificación , Fibrinolíticos/efectos adversos , Hemorragia/inducido químicamente , Humanos , Factores de Riesgo , Factores de TiempoRESUMEN
Acute kidney injury (AKI) is associated with significant morbidity and mortality. Its prevalence is increasing. Risk factors are older age, diabetes, atherosclerosis, medications, heart failure, male sex, and even mild chronic renal failure. Early detection of AKI is essential, as is the prevention of AKI related to hypovolaemia, contrast agents and nephrotoxic medications. No medication is available for developed AKI, the only therapeutic option being renal replacement therapy. Thus, prevention by adequate fluid therapy, optimisation of renal perfusion pressure and exclusion of post-renal causes of AKI are crucial. To date, the long-term outcome in AKI is unsatisfactory and the costs are high.