The RSNA Cervical Spine Fracture CT Dataset.

This dataset is composed of cervical spine CT images with annotations related to fractures; it is available at https://www.kaggle.com/competitions/rsna-2022-cervical-spine-fracture-detection/.

Feasibility and Cost Analysis of Portable MRI Implementation in a Remote Setting in Canada.

OBJECTIVE: To conduct feasibility and cost analysis of portable MRI implementation in a remote setting where MRI access is otherwise unavailable. METHODS: Portable MRI (ultra-low field, 0.064T) was installed in Weeneebayko General Hospital, Moose Factory, Ontario. Adult patients, presenting with any indication for neuroimaging, were eligible for study inclusion. Scanning period was from November 14, 2021, to September 6, 2022. Images were sent via a secure PACS network for Neuroradiologist interpretation, available 24/7. Clinical indications, image quality, and report turnaround time were recorded. A cost analysis was conducted from a healthcare system's perspective in 2022 Canadian dollars, comparing cost of portable MRI implementation to transporting patients to a center with fixed MRI. RESULTS: Portable MRI was successfully implemented in a remote Canadian location. Twenty-five patients received a portable MRI scan. All studies were of diagnostic quality. No clinically significant pathologies were identified on any of the studies. However, based on clinical presentation and limitations of portable MRI resolution, it is estimated that 11 (44%) of patients would require transfer to a center with fixed MRI for further imaging workup. Cost savings were $854,841 based on 50 patients receiving portable MRI over 1 year. Five-year budget impact analysis showed nearly $8 million dollars saved. CONCLUSIONS: Portable MRI implementation in a remote setting is feasible, with significant cost savings compared to fixed MRI. This study may serve as a model to democratize MRI access, offer timely care and improved triaging in remote areas where conventional MRI is unavailable.

Aplicaciones terapéuticas del eculizumab / Therapeutic applications of eculizumab

Introducción: El eculizumab es un anticuerpo monoclonal de tipo IgG diseñado para el tratamiento de la hemoglobinuria paroxística nocturna (HPN), en el que su diana farmacológica forma parte del sistema del complemento. Su mecanismo de acción ha permitido implementarlo en el tratamiento de enfermedades huérfanas, como el síndrome urémico hemolítico atípico (SUHa), trastorno del espectro de la neuromielitis óptica (TENMO) y miastenia gravis, cuya incidencia, es baja. Asimismo, es viable en el tratamiento de Guillain Barré y el síndrome antifosfolípido catastrófico (CAPS). Objetivo: Evidenciar aplicaciones terapéuticas del eculizumab y beneficios más significativos en algunos padecimientos. Materiales y métodos: Se realizó búsqueda bibliográfica en el periodo 2010-2021, en bases de datos: Google Scholar, Science Direct, PubMed y Scielo, utilizando como palabra clave "eculizumab". Posteriormente, se afinó la búsqueda utilizando palabras claves asociadas a enfermedades tratadas con este medicamento. Resultados: Se identificó el mecanismo de acción del fármaco y su efecto sobre la patogénesis de hemoglobinuria paroxística nocturna, síndrome urémico atípico, miastenia gravis generalizada refractaria, trastorno del espectro de la neuromielitis óptica, síndromes antifosfolípidos catastrófico y Guillain-Barré. Conclusiones: El eculizumab tiene una alta seguridad y capacidad para tratar y disminuir síntomas de diversas enfermedades que involucran el sistema del complemento.

Introduction: Eculizumab is an IgG type monoclonal antibody designed to treat paroxysmal nocturnal hemoglobinuria (PNH) and its pharmacological target is a member of the complement system. Its mechanism of action has permitted its use in the treatment of orphan diseases such as atypical hemolytic uremic syndrome (aHUS), neuromyelitis optic spectrum disorder (NMOSD), and myasthenia gravis, all of which have a low incidence. Likewise, eculizumab is a viable treatment for Guillain Barré and catastrophic antiphospholipid syndrome (CAS). Objective: To describe the therapeutic applications of eculizumab and its most significant benefits in some illnesses. Materials and methods: A bibliographic search was carried out during the 2010-2021 period in Google Scholar, Science Direct, PubMed and Scielo databases using the keyword eculizumab. Then, the search was refined by using keywords associated with diseases treated with this medication. Results: The mechanism of action of the antibody and its effect on the pathogenesis of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, refractory generalized myasthenia gravis, neuromyelitis optic spectrum disorder, catastrophic antiphospholipid syndrome, and Guillain Barré were identified. Conclusions: Eculizumab has high safety and capacity in treating and diminishing symptoms of diverse illnesses, which involve the complement system.

Epidemiological Review of Spinal Cord Injury due to Road Traffic Accidents in Latin America.

Spinal cord injury (SCI) is a disease that affects the normal function of the spinal cord. Road traffic accidents (RTAs) represent the main cause of SCI worldwide. SCI may generate physical disability and economic dependency, which is especially significant in low- and middle-income countries such as most of the Latin American countries. The main objective of this study was to present an epidemiological review of SCI secondary to RTAs. Stronger evidence on this condition in Latin America is important for future-specific data collection and prevention strategies. A literature review was carried out using specific search strategies in databases of indexed journals from the period 2000 to 2019. Data on SCI secondary to RTAs in the Latin American region were collected and analyzed. After initial screening and removal of duplicates, 16 articles met the inclusion criteria and were chosen for analysis. Data from 7 Latin American countries were retrievable. On average, RTAs were responsible for 40.81% of SCI. Data from different studies are heterogeneous. Car accidents and moto accidents were equally responsible for SCIs (50.61% vs. 49.06%). The thoracic segments were the most commonly affected (57.87%). Males in their 30s were the most affected category (76.6%). SCI due to RTAs may represent a severe but preventable condition that affects mostly men in their productive age, generating important social and economic issues. Data about this condition in Latin America are scarce, and could limit prevention and treatment strategies. Prospective data collection about this condition is recommended.

CT-based radiomics model with machine learning for predicting primary treatment failure in diffuse large B-cell Lymphoma.

Biomarkers which can identify Diffuse Large B-Cell Lymphoma (DLBCL) likely to be refractory to first-line therapy are essential for selecting this population prior to therapy initiation to offer alternate therapeutic options that can improve prognosis. We tested the ability of a CT-based radiomics approach with machine learning to predict Primary Treatment Failure (PTF)-DLBCL from initial imaging evaluation. Twenty-six refractory patients were matched to 26 non-refractory patients, yielding 180 lymph nodes for analysis. Manual 3D delineation of the total node volume was performed by two independent readers to test the reproducibility. Then, 1218 hand-crafted radiomic features were extracted. The Random Forests machine learning approach was used as a classifier for constructing the prediction models. Seventy percent of the nodes were randomly assigned to a training set and the remaining 30% were assigned to an independent test set. The final model was tested on the dataset from the 2 readers, showing a mean accuracy, sensitivity and specificity of 73%, 62% and 82%, respectively, for distinguishing between refractory and non-refractory patients. The area under the receiver operating characteristic curve (AUC) was 0.83 and 0.79 for the two readers. We conclude that machine learning CT-based radiomics analysis is able to identify a priori PTF-DLBCL with a good accuracy.

Assessment of the impact of inpatient infectious events in pediatric patients with newly diagnosed acute leukemia at Dr. Robert Reid Cabral Children's Hospital, Dominican Republic.

Survival rates for pediatric acute leukemia vary dramatically worldwide. Infections are a leading cause of morbidity and mortality, and the impact is amplified in low and middle-income countries. Defining the epidemiology of infection in a specific health care setting is paramount to developing effective interventions. This study aimed to define the epidemiology of and outcomes from infection in children with acute leukemia treated in a large public pediatric hospital in the Dominican Republic. A retrospective cohort was assembled of children newly diagnosed with acute leukemia between July 1, 2015 to June 30, 2017 at Hospital Infantil Dr. Robert Reid Cabral in Santo Domingo. Patients were identified from the Pediatric Oncology Network Database (PONDTM) and hospital admissions from the Oncology admissions logbook. Medical records and microbiology results were reviewed to identify all inpatient invasive infections. Distance from a child's home to the hospital was determined using ArcGIS by Esri. Infection rates were described in discrete time periods after diagnosis and risk factors for invasive infection were explored using negative binomial regression. Overall, invasive infections were common and a prominent source of death in this cohort. Rates were highest in the first 60 days after diagnosis. Gastroenteritis/colitis, cellulitis, and pneumonia were most frequent, with bacteremia common early on. Multidrug resistant bacteria were prevalent among a small number of positive cultures. In a multivariate negative binomial regression model, age ≥ 10 years and distance from the hospital > 100 km were each protective against invasive infection in the first 180 days after diagnosis, findings that were unexpected and warrant further investigation. Over one-third of patient deaths were related to infection. Interventions aimed at reducing infection should target the first 60 days after diagnosis, improved supportive care inside and outside the hospital, and increased antimicrobial stewardship and infection prevention and control measures.

Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop.

Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOP-mutant ACVR1 or form NSCs with wild-type ACVR1. To explore the role of the NSC, we generated 'agonist-only' Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1. Using one of these muteins, we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSC's physiological role in corresponding knock-in mice.

Activin A does not drive post-traumatic heterotopic ossification.

Heterotopic ossification (HO), the formation of ectopic bone in soft tissues, has been extensively studied in its two primary forms: post-traumatic HO (tHO) typically found in patients who have experienced musculoskeletal or neurogenic injury and in fibrodysplasia ossificans progressiva (FOP), where it is genetically driven. Given that in both diseases HO arises via endochondral ossification, the molecular mechanisms behind both diseases have been postulated to be manifestations of similar pathways including those activated by BMP/TGFß superfamily ligands. A significant step towards understanding the molecular mechanism by which HO arises in FOP was the discovery that FOP causing ACVR1 variants trigger HO in response to activin A, a ligand that does not activate signaling from wild type ACVR1, and that is not inherently osteogenic in wild type settings. The physiological significance of this finding was demonstrated by showing that activin A neutralizing antibodies stop HO in two different genetically accurate mouse models of FOP. In order to explore the role of activin A in tHO, we performed single cell RNA sequencing and compared the expression of activin A as well as other BMP pathway genes in tHO and FOP HO. We show that activin A is expressed in response to injury in both settings, but by different types of cells. Given that wild type ACVR1 does not transduce signal when engaged by activin A, we hypothesized that inhibition of activin A will not block tHO. Nonetheless, as activin A was expressed in tHO lesions, we tested its inhibition and compared it with inhibition of BMPs. We show here that anti-activin A does not block tHO, whereas agents such as antibodies that neutralize ACVR1 or ALK3-Fc (which blocks osteogenic BMPs) are beneficial, though not completely curative. These results demonstrate that inhibition of activin A should not be considered as a therapeutic strategy for ameliorating tHO.

Evaluación de condiciones de extracción asistida por ultrasonido de compuestos bioactivos de cáscara de pitahaya amarilla / Evaluation of conditions of ultrasound assisted extraction of yellow pitahaya peel bioactive compounds / Avaliação das condições da extração com ultrassom dos compostos bioactivos da casca da pitaia amarela

Resumen Introducción: la extracción de los polifenoles ha tomado un interés debido a la relación que tiene con la prevención del estrés oxidativo y efectos benéficos sobre la salud en la prevención de enfermedades no transmisibles; estos están comúnmente en algunas frutas por lo que su extracción se ha convertido en una tendencia para obtener productos de alto valor agregado. El ultrasonido es una técnica que puede disminuir el tiempo de extracción de estos biocomponentes. Objetivo: evaluar las condiciones de la extracción asistida por ultrasonido de polifenoles con actividad antioxidantes en cáscara de pitahaya amarilla deshidratada. Materiales y métodos: Se deshidrataron las cáscaras y construyó cinéticas de secado a 60°C, con el fin de disminuir las reacciones de deterioro. Para la extracción, una solución de etanol al 96% (V/V) fue usada como disolvente, en una relación cáscara-disolvente 1:1. El proceso fue realizado a 25 °C en un sistema de ultrasonido indirecto con una frecuencia de 37 kHz. Se usó un diseño central compuesto, fueron evaluados el efecto de la potencia (40 - 80%) y tiempo de sonicación (11,90 - 33,10 minutos). Se hizo extracción con el método soxhlet (control). Los polifenoles totales y capacidad antioxidantes fue determinado por lo métodos Folin-Ciocalteau y ABTS respectivamente. Resultados: Bajos tiempos y altas potencias de sonicación fueron asociados con incremento en la extracción de polifenoles y capacidad antioxidante. En particular, la extracción asistida con ultrasonido con 60% de potencia y 11 minutos, se obtuvo un 77% más de polifenoles que 24 horas de proceso con método Soxhlet. Conclusión: El ultrasonido tiene potencial en comparación con la técnica tradicional para reducir el tiempo de procesamiento en extracción de biocomponentes, en este caso aprovechar la cáscara de pitahaya amarilla que es considerada como un residuo, se encontraron concentraciones de polifenoles de 973,10 mg/L que pueden ser extraídos por ultrasonido a 222 W de potencia nominal (60%), 35kHz de frecuencia y 22 minutos y con una capacidad antioxidante superior al 90%.

Abstract Introduction: the extraction of polyphenols has taken an interest due to the relationship it has with the prevention of oxidative stress and beneficial effects on health in the prevention of non-communicable diseases. These are commonly found in some fruits, so their extraction has become a trend to obtain products with high added value. Ultrasound is a technique that can decrease the extraction time of these biocomponents. Objective: the main objective of this work was to evaluate the conditions of the ultrasound-assisted extraction of polyphenols with antioxidant activity in dehydrated peel yellow pitahaya. Materials and methods: the kinectis drying was made at 60 °C, in order to decrease deterioration reactions. For the extraction, a solution of 96% ethanol (V / V) was used as disolvent; the ratio Peel-Disolvent was 1:1. The process was performed at 25 °C and 37 kHz frequency. A central composite design was used, in which the effect of power (40 - 80%) and ultrasonication time (11.90 -33.10 minutes) were evaluated. One control point was evaluated with Soxhlet extraction. The extracted amount of polyphenols and antioxidant capacity was determined by Folin-Ciocalteau and ABTS methods, respectively. Results: lower time exposures and higher sonication power were associated with increases in polyphenols and antioxidant capacity. In particular, ultrasound-assisted extraction in 60% power and 11 min, obtained 77% more polyphenols than 24-h standard method (Soxhlet). Conclusion: Ultrasound has potential compared to the traditional technique to reduce the processing time in biocomponent extraction, in this case taking advantage of the yellow pitahaya peel that is considered as a residue, polyphenol concentrations of 973.10 mg / L were found that They can be extracted by ultrasound at 222 W nominal power (60%), 35kHz frequency and 22 minutes and with an antioxidant capacity of over 90%.

Resumo Introdução: Muita atenção tem o efeito benéfico dos polifenóis e antioxidantes na obesidade relacionada ao estresse oxidativo. O ultra-som é uma técnica que pode diminuir o tempo de extração desses biocompostos. A extração de polifenóis interessou-se pela relação que tem com a prevenção do estresse oxidativo e efeitos benéficos à saúde na prevenção de doenças não transmissíveis; como são comumente encontradas em algumas frutas, sua extração tornou-se uma tendência para obter produtos com alto valor agregado. O ultrassom é uma técnica que pode diminuir o tempo de extração desses biocomponentes. Objetivo: foi avaliar as condições da extração assistida por ultrassom de polifenóis com atividade antioxidante em pitaia amarela desidratada. Materiais e métodos: as cascas foram desidratadas e construídas cinéticas de secagem a 60 °C, a fim de diminuir as reações de deterioração. Para extração, utilizou-se uma solução de etanol 96% (V/V) como dissolvente, numa proporção escudo-dissolvente 1:1. O processo foi feito a 25°C e uma frequência de 37 kHz. Foi utilizado μM projeto central composto, avaliando-se o efeito da potência (40-80%) e do tempo de sonificação (11,9-33,1 minutos). A extração foi feita com o método soxhlet (controle). A quantidade de polifenóis e capacidade antioxidantes extraídos foi determinada pelos métodos Folin-Ciocalteau e ABTS, respectivamente. Resultados: os tempos baixos e as altas potências de sonicação foram associados com aumento da extração de polifenóis e antioxidantes. Em particular, a extração assistida com ultra-som ao 60% de potência e 11 minutos, 77% a mais de polifenóis foram obtidos a 24 horas do método soxhlet. Conclusão: Ultra-som tem o potencial comparado à técnica tradicional de reduzir o tempo de processamento na extração de biocomponentes, neste caso, aproveitando a casca de pitaiaiás amarela que é considerada μM resíduo, foram encontradas concentrações de polifenóis de 973,10 mg / L que. Eles podem ser extraídos por ultrassom a 222 W de potência nominal (60%), frequência de 35kHz e 22 minutos e com uma capacidade antioxidante acima de 90%..

Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.

Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

Milrinone for refractory cerebral vasospasm with delayed cerebral ischemia.

OBJECTIVE: Intravenous (IV) milrinone is a promising option for the treatment of cerebral vasospasm with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, data remain limited on the efficacy of treating cases that are refractory to standard therapy with IV milrinone. The aim of this study was to determine predictors of refractory vasospasm/DCI despite treatment with IV milrinone, and to analyze the outcome of rescue therapy with intraarterial (IA) milrinone and/or mechanical angioplasty. METHODS: The authors conducted a retrospective cohort study of all patients with aSAH admitted between 2010 and 2016 to the Montreal Neurological Institute and Hospital. Patients were stratified into 3 groups: no DCI, standard therapy, and rescue therapy. The primary outcome was frequency of DCI-related cerebral infarction identified on neuroimaging before hospital discharge. Secondary outcomes included functional outcome reported as modified Rankin Scale (mRS) score, and segment reversal of refractory vasospasm. RESULTS: The cohort included 322 patients: 212 in the no DCI group, 89 in the standard therapy group, and 21 in the rescue therapy group. Approximately half (52%, 168/322) were admitted with poor-grade aSAH at treatment decision (World Federation of Neurosurgical Societies grade III-V). Among patients with DCI and imaging assessing severity of vasospasm, 62% (68/109) had moderate/severe radiological vasospasm on DCI presentation. Nineteen percent (21/110) of patients had refractory vasospasm/DCI and were treated with rescue therapy. Targeted rescue therapy with IA milrinone reversed 32% (29/91) of the refractory vasospastic vessels, and 76% (16/21) of those patients experienced significant improvement in their neurological status within 24 hours of initiating therapy. Moderate/severe radiological vasospasm independently predicted the need for rescue therapy (OR 27, 95% CI 8.01-112). Of patients with neuroimaging before discharge, 40% (112/277) had developed new cerebral infarcts, and only 21% (23/112) of these were vasospasm-related. Overall, 65% (204/314) of patients had a favorable functional outcome (mRS score 0-2) assessed at a median of 4 months (interquartile range 2-8 months) after aSAH, and there was no difference in functional outcome between the 3 groups (p = 0.512). CONCLUSIONS: The aggressive use of milrinone was safe and effective based on this retrospective study cohort and is a promising therapy for the treatment of vasospasm/DCI after aSAH.

CAPACIDAD ANTIOXIDANTE Y ANTIMICROBIANA DE TUBÉRCULOS ANDINOS (Tropaeolum tuberosum y Ullucus tuberosus) / ANTIMICROBIAL AND ANTIOXIDANT CAPACITY OF ANDEAN TUBERS (Tropaeolum tuberosum y Ullucus tuberosus)

RESUMEN Los tubérculos andinos formaron parte de la dieta de poblaciones originarias y son considerados como alimentos de alta calidad nutricional; sin embargo, en la actualidad, su uso ha disminuido. En este estudio, se plantea, como objetivo, evaluar características funcionales (capacidad antioxidante y antimicrobiana) de dos tubérculos consumidos tradicionalmente en Colombia, cubio (Tropaeolum tuberosum) y ulluco (Ullucus tuberosus). Para esto, se recolectaron tallos, hojas y tubérculo de cubio y de ulluco, se secaron a 38°C, por 90 horas y se realizaron extractos con etanol al 50% v/v. En los extractos obtenidos, se midió la capacidad antioxidante, por las técnicas DPPH y ABTS y el efecto inhibitorio en Escherichia coli, Lactobacillus fermentum y Cándida utilis, mediante la técnica de discos. Se encontró alto porcentaje de capacidad antioxidante en todas las partes de la planta en ambos tubérculos; las que presentaron mayor actividad son hojas y tallos. En la capacidad antimicrobiana, el cubio tuvo un efecto bacteriostático sobre C. utilis, mientras que el ulluco tuvo un efecto sobre E. coli. Debido a lo anterior, estos dos tubérculos poseen potencial para la extracción de compuestos antioxidantes y antimicrobianos permitiendo, de esta manera, establecer alternativas de uso para los tubérculos y subproductos (hojas y tallos).

ABSTRACT Andean tubers formed part of the diet of native populations and are considered as foods of high nutritional quality, however today its use has waned. This study proposes to evaluate functional characteristics (antioxidant and antimicrobial capacity) of two tubers traditionally consumed in Colombia, cubio (Tropaeolum tuberosum) and ulluco (Ullucus tuberosus). For this were collected stems, leaves and tuber of cubio and ulluco, were dried up to 38°C for 90 hours, and extracts were made with ethanol 50% v/v. In the extracts was measured the antioxidant capacity by DPPH and ABTS techniques and the inhibitory effect on Escherichia coli, Lactobacillus fermentum, and Candida utilis, using the technique of discs. Found higher antioxidant capacity in all parts of the plant in both tubers, however, which showed greater activity are leaves and stems. The antimicrobial capacity, the cubio had a bacteriostatic effect on C. utilis, while the ulluco had an effect on E. coli. Due to the above, these two tubers have potential for the extraction of antioxidant compounds, antibiotics, thus allowing establish alternatives of use for tubers and by products (leaves and stems).

Anatomical Variations of the Vertebral Artery in the Upper Cervical Spine: Clinical Relevance for Procedures Targeting the C1/C2 and C2/C3 Joints.

BACKGROUND AND OBJECTIVES: Accidental breach of the vertebral artery (VA) during the performance of cervical pain blocks can result in significant morbidity. Whereas anatomical variations have been described for the foraminal (V2) segment of the VA, those involving its V3 portion (between the C2 transverse process and dura) have not been investigated and may be of importance for procedures targeting the third occipital nerve or the lateral atlantoaxial joint. METHODS: Five hundred computed tomography angiograms of the neck performed in patients older than 50 years for the management of cerebrovascular accident or cervical trauma (between January 2010 and May 2016) were retrospectively and independently reviewed by 2 neuroradiologists. Courses of the VA in relation to the lateral aspect of the C2/C3 joint and the posterior surface of the C1/C2 joint were examined. For the latter, any medial encroachment of the VA (or one of its branches) was noted. The presence of a VA loop between C1 and C2 and its distance from the upper border of the superior articular process (SAP) of C3 were also recorded. If the VA loop coursed posteriorly, its position in relation to 6 fields found on the lateral aspects of the articular pillars of C2 and C3 was tabulated. RESULTS: At the C1/C2 level, the VA coursed medially over the lateral quarter of the dorsal joint surface in 1% of subjects (0.6% and 0.4% on the left and right sides, respectively; P = 0.998). A VA loop originating between C1 and C2 was found to travel posteroinferiorly over the anterolateral aspect of the inferior articular pillar of C2 in 55.5% of patients on the left and 41.9% on the right side (P < 0.001), as well as over the SAP of C3 in 0.4% of subjects. When present in the quadrant immediately cephalad to the C3 SAP, VA loops coursed within 2.0 ± 1.5 and 3.3 ± 2.5 mm on the left and right sides, respectively, of its superior aspect (P < 0.001). CONCLUSIONS: The VA commonly travels adjacent to areas targeted by third occipital nerve procedures and more rarely over the access point for lateral atlantoaxial joint injections. Modifications to existing techniques may reduce the risk of accidental VA breach.

ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodically exuberant heterotopic ossification (HO), whereby skeletal muscle is abnormally converted into misplaced, but histologically normal bone. This HO leads to progressive immobility with catastrophic consequences, including death by asphyxiation. FOP results from mutations in the intracellular domain of the type I BMP (bone morphogenetic protein) receptor ACVR1; the most common mutation alters arginine 206 to histidine (ACVR1(R206H)) and has been thought to drive inappropriate bone formation as a result of receptor hyperactivity. We unexpectedly found that this mutation rendered ACVR1 responsive to the activin family of ligands, which generally antagonize BMP signaling through ACVR1 but cannot normally induce bone formation. To test the implications of this finding in vivo, we engineered mice to carry the Acvr1(R206H) mutation. Because mice that constitutively express Acvr1[R206H] die perinatally, we generated a genetically humanized conditional-on knock-in model for this mutation. When Acvr1[R206H] expression was induced, mice developed HO resembling that of FOP; HO could also be triggered by activin A administration in this mouse model of FOP but not in wild-type controls. Finally, HO was blocked by broad-acting BMP blockers, as well as by a fully human antibody specific to activin A. Our results suggest that ACVR1(R206H) causes FOP by gaining responsiveness to the normally antagonistic ligand activin A, demonstrating that this ligand is necessary and sufficient for driving HO in a genetically accurate model of FOP; hence, our human antibody to activin A represents a potential therapeutic approach for FOP.

Mineralocorticoid receptor antagonists attenuate pulmonary inflammation and bleomycin-evoked fibrosis in rodent models.

Accumulating evidence indicates protective actions of mineralocorticoid antagonists (MR antagonists) on cardiovascular pathology, which includes blunting vascular inflammation and myocardial fibrosis. We examined the anti-inflammatory and anti-fibrotic potential of MR antagonists in rodent respiratory models. In an ovalbumin allergic and challenged Brown Norway rat model, the total cell count in nasal lavage was 29,348 ± 5451, which was blocked by spironolactone (0.3-60 mg/kg, p.o.) and eplerenone (0.3-30 mg/kg, p.o.). We also found that MR antagonists attenuated pulmonary inflammation in the Brown Norway rat. A series of experiments were conducted to determine the actions of MR blockade in acute/chronic lung injury models. (1) Ex vivo lung slice rat experiments found that eplerenone (0.01 and 10 µM) and spironolactone (10 µM) diminished lung hydroxyproline concentrations by 55 ± 5, 122 ± 9, and 83 ± 8%. (2) In in vivo studies, MR antagonists attenuated the increases in bronchioalveolar lavage (BAL) neutrophils and macrophages caused by lung bleomycin exposure. In separate studies, bleomycin (4.0 U/kg, i.t.) increased lung levels of hydroxyproline by approximately 155%, which was blocked by spironolactone (10-60 mg/kg, p.o.). In a rat Lipopolysaccharide (LPS) model, spironolactone inhibited acute increases in BAL cytokines with moderate effects on neutrophils. Finally, we found that chronic LPS exposure significantly increased end expiratory lung and decreased lung elastance in the mouse. These functional effects of chronic LPS were improved by MR antagonists. Our results demonstrate that MR antagonists have significant pharmacological actions in the respiratory system.

Steroidal C-21 heteroaryl thioethers. Part 3: pregn-4-eno-[3,2-c]pyrazole fused A ring modified steroids as selective glucocorticoid receptor modulators (dissociated steroids).

The introduction of A ring pyrazole modification to the hydrocortisone C-21 heteroaryl thioethers generated compounds with excellent transrepression potency (IL-8 inhibition) compared to their hydrocortisone analogs. However, the transcriptional transactivation activity of these compounds were considerably higher than the corresponding hydrocortisone analogs. Among all the compounds evaluated, a quinoxaline thioether modification demonstrated the best overall in vitro separation.

Steroidal C-21 heteroaryl thioethers (Part 2): discovery of orally bioavailable selective glucocorticoid receptor modulators (dissociated steroids).

The prednisolone C-21 heteroaryl thioethers have been synthesized and evaluated in cell based transrepression and transactivation assays. Most of the compounds demonstrated weak transactivational activity in both human and rat tyrosineaminotransferase functional assay while keeping potent anti-inflammatory activity. The benzimidazole thioether 7 exhibited comparable anti-inflammatory activity and improved safety profile compared to the classical oral steroid prednisolone.

Estenosis del canal auditivo interno (CAI): hallazgos por imagen / Internal auditory canal (IAC) stenosis: imaging findings

Objetivos: Describir los hallazgos por imagen en tomografía computarizada (TAC ) y resonancia magnética (RM) en una paciente con estenosis del CAI. Describir el desarrollo embriológico de las estructuras del CAI y la historia natural de la estenosis del CAI . Métodos: Se presenta el caso de una paciente de 4 años de edad con diagnóstico de cardiopatía congénita, hipoacusia neurosensorial (HNS ) y otitis media recurrente bilateral, y a quien se realizó TAC del hueso temporal con imágenes axiales y reconstrucciones coronales, en las cuales se observa disminución del diámetro de la luz del CAI izquierdo (menor de 2 mm), ausencia del CAI derecho y estructuras del oído interno de características normales, compatibles con estenosis del CAI izquierdo. Las imágenes de RM demuestran la estenosis del CAI izquierdo, sin observarse las estructuras nerviosas dentro de éste, compatible con hipoplasia/aplasia del nervio vestibulococlear. Resultados: Se describen brevemente la patología, el origen embriológico y la importancia de la asociación de la estenosis delCAI a hipoplasia/aplasia del nervio vestibulococlear en el diagnóstico diferencial de las causas de HNS , que contraindican la realización de implante coclear. Conclusiones: La estenosis del CAI e hipoplasia/aplasia del nervio vestibulococlear es un diagnóstico para tener en cuenta dentro de las causas de HNS , y su diagnóstico puede realizarse a través de TAC y de RM.

Objectives: To describe the computed tomography (CT) and magnetic resonance (MR) findings in a patient with a diagnosis of internal auditory canal (IAC) stenosis. To describe the embryological development of the IAC structures and the natural history of IAC stenosis. Methods: A 4 year old girl presents with sensorineural hearing loss and bilateral recurrent otitis media. The temporal bone CT shows diminished left IAC diameter (less than 2 mm),right IAC absence and normal inner ear structures. These findings are pathognomonic for left IAC stenosis. The MR findings include left IAC stenosis and IAC neural structures absence secondary to aplasia of the vestibulocochlear nerve on each IAC . Results: Hypoplasia/aplasia of the vestibulocochlear nerve in association with IAC stenosis is an important consideration in the differential diagnosis of sensorineural hearing loss, as it is a relative contraindication for cochlear implant placement. Conclusions: IAC stenosis and vestibulocochlear nerve hypoplasia/aplasia must be excluded as an etiology of sensorineural hearing loss. The diagnosis can be made by CT and MR.

Concomitant activity of histamine and cysteinyl leukotrienes on porcine nasal mucosal vessels and nasal inflammation in the rat.

BACKGROUND: Histamine and cysteinyl leukotrienes are pivotal mast cell mediators which contribute considerably and likely complementary to the symptoms of allergic rhinitis. Currently, we sought to explore the direct actions of histamine and leukotriene D(4) (LTD(4)), a cysteinyl leukotriene, on porcine nasal arteries and veins. We also studied combined blocks of histamine and cysteinyl leukotrienes using loratadine and montelukast in an in vivo model of allergy-mediated nasal inflammation. METHODS: For the evaluation of the action of histamine and LTD(4) on arteries and veins, porcine nasal mucosa was isolated and cut into slices (100-300 microm thick). Real-time images of the nasal arteries and veins were recorded and vessel activities estimated by changes in cross-sectional area before and after the tested drugs. For the in vivo studies, the effect of loratadine and montelukast given alone and in combination was examined on upper airway inflammation in ovalbumin-sensitized and -challenged Brown Norway rats. RESULTS: Both histamine (0.001-10 micromol/l) and LTD(4) (0.001-10 micromol/l) produced a concentration-dependent increase in the lumen area of nasal mucosa arteries and veins. Histamine (0.01 micromol/l) alone produced a 24 and 12% increase in cross-sectional areas of arteries and veins, respectively. LTD(4) (0.001 micromol/l) alone increased artery and vein dilation by about 17 and 9%, respectively. Combination treatment with histamine (0.01 micromol/l) and LTD(4) (0.001 micromol/l) increased vessel dilation by 65% (arteries) and 26% (veins). In our in vivo Brown Norway rat studies, oral loratadine (0.01-10 mg/kg) and montelukast (0.01-10 mg/kg) significantly reduced antigen-induced total nasal inflammatory cell infiltration in a dose-dependent manner. The antiinflammatory dose-response curve of loratadine was shifted to the left when studied in combination with montelukast (0.01 mg/kg). Similarly, the dose-response characteristics of montelukast (0.01-10 mg/kg) was shifted in the presence of loratadine (0.01 mg/kg). CONCLUSION: Our studies support the position that histamine and cysteinyl leukotrienes may act collaboratively to elicit allergic nasal pathologies such as upper airway inflammation and nasal vessel dilation (which may translate into increased nasal mucosal engorgement). Furthermore, the current results are supportive of the hypothesis that combined treatment of allergic rhinitis with an H(1) receptor antagonist and a CysLT(1) receptor antagonist may have greater benefit than sole treatment with these agents alone.