Forced normalization: A systematic review Calle‐López, Yamile; Ladino, Lady Diana; Benjumea‐Cuartas, Vanessa ...
Epilepsia,
August 2019, Volume:
60, Issue:
8
Journal Article
Peer reviewed
Open access
Objective
Forced normalization (FN) is an intriguing phenomenon characterized by the emergence of psychiatric disturbances following the establishment of seizure control or reduction in the epileptic ...activity in a patient with previous uncontrolled epilepsy. We aim to describe the clinical characteristics of the condition.
Methods
We conducted a systematic review on MEDLINE, EMBASE, Cochrane, and Scielo from January 1953 to January 2018. Clinical, electrographic, and imaging data were gathered. We considered all outcomes in children and adults. We performed no meta‐analyses due to the limited available data.
Results
Of 2606 s identified, 36 fulfilled the FN diagnostic criteria; 193 FN episodes were evaluated and 77 of them were analyzed extensively. Sixty percent of cases were female. Mean age ± standard deviation (SD) was 28.3 ± 14.2 years. The majority of patients had focal (80%) symptomatic (44%) epilepsy. Most patients reported a high ictal frequency (58%) and were on polytherapy (51%). Patients presented psychosis (86.4%), mood disorders (25.8%), and dissociation (4.5%) as the main manifestations. In the psychosis group, persecutory (52.6%) and reference (47.3%) delusions were frequent. FN was provoked by an antiepileptic drug (AED) (48.5%) mainly levetiracetam, epilepsy surgery (31.8%), or vagus nerve stimulation (13.6%). Treatment was homogeneous including anticonvulsant withdrawal (47%) or taper (25%); antipsychotics were initiated in the majority of cases (73%). Psychiatric symptoms were partially controlled in 35%, with complete resolution of symptoms in the remaining 65% of cases. The majority of patients (87%) with AED trigger and withdrawal presented complete resolution of symptoms in comparison to 28.5% of patients triggered by surgery.
Significance
Forced normalization is an entity whose pathophysiology remains uncertain. Antipsychotic drug use does not predict complete resolution of psychiatric symptoms in comparison with AED withdrawal. Although there is a positive response to treatment in patients with FN triggered by drugs, the prognosis is obscure in patients with surgery triggered FN.
Human leishmaniasis is a neglected tropical disease which affects nearly 1.5 million people every year, with Mexico being an important endemic region. One of the major defense mechanisms of these ...parasites is based in the polyamine metabolic pathway, as it provides the necessary compounds for its survival. Among the enzymes in this route, trypanothione reductase (TryR), an oxidoreductase enzyme, is crucial for the Leishmania genus’ survival against oxidative stress. Thus, it poses as an attractive drug target, yet due to the size and features of its catalytic pocket, modeling techniques such as molecular docking focusing on that region is not convenient. Herein, we present a computational study using several structure-based approaches to assess the druggability of TryR from L. mexicana, the predominant Leishmania species in Mexico, beyond its catalytic site. Using this consensus methodology, three relevant pockets were found, of which the one we call σ-site promises to be the most favorable one. These findings may help the design of new drugs of trypanothione-related diseases.
The cytotoxic and antifungal capacity of a set of turbomycin-based alkaloids, assembled by multicomponent reactions through exposure to near-infrared light (
λ
= 1.1 μm) in the presence of organic ...acid, was tested against six cancer cell lines (SW620, SW480, HeLa, K562, MCF-7, and Calo) and three life-threatening fungi (
C. albicans
,
C. parapsilosis
, and
C. neoformans
). Notably, the structurally elaborated compounds (> 10
3
Da) showed an antifungal effect against
C. parapsilosis
and
C. neoformans
at a concentration of 2.4 mM comparable to ketoconazole (22 vs. 20 mm). In contrast, its lower molecular weight homologous (< 500 Da) exhibited substantially the best cytotoxic effect against the growth of the colon adenocarcinoma cell lines SW620 and WS408 (IC
50
= 12.56 ± 3.3 μmol and 13.9 ± 2.7 μmol), values slightly higher than the m-AMSA positive control (IC
50
= 8.3 ± 2.6 and 7.4 ± 2.04 μmol). Highlight that only regioisomers containing the 1,1′-dimethyl-, 2,2′-dimethyl-, and 2,2′-diphenyl-DIM subunits attached on phenyl ring in a 1,3-substitution pattern exhibit substantial cytotoxic and antifungal effect.
Graphic abstract
The continuous pharmacological advances in antiretroviral treatment (ART) and the increasing understanding of HIV drug resistance has led to a change in the paradigm of ART optimization in the ...setting of the viral suppression of treatment-experienced patients with the emerging evidence of the effectiveness and safety of dual therapies. The aim of this study is to determine the antiviral efficacy and safety of switching to Dolutegravir + Lamivudine in people living with HIV, and to analyze the rate of patients with virologic failure (VF). A total of 200 patients were included with a median age of 51 years, 189 cells/µL of nadir CD4+, 13 years on ART and four previous ART regimens. Among the 168 patients who completed a follow-up at 48 weeks, a total of five VFs occurred, resulting in a 2.98% (5/168) VF rate. The results of the intention-to-treat analysis were a VF rate of 2.54% (5/197), and the rate of patients/year with viral suppression was 98.3% (298/303) in the observed data analysis. We observed a significant improvement in mean CD4 lymphocytes, the CD4/CD8 ratio and lipid profiles. The optimization of ART to DTG plus 3TC is a cost-effective switch option for treatment-experienced HIV patients, and also improves their lipid profiles.
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•HCV-infected PWID achieve high SVR12 rates with IFN-free antiviral regimens in clinical practice.•PWID have lower SVR12 rates than patients who never used drugs.•Active drug use ...during antiviral treatment was an independent predictor of lower response, opioid agonist therapy was not.•The main reasons for non-response among PWID are discontinuations due to adverse events and, particularly, drop-outs.
People who inject drugs (PWID) and are on opioid agonist therapy (OAT) might have lower adherence to direct-acting antivirals (DAAs) against hepatitis C virus (HCV) and, therefore, lower rates of sustained virologic response (SVR). Because of this, we compared the SVR rates to interferon-free DAA combinations in individuals receiving OAT and those not receiving OAT in a real-world setting.
The HEPAVIR-DAA cohort, recruiting HIV/HCV-coinfected patients (NCT02057003), and the GEHEP-MONO cohort (NCT02333292), including HCV-monoinfected individuals, are ongoing prospective multicenter cohorts of patients receiving DAAs in clinical practice. We compared SVR 12 weeks after treatment (SVR12) in non-drug users and PWID, including those receiving or not receiving OAT. Intention-to-treat and per protocol analyses were performed.
Overall, 1,752 patients started interferon-free DAA treatment. By intention-to-treat analysis, 778 (95%, 95% CI 93%–96%) never injectors, 673 (92%, 95% CI 89%–93%) PWID not on OAT and 177 (89%, 95% CI 83%–92%) PWID on OAT achieved SVR12 (p = 0.002). SVR12 rates for ongoing drug users (with or without OAT) were 68 (79%) compared with 1,548 (95%) for non-drug users (p <0.001). Among ongoing drug users, 15 (17%) were lost-to-follow-up, and 3 (3.5%) became reinfected. In the per protocol analysis, 97% never injectors, 95% PWID not on OAT and 95% PWID on OAT achieved SVR12 (p = 0.246). After adjustment, ongoing drug use was associated with SVR12 (intention-to-treat) and OAT use was not.
HCV-infected PWID achieve high SVR12 rates with DAAs whether they are on OAT or not, but their response rates are lower than those of patients who never used drugs. This is mainly attributable to more frequent loss to follow-up. Accounting for active drug use during DAA therapy nearly closed the gap in SVR rates between the study groups.
Patients with hepatitis C virus infection who are on opioid agonist therapy can achieve high cure rates with current treatments. The use of illicit drugs during treatment can drive drop-outs and reduce cure rates. However, hepatitis C can be cured in most of those using drugs who complete treatment and follow-up.
Clinical trial number: HEPAVIR-DAA cohort, NCT02057003; GEHEP-MONO cohort, NCT02333292.
El artículo tiene como objetivo general describir las medidas de no repetición ordenadas por los órganos convencionales de Naciones Unidas para los Estados latinoamericanos que han tenido comisiones ...de la verdad. El resultado se consigue mediante el desarrollo de una investigación cualitativa, básica y jurídica, que utiliza el método analítico deductivo e inductivo, y centra su análisis en la práctica internacional de los comités. A partir de esta labor, se obtuvo que siete órganos de tratados de derechos humanos han recomendado medidas de no repetición en el marco del mecanismo de comunicación individual y que, además, estas medidas se clasifican en generales y específicas. Las primeras son aquellas en las cuales los comités determinan la violación del tratado base y recomiendan al Estado que adopte las medidas adecuadas y efectivas para que los hechos no vuelvan a ocurrir. Entre tanto, en las segundas han extendido recomendaciones en seis variantes, entre ellas, reformas normativas, creación de programas en derechos humanos, capacitación en derechos humanos, destinación de recursos o adecuaciones de instalaciones públicas, acceso a la justicia e imposición de sanciones y acceso a información.
Resumen Introducción: la malnutrición y la sarcopenia son frecuentes en la población con cirrosis hepática y generan un impacto negativo en el estado funcional y la esperanza de vida de estos ...pacientes. Existen múltiples herramientas para la valoración de la malnutrición y la sarcopenia en los pacientes con cirrosis hepática. Algunas de estas herramientas son de fácil aplicación y reproducibilidad, lo que facilita su aplicación global. Objetivo: valorar la malnutrición y la sarcopenia en la cirrosis hepática y comparar distintas herramientas diagnósticas aplicables en esta población. Método: se realizó un estudio analítico de corte transversal con muestreo a conveniencia mediante inclusión continua de pacientes con cirrosis hepática en un hospital de tercer nivel durante diciembre de 2018 a mayo de 2019. Se realizó la valoración nutricional con la antropometría del brazo, el índice de masa corporal (IMC) y el algoritmo del Royal Free Hospital Subjetive Global Assessment (RFH-SGA). Para la valoración de la sarcopenia se aplicó la fuerza de agarre de la mano con un dinamómetro. Los resultados se reportaron en medidas de tendencia central expresadas en frecuencia y porcentaje. Se realizó un coeficiente de correlación con Tau-b de Kendall en las variables no paramétricas, considerándose como valor estadísticamente significativo una p < 0,05. Resultados: se incluyeron un total de 103 pacientes, predominando el género masculino (79,6 %), con una edad media de 51 años. La etiología más frecuente de la cirrosis hepática fue el consumo de alcohol (68 %), predominando la clase Child-Pugh C (57,3 %) con una media de MELD de 21,9 (± 8,9). Se reportó una media de IMC con peso seco de 25,2 kg/m2 y, respecto a la clasificación de la OMS, un 7,8 % se encontraban en bajo peso y un 59,2 % en malnutrición según la RFH-SGA. Un 88,3 % presentó sarcopenia al utilizar la fuerza de agarre de la mano, cuyo valor medio fue de 18,99 kg. Se realizó una correlación con Tau b de Kendall entre IMC y RFH-SGA sin evidenciarse ninguna asociación significativa, al igual que entre los percentiles de la circunferencia muscular media de brazo (MAMC) y la fuerza de agarre de la mano. Conclusiones: la valoración integral de la cirrosis hepática debe incluir el escrutinio de la malnutrición y la sarcopenia, existiendo herramientas de fácil acceso y aplicación segura validadas en esta población, como la valoración antropométrica, el RFH-SGA y la fuerza de agarre de la mano.
Despite high response rates associated to hepatitis C virus (HCV) treatment, no protective immunity is acquired, allowing for reinfection and continued infectiousness. Distinguishing between relapse ...and reinfection is crucial for patient counselling and to choose the most appropriate retreatment. Here, refined phylogenetic analysis using multiple genes served to assess genotype and reinfection for 53 patients for whom the virus was sampled before start of therapy and at time of sustained virological response evaluation at week 12. At baseline, genotypes were determined as HCV1a (41.5%), HCV1b (24.5%), HCV4 (18.9%) and HCV3a (15.1%), while six cases revealed to be discordantly assigned by phylogeny and commercial assays. Overall, 60.4% was co-infected with HIV. The large majority was classified as people who inject drugs (78.6%), often co-infected with HIV. Transmission was sexual in seven cases, of which five in HIV-positive men-who-have-sex-with-men. Overall, relapse was defined for 44 patients, while no conclusion was drawn for four patients. Five patients were reinfected with a different HCV strain, of which three with a different genotype, showing that phylogeny is needed not only to determine the genotype, but also to distinguish between relapse and intra-subtype reinfection. Of note, phylogenies are more reliable when longer fragments of the viral genome are being sequenced.
Background. Antiretroviral drugs with a lower potential to induce hepatic steatosis in human immunodeficiency virus (HIV) infection need to be identified. We compared the effect of switching ...efavirenz (EFV) to raltegravir (RAL) on hepatic steatosis among HIV-infected patients with nonalcoholic fatty liver disease (NAFLD) receiving EFV plus 2 nucleoside analogues. Methods. HIV-infected patients on EFV plus tenofovir/emtricitabine or abacavir/lamivudine with NAFLD were randomized 1:1 to switch from EFV to RAL (400 mg twice daily), maintaining nucleoside analogues unchanged, or to continue with EFV plus 2 nucleoside analogues. At baseline, eligible patients should show controlled attenuation parameter (CAP) values ≥238 dB/m. Changes in hepatic steatosis at 48 weeks of follow-up over baseline levels were measured by CAP. Results. Overall, 39 patients were included, and 19 of them were randomized to switch to RAL. At week 48, median CAP for the RAL group was 250 (Q1–Q3, 221–277) dB/m and 286 (Q1–Q3, 269–314) dB/m for the EFV group (P = .035). The median decrease in CAP values was −20 (Q1–Q3, −67 to 15) dB/m for the RAL arm and 30 (Q1–Q3, −17 to 49) dB/m for the EFV group (P = .011). CAP values <238 dB/m at week 48 were observed in 9 (47%) patients on RAL and 3 (15%) individuals on EFV (P = .029). Conclusions. After 48 weeks, HIV-infected individuals switching EFV to RAL showed decreases in the degree of hepatic steatosis, as measured by CAP, compared with those continuing with EFV. In addition, the proportion of patients without significant hepatic steatosis after 48 weeks was greater for those who switched to RAL. Clinical Trials Registration. NCT01900015.
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