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B-cell lymphoma 2 (BCL2)-type proteins are key regulators of the intrinsic or mitochondrial pathway for apoptosis. Since escape from apoptosis is one the main ‘hallmarks of cancer’, BCL2 inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL). Multiple clinical trials have shown efficacy of these agents in patients with relapsed/refractory disease with a favorable toxicity profile. Moreover, some clinical trials indicate that combination with monoclonal antibodies and other novel agents may enhance their effect.

La leucemia linfocítica crónica (LLC) es una proliferación de linfocitos B maduros que constituye una de las neoplasias hematológicas más prevalentes. Su tratamiento ha evolucionado en las últimas décadas hasta considerarse la inmunoquimioterapia a base de fludarabina, ciclofosfamida y rituximab el tratamiento de elección en pacientes de riesgo estándar y con buena situación funcional. Sin embargo, la caracterización de subgrupos biológicos de alto riesgo y la presentación de esta enfermedad en pacientes de edad avanzada y/o con comorbilidad ha llevado en los últimos años al desarrollo y aprobación de tratamientos dirigidos, especialmente los inhibidores del receptor del linfocito B. La presente revisión repasa las estrategias terapéuticas convencionales y se centra en las nuevas moléculas que ya constituyen elementos prometedores del actual panorama terapéutico de la LLC.

Traditionally, the uncertainty models for segments and lines and positional accuracy assessment methods based on lines have worked with 2D elements. But the increasing availability of 3D data leads us to conjecture the need to adapt existing models and methods for this type of data. This paper gathers for the first time in a single paper the uncertainty models for segments and lines and positional accuracy assessment methods based on lines, incorporating the 3D case. Thus, this paper is intended as a reference document for those readers who are interested in this field.

El síndrome del folículo vacío es una situación en la cual, repetidamente, no se recuperan ovocitos durante la punción-aspiración folicular. Existen 2 tipos de síndrome del folículo vacío: el falso y el genuino. Se presenta el caso clínico de una paciente de 38 años con esterilidad primaria de un año de evolución. Ante un estudio básico de esterilidad normal, se realizaron 4 ciclos de IAC, que resultaron fallidos. Se decidió realizar FIV-ICSI, llevándose a cabo un total de 3 ciclos; el primero, protocolo de estimulación con análogo largo, y los ciclos restantes, protocolo de estimulación con antagonista. En todos los casos se constató la ausencia de errores en la medicación y unos niveles de gonadotropina coriónica humana óptimos. Se llega al diagnóstico de síndrome del folículo vacío genuino, pues a pesar de obtener un desarrollo folicular y niveles adecuados de gonadotropina coriónica humana prepunción, no se obtienen ovocitos durante la misma. La ovodonación actualmente es la mejor alternativa.

To analyse the occupational safety measures used by clinical embryologists and their relationship with conditions in the workplace.

Iron deficiency in congestive heart failure (CHF), with or without concomitant anaemia, is associated with health-related quality of life, NYHA functional class, and exercise capacity. Prospective, randomised studies have demonstrated that correcting iron deficiency improves the quality of life and functional status of patients with CHF, including those who do not have anaemia.

La obesidad está reconocida como enfermedad crónica que influye en múltiples patologías y puede producir problemas de fertilidad y malos resultados en técnicas de reproducción asistida. Así se comprueba en las pacientes tratadas en nuestra Unidad de Reproducción cuando se asigna el punto de corte de índice de masa corporal (IMC) en 32.

In this study we describe the adaptation of several 2D positional control methodologies based on linear elements to 3D. The selected methods have been used previously in several studies for controlling different kinds of lines and cartographic products, but always in a planimetric way. This study analyses the consequences of the inclusion of the heights in these methods by adapting the processes of calculation to the Z component. The methods to be adapted have been selected from the literature and are related to those based on calculations of distances and areas. The proposed methodology is applied to a real case, more concretely to a road extracted from two official databases in Spain, in order to check it and as a preliminary test for performing future 3D positional controls using these methods.

La diabetes es una de las complicaciones metabólicas más frecuentes de la gestación y se asocia a un incremento del riesgo de morbimortalidad maternal y fetal, que pueden evitarse y/o reducirse con un adecuado control. En la diabetes pregestacional, la preparación específica previa a la gestación es indispensable para intentar conseguir un control glucémico lo más próximo a la normalidad, evaluar complicaciones y revisar las pautas de tratamientos farmacológicos. En el caso de la diabetes gestacional, el tratamiento de esta entidad ha demostrado disminuir la tasa de complicaciones maternas y perinatales, por lo que su diagnóstico está justificado. En relación con la estrategia diagnóstica, ante la falta de consenso y la controversia desatada tras la aparición de los nuevos criterios IADPSG, el grupo ha decidido mantener la misma estrategia diagnóstica en 2 pasos y con los mismos puntos de corte hasta disponer de datos sólidos que avalen la introducción de nuevos criterios.

In this paper, we use control methodologies based on lines to detect the type of positional errors which affect a spatial database (SDB) and more concretely the presence of systematic errors. The methodology involves determination of the displacement vectors between the lines and a graphical and statistical study of the components obtained. The graphical analysis enables the detection of spatial patterns of displacement; the presence or absence of systematic errors is then confirmed by statistical analysis. We have applied this method to detect systematic errors on a set of lines with introduced displacements, rotations and scale changes. The results show the viability of the method. All the bias effects introduced were detected, both qualitatively and quantitatively. The detection method has the potential to minimize the effects of such displacements in the SDBs.

Nadeu: Janssen: Honoraria. Giné:Gilead: Research Funding; Janssen: Research Funding; Roche: Research Funding. Armando:Janssen: Research Funding; Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

La hipercolesterolemia familiar y la apo B-100 defectuosa familiar resultan fenotípicamente indistinguibles. Hoy día es posible diferenciarlas mediante la realización de un análisis genético.

We have identified a mutation (-49C>T) in the low-density lipoprotein receptor (LDLR) gene in a Spanish familial hypercholesterolemia (FH) patient. The mutation maps within repeat 3 of the LDLR gene promoter. This region binds Sp1 and collaborates with repeat 2 in the regulation of LDLR gene by sterols. To evaluate whether the mutation influenced the activity of the promoter, luciferase reporter plasmids containing 296 bp of the proximal promoter region were constructed. In transient transfection assays in HepG2 cells, the mutation resulted in an 80% reduction of promoter activity. Also, gel-shift assays demonstrated that the mutation severely affects Sp1 binding. However, the mutated promoter still retains the ability to respond to low sterol concentrations. As the analysis of the LDLR gene did not reveal any other changes, we conclude that the -49C>T mutation is the cause of FH in the patient. The analysis of the proband's pedigree indicated that not all the members of the family having the mutation disclose a FH phenotype.These results support the view that factors other than the presence of the mutation are important in the determination of the clinical phenotype in FH.

Background Type III hyperlipoproteinemia is characterized by the accumulation of chylomicron and very low density lipoprotein (VLDL) remnants. Individuals with this disorder have a high risk of premature atherosclerosis, and hypolipidemic drugs are useful in their management. Methods We compared, in a double-blind, placebo-controlled, randomized crossed study, the effects of gemfibrozil (1200 mg/day) and simvastatin (20 mg/day) on lipids, apolipoprotein AI, apolipoprotein B, and apolipoprotein E and on lipids and apolipoprotein B content in VLDL, intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in 10 patients with type III hyperlipoproteinemia. Results Levels of total cholesterol, VLDL cholesterol, IDL cholesterol, and apolipoprotein B decreased with both drugs. Larger reductions in triglycerides (109 +/- 28.2 mg/dL, P = .005), VLDL cholesterol (24.7 +/- 10.9 mg/dL, P = .05), and VLDL triglycerides (86.3 +/- 20.2 mg/dL, P = .003) were obtained with gemfibrozil compared with simvastatin. LDL cholesterol reduction was more effective with simvastatin than with gemfibrozil (44.3 +/- 17.1 mg/dL, P = .03). HDL cholesterol after gemfibrozil was 5.71 +/- 2.37 mg/dL higher than after simvastatin. Conclusions In patients with type III hyperlipoproteinemia gemfibrozil is more effective in reducing total triglyceride and VLDL lipid levels than simvastatin, and simvastatin is better in reducing LDL cholesterol than gemfibrozil is. IDL and apolipoprotein E levels were reduced similarly with both drugs. (Am Heart J 1999;138:156-62.)

Objective. To investigate the frequency of lumbosacral pains and sacroiliitis as late sequela of severe pelvic inflammatory disease (PID) confirmed by laparoscopy or laparotomy.Design. The sacroiliac joints were examined radiographically and scintigraphically to search for signs of reactive sacroiliitis.Setting. Department of Obstetrics and Gynecology, Hospital General Virgen de las Nieves, Granada, Spain.Patients. Thirty-five out of 70 women admitted with severe clinical symptoms of PID during a five-year period. PID was confirmed by laparoscopy or laparotomy.Measurements. The sacroiliac joints were examined radiographically, and bone scintigraphic studies of the pelvic girdle were performed with technetium labelled pyrophosphate.Results. Twenty out of 35 patients reported lumbosacral pain. The bone scintigraphic findings were positive for sacroiliitis in 18 out of 33 patients (54.6%), and the radiographic findings were positive in 11 women (33.3%).Conclusions. Patients with previous severe clinical PID complaining of lumbosacral pains may be offered a bone scintigraphy, a sensitive procedure using low-dose radiation, to search for early signs of reactive sacroiliitis.

Objective.To investigate the frequency of lumbosacral pains and sacroiliitis as late sequela of severe pelvic inflammatory disease (PID) confirmed by laparoscopy or laparotomy.Design.The sacroiliac joints were examined radiographically and scintigraphically to search for signs of reactive sacroiliitis.Setting.Department of Obstetrics and Gynecology, Hospital General Virgen de las Nieves, Granada, Spain.Patients.Thirty-five out of 70 women admitted with severe clinical symptoms of PID during a five-year period. PID was confirmed by laparoscopy or laparotomy.Measurements.The sacroiliac joints were examined radiographically, and bone scintigraphic studies of the pelvic girdle were performed with 99technetium labelled pyrophosphate.Results.Twenty out of 35 patients reported lumbosacral pain. The bone scintigraphic findings were positive for sacroiliitis in 18 out of 33 patients (54.6), and the radiographic findings were positive in 11 women (33.3).Conclusions.Patients with previous severe clinical PID complaining of lumbosacral pains may be offered a bone scintigraphy, a sensitive procedure using low-dose radiation, to search for early signs of reactive sacroiliitis.

OBJECTIVE: To determine the serum levels of FSH, LH, PRL, estradiol, progesterone and testosterone in umbilical vein blood in a group of normal neonates. METHOD: Umbilical vein blood was obtained for serum analyses from 52 newborns (25 females and 27 males) in the Maternity of the Hospital Regional Virgen de las Nieves, Granada (Spain) and means were compared with Student's t-test. RESULT: Mean values of prolactin, estradiol and progesterone were similar in both sexes. The levels of gonadotropins in umbilical vein blood found were significantly higher in newborn males than in females (P < 0.001 for LH, P < 0.007 for FSH). Testosterone levels were higher in male neonates than in females (P < 0.004). CONCLUSION: Our data reflect the dynamic state of male fetal endocrinological status in comparison to female fetuses, and strongly suggest that the mechanisms of hormonal regulation differ in the two sexes.

This study was designed to investigate the lipidic profile of fibrocystic breast disease. The study entailed measuring total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), very low-density lipoprotein-cholesterol (VLDL-C) and triglyceride levels in the serum of 50 women with fibrocystic breast disease without macrocysts, and in the serum and breast cyst fluid of 60 women with fibrocystic breast disease and macrocysts. The relationships between the lipids analyzed in the cyst fluid and intracystic estradiol, progesterone, dehydroepiandrosterone sulfate, testosterone and 17α-hydroxyprogesterone were studied. No differences were found for serum lipid levels between the two groups of patients. The levels of total cholesterol and HDL-C were found to be significantly higher, and the levels of triglycerides and VLDL- C significantly lower in breast cyst fluid compared to serum. In cysts with high potassium concentrations, we found a higher concentration of cholesterol and HDL-C and a lower concentration of LDL-C than in cysts with a potassium/sodium ratio < 3. No significant differences were found in cystic levels of triglycerides and VLDL-C. Multiple regression analysis showed that the only intracystic variable, which was, in part, positively responsible for the hormone levels measured, was HDL-C. These data suggest that local steroidogenesis in fibrocystic breast disease uses HDL-C as the substrate.

El linfoma folicular, el linfoma indolente más frecuente, se origina en los linfocitos B del centro germinal del folículo linfoide y se caracteriza por la traslocación t(14;18). Clínicamente se manifiesta por la presencia de adenopatías, que pueden asociarse a síntomas constitucionales o citopenias. El diagnóstico se establece mediante la observación de una proliferación linfoide B de patrón nodular en la biopsia ganglionar, y la estadificación mediante una PET-TC y una biopsia de médula ósea. Una proporción significativa de pacientes no requiere tratamiento inmediato. Si lo requieren, suele estar basado en inmunoterapia anti-CD20 asociada o no a quimioterapia. A pesar de que la mayoría de los pacientes presentan una supervivencia global prolongada, las recaídas son muy frecuentes, y la recaída precoz y la transformación a un linfoma agresivo confieren un mucho peor pronóstico. Se encuentran en desarrollo nuevos tratamientos que cambiarán las perspectivas de estos pacientes en un futuro próximo.

Alterations in bone and mineral metabolism are very common in chronic kidney disease (CKD). The increase in phosphate levels leads to bone disease, risk of calcification and greater mortality, so any strategy aimed at reducing them should be welcomed. The latest drug incorporated into the therapeutic arsenal to treat hyperphosphataemia in CKD is Sucroferric Oxyhydroxide (SFO).

ABSTRACT: The study of lymphocyte subsets from human follicular fluid (FF) provides an opportunity to evaluate immunological features of the ovary. We investigated the mononuclear cell subsets in FF and peripheral blood obtained at the time of laparoscopy from ten in vitro fertilization (IVF) patients. Midcycle nonpregnant peripheral blood was used as the control. A marked increase in the proportion of monocytes (CD14+) was observed in FF. Although FF was enriched with CD8+lymphocytes, a decrease in the proportion of CD4+lymphocytes was observed. “Memory” T cells in FF, identified by the CD4+CD45R−phenotype, predominated over “naive” T cells (CD4+CD45R+) at a ratio of 2:1, which differs from the ratio yielded by control blood samples (1:1). The percentage of activated T cells (CD3+HLA‐DR+cell) increased significantly in FF. When lymphocyte subsets were studied in the peripheral blood of IVF patients, changes similar to but less significant than those in FF were found. These data support the concept that lymphocytes play an important role in ovarian physiology.

Introduction: Previous studies have highlighted the potential of cell-free DNA (cfDNA) to assess the mutational profile and copy number alterations (CNA) in diffuse large B-cell lymphoma (DLBCL), usually performed in tissue biopsies, both at diagnosis and relapse. In addition, the quantitative levels of cfDNA might be a surrogate of the lymphoma tumor burden and could therefore predict response to therapy, progression-free survival (PFS) and overall survival (OS). The aim of this study was to analyze the mutational profile and CNA at diagnosis using cfDNA, to compare these results with those obtained from formalin-fixed paraffin-embedded (FFPE) biopsies, and to estimate the correlation of pre-treatment levels of cfDNA with FDG-PET/CT Total Metabolic Tumor Volume (TMTV) and their impact in the outcome of DLBCL patients.

Sancho: SERVIER: Honoraria; SANOFI: Honoraria; Novartis: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; JANSSEN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ROCHE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GILEAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CELLTRION: Consultancy; Kern-Pharma: Honoraria; Sandoz: Consultancy. Lopez Jimenez:GILEAD SCIENCES: Honoraria, Other: Education funding. Ramirez Payer:GILEAD SCIENCES: Research Funding. Cordoba:Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Kyowa-Kirin: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; FUNDACION JIMENEZ DIAZ UNIVERSITY HOSPITAL: Employment; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy. Martín:Kiowa Kirin: Consultancy; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; iQone: Consultancy; Teva: Research Funding; Janssen: Honoraria, Other: Travel Expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Expenses; Servier: Honoraria, Other: Travel Expenses. Armando:Roche: Consultancy, Research Funding; Janssen: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Ramirez Payer: GILEAD SCIENCES: Research Funding. Terol:Astra Zeneca: Consultancy; Gilead: Research Funding; Abbvie: Consultancy; Janssen: Consultancy, Research Funding; Roche: Consultancy. Lopez-Guillermo:Celgene: Consultancy, Research Funding; Janssen: Research Funding; Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding.

Montserrat: Pharmacyclics: Consultancy; Vivia Biotech: Equity Ownership; Janssen: Honoraria, Other: travel, accommodations, expenses; Gilead: Consultancy, Other: Expert Testimony; Morphosys: Other: Expert Testimony.

Background: Survival of pts with chronic lymphocytic leukemia (CLL) ranges from a few years to a normal lifespan. Clinical stages (i.e. Rai, Binet) are the basis for CLL prognostication but do not reflect the complex biology of CLL, which ultimately shapes the disease heterogeneity. Recently, a CLL-International Prognostic Index (CLL-IPI) which includes five clinical and biological variables (i.e. age, IGHVmutational status, del(17p), beta2-microglobulin [B2M] and Rai or Binet stages) and stratifies pts into four different categories has been proposed. This prognostic index is obtained by the sum of the score given to each parameter and includes dichotomized continuous variables. The aim of this study was to determine whether a prognostic model based only on biomarkers could separate CLL patients with different outcomes and simplify the CLL-IPI.