Perirenal fat is related to carotid intima-media thickness in children.

BACKGROUND/OBJECTIVES: It is well known that increased abdominal fat is associated with cardiovascular (CV) risk. Perirenal fat has been recently associated with CV risk in adults. However, studies with children are lacking. We investigated the relationship of perirenal fat and other abdominal fat depots (including preperitoneal, intra-abdominal and subcutaneous fat) with carotid intima-media thickness (cIMT-a surrogate marker of CV risk) in prepubertal children, so as to identify novel markers that can be easily assessed and used in the early prevention of cardiovascular disease. SUBJECTS/METHODS: Subjects were 702 asymptomatic prepubertal Caucasian children (418 lean, 142 overweight and 142 obese) who were recruited in a primary care setting. Ultrasound measurements (perirenal, preperitoneal, intra-abdominal and subcutaneous fat and cIMT), clinical (body mass index (BMI) and systolic blood pressure) and metabolic parameters (insulin resistance (HOMA-IR), high molecular weight (HMW) adiponectin and serum lipids) were assessed. RESULTS: Perirenal fat was associated with diverse metabolic and CV risk factors in all the studied subjects. However, in overweight and obese children, perirenal fat was mostly associated with cIMT (P<0.001) and was the only fat depot that showed independent associations with cIMT in multivariate analyses (overweight chidren: ß=0.250, P=0.003, r2=12.8%; obese children: ß=0.254, P=0.002, r2=15.5%) after adjusting for BMI, gender, age and metabolic parameters. Perirenal fat was also the only fat depot that showed independent associations with HMW-adiponectin in obese children (ß=-0.263, P=0.006, r2=22.8%). CONCLUSIONS: Perirenal fat is the main abdominal fat depot associated with cIMT, especially in overweight and obese children, and may thus represent a helpful parameter for assessing CV risk in the pediatric population.

The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.

Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), especially for the poor prognostic subgroup of NOTCH1-mutated patients. Here, we report that the γ-secretase inhibitor PF-03084014 inhibits the constitutive Notch activation and induces selective apoptosis in CLL cells carrying NOTCH1 mutations. Combination of PF-03084014 with fludarabine has a synergistic antileukemic effect in primary NOTCH1-mutated CLL cells, even in the presence of the protective stroma. At transcriptional level, PF-03084014 plus fludarabine treatment induces the upregulation of the proapoptotic gene HRK and the downmodulation of MMP9, IL32 and RAC2 genes that are related to invasion and chemotaxis. PF-03084014 also overcomes fludarabine-mediated activation of nuclear factor-κB signaling. Moreover, this combination impairs angiogenesis and CXCL12-induced responses in NOTCH1-mutated CLL cells, in particular those related to tumoral migration and invasion. Importantly, all these collaborative effects are specific for NOTCH1 mutation and do not occur in unmutated cases. In conclusion, we provide evidence that Notch is a therapeutic target in CLL cases with NOTCH1-activating mutations, supporting the use of Notch pathway inhibitors in combination with chemotherapy as a promising approach for the treatment of these high-risk CLL patients.

Cell death targeting therapies in B lymphoid malignancies.

Programmed cell death, commonly associated with the term apoptosis, is an integrated intracellular program that plays a critical role in lymphoid tissue homeostasis. Alterations in this highly regulated process is a common feature of most lymphoid malignancies, thus facilitating tumor escape from traditional chemotherapeutic agents whose main endpoint is the induction of tumor cell death. In the last years, enormous progress has been made in understanding the deregulated signals that could lead to ineffective apoptosis in B lymphoid tumors. Consequently, several new strategies have been designed to modulate the key molecules of life-and-death decisions. Numerous novel approaches are being validated and some of them have progressed to clinical testing or have even been approved in a record time. In this review we will focus on current therapies that have demonstrated to trigger efficiently cell death in B lymphoid neoplasms, either by directly targeting the intracellular apoptotic machinery or by modulating different factors involved in its regulation.

Interrupción del embarazo. Estudio comparativo entre diferentes pautas de inducción médica / Pregnancy termination. Comparative study among distinct medical induction regimens

Objetivo: Comparar la eficacia entre diferentes pautas de inducción médica empleadas para la interrupción del embarazo de segundo trimestre. Material y métodos: Análisis retrospectivo de 145 gestantes de 13 a 22 semanas que se expusieron a una interrupción mediante 4 métodos: 1) prostaglandina F2α intraamniótica y E2 endocervical; 2) prostaglandina E2 endocervical; 3) prostaglandina E1 vaginal y oral, y 4) prostaglandina E1 vaginal. Todos ellos seguidos de oxitocina. Resultados: La duración media de expulsión fue de 20,2 ± 7,6; 17,5 ± 8,2; 16,8 ± 8,7 y 12,6 ± 4,2 h, respectivamente. Las diferencias son estadísticamente significativas cuando se analiza la duración media de manera global (p = 0,02, ANOVA) y en no primigestas (p = 0,02, ANOVA). El porcentaje de expulsiones espontáneas antes de las 12 h fue del 5,5, el 31, el 32,5 y el 50%, respectivamente (p = 0,002, χ2). Únicamente aparecen fracasos y efectos secundarios graves (1 caso de coagulación intravascular diseminada) con la prostaglandina E2 endocervical. Conclusiones: La administración vaginal de prostaglandina E1 presenta una menor duración media de expulsión y una mayor tasa de expulsión espontánea a las 12 h

Objective: To compare the effectiveness of distinct medical induction regimens used for second trimester abortions. Materials and methods: We performed a retrospective review of 145 pregnancies between 13 and 22 weeks that underwent an induced abortion using four different methods: 1) intra-amniotic prostaglandin F2α and endocervical E2; 2) endocervical prostaglandin E2; 3) intravaginal and oral prostaglandin E1; and 4) intravaginal prostaglandin E1. All these methods were followed by oxytocin infusion. Results: The mean induction to abortion interval was 20.2 ± 7.6 h; 17.5 ± 8.2 h; 16.8 ± 8.7 h, and 12.6 ± 4.2 h, respectively. The differences were statistically significant when the mean interval was analyzed globally (p = 0.02, ANOVA) and in non-primigravidas (p = 0.02, ANOVA). The rate of successful abortions within 12 hours was 5.5%, 31%, 32.5% and 50%, respectively (p = 0.002 χ2 test). Surgical abortion and serious side effects (one case of disseminated intravascular coagulation) occurred only with prostaglandin E2. Conclusions: Vaginal administration of prostaglandin E1 resulted in a shorter mean induction to abortion interval and a higher rate of successful abortions within 12 hours

Cribado bioquímico-ecográfico de las aneuploidías en el primer trimestre. Metodología y resultados / First-trimester biochemical-ultrasound aneuploidy screening. Methodology and results

Objetivo: Valorar la eficacia del cribado bioquímico-ecográfico de las aneuploidías en el primer trimestre de la gestación así como describir detalladamente la metodología utilizada. Sujetos y métodos: Estudio prospectivo en 3.492 gestantes, portadoras de un feto único, en las que se realiza el cribado bioquímico mediante la fracción beta libre de la gonadotropina coriónica humana y la proteína plasmática A asociada al embarazo, entre las 8 y las 13 semanas de gestación, y el cribado ecográfico, entre las 11 y las 13 semanas, con la medición de la longitud cefalocaudal y del grosor de la translucencia nucal. Se exponen los procedimientos epidemiológico-matemáticos utilizados para estimar el riesgo de que una gestante sea portadora de un feto afectado de aneuploidía. Resultados: El cribado bioquímico ecográfico del primer trimestre ha permitido detectar, en esta serie, el 83 por ciento (10 de 12) de las trisomías 21, el 86 por ciento (18 de 21) de las trisomías autosómicas y el 82 por ciento (23 de 28) de todas las aneuploidías, para una tasa de falsos positivos del 5,4 por ciento. Conclusiones: Este tipo de cribado presenta una alta efectividad pero precisa una metodología adecuada para la obtención de resultados óptimos (AU)