Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva.

Currently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues owing to dysregulated activity of the bone morphogenetic protein (BMP) receptor kinase ALK2 (also known as ACVR1). From a screen of known biologically active compounds, we identified saracatinib as a potent ALK2 kinase inhibitor. In enzymatic and cell-based assays, saracatinib preferentially inhibited ALK2, compared with other receptors of the BMP/TGF-ß signaling pathway, and induced dorsalization in zebrafish embryos consistent with BMP antagonism. We further tested the efficacy of saracatinib using an inducible ACVR1Q207D-transgenic mouse line, which provides a model of heterotopic ossification (HO), as well as an inducible ACVR1R206H-knockin mouse, which serves as a genetically and physiologically faithful FOP model. In both models, saracatinib was well tolerated and potently inhibited the development of HO, even when administered transiently following soft tissue injury. Together, these data suggest that saracatinib is an efficacious clinical candidate for repositioning in FOP treatment, offering an accelerated path to clinical proof-of-efficacy studies and potentially significant benefits to individuals with this devastating condition.

Tomografía computarizada 3D con técnica de A-GI-VA (Ali-Giacomotti-Vassaro). Nuevo instrumento de diagnóstico de la estructura nasal A-GI-VA (Alí-Giacomotti-Vassaro) / A novel 3D computed tomography scan technique for diagnosis of the nasal structure

Introducción y objetivo: La rinoplastia estética es uno de los procedimientos quirúrgicos más desafiantes, en donde converge una estructura tridimensional compuesta de tejido óseo, cartilaginoso y tegumentario, que debe ser interpretada y modificada como un todo para la obtención de un resultado óptimo. La técnica A-GI-VA nos abre una ventana nueva para evaluar la anatomía nasal, principalmente los cartílagos nasales, sus relaciones entre sí y su disposición anatómica exacta, indispensable para el buen tratamiento de los mismos. Material y método: Realizamos tomografías axiales computarizadas con reconstrucción tridimensional mediante tomógrafo helicoidal de múltiples cortes para analizar la estructura de los cartílagos nasales y su relación con la piel. Resultados: Identificamos con precisión los componentes osteocartilaginosos de la nariz como ayuda en la planificación de la cirugía nasal. Conclusiones: Mediante la utilización de la técnica A-GI-VA podemos determinar con precisión la estructura nasal para su posterior clasificación y/o tratamiento

Background and objective: Aesthetic rhinoplasty is one of the most challenging surgical procedures, where a bony and a cartilaginous framework covered by skin meet into a tridimensional structure that must be interpreted and modified as one to obtain a successful result. Methods: A regular 3D CT scan of the maxillofacial area with shaded surface display (SSD) technique is used to get a precise evaluation of the nasal cartilages and their relationship with the skin. Results: We obtained a greater detail of the nasal structure, both of its components: bone cartilage in order to improve nasal surgery planning. Conclusions: The A-GI-VA technique allows us to depict the nasal anatomy and determine a better surgery planning

Utilización del doble plano invertido en el tratamiento de la mama tuberosa / Inverted double plane use in the treatment of tuberous breast

Introducción y Objetivo: La mama tuberosa es una anomalía congénita que se evidencia en la pubertad con un alto índice de presentación. Se caracteriza por alteraciones en la forma y estructura de la mama, con mayor afectación del polo inferior. Presentamos nuestra experiencia de 3 años en corrección de la mama tuberosa con la técnica de doble plano invertido con colgajo de pectoral mayor y evaluamos los resultados obtenidos. Material y Método: Estudio prospectivo de 3 años sobre 12 pacientes intervenidas quirúrgicamente utilizando como alternativa de tratamiento un colgajo publicado por nosotros que utiliza el músculo pectoral mayor en su porción distal, irrigado por las perforantes internas (doble plano invertido), que proporciona mayor cobertura del implante en la zona problema. Resultados: Obtuvimos un porcentaje de satisfacción del 83% de las pacientes intervenidas, evaluado mediante tabla de satisfacción a los 8 meses de postoperatorio. Conclusiones: En nuestra experiencia, la técnica de doble plano invertido con colgajo de pectoral mayor para la plastia de mamas tuberosas otorga mayor cobertura en el polo inferior por utilizar cobertura muscular, con una anatomía constante, segura y conocida

Background and Objective: The tuberous breast is a congenital anomaly that can be evidenced throughout puberty with a high rate of presentation. It is characterized by alterations in form and structure, the lower pole being the most usual condition. We present our 3 year experience using the double inverted plane technique in the correction of tuberous breast and evaluate our results. Methods: Prospective 3 year study on 12 patients using as an alternative to the treatment an our authorship flap that uses the pectoralis major muscle in its distal portion, irrigated by the internal perforators (inverted dual plane), which provides greater coverage of the implant in the problem zone. Results: A 83% percentage of patients'satisfaction was obtanined with the proposed technique; results were evaluated by means of a satisfaction table at 8 months postoperative period. Conclusions: In our experience, the inverted double plane technique with pectoralis major flap for tuberous breast plasty, provides greater coverage in the lower pole by using muscle coverage, with a constant, safe and known anatomy

Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification.

Fibrodysplasia ossificans progressiva (FOP), a congenital heterotopic ossification (HO) syndrome caused by gain-of-function mutations of bone morphogenetic protein (BMP) type I receptor ACVR1, manifests with progressive ossification of skeletal muscles, tendons, ligaments, and joints. In this disease, HO can occur in discrete flares, often triggered by injury or inflammation, or may progress incrementally without identified triggers. Mice harboring an Acvr1R206H knock-in allele recapitulate the phenotypic spectrum of FOP, including injury-responsive intramuscular HO and spontaneous articular, tendon, and ligament ossification. The cells that drive HO in these diverse tissues can be compartmentalized into two lineages: an Scx+ tendon-derived progenitor that mediates endochondral HO of ligaments and joints without exogenous injury, and a muscle-resident interstitial Mx1+ population that mediates intramuscular, injury-dependent endochondral HO. Expression of Acvr1R206H in either lineage confers aberrant gain of BMP signaling and chondrogenic differentiation in response to activin A and gives rise to mutation-expressing hypertrophic chondrocytes in HO lesions. Compared to Acvr1R206H, expression of the man-made, ligand-independent ACVR1Q207D mutation accelerates and increases the penetrance of all observed phenotypes, but does not abrogate the need for antecedent injury in muscle HO, demonstrating the need for an injury factor in addition to enhanced BMP signaling. Both injury-dependent intramuscular and spontaneous ligament HO in Acvr1R206H knock-in mice were effectively controlled by the selective ACVR1 inhibitor LDN-212854. Thus, diverse phenotypes of HO found in FOP are rooted in cell-autonomous effects of dysregulated ACVR1 signaling in nonoverlapping tissue-resident progenitor pools that may be addressed by systemic therapy or by modulating injury-mediated factors involved in their local recruitment.

Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants.

There are currently no effective therapies for fibrodysplasia ossificans progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure-activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-ß type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-ß inhibition. The study also highlights a potent 2-methylpyridine derivative 10 (LDN-214117) with a high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for preclinical development. Contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compounds demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clinical relevance for the diverse ALK2 mutant proteins associated with FOP and DIPG.

Body mass index predictive of sputum culture conversion among MDR-TB patients in Indonesia.

SETTING: Programmatic management of drug-resistant tuberculosis at Persahabatan Hospital, Jakarta, Indonesia. OBJECTIVE: To evaluate the association between body mass index (BMI) and sputum culture conversion during treatment for multidrug-resistant tuberculosis (MDR-TB). DESIGN: We conducted a retrospective cohort study of 212 MDR-TB patients. MDR-TB was confirmed using culture in liquid medium and line-probe assay. Patients were treated with a standardised regimen unless they were resistant to any of the drugs tested. Study outcomes were time to culture conversion (primary) and probability of conversion within 4 months (secondary). Data were analysed using Kaplan-Meier curves, discrete time-survival analysis and Poisson regression. RESULTS: Compared to patients with normal weight (BMI ≥18.5 kg/m(2)), severely underweight patients (BMI <16 kg/m(2)) had longer time to initial conversion (adjusted hazard ratio [aHR] 0.55, 95%CI 0.37-0.84) and a lower probability of sputum culture conversion within 4 months (adjusted relative risk 0.67, 95%CI 0.54-0.83). Other predictors for longer sputum culture conversion were female sex (aHR 0.55, 95%CI 0.39-0.78), resistance to injectables (aHR 0.59, 95%CI 0.42-0.83) and high baseline smear grade (aHR 0.33, 95%CI 0.18-0.60). CONCLUSION: Severe underweight was associated with longer time to initial sputum culture conversion among MDR-TB patients.

A new class of small molecule inhibitor of BMP signaling.

Growth factor signaling pathways are tightly regulated by phosphorylation and include many important kinase targets of interest for drug discovery. Small molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 (ACVR1) are needed urgently to treat the progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). Dorsomorphin analogues, first identified in zebrafish, remain the only BMP inhibitor chemotype reported to date. By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189. K02288 specifically inhibited the BMP-induced Smad pathway without affecting TGF-ß signaling and induced dorsalization of zebrafish embryos. Comparison of the crystal structures of ALK2 with K02288 and LDN-193189 revealed additional contacts in the K02288 complex affording improved shape complementarity and identified the exposed phenol group for further optimization of pharmacokinetics. The discovery of a new chemical series provides an independent pharmacological tool to investigate BMP signaling and offers multiple opportunities for pre-clinical development.

Development of an ALK2-biased BMP type I receptor kinase inhibitor.

The bone morphogenetic protein (BMP) signaling pathway has essential functions in development, homeostasis, and the normal and pathophysiologic remodeling of tissues. Small molecule inhibitors of the BMP receptor kinase family have been useful for probing physiologic functions of BMP signaling in vitro and in vivo and may have roles in the treatment of BMP-mediated diseases. Here we describe the development of a selective and potent inhibitor of the BMP type I receptor kinases, LDN-212854, which in contrast to previously described BMP receptor kinase inhibitors exhibits nearly 4 orders of selectivity for BMP versus the closely related TGF-ß and Activin type I receptors. In vitro, LDN-212854 exhibits some selectivity for ALK2 in preference to other BMP type I receptors, ALK1 and ALK3, which may permit the interrogation of ALK2-mediated signaling, transcriptional activity, and function. LDN-212854 potently inhibits heterotopic ossification in an inducible transgenic mutant ALK2 mouse model of fibrodysplasia ossificans progressiva. These findings represent a significant step toward developing selective inhibitors targeting individual members of the highly homologous BMP type I receptor family. Such inhibitors would provide greater resolution as probes of physiologic function and improved selectivity against therapeutic targets.

Recent patents for detecting the species of origin in animal feedstuff, and raw and processed meat products.

The value of the traceability and labeling of food is attributable to two main aspects: health safety and/or product or process certification. The identification of the species related to meat production is still a major concern for economic, religious and health reasons. Many approaches and technologies have been used for species identification in animal feedstuff and food. The early methods for meat products identification include physical, anatomical, histological and chemical. Since 1970, a variety of methods were developed, these include electrophoresis (i.e. isoelectrofocusing), chromatography (i.e. HPLC), immunological techniques (i.e. ELISA), Nuclear Magnetic Resonance, Mass Spectrometry and PCR (DNA and RNA based methods). The recent patents on species detection in animal feedstuffs, raw meat and meat processed products, listed in this work, are mainly based on monoclonal antibodies and PCR, especially RT-PCR. The new developments under research are looking for more sensible, specific, less time consuming and quantitatively detection methods, which can be used in highly processed or heated treated meat food.

Sincronía ventricular en pacientes con bloqueo de rama del haz de his / Ventricular synchrony in patients with bundle branch block

Los trastornos de conducción representan un marcador de mál pronóstico en pacientes con cardiopatía. El objetivo fundamental fue evaluar la sincronía ventricular en pacientes con bloqueo de rama derecha del haz de His (BRDHH) y bloqueo de rama izquierda del haz de His (BRIHH). Estudio prospectivo, observacional, transversal, no experimental. Se evaluaron 45 pacientes: 25 con BRDHH y 20 con BRIHH e igual número de controles, que consultaron a la Emergencia de Adultos del Hospital "Dr. Alfredo Van Grieken", entre marzo y septiembre de 2008. Con ecocardiógrafo HP SONOS 5500 se determinó retardo intraventricular (RIV) según método de Pitzalis. Se observó RIV significativamente mayor en pacientes con BRIHH (x: 194,25 ± 73,33) que en BRDHH (x: 81,8 ± 39,23) y que en los controles (x: 21,96 ± 14,18), (P<0,01). La fracción de eyección (FE) fue menor en BRIHH (X: 35,05 ± 15,26) que en BRDHH (x: 57,28 ± 13,56) y que en controles (x: 63,49 ± 13,36), (P<=0,01). Se encontró correlación negativa significativa entre el RIV de BRIHH y la FE (r: 5,32, p: 0,05), la correlación entre la anchura del QRS y el RIV no fue significativa en BRDHH (r: 0,144), p: NS) ni en BRIHH (r: 0,160, p: NS). Se determinó asincronía intraventricular en 12% de los pacientes con BRDHH y en el 85% con BRIHH, 40% de este grupo falleció antes de culminar el estudio. La asincronía intraventricular en pacientes con BRIHH representa un riesgo de mortalidad cardiovascular elevado, lo cual nos obliga a implementar medidas profilácticas en la aparición de complicaciones y seleccionar a los pacientes para resincronización cardíaca.

Conduction disorders represent a marker of poor pronosis in patients with heart disease. The primary objective was to evaluate the ventricular synchrony in patients with right block (RBBB) and left bundle branch block (LBBB). Prospective, observational, cross-sectional, non experimental study. A total of 45 patients were evaluated: 25 with RBBB and 20 with LBBB and an equal number ofcontrols, that consulted the Adult Emergency Hospital "Dr. Alfredo Van Grieken", between march and septiember of 2008. Echocardiographic HP SONOS 5500 was used to determine intraventricular delay (IVD) by the Pitzalis method. IVD was significantly higher in patients with LBBB (x: 194.25 ± 73.33) thain in RBBB (x: 81.8 ± 39.23) and that in the controls (x: 21.96 ± 14.18), (P<0.01). The ejection fraction (EF) was lower in LBBB (x: 35.05 ± 15.26) than in RBBB (x: 57.28 ± 13.56) as well as control (x: 63.49 ±13.36). (P<0.01). Significant negative correlation was found between the IVD of LBBB and EF (r= 5.32, P: 0.05), the correlation betwen the width of the QRS and the IVD was not significant in RBBB (r: 0144, p: NS) nor in LBBB (r: 0160, p: NS). Intraventricular asynchrony was found in 12% of patients with RBBB. Death occurred in 40% of this group before completion of the study. Intraventricular asynchrony in patients with LBBB represents an elevated risk of cardiovascular mortality, which prophylactic measures to avoid complications and to select patients for cardiac resynchronization.

Colgajo de pectoral mayor basado en perforantes internas inferiores: dual plane invertido / Pectoralis major flap based on perforating internal inverted lower-dual plane

El polo inferior de la mama en ocasiones puede estar afectado en su espesor por diferentes causas, tales como el simple paso del tiempo, resecciones oncológicas, extrusiones protésicas por infecciones, seromas, fístulas, etc. Se describe en este trabajo una alternativa quirúrgica para brindar una mayor cobertura en el cuadrante inferointerno de la glándula, utilizando un colgajo del músculo pectoral en su porción distal, basada en la irrigación de sus perforantes internas.

In occasions, an inferior breast pole can be affected in its thickness due to different causes such as merely overtime, oncology resections, implant exposure caused by infection, seromas, fitulas, etc. This paper describes a surgical alternative to provide a greater coverage in the inferior-internal quadrant, empoying a pectoral muscle flap in its distal position based in the irrigation of its internal perforating artery.

Afecciones quirúrgicas en el recién nacido: Nuestras estadísticas años 2002 - 2003

Las afecciones quirúrgicas en el neonato tienen una alta morbimortalidad, por la condición de recién nacido, los trastornos ocasionados por la enfermedad de base así como por la injuria provocada posteriormente por la intervención quirúrgica. Se realizó un estudio retrospectivo por la intervención quirúrgica. Se realizó un estudio retrospectivo, longitudinal de todos los neonatos a los cuales se le diagnosticó patologías quirúrgicas en el periodo comprendido entre enero de 2002 hasta diciembre de 2003 en la provincia de Pinar del Río (Cuba) con el objetivo de analizar el comportamiento diagnóstico y terapéutico de estos pacientes. En esta etapa se intervinieron quirúrgicamente 24 recién nacidos, la mayoría fueron masculinos (17), la operación se realizó con menos de 24 horas de nacido en 14 casos, las afecciones quirúrgicas más frecuentes fueron las de intestino delgado con 7 pacientes y la supervivencia fue de un 100 por cento, logrando la mejor tasa de supervivencia de los últimos años en este territorio...(AU)