Characterization of hereditary transthyretin cardiac amyloidosis in Spain.

INTRODUCTION AND OBJECTIVES: Hereditary transthyretin amyloidosis (hATTR) is a disease caused by mutations in the transthyretin gene that frequently shows cardiac involvement due to amyloid deposition in the myocardium. Our objective was to identify cardiac involvement in a Spanish cohort. METHODS: Retrospective multicenter study of patients diagnosed with hATTR with cardiac involvement from Spanish centers. We collected demographic, clinical, and genetic data. RESULTS: A total of 181 patients from 26 centers were included (65.2% men, with a median age at diagnosis of 62 years). The most frequent mutations were Val50Met (67.7%) and Val142Ile (12.4%). The main reason for consultation was extracardiac symptoms (69%), mainly neurological. The mean N-terminal pro-B-type natriuretic peptide level was 2145±3586 pg/mL. The most characteristic electrocardiogram findings were a pseudoinfarct pattern (25.9%) and atrioventricular block (25.3%). Mean ventricular thickness was 15.4±4.1mm. Longitudinal strain was reduced in basal segments by 29.4%. Late diffuse subendocardial enhancement was observed in 58.8%. Perugini grade 2 or 3 uptake was observed in 75% of scintigraphy scans. During follow-up, 24.9% of the patients were admitted for heart failure, 34.3% required a pacemaker, and 31.6% required a liver transplant. One third (32.5%) died during follow-up, mainly due to heart failure (28.8%). The presence of non-Val50Met mutations was associated with a worse prognosis. CONCLUSIONS: HATTR cardiac amyloidosis in Spain shows heterogeneous genetic and clinical involvement. The prognosis is poor, mainly due to cardiac complications. Consequently early diagnosis and treatment are vital.

[High-risk drug use: epidemiological pattern through hair testing in the forensic context]. / Drogas y consumo de alto riesgo: patrón epidemiológico a partir de análisis de cabello en el contexto forense.

OBJECTIVE: The basic sources of information on drug use are epidemiological surveys, although they have some limitations: their results may be conditioned by the lack of veracity of the responses and the sampling method makes it difficult to detect lowprevalence behaviours in target populations. This study aimed to establish the epidemiological pattern of drug use in the population undergoing drug testing in hair, in the framework of judicial investigations, in order to provide an additional approach to the knowledge of high-risk drug use. METHODS: A cross-sectional study on drug use was conducted on the population subjected to drug testing in hair (N=5,292) in the forensic context. Prevalence of cannabis, cocaine, heroin, ketamine, amphetamine (AP), methamphetamine (MA), 3,4-methylenedioxy- methamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxy-N-ethylamphetamine (MDEA) and methadone uses were obtained. Association between drug use and demographics, and trends of prevalence over the period were analysed using the Pearson Chi-square test. Frequency distribution of drug concentrations in hair was obtained and it was assessed in relation to gender and age using the non-parametric Mann-Whitney U and Kruskal-Wallis H methods. RESULTS: During the period 2013-2015, prevalence of cocaine use was particularly high (49%), rating second among the population studied, after cannabis use (54%). Proportions of heroin, methadone, MDMA and amphetamine use ranged from 10% to 18%. There was a significant increase in prevalence of MDMA, heroin and amphetamine use during the period 2013-2015, as well as a significant decrease in methadone use. The rates of cannabis, cocaine and MDMA use were higher in men, whereas methadone use was higher among women. CONCLUSIONS: Cannabis and cocaine are the most frequently abused drugs among the population undergoing drug testing in hair in the framework of judicial investigations over the three-year period, although the proportions of heroin, MDMA and amphetamine users show an increasing trend. Drug use patterns vary according to age and sex, with a decrease in cannabis and MDMA use and an increase in heroin and methadone use as age increased; cannabis, cocaine and MDMA use are more prevalent among men and methadone use among women.

OBJETIVO: Las encuestas epidemiológicas son las fuentes básicas de información sobre el consumo de drogas, aunque presentan algunas limitaciones en este campo: sus resultados pueden verse condicionados por la falta de veracidad de las respuestas y el método de muestreo dificulta la detección de comportamientos de baja prevalencia en las poblaciones diana. El objetivo de esta investigación fue establecer el patrón epidemiológico del consumo de drogas en la población sometida a análisis de drogas en cabello en el marco de investigaciones judiciales, con el fin de aportar una fuente de información adicional al conocimiento del consumo de drogas de alto riesgo. METODOS: Se realizó un estudio transversal de consumo de drogas en la población sometida a análisis de drogas en cabello en el contexto forense (N=5.292). Se obtuvo la prevalencia de consumo de cannabis, cocaína, heroína, ketamina, anfetamina (AP), metanfetamina (MA), 3,4-metilendioxi-metanfetamina (MDMA), 3,4-metilendioxianfetamina (MDA), 3,4-metilendioxi-N-etilamphetamina (MDEA) y metadona. Se analizó la asociación entre el consumo de drogas y los factores demográficos, así como de sus tendencias, mediante la prueba de Chicuadrado de Pearson. Se obtuvo la distribución de frecuencias de las concentraciones de drogas en cabello y se evaluó en relación con el sexo y la edad, utilizando los métodos no paramétricos U de Mann-Whitney y H de Kruskal-Wallis. RESULTADOS: En el periodo 2013-2015, la prevalencia de consumo de cocaína fue particularmente elevada (49%) en la población estudiada, próxima a la de cannabis (54%). Las tasas de consumo de heroína, metadona, MDMA y anfetamina resultaron entre un 10% y mun 18%. Durante el período estudiado, se registró un aumento significativo del consumo de MDMA, heroína y anfetamina, así como una disminución significativa del consumo de metadona. CONCLUSIONES: Cannabis y cocaína son las drogas de abuso más frecuentes entre la población sometida a análisis de drogas en cabello en el marco de investigaciones judiciales en el periodo estudiado, si bien las proporciones de consumidores de heroína, MDMA y anfetamina muestran una tendencia creciente. Los patrones de consumo varían en función de la edad y del sexo, observándose disminución del consumo de cannabis y MDMA e incremento del consumo de heroína y metadona al aumentar la edad. El consumo de cannabis, cocaína y MDMA resulta más prevalente en hombres y el de metadona en mujeres.

Drogas y consumo de alto riesgo: patrón epidemiológico a partir de análisis de cabello en el contexto forense / High-risk drug use: epidemiological pattern through hair testing in the forensic context

OBJETIVO: Las encuestas epidemiológicas son las fuentes básicas de información sobre el consumo de drogas, aunque presentan algunas limitaciones en este campo: sus resultados pueden verse condicionados por la falta de veracidad de las respuestas y el método de muestreo dificulta la detección de comportamientos de baja prevalencia en las poblaciones diana. El objetivo de esta investigación fue establecer el patrón epidemiológico del consumo de drogas en la población sometida a análisis de drogas en cabello en el marco de investigaciones judiciales, con el fin de aportar una fuente de información adicional al conocimiento del consumo de drogas de alto riesgo. MÉTODOS: Se realizó un estudio transversal de consumo de drogas en la población sometida a análisis de drogas en cabello en el contexto forense (N=5.292). Se obtuvo la prevalencia de consumo de cannabis, cocaína, heroína, ketamina, anfetamina (AP), metanfetamina (MA), 3,4-metilendioxi-metanfetamina (MDMA), 3,4-metilendioxianfetamina (MDA), 3,4-metilendioxi-N-etilamphetamina (MDEA) y metadona. Se analizó la asociación entre el consumo de drogas y los factores demográficos, así como de sus tendencias, mediante la prueba de Chicuadrado de Pearson. Se obtuvo la distribución de frecuencias de las concentraciones de drogas en cabello y se evaluó en relación con el sexo y la edad, utilizando los métodos no paramétricos U de Mann-Whitney y H de Kruskal-Wallis. RESULTADOS: En el periodo 2013-2015, la prevalencia de consumo de cocaína fue particularmente elevada (49%) en la población estudiada, próxima a la de cannabis (54%). Las tasas de consumo de heroína, metadona, MDMA y anfetamina resultaron entre un 10% y mun 18%. Durante el período estudiado, se registró un aumento significativo del consumo de MDMA, heroína y anfetamina, así como una disminución significativa del consumo de metadona. CONCLUSIONES: Cannabis y cocaína son las drogas de abuso más frecuentes entre la población sometida a análisis de drogas en cabello en el marco de investigaciones judiciales en el periodo estudiado, si bien las proporciones de consumidores de heroína, MDMA y anfetamina muestran una tendencia creciente. Los patrones de consumo varían en función de la edad y del sexo, observándose disminución del consumo de cannabis y MDMA e incremento del consumo de heroína y metadona al aumentar la edad. El consumo de cannabis, cocaína y MDMA resulta más prevalente en hombres y el de metadona en mujeres

OBJECTIVE: The basic sources of information on drug use are epidemiological surveys, although they have some limitations: their results may be conditioned by the lack of veracity of the responses and the sampling method makes it difficult to detect lowprevalence behaviours in target populations. This study aimed to establish the epidemiological pattern of drug use in the population undergoing drug testing in hair, in the framework of judicial investigations, in order to provide an additional approach to the knowledge of high-risk drug use. METHODS: A cross-sectional study on drug use was conducted on the population subjected to drug testing in hair (N=5,292) in the forensic context. Prevalence of cannabis, cocaine, heroin, ketamine, amphetamine (AP), methamphetamine (MA), 3,4-methylenedioxy- methamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxy-N-ethylamphetamine (MDEA) and methadone uses were obtained. Association between drug use and demographics, and trends of prevalence over the period were analysed using the Pearson Chi-square test. Frequency distribution of drug concentrations in hair was obtained and it was assessed in relation to gender and age using the non-parametric Mann-Whitney U and Kruskal-Wallis H methods. RESULTS: During the period 2013-2015, prevalence of cocaine use was particularly high (49%), rating second among the population studied, after cannabis use (54%). Proportions of heroin, methadone, MDMA and amphetamine use ranged from 10% to 18%. There was a significant increase in prevalence of MDMA, heroin and amphetamine use during the period 2013-2015, as well as a significant decrease in methadone use. The rates of cannabis, cocaine and MDMA use were higher in men, whereas methadone use was higher among women. CONCLUSIONS: Cannabis and cocaine are the most frequently abused drugs among the population undergoing drug testing in hair in the framework of judicial investigations over the three-year period, although the proportions of heroin, MDMA and amphetamine users show an increasing trend. Drug use patterns vary according to age and sex, with a decrease in cannabis and MDMA use and an increase in heroin and methadone use as age increased; cannabis, cocaine and MDMA use are more prevalent among men and methadone use among women

Impact of inosine triphosphatase gene variants on the risk of anemia in HIV/hepatitis C virus-coinfected patients treated for chronic hepatitis C.

The role of rs1127354/rs7270101 alleles at the inosine triphosphatase (ITPA) gene on ribavirin-induced anemia was assessed in 74 patients with hepatitis C virus and human immunodeficiency virus coinfection. Anemia developed in 80% of patients with normal ITPA activity compared with 33% of those with reduced ITPA activity. In contrast, ITPA variants did not influence sustained virological response.

Synthesis and cytotoxic evaluation of 6-(3-pyrazolylpropyl) derivatives of 1,4-naphthohydroquinone-1,4-diacetate.

Several new 6-(3-pyrazolylpropyl) derivatives of 1,4-naphthohydroquinone-1,4-diacetate (NHQ-DA) have been prepared by chemical modifications of the Diels-Alder adduct of alpha-myrcene and 1,4-benzoquinone. All these new compounds and precursors have been evaluated in vitro for their cytotoxicity against cultured human cancer cells of MB-231 breast-adeno carcinoma, A-549 lung carcinoma, and HT-29 colon carcinoma. GI(50) values ranged in and below the micromolar concentration level.

Cytotoxic-antineoplastic derivatives of prenyl-1,2-naphthohydroquinone.

Several new prenyl-1,2-naphthohydroquinone derivatives have been prepared by chemical modifications of Diels-Alder products which were obtained from cycloaddition of alpha-myrcene to 1,2-benzoquinone and then evaluated in vitro for their cytotoxic activity against A-549 lung carcinoma, HT-29 colon carcinoma, and MB-231 breast adeno-carcinoma culture cells. Most of them exhibited GI50 values in the microM-concentration level.

New cytotoxic diterpenylnaphthohydroquinone derivatives obtained from a natural diterpenoid.

Diterpenylquinone/hydroquinone derivatives were prepared through Diels-Alder cycloaddition between natural myrcecommunic acid or its methyl ester and p-benzoquinone (p-BQ), using BF(3).Et(2)O as catalyst or under microwave (Mw) irradiation. Acetyl, methyl and benzyl derivatives of several diterpenylnaphthohydroquinone were prepared from cycloadducts following two basic synthetic strategies, either protection before aromatisation or viceversa. Some of them were further functionalised at the B-ring of the decaline core. Most of the new compounds were evaluated and some of them resulted cytotoxic against several tumour cell lines with IC(50) values under the microM level.

New cytotoxic furoquinones obtained from terpenyl-1,4-naphthoquinones and 1,4-anthracenediones.

A series of new furoterpenyl-1,4-naphtho(anthra)quinones have been prepared via oxidative cyclization of the corresponding 2-hydroxy-3-butenyl-1,4-naphtho(anthra)quinones. Depending on the reaction conditions the 1,2-quinones or the 1,4-quinones were obtained. Several new furo-1,4-anthraquinones were also obtained by condensation of 2,3-dichloroquinones with 1,3-dicarbonyls. The compounds synthesized have been evaluated for their cytotoxicity against neoplastic cell lines, some of them being effective below the micromolar level.

Pathogenic significance of hypertrophic mesothelial cells in peritoneal effluent and ex vivo culture.

The presence of hypertrophic mesothelial cells (HMCs) in peritoneal effluent (PE) has been considered a possible marker for peritoneal sclerosis. We conducted the present study to evaluate if the presence of HMCs in PE or in culture was related to peritoneal function alterations or to the development of sclerosing peritonitis. We prospectively studied 32 new peritoneal dialysis (PD)patients every 4 months, determining the presence of HMCs in culture (completing 129 studies in total). We isolated mesothelial cells from nocturnal PE and cultured them ex vivo in T-25 flasks. Cell morphology was estimated using the May-Grünwald/Giemsa method. We also examined the histories of a large patient group to determine HMCs directly in PE, and we evaluated 4 of those patients (6%) who showed persistent HMCs. In 10 of 32 prospectively studied patients, we found HMCs during the culture phase. The cells appeared in the first evaluation in 4 patients and in subsequent cultures in the remaining 6 patients. Ultrafiltration (UF) and solute transport capacity in the 10 patients were similar to those of patients who did not show HMCs. Demographic parameters were not different between the two groups. None of the prospectively studied patients showed any clinical or peritoneal functional abnormality during the study. Cultures performed after the observation of HMCs showed very poor growth capacity. The evolution of the 4 patients in the historic group occurred as follows: We 1 patient transferred to hemodialysis 2 years after the observation of HMCs. 1 patient died of an unrelated cause after 1 year on PD. 1 patient received a successful kidney graft 5 years after the observation of HMCs. 1 patient developed type I UF failure 10 years after the first observation.

Synthesis, cytotoxicity and antiviral activity of podophyllotoxin analogues modified in the E-ring.

Several podophyllotoxin derivatives modified in the E-ring were prepared and evaluated for their cytotoxicity on four neoplastic cell lines (P-388, A-549, HT-29 and MEL-28) and for their antiherpetic activity against Herpes simplex virus type II. The trimethoxyphenyl moiety was oxidized to ortho-quinone and further condensed with diamines and enamines to form different heterocycles. Most of the compounds maintained their cytotoxicity at the muM level and some of them showed antiherpetic activity.

Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells.

BACKGROUND: During continuous ambulatory peritoneal dialysis, the peritoneum is exposed to bioincompatible dialysis fluids that cause denudation of mesothelial cells and, ultimately, tissue fibrosis and failure of ultrafiltration. However, the mechanism of this process has yet to be elucidated. METHODS: Mesothelial cells isolated from effluents in dialysis fluid from patients undergoing continuous ambulatory peritoneal dialysis were phenotypically characterized by flow cytometry, confocal immunofluorescence, Western blotting, and reverse-transcriptase polymerase chain reaction. These cells were compared with mesothelial cells from omentum and treated with various stimuli in vitro to mimic the transdifferentiation observed during continuous ambulatory peritoneal dialysis. Results were confirmed in vivo by immunohistochemical analysis performed on peritoneal-biopsy specimens. RESULTS: Soon after dialysis is initiated, peritoneal mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype with a progressive loss of epithelial morphology and a decrease in the expression of cytokeratins and E-cadherin through an induction of the transcriptional repressor snail. Mesothelial cells also acquire a migratory phenotype with the up-regulation of expression of alpha2 integrin. In vitro analyses point to wound repair and profibrotic and inflammatory cytokines as factors that initiate mesothelial transdifferentiation. Immunohistochemical studies of peritoneal-biopsy specimens from patients undergoing continuous ambulatory peritoneal dialysis demonstrate the expression of the mesothelial markers intercellular adhesion molecule 1 and cytokeratins in fibroblast-like cells entrapped in the stroma, suggesting that these cells stemmed from local conversion of mesothelial cells. CONCLUSIONS: Our results suggest that mesothelial cells have an active role in the structural and functional alteration of the peritoneum during peritoneal dialysis. The findings suggest potential targets for the design of new dialysis solutions and markers for the monitoring of patients.

Cytotoxic-antineoplastic activity of hydroquinone derivatives.

Several myrcenylhydroquinone derivatives have been evaluated for their cytotoxic activity against three neoplastic cell line cultures and compared with the activity previously observed on other neoplastic systems. Also a new series of this type of compounds has been prepared and the compounds synthesised have been evaluated by their GI(50) values.