¿Es apropiada la aplicación de la nueva ecuación Chronic Kidney Disease Epidemiology Consortium (CKD-EPI 2021) en la población española? / Is the use of the new Chronic Kidney Disease Epidemiology Consortium (CKD-EPI 2021) formula appropriate for the Spanish population?

Introducción Las sociedades estadounidenses de nefrología recomiendan cambiar la ecuación CKD-EPI 2009 por la nueva CKD-EPI 2021, que no incluye el coeficiente de raza, para estimar la tasa de filtrado glomerular (TFGe). Se desconoce cómo podría afectar este cambio a la distribución de la enfermedad renal de la población española predominantemente caucásica. Métodos Se estudiaron dos cohortes de adultos de la provincia de Cádiz, BD-SIDICA (n=264.217 personas) y BD-PANDEMIA (n=64.217), que disponían de mediciones de creatinina plasmática entre 2017 y 2021. Se calcularon los cambios de la TFGe y la consecuente reclasificación en las diferentes categorías de la clasificación KDIGO-2012 al modificar la ecuación CKD-EPI 2009 por la de 2021. Resultados En comparación con la ecuación de 2009, CKD-EPI-21 arrojó una TFGe más alta, con una mediana de 3,8mL/min/1,73m2 (IQR: 2,98-4,48) en BD-SIDICA y de 3,89mL/min/1,73m2 (IQR: 3,05-4,55) en BD-PANDEMIA. Como primera consecuencia, del total de la población, el 15,3% en BD-SIDICA y el 15,1% en BD-PANDEMIA y el 28,1% y el 27,3%, respectivamente, de la población con enfermedad renal (G3-G5), se reclasificó a una categoría de TFGe más alta y ningún sujeto a una más grave. Como segunda consecuencia, la prevalencia de la enfermedad renal disminuyó del 9% al 7,5% en ambas cohortes. Conclusiones Implementar la ecuación CKD-EPI-21 en la población española, predominantemente caucásica, aumentaría la TFGe en una cantidad modesta (mayor en hombres y con mayor edad o TFG) y una proporción importante de la población se clasificaría en una categoría de TFGe superior, con la consiguiente disminución de la prevalencia de la enfermedad renal (AU)

Introduction United States nephrology societies recommend changing from the CKD-EPI 2009 equation to the new CKD-EPI 2021 equation, which does not include the race coefficient, for calculating estimated glomerular filtration rate (eGFR). It is unknown how this change might affect the distribution of kidney disease in the predominantly Caucasian Spanish population. Methods Two databases of adults from the province of Cádiz, DB-SIDICA (n=264,217) and BD-PANDEMIC (n=64,217), that had plasma creatinine measurements recorded between 2017 and 2021 were studied. Changes in eGFR and the consequent reclassification into different categories of the KDIGO2012 classification resulting from substituting the CKD-EPI 2009 equation for the 2021 equation were calculated. Results Compared to the 2009 equation, CKD-EPI 2021 yielded a higher eGFR, with a median of 3.8mL/min/1.73m2 (IQR: 2.98-4.48) in DB-SIDICA and 3.89mL/min/1.73m2 (IQR: 3.05-4.55) in DB-PANDEMIA. The first consequence was that 15.3% of the total population in DB-SIDICA and 15.1% of the total population in DB-PANDEMIA were reclassified into a higher category of eGFR, as were 28.1% and 27.3%, respectively, of the population with CKD (G3-G5); no subjects were classified into the more severe category. The second consequence was that the prevalence of kidney disease decreased from 9% to 7.5% in both cohorts. Conclusions Implementing the CKD-EPI 2021 equation in the Spanish population, which is predominantly Caucasian, would increase eGFR by a modest amount (greater in men and those who are older or have a higher GFR). A significant proportion of the population would be classified into a higher eGFR category, with a consequent decrease in the prevalence of kidney disease (AU)

Is the use of the new Chronic Kidney Disease Epidemiology Consortium (CKD-EPI 2021) formula appropriate for the Spanish population?

INTRODUCTION: United States nephrology societies recommend changing from the CKD-EPI 2009 equation to the new CKD-EPI 2021 equation, which does not include the race coefficient, for calculating estimated glomerular filtration rate (eGFR). It is unknown how this change might affect the distribution of kidney disease in the predominantly Caucasian Spanish population. METHODS: Two databases of adults from the province of Cádiz, DB-SIDICA (N=264,217) and DB-PANDEMIA (N=64,217), that had plasma creatinine measurements recorded between 2017 and 2021 were studied. Changes in eGFR and the consequent reclassification into different categories of the KDIGO 2012 classification resulting from substituting the CKD-EPI 2009 equation for the 2021 equation were calculated. RESULTS: Compared to the 2009 equation, CKD-EPI 2021 yielded a higher eGFR, with a median of 3.8mL/min/1.73m2 (IQR 2.98-4.48) in DB-SIDICA and 3.89mL/min/1.73m2 (IQR 3.05-4.55) in DB-PANDEMIA. The first consequence was that 15.3% of the total population in DB-SIDICA and 15.1% of the total population in DB-PANDEMIA were reclassified into a higher category of eGFR, as were 28.1% and 27.3%, respectively, of the population with CKD (G3-G5); no subjects were classified into the more severe category. The second consequence was that the prevalence of kidney disease decreased from 9% to 7.5% in both cohorts. CONCLUSIONS: Implementing the CKD-EPI 2021 equation in the Spanish population, which is predominantly Caucasian, would increase eGFR by a modest amount (greater in men and those who are older or have a higher GFR). A significant proportion of the population would be classified into a higher eGFR category, with a consequent decrease in the prevalence of kidney disease.

Liderazgo de la mujer en la investigación clínica: estudio observacional retrospectivo durante dos décadas en España / Women's leadership in clinical research: A retrospective observational study over two decades in Spain

Antecedentes y objetivo Los datos disponibles avalan las diferencias por género en el liderazgo de las investigaciones clínicas (IC). Este estudio analiza en qué medida las mujeres lideran estas investigaciones. Materiales y métodos Estudio observacional retrospectivo en un hospital universitario terciario asociado a uno de los institutos de investigación sanitaria más importantes de España. Analizamos los investigadores principales (IP) por género (2001-2020). Variable principal: proporción de IC lideradas por mujeres durante el período de estudio. Variables secundarias: diferencias de IP por género según el tipo de estudio: ensayos clínicos (EC) o estudios de no-intervención (ENI) y según la financiación. Fuentes de datos: registros del Comité de Ética en Investigación con medicamentos (CEIm) y del Departamento de Recursos Humanos. Resultados Durante el estudio, el CEIm aprobó 8.466 protocolos; el 52% (4.408/8.466) fueron EC y el resto, ENI. Las mujeres lideraron un 39,7% (3.360/8.466) del total. La brecha de género se observó principalmente en EC: las mujeres fueron IP de un 31,5% de ellos (1.391/4.408) y de un 48,5% (1.969/4.058) de los ENI. Ello a pesar de la tendencia creciente del número de facultativas. Los estudios de financiación privada fueron más comúnmente liderados por hombres. Conclusiones Nuestros resultados demuestran que existe una infrarrepresentación de las mujeres en puestos de liderazgo en la investigación, principalmente en aquellos con financiación privada. Este estudio refuerza la idea de que todavía queda un largo camino por recorrer en este campo. Se necesitan más estudios para la identificación de diferencias existentes que permitan implantar cambios a nivel institucional y cultural que promuevan la igualdad de género en el ámbito de la investigación clínica (AU)

Background and objective Available data support differences by gender in the leadership of clinical investigations (CI). This study analyzes to what extent women lead these investigations. Materials and method Observational-retrospective study in a tertiary university hospital associated with one of the most important health research institutes in Spain. We analyzed the principal investigators (PI) by gender from 2001 to 2020. Main outcome: proportion of CI led by female doctors (FD) during the study period. Secondary outcomes: differences in PI by gender according to the type of study: clinical trials (CT) or non-interventional-researches (NIR) and according to type of funding. Data sources: Research Ethics Committee (REC) and Human Resources Department registries. Result During the study, the REC approved 8,466 protocols, 52% (4,408/8,466) were EC, the rest were NIR. Women led 39.7% (3,360/8,466) of the total. The gender gap was observed mainly in EC: FD were IP of 31.5% of them (1,391/4,408) and 48.5% (1,969/4,058) of NIR. This despite the increasing trend in the number of FD staff. By type of funding, when the studies were supported by private sector there was a wider gap markedly unfavorable for women. Conclusions Our results show that there is underrepresentation of women in research leadership, mainly those with private financing. This study reinforces the idea that there is still a long way to go in this field. More studies are necessary to identify the existing differences that allow the implementation of actions at the institutional and cultural level that promote gender equality in the field of clinical research (AU)

Women's leadership in clinical research: A retrospective observational study over two decades in Spain.

BACKGROUND AND OBJECTIVE: Available data support differences by gender in the leadership of clinical investigations (CI). This study analyzes to what extent women lead these investigations. MATERIALS AND METHODS: Observational-retrospective study in a tertiary university hospital associated with one of the most important health research institutes in Spain. We analyzed the principal investigators (PI) by gender from 2001 to 2020. MAIN OUTCOME: proportion of CI led by female doctors (FD) during the study period. SECONDARY OUTCOMES: differences in PI by gender according to the type of study: clinical trials (CT) or non-interventional-researches (NIR) and according to type of funding. DATA SOURCES: Research Ethics Committee (REC) and Human Resources Department registries. RESULTS: During the study, the REC approved 8466 protocols, 52% (4408/8466) were EC, the rest were NIR. Women led 39.7% (3360/8466) of the total. The gender gap was observed mainly in EC: FD were IP of 31.5% of them (1391/4408) and 48.5% (1969/4058) of NIR. This despite the increasing trend in the number of FD staff. By type of funding, when the studies were supported by private sector there was a wider gap markedly unfavorable for women. CONCLUSIONS: Our results show that there is underrepresentation of women in research leadership, mainly those with private financing. This study reinforces the idea that there is still a long way to go in this field. More studies are necessary to identify the existing differences that allow the implementation of actions at the institutional and cultural level that promote gender equality in the field of clinical research.

Atención farmacéutica domiciliaria como servicio remunerado en Gipuzkoa / Home-based pharmaceutical care as a paid service in Gipuzkoa

JUSTIFICACION: la asistencia sanitaria a domicilio es una de las estrategias que impulsan las administraciones sanitarias para pacientes pluripatológicos que viven en sus domicilios y que debido a su vulnerabilidad no pueden desplazarse a los centros sanitarios. El programa piloto “Hauskor” liderado por la Fundación Hurkoa, junto con la coordinación del Colegio Oficial de Farmacéuticos de Gipuzkoa (COFG), incluye farmacias comunitarias (FC) de Gipuzkoa que participan en la gestión de la medicación de pacientes en fragilidad social.OBJETIVO: implementar un servicio de atención farmacéutica domiciliaria (AFD) remunerado a pacientes frágiles incluidos en el programa “Hauskor” de la Fundación Hurkoa.MATERIAL Y METODOS: se diseñó un programa de AFD a pacientes frágiles entre la Fundación Hurkoa y el COFG, consistente en una revisión del botiquín, revisión del uso de la medicación a domicilio e intervenciones dirigidas en función de las incidencias detectadas, empleando sistemas personalizados de dosificación en aquellos pacientes que lo requirieran. En el programa participaron 5 FC de los municipios de Pasaia y Azkoitia de Gipuzkoa, que intervinieron sobre 6 pacientes. Tras los buenos resultados en salud y la buena satisfacción reportada por los pacientes, se elaboró un informe al programa “Hauskor” para lograr la remuneración del servicio a las farmacias participantes.RESULTADOS: a lo largo del año 2021, las farmacias participantes, prestaron el servicio a 6 pacientes. En cuanto a los resultados clínicos, destacar que en todas las revisiones de botiquín se encontraron medicamentos caducados o no utilizados y se retiraron entre 1-2 medicamentos a todos los pacientes. La remuneración de este nuevo servicio se obtuvo del programa “Hauskor”, de ayudas para apoyar las actividades de innovación, investigación y desarrollo social de la Diputación Foral de Gipuzkoa. (AU)

Suitability of therapeutic effort in paediatric intensive care units: Opinion and attitude of professionals. / Adecuación del esfuerzo terapéutico en unidades de cuidados intensivos pediátricos: opinión y actitud de los profesionales.

OBJECTIVE: To determine the opinion and describe the attitude of different health professionals on suitability of therapeutic effort. METHOD: Multi-centre, cross-sectional observational study carried out with nurses and doctors who work in the paediatric intensive care units of four hospitals in the Madrid region. A self-administered questionnaire, previously piloted to assess its viability, was used and a sealed box was set up at the nursing station to hand it in. The analysis was performed using SPSS 21.0 software. RESULTS: The 98.9% of the respondents were in favour of suitability of therapeutic effort. Doctors consider that the decision is made with the agreement of the multidisciplinary staff and the child's parents (48.8%). Of the nurses, 51.1% believe that the decision is made by agreement with the doctors and parents. Of the nurses, 65.5% state that they are never asked about decision-making for their patients. Of the doctors, 75% are always or almost always asked. Fifty-seven percent of the nurses and 83% of the doctors feel capable of making decisions about suitability of therapeutic effort. Of the professionals, 77.2% believe that suitability is used less often than required. CONCLUSIONS: There are differences between doctors and nurses both in the perception of the decision-making model and in the way to proceed. Professionals seem not to follow any protocols or circuits in the decision-making process.

A novel Carcinoembryonic Antigen (CEA)-Targeted Trimeric Immunotoxin shows significantly enhanced Antitumor Activity in Human Colorectal Cancer Xenografts.

Immunotoxins are chimeric molecules, which combine antibody specificity to recognize and bind with high-affinity tumor-associated antigens (TAA) with the potency of the enzymatic activity of a toxin, in order to induce the death of target cells. Current immunotoxins present some limitations for cancer therapy, driving the need to develop new prototypes with optimized properties. Herein we describe the production, purification and characterization of two new immunotoxins based on the gene fusion of the anti-carcinoembryonic antigen (CEA) single-chain variable fragment (scFv) antibody MFE23 to α-sarcin, a potent fungal ribotoxin. One construct corresponds to a conventional monomeric single-chain immunotoxin design (IMTXCEAαS), while the other one takes advantage of the trimerbody technology and exhibits a novel trimeric format (IMTXTRICEAαS) with enhanced properties compared with their monomeric counterparts, including size, functional affinity and biodistribution, which endow them with an improved tumor targeting capacity. Our results show the highly specific cytotoxic activity of both immunotoxins in vitro, which was enhanced in the trimeric format compared to the monomeric version. Moreover, the trimeric immunotoxin also exhibited superior antitumor activity in vivo in mice bearing human colorectal cancer xenografts. Therefore, trimeric immunotoxins represent a further step in the development of next-generation therapeutic immunotoxins.

Prevención y tratamiento de la enfermedad infecciosa en personas con diabetes / Prevention and treatment of infectious diseases in diabetic patients

Es conocida la relación bidireccional entre enfermedades infecciosas y diabetes. Las personas con diabetes tienen mayor riesgo de presentar enfermedades infecciosas, pudiendo ser estas de mayor severidad; y por otro lado, las enfermedades infecciosas desestabilizan el control metabólico de las personas con diabetes. El envejecimiento importante de la población es debido en parte al aumento de la supervivencia de pacientes con enfermedades crónicas, entre ellas la diabetes. Mejorar la prevención de enfermedades infecciosas en este grupo de población podría disminuir las complicaciones de estas enfermedades, así como las consecuencias de la desestabilización de la enfermedad de base (morbilidad, discapacidad, ingresos hospitalarios, costes sanitarios, tasas de mortalidad), mejorando además la calidad de vida de las personas con diabetes. La presente revisión expone el tratamiento de las enfermedades infecciosas en personas con diabetes y el abordaje de las enfermedades inmunoprevenibles con las vacunas recomendadas en la actualidad

The bidirectional relationship between infectious diseases and diabetes is well-known. On the one hand, diabetes patients are at a higher risk of presenting with infectious diseases, possibly with more severity, and on the other hand, infectious diseases impair metabolic control in patients with diabetes. Population ageing arises partly due to an increased survival rate in chronic diseases, of which diabetes is amongst them. Improving infectious disease prevention could reduce complications arising from the former diseases, consequences of decompensated diabetes condition (morbidity, incapacity, hospital admissions, healthcare costs, and mortality rates) and result in improved quality of life in patients with diabetes. The current review presents the treatment of infectious diseases in patients with diabetes and the dealing with immuno-preventable diseases with the currently advised vaccinations

[Prevention and treatment of infectious diseases in diabetic patients]. / Prevención y tratamiento de la enfermedad infecciosa en personas con diabetes.

The bidirectional relationship between infectious diseases and diabetes is well-known. On the one hand, diabetes patients are at a higher risk of presenting with infectious diseases, possibly with more severity, and on the other hand, infectious diseases impair metabolic control in patients with diabetes. Population ageing arises partly due to an increased survival rate in chronic diseases, of which diabetes is amongst them. Improving infectious disease prevention could reduce complications arising from the former diseases, consequences of decompensated diabetes condition (morbidity, incapacity, hospital admissions, healthcare costs, and mortality rates) and result in improved quality of life in patients with diabetes. The current review presents the treatment of infectious diseases in patients with diabetes and the dealing with immuno-preventable diseases with the currently advised vaccinations.

Alcohol binge disrupts the rat intestinal barrier: the partial protective role of oleoylethanolamide.

BACKGROUND AND PURPOSE: Chronic alcohol consumption alters the gut-brain axis, but little is known about alcohol binge episodes on the functioning of the intestinal barrier. We investigated the influence of ethanol binges on bacterial translocation, gut inflammation and immunity, and tight junction (TJ) structure and the ability of the biolipid oleoylethanolamide (OEA) to prevent ethanol binge-induced intestinal barrier dysfunction. EXPERIMENTAL APPROACH: OEA was injected i.p. before repeated ethanol administration by oral gavage. Plasma, spleen, liver and mesenteric lymph nodes (MLN) were collected in sterile conditions for determination of bacterial load. Immune/inflammatory parameters, TJ proteins and apoptotic markers were determined in colonic tissue by RT-PCR and Western blotting. TJ ultrastructure was examined by transmission electron microscopy. KEY RESULTS: Ethanol binges induced bacterial translocation to the MLN (mainly) and spleen. Colonic tissues showed signs of inflammation, and activation of innate (Toll-like receptor-4) and adaptive (IgA) immune systems and TJ proteins (occludin and claudin-3) were decreased after ethanol binges. Pretreatment with OEA reduced intestinal inflammation and immune activation and partially preserved the TJ structure affected by alcohol binges but had no effect on alcohol-induced apoptosis. Ultrastructural analyses of colonic TJs revealed dilated TJs in all ethanol groups, with less electron-dense material in non-pretreated rats. The protective effects of i.p. OEA did not reduce bacterial translocation to the MLN. However, intragastric OEA administration significantly reduced plasma LPS levels and bacterial translocation to the MLN. CONCLUSION AND IMPLICATIONS: OEA-based pharmacotherapies could potentially be useful to treat disorders characterized by intestinal barrier dysfunction, including alcohol abuse.

La secuenciación masiva (NGS) como método diagnóstico en la enfermedad de Stargardt / Next generation sequencing in the diagnosis of Stargardt's disease

Introducción: La enfermedad de Stargardt es la maculopatía más frecuente en la edad infantil y adulta. Presenta un origen genético por afectación principalmente del gen ABCA4 con herencia autosómica recesiva. Se trata de un gen con características especiales por su gran tamaño y comportamiento, mostrando una elevada tasa de mutaciones. La aparición, desarrollo y accesibilidad económica de las técnicas de secuenciación masiva permiten realizar el diagnóstico genético de la enfermedad de Stargardt. Pacientes y métodos: Se presentan 2 casos clínicos diagnosticados genéticamente de enfermedad de Stargardt mediante la realización de un panel de secuenciación masiva de 298 genes. Resultados: Los pacientes presentaban un fenotipo de maculopatía de ojo de buey con ausencia de flecks y las siguientes mutaciones: c.G5882A:p.Gly1961Glu y c.C3056T:p.T1019M para el caso 1; c.G5882A:p.Gly1961Glu y c.287del:p.Asn96Thrfs·19 para el caso 2. Ambos pacientes comparten la mutación c.G588A:2p.Gly1961Glu que explica su fenotipo similar característico. Conclusiones: La secuenciación masiva es especialmente útil en la enfermedad de Stargardt, pues el gen ABCA4 presenta un gran tamaño y elevada heterogeneidad polimórfica, que se traduce en una amplia variabilidad clínica (AU)

Introduction: Stargardt's disease is the most frequent form of inherited macular dystrophy in children and adults. It is a genetic eye disorder caused by mutations in ABCA4 gene with an autosomal recessive inheritance. ABCA4 is a very polymorphic and large gene containing 50 exons. The development of next generation sequencing (NGS) can be used for the genetic diagnosis of this disease. Patients and methods: A report is presented on two patients with a clinical diagnosis of Stargardt's disease whose genetic confirmation was performed by a NGS panel of 298 genes. Results: Clinically, the patients showed bull's eye maculopathy and absence of flecks, and genetically they shared the Gly1961Glu mutation that could explain their common phenotype, together with c.C3056T:p.T1019M for case 1, and c.287del:p.Asn96Thrfs·19 for case 2. Conclusions: NGS is particularly useful in the diagnosis of Stargardt's disease as ABCA4 is a large gene with a high allelic heterogeneity that causes a wide range of clinical manifestations (AU)

mTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review.

Smith-Kingsmore syndrome (SKS) OMIM #616638, also known as MINDS syndrome (ORPHA 457485), is a rare autosomal dominant disorder reported so far in 23 patients. SKS is characterized by intellectual disability, macrocephaly/hemi/megalencephaly, and seizures. It is also associated with a pattern of facial dysmorphology and other non-neurological features. Germline or mosaic mutations of the mTOR gene have been detected in all patients. The mTOR gene is a key regulator of cell growth, cell proliferation, protein synthesis and synaptic plasticity, and the mTOR pathway (PI3K-AKT-mTOR) is highly regulated and critical for cell survival and apoptosis. Mutations in different genes in this pathway result in known rare diseases implicated in hemi/megalencephaly with epilepsy, as the tuberous sclerosis complex caused by mutations in TSC1 and TSC2, or the PIK3CA-related overgrowth spectrum (PROS). We here present 4 new cases of SKS, review all clinical and molecular aspects of this disorder, as well as some characteristics of the patients with only brain mTOR somatic mutations.

Randomised crossover trial showed that using breast milk or sucrose provided the same analgesic effect in preterm infants of at least 28 weeks.

AIM: Repeated, ongoing exposure to pain influences the growth, cognitive and motor functions, behaviour, personality and neurodevelopment of preterm infants. We compared the analgesic effects of expressed breast milk (EBM) and 24% oral sucrose on preterm neonates during venipuncture. METHODS: This multicentre randomised, noninferiority, crossover trial focused on five neonatal university units in Madrid, Spain, from October 2013 to October 2014. It comprised 66 preterm infants born at less than 37 weeks and randomly split into two groups. They received either EBM or sucrose two minutes before venepuncture, together with nonnutritive sucking and swaddling, then the opposite procedure at a later point. Pain was measured with the premature infant pain profile (PIPP) and crying was also measured. RESULTS: There were no statistically significant differences between the groups. The PIPP scores were seven (4-9) with breast milk and six (4-8.25) with sucrose (p = 0.28). The 11 infants born at under 28 weeks of age showed higher median scores of nine (9-14) for breast milk and four (4-7) for sucrose (p = 0.009). CONCLUSION: EBM and 24% sucrose had the same analgesic effect during venipuncture in most of the preterm neonates, but sucrose worked better in extremely preterm infants.

Next generation sequencing in the diagnosis of Stargardt's disease. / La secuenciación masiva (NGS) como método diagnóstico en la enfermedad de Stargardt.

INTRODUCTION: Stargardt's disease is the most frequent form of inherited macular dystrophy in children and adults. It is a genetic eye disorder caused by mutations in ABCA4 gene with an autosomal recessive inheritance. ABCA4 is a very polymorphic and large gene containing 50 exons. The development of next generation sequencing (NGS) can be used for the genetic diagnosis of this disease. PATIENTS AND METHODS: A report is presented on two patients with a clinical diagnosis of Stargardt's disease whose genetic confirmation was performed by a NGS panel of 298 genes. RESULTS: Clinically, the patients showed bull's eye maculopathy and absence of flecks, and genetically they shared the Gly1961Glu mutation that could explain their common phenotype, together with c.C3056T:p.T1019M for case 1, and c.287del:p.Asn96Thrfs*19 for case 2. CONCLUSIONS: NGS is particularly useful in the diagnosis of Stargardt's disease as ABCA4 is a large gene with a high allelic heterogeneity that causes a wide range of clinical manifestations.

Pharmacogenetic biomarkers of response in Crohn's disease.

Crohn's disease (CD) is a chronic condition, which affects the immune system. It can also affect any part of the digestive tract and be associated with external manifestations. The causes of the disease remain unknown, although it seems to be the result of a combination of factors, such as genetic predisposition, environment, lifestyle and the composition of the microbiota, among others. The treatment protocol begins with a change in eating and smoking habits, and is continued with different lines of treatment, including corticosteroids, immunomodulators and biologic therapy (infliximab and adalimumab), which have shown differences in response among patients, especially with biologic treatment. Several studies have considered the possibility that these differences in response are caused by the genetic variability of patients. Many genes have been investigated as potential predictors of response to biological drugs, such as ADAM17, ATG16L1, EMSY, CASP9, CCNY, CNTN5, FASLG, FCGR, NOD2, PTGER4, IL13, IL1B, IL27, IL11, IL17F, TNF and TNFR genes. In this review, we will gather the information on influence of gene polymorphisms investigated to date on response to biological drugs in CD patients.

Clinicobiological features and prognostic impact of diffuse large B-cell lymphoma component in the outcome of patients with previously untreated follicular lymphoma.

BACKGROUND: The co-existence at diagnosis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) components (FL/DLBCL) has been considered a transformed lymphoma and accordingly treated although clinicobiological information on these patients is scarce. The aim of this study was to analyze the initial features and outcome of FL/DLBCL patients in the rituximab era. PATIENTS AND METHODS: All patients consecutively diagnosed at a single institution with FL/DLBCL (n = 40), as well as those with pure FL (n = 328) or de novo DLBCL (n = 510) as controls. RESULTS: The proportion of the DLBCL component was highly variable (median 50%). In 29 FL/DLBCL cases analyzed, the cell of origin was GCB in 86%, ABC in 10% and unclassifiable in 4%. NOTCH1-2 was mutated in 10% of these cases. The proportion of DLBCL component did not impact on overall survival (OS). Regarding initial characteristics, patients with FL/DLBCL were closer to FL in terms of primary nodal origin, good performance status and advanced stage, whereas the other features were intermediate between FL and DLBCL. FL/DLBCL patients were treated as DLBCL with no further intensification. Complete response and primary refractory rates were 65% and 20%, respectively, with these figures being similar to DLBCL and worse than FL. Progression-free survival and OS were intermediate between FL and DLBCL (5-year OS: 85%, 73% and 63% for FL, FL/DLBCL and DLBCL, respectively). FL/DLBCL histology did not reach independent prognostic value for OS in the multivariate analyses. CONCLUSIONS: The outcome of FL/DLBCL patients is not worse than that of de novo DLBCL. These cases should be treated with immunochemotherapy as DLBCL, but intensification with ASCT may not be necessary. The biological insights of FL/DLBCL warrants further genetic and molecular studies.

Broadening the phenotypic spectrum of POP1-skeletal dysplasias: identification of POP1 mutations in a mild and severe skeletal dysplasia.

Processing of Precursor 1 (POP1) is a large protein common to the ribonuclease-mitochondrial RNA processing (RNase-MRP) and RNase-P (RMRP) endoribonucleoprotein complexes. Although its precise function is unknown, it appears to participate in the assembly or stability of both complexes. Numerous RMRP mutations have been reported in individuals with cartilage-hair hypoplasia (CHH) but, to date, only three POP1 mutations have been described in two families with features similar to anauxetic dysplasia (AD). We present two further individuals, one with severe short stature and a relatively mild skeletal dysplasia and another in whom AD was suspected. Biallelic POP1 mutations were identified in both. A missense mutation and a novel single base deletion were detected in proband 1, p.[Pro582Ser]:[Glu870fs*5]. Markedly reduced abundance of RMRP and elevated levels of pre5.8s rRNA was observed. In proband 2, a homozygous novel POP1 mutation was identified, p.[(Asp511Tyr)];[(Asp511Tyr)]. These two individuals show the phenotypic extremes in the clinical presentation of POP1-dysplasias. Although CHH and other skeletal dysplasias caused by mutations in RMRP or POP1 are commonly cited as ribosomal biogenesis disorders, recent studies question this assumption. We discuss the past and present knowledge about the function of the RMRP complex in skeletal development.