Prospective study of HDR brachytherapy (BT), external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT): 10-years experience of an MRI-guided approach.

OBJECTIVES: To evaluate the predictive factors for biochemical failure and distant metastases in a prospective cohort of patients with localized prostate cancer treated with the combination of HDR BT and EBRT. METHODS AND MATERIALS: Patients with intermediate (IR) or high-risk (HR) prostate adenocarcinoma received a single fraction of HDR of 15 Gy combined with RT of 37.5 Gy in 15 fractions. ADT duration was used depending on risk-group. Descriptive analyses were performed. Univariate and multivariate Hazard Ratios were obtained. Finally, the Kaplan-Meier model was used to describe the survival of the events of interest. RESULTS: 309 patients were treated prospectively (199 were IR and 110 HR). Median age was 72 years; 58.3 % were MRI stage ≤ T2c, 34.1 % T3a and 7.6 % T3b; ISUP-grade 1-3 in 78.9 % and ISUP 4-5 in 21.1 %. 71.8 % of patients had ≤ 50 % positive-cores in biopsy and 28.2 % had > 50 %. Median pre-treatment PSA was 9.9 ng/mL. After a median follow-up of 88 months, 41 patients presented biochemical failure and 18 developed distant metastases. Multivariate cox-regression analyses found that MR-T3b Stage (HR 3.88, p = 0.001) and ADT use (HR 3.99, p = 0.03) were the only predictive factors for biochemical failure and the number of positive cores (>50 %) the only independent predictive factor of distant metastases (HR 4.36, p = 0.002). CONCLUSIONS: Patients with mpMRI evidence of invasion of the SV and involvement of more than 50% of the cores in the prostate biopsy are patients with a higher risk of presenting a biochemical recurrence or developing metastasis due to their prostate cancer, respectively.

3D Printing and Surgical Simulation for Management of Large and Giant Congenital Melanocytic Nevi.

Tissue expansion with subsequent adjacent tissue transfer is often the preferred and sometimes the only option for reconstruction of large and giant congenital melanocytic nevi. Successful reconstruction with maximal efficiency and optimal aesthetic outcome requires careful planning of the tissue transfer, which itself requires careful selection of the tissue expander size and positioning. Unfortunately, there is little opportunity to gain experience in these skills due to the rarity of this condition. In situations where there is a rare condition that requires a complex technical procedure with much interoperative decision-making, surgical experience can be supplemented with the use of surgical simulation. In this article, we report on the use of three-dimensional patient imaging, three-dimensional printing, and surgical simulation for planning the reconstruction of large and giant congenital melanocytic nevi. We describe how this technology allows us to simulate multiple different approaches to expander placement and adjacent tissue transfer. We also describe how these simulations can be used to create cutting guides to guide final incision design and reduce intraoperative decision-making. Finally, we discuss how these models can be used to educate patients and families about the process and outcomes of nevus excision and reconstruction.

Design, synthesis and antiplasmodial evaluation of new amide-, carbamate-, and ureido-type harmicines.

Malaria, one of the oldest parasitic diseases, remains a global health threat, and the increasing resistance of the malaria parasite to current antimalarials is forcing the discovery of new, effective drugs. Harmicines, hybrid compounds in which harmine/ß-carboline alkaloids and cinnamic acid derivatives are linked via an amide bond or a triazole ring, represent new antiplasmodial agents. In this work, we used a multiple linear regression technique to build a linear quantitative structure-activity relationship (QSAR) model, based on a group of 40 previously prepared amide-type (AT) harmicines and their antiplasmodial activities against erythrocytic stage of chloroquine-sensitive strain of P. falciparum (Pf3D7). After analysing the QSAR model, new harmicines were designed and synthesized: six amide-type, eleven carbamate-type and two ureido-type harmicines at the N-9 position of the ß-carboline core. Subsequently, we evaluated the antiplasmodial activity of the new harmicines against the erythrocytic and hepatic stages of the Plasmodium life cycle in vitro and their antiproliferative activity against HepG2 cells. UT harmicine (E)-1-(2-(7-methoxy-1-methyl-9H-pyrido[3,4-b]indol-9-yl)ethyl)-3-(3-(3-(trifluoromethyl)phenyl)allyl)urea at the N-9 position of the ß-carboline ring exhibited pronounced antiplasmodial activity against both the erythrocytic and the hepatic stages of the Plasmodium life cycle, accompanied by good selectivity towards Plasmodium.

Size And Locomotor Ecology Have Differing Effects on the External and Internal Morphologies of Squirrel (Rodentia: Sciuridae) Limb Bones.

Mammals exhibit a diverse range of limb morphologies that are associated with different locomotor ecologies and structural mechanics. Much remains to be investigated, however, about the combined effects of locomotor modes and scaling on the external shape and structural properties of limb bones. Here, we used squirrels (Sciuridae) as a model clade to examine the effects of locomotor mode and scaling on the external shape and structure of the two major limb bones, the humerus and femur. We quantified humeral and femoral morphologies using 3D geometric morphometrics and bone structure analyses on a sample of 76 squirrel species across their four major ecotypes. We then used phylogenetic generalized linear models to test how locomotor ecology, size, and their interaction influenced morphological traits. We found that size and locomotor mode exhibit different relationships with the external shape and structure of the limb bones, and that these relationships differ between the humerus and femur. External shapes of the humerus and, to a lesser extent, the femur are best explained by locomotor ecology rather than by size, whereas structures of both bones are best explained by interactions between locomotor ecology and scaling. Interestingly, the statistical relationships between limb morphologies and ecotype were lost when accounting for phylogenetic relationships among species under Brownian motion. That assuming Brownian motion confounded these relationships is not surprising considering squirrel ecotypes are phylogenetically clustered; our results suggest that humeral and femoral variation partitioned early between clades and their ecomorphologies were maintained to the present. Overall, our results show how mechanical constraints, locomotor ecology, and evolutionary history may enact different pressures on the shape and structure of limb bones in mammals.

EspañolLos mamíferos exhiben una amplia gama de morfologías de las extremidades, las cuales están asociadas con diferentes ecologías de locomoción y mecánicas estructurales. Sin embargo, aún queda mucho por investigar sobre cómo los tipos de locomoción y el tamaño corporal han afectado conjuntamente la forma externa y las propiedades estructurales de los huesos de las extremidades. En este estudio, usamos al clado de las ardillas (Sciuridae) como un modelo para examinar los efectos del tipo de locomoción y el tamaño en la forma externa y la estructura de los dos huesos principales de las extremidades, el húmero y el fémur. Utilizando morfometría geométrica en 3D y análisis de estructura ósea, cuantificamos la morfología humeral y femoral en una muestra de 76 especies de ardillas que abarcan sus cuatro ecotipos principales. Posteriormente, usamos modelos filogenéticos generalizados lineales para investigar cómo la ecología locomotora, el tamaño, y la interacción entre estos factores influencian los rasgos morfológicos. Encontramos que el tamaño y el tipo de locomoción exhiben diferentes relaciones con la forma externa y la estructura de los huesos de las extremidades, y que estas relaciones difieren entre el húmero y el fémur. La variación de la forma externa del húmero y, en menor medida, del fémur está más relacionada con la ecología locomotora que con el tamaño. Por otro lado, las diferencias en la estructura de ambos huesos se explican mejor por una combinación de efectos de la ecología locomotora y el tamaño. Curiosamente, las relaciones estadísticas entre la morfología de las extremidades y el ecotipo se pierden al incorporar las relaciones filogenéticas entre las especies bajo un modelo de movimiento browniano. El hecho de que asumir un modelo de movimiento browniano modifique estas relaciones no es sorprendente, considerando que los ecotipos de ardillas están agrupados filogenéticamente. Nuestros resultados además sugieren que la variación en morfología humeral y femoral se dividieron tempranamente entre clados y estas ecomorfologías se mantuvieron hasta el presente.En general, nuestros resultados demuestran cómo las restricciones mecánicas, la ecología locomotora y la historia evolutiva pueden ejercer diferentes presiones sobre la forma y la estructura de los huesos de las extremidades en los mamíferos.

Utility of a buccal swab point-of-care test for the IFNL4 genotype in the era of direct acting antivirals for hepatitis C virus.

BACKGROUND: The CC genotype of the IFNL4 gene is known to be associated with increased Hepatitis C (HCV) cure rates with interferon-based therapy and may contribute to cure with direct acting antivirals. The Genedrive® IFNL4 is a CE marked Point of Care (PoC) molecular diagnostic test, designed for in vitro diagnostic use to provide rapid, real-time detection of IFNL4 genotype status for SNP rs12979860. METHODS: 120 Participants were consented to a substudy comparing IFNL4 genotyping results from a buccal swab analysed on the Genedrive® platform with results generated using the Affymetix UK Biobank array considered to be the gold standard. RESULTS: Buccal swabs were taken from 120 participants for PoC IFNL4 testing and a whole blood sample for genetic sequencing. Whole blood genotyping vs. buccal swab PoC testing identified 40 (33%), 65 (54%), and 15 (13%) had CC, CT and TT IFNL4 genotype respectively. The Buccal swab PoC identified 38 (32%) CC, 64 (53%) CT and 18 (15%) TT IFNL4 genotype respectively. The sensitivity and specificity of the buccal swab test to detect CC vs non-CC was 90% (95% CI 76-97%) and 98% (95% CI 91-100%) respectively. CONCLUSIONS: The buccal swab test was better at correctly identifying non-CC genotypes than CC genotypes. The high specificity of the Genedrive® assay prevents CT/TT genotypes being mistaken for CC, and could avoid patients being identified as potentially 'good responders' to interferon-based therapy.

Entorno inflamatorio diferencial en pacientes con osteoporosis y diabetes mellitus tipo 2 / Differential inflammatory environment in patients with osteoporosis and type 2 diabetes mellitus

Objetivo: La diabetes mellitus tipo 2 (DM2) y la osteoporosis son enfermedades asociadas con un entorno pro-inflamatorio, cuya prevención mediante nuevas estrategias terapéuticas podría evitar su desarrollo. Sin embargo, existe un escaso número de estudios que evalúen el perfil inflamatorio de la osteoporosis en pacientes con DM2.El objetivo de este estudio se centró en evaluar la respuesta inflamatoria inmunitaria mediante concentraciones séricas de nueve citocinas, dos de ellas de carácter anti-inflamatorio (IL-10, IL-5) y seis pro-inflamatorias (IL-2, IL-6, IL-12 (p70), IL-17A, TNFα e IFNɣ) en 163 individuos con DM2 y 47 controles. Una subpoblación, formada por 43 pacientes DM2 sin osteoporosis, y 33 con osteoporosis, fue analizada en más profundidad a nivel de parámetros óseos. Además, hemos evaluado las hormonas calciotropas, los marcadores de remodelado óseo, densidad mineral ósea y fracturas vertebrales en la población, y hemos analizado la relación de las citocinas ensayadas con la DM2, la osteoporosis y las fracturas vertebrales prevalentes.Los pacientes con DM2 tenían concentraciones séricas significativamente más altas de IL-10 en comparación con el grupo control (0,5±1 vs. 0,14±0,3 pg/ml; p=0,016) y los niveles de IL-12 p70 se mostraron más bajos en pacientes con DM2 respecto a los controles (2,9±1,6 vs. 3,9±3,1 pg/ml; p=0,027).En el grupo de pacientes con DM2 y osteoporosis, los niveles de la citocina IL-6 resultaron elevados respecto al grupo de DM2 sin osteoporosis (10,9±14,6 vs. 4,5±7,0; p=0,017). También se observó una asociación de IL-5, siendo sus niveles más bajos en el grupo DM2 con osteoporosis (1,7±0,2 vs. 3,8±0,6; p=0,032). Además, la IL-5 mostró una correlación directa con los niveles del biomarcador de formación ósea fosfatasa alcalina ósea (r=0,277, p=0,004) en la subpoblación de pacientes con DM2. El resto de citocinas no mostraron diferencias significativas. (AU)

Upper motor neurons are a target for gene therapy and UCHL1 is necessary and sufficient to improve cellular integrity of diseased upper motor neurons.

There are no effective cures for upper motor neuron (UMN) diseases, such as amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and hereditary spastic paraplegia. Here, we show UMN loss occurs independent of spinal motor neuron degeneration and that UMNs are indeed effective cellular targets for gene therapy, which offers a potential solution especially for UMN disease patients. UCHL1 (ubiquitin C-terminal hydrolase-L1) is a deubiquitinating enzyme crucial for maintaining free ubiquitin levels. Corticospinal motor neurons (CSMN, a.k.a UMNs in mice) show early, selective, and profound degeneration in Uchl1nm3419 (UCHL1-/-) mice, which lack all UCHL1 function. When UCHL1 activity is ablated only from spinal motor neurons, CSMN remained intact. However, restoring UCHL1 specifically in CSMN of UCHL1-/- mice via directed gene delivery was sufficient to improve CSMN integrity to the healthy control levels. In addition, when UCHL1 gene was delivered selectively to CSMN that are diseased due to misfolded SOD1 toxicity and TDP-43 pathology via AAV-mediated retrograde transduction, the disease causing misfolded SOD1 and mutant human TDP-43 were reduced in hSOD1G93A and prpTDP-43A315T models, respectively. Diseased CSMN retained their neuronal integrity and cytoarchitectural stability in two different mouse models that represent two distinct causes of neurodegeneration in ALS.

Efecto de la suplementación con vitamina D en los efectos secundarios musculoesqueléticos relacionados con los inhibidores de la aromatasa para el cáncer de mama: cohorte B-ABLE / Effect of vitamin D supplementation on aromatase inhibitor-related musculoskeletal side effects for breast cancer: B-ABLE cohort

Objetivo: Evaluar el efecto de la suplementación con vitamina D en las complicaciones musculoesqueléticas relacionadas con el tratamiento con inhibidores de la aromatasa (IA) en pacientes con cáncer de mama. Material y métodos: Estudio observacional prospectivo de mujeres en tratamiento con IA, reclutadas en la cohorte B-ABLE. Las pacientes con niveles séricos iniciales de 25(OH)D (25-hidroxivitamina D) <30 ng/ml recibieron una dosis de 16.000 UI de calcifediol oral cada 2 semanas. La artralgia y la pérdida ósea relacionadas con los IA se evaluaron a los 3 meses y al año de seguimiento, respectivamente. Los análisis de asociación del status de vitamina D a los 3 meses con eventos musculoesqueléticos se realizaron mediante modelos de regresión lineal multivariante ajustados. Además, se evaluó la asociación del dolor incidente, definido como pacientes sin dolor articular inicial, pero con una escala visual analógica (EVA) >0 a los 3 meses, mediante regresión logística. Resultados: La suplementación con vitamina D al inicio del tratamiento con IA disminuyó el riesgo tanto de artralgia incidente como de su empeoramiento. El umbral efectivo de 25(OH)D en suero para reducir el dolor articular se estableció en 40 ng/ml. Sin embargo, este umbral no se relacionó significativamente con los cambios óseos al año de seguimiento. No obstante, los niveles de vitamina D se correlacionaron inversamente con la pérdida ósea de la columna lumbar (CL) (β=0,177% [IC 95%: 0,014 a 0,340]). Conclusiones: La administración de suplementos de vitamina D con el objetivo de alcanzar niveles séricos de 25OHD de al menos 40 ng/ml es protectora para la artralgia. Los niveles de vitamina D a los tres meses podrían predecir el riesgo de pérdida ósea en CL al año de tratamiento con IA. Por lo tanto, se recomiendan dosis altas de vitamina D en estas pacientes, que son más propensas a sufrir afecciones musculoesqueléticas. (AU)

Objetive: To assess the effect of vitamin D supplementation on musculoskeletal complications related to aromatase inhibitor (AI) treatment in patients with breast cancer. Material and methods: Prospective observational study of women undergoing AI treatment, recruited in the B-ABLE cohort. Patients with baseline serum 25 (OH) D (25-hydroxyvitamin D) levels <30 ng/ml received a 16,000 IU dose of oral calcifediol every 2 weeks. Arthralgia and bone loss related to AIs were assessed at 3 months and 1 year of followup, respectively. The association analyzes of vitamin D status at 3 months with musculoskeletal events were carried out using adjusted multivariate linear regression models. In addition, the association of incident pain, defined as patients without initial joint pain, but with a visual analog scale (VAS) >0 at 3 months, was evaluated using logistic regression. Results: Vitamin D supplementation at the start of AI treatment decreased the risk of both incident arthralgia and its worsening. The effective threshold of 25 (OH) D in serum to reduce joint pain was established at 40 ng/ml. However, this threshold was not significantly related to bone changes at one year of follow-up. However, vitamin D levels were inversely correlated with lumbar spine bone loss (LS) (β=0.177% [95% CI: 0.014 to 0.340]). Conclusions: Vitamin D supplementation aimed at achieving serum 25(OH)D levels of at least 40 ng/ml is protective for arthralgia. Vitamin D levels at three months could predict the risk of bone loss in LS at one year of AI treatment. Therefore, high doses of vitamin D are recommended in these patients, who are more prone to musculoskeletal conditions. (AU)

Sensory adaptations reshaped intrinsic factors underlying morphological diversification in bats.

BACKGROUND: Morphological evolution may be impacted by both intrinsic (developmental, constructional, physiological) and extrinsic (ecological opportunity and release) factors, but can intrinsic factors be altered by adaptive evolution and, if so, do they constrain or facilitate the subsequent diversification of biological form? Bats underwent deep adaptive divergences in skull shape as they evolved different sensory modes; here we investigate the potential impact of this process on two intrinsic factors that underlie morphological variation across organisms, allometry, and modularity. RESULTS: We use comparative phylogenetic and morphometric approaches to examine patterns of evolutionary allometry and modularity across a 3D geometric morphometric dataset spanning all major bat clades. We show that allometric relationships diverge between echolocators and visually oriented non-echolocators and that the evolution of nasal echolocation reshaped the modularity of the bat cranium. CONCLUSIONS: Shifts in allometry and modularity may have significant consequences on the diversification of anatomical structures, as observed in the bat skull.

TICACOS international: A multi-center, randomized, prospective controlled study comparing tight calorie control versus Liberal calorie administration study.

Since the first TICACOS study, 3 additional studies have been published comparing a medical nutrition therapy guided by indirect calorimetry to a regimen prescribed on the basis of predictive equations. A recent guidelines document included a meta-analysis including these 4 papers and found a trend for improvement (OR 0.98-1.48) in favor of medical nutrition therapy guided by indirect calorimetry in terms of survival. The aim of our study was to perform a multicenter prospective, randomized, controlled non blinded study in critically patients to assess the added value for measuring daily resting energy expenditure as a guide for nutritional support. The primary objective was to decrease infectious rate of these critically ill patients. MATERIAL AND METHODS: This phase III, multi-center, randomized, controlled non blinded study was planned to include 580 newly-admitted, adult ventilated ICU patients that were planned to stay more than 48 h in the ICU departments. The nutritional support was aimed to meet 80-100% of energy requirement measured by indirect calorimetry. The calorie needs were determined by IC in the Study group and by an equation (20-25 kcal/kg ideal body weight/day) in the Control Group. The ICU staff was trained to strive to supply 80-100% of a patient's energy requirements through artificial nutrition, preferably enteral feeding. Primary endpoint was infection rate and secondary endpoints included other morbidities and mortality during ICU, at 90 and 180 days. Comparison between the study and the control group was performed using T test for equality of means (independent samples test). Correlations were performed using the Pearson correlation test. A p level of 0.05 or below was considered as significant. Cross tabs procedure used Chi-square test for testing differences in complication rates, length of stay and length of ventilation. Correlations between energy balances and complications was also be tested using one way analysis as well as ANOVA analysis between groups and within groups. Kaplan Meir curves assessed the proportion of surviving patients in the 2 groups. RESULTS: Seven centers with a calorimeter available participated to the study. Due to slow inclusion rate, the study was stopped after 6 years and after inclusion of 417 patients only. From the 417 intended to treat patients, 339 followed the protocol. There was no differences between control and study groups in terms of age, sex BMI, SOFA (7.1 ± 3.1 vs 7.4 ± 3.3) and APACHE II scores (22.4 ± 7.9 vs 22.2 ± 7.4). The rate of infection (40 vs 31), including pneumonia rate, need for surgery, dialysis requirement, length of ventilation, ICU length of stay, and hospital length of stay were not different between groups. Mortality (30 in the control vs 21 in the study group) was not significantly different between groups. The decreased mortality observed in the study group when added to previous studies may have a positive effect on the meta-analysis previously published. CONCLUSION: Tight Calorie Control guided by indirect calorimetry decreased the rate of infection and mortality but not significantly. This may be explained by the not relatively small sample size. There results together with the previous 4 prospective randomized studies, may improve the results of the meta-analysis exploring the effects of IC guided nutrition on mortality.

Recomendaciones para el tratamiento nutrometabólico especializado del paciente crítico: consecuencias de la desnutrición en el paciente crítico y valoración del estado nutricional. Grupo de Trabajo de Metabolismo y Nutrición de la Sociedad Española de Medicina Intensiva, Crítica y Unidades Coronarias (SEMICYUC) / Recommendations for specialized nutritional-metabolic management of the critical patient: Consequences of malnutrition in the critically ill and assessment of nutritional status. Metabolism and Nutrition Working Group of the Spanish Society of Intensive and Critical Care Medicine and Coronary Units (SEMICYUC)

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A Fruitful Endeavor: Scent Cues and Echolocation Behavior Used by Carollia castanea to Find Fruit.

Frugivores have evolved sensory and behavioral adaptations that allow them to find ripe fruit effectively, but the relative importance of different senses in varying foraging scenarios is still poorly understood. Within Neotropical ecosystems, short-tailed fruit bats (Carollia: Phyllostomidae) are abundant nocturnal frugivores that rely primarily on Piper fruits as a food resource. Previous research has demonstrated that Carollia employs olfaction and echolocation to locate Piper fruit, but it is unknown how their sensory use and foraging decisions are influenced by the complex diversity of chemical cues that fruiting plants produce. Using free-ranging C. castanea and their preferred food, Piper sancti-felicis, we conducted behavioral experiments to test two main hypotheses: (1) foraging decisions in C. castanea are primarily driven by ripe fruit scent and secondarily by vegetation scent, and (2) C. castanea re-weights their sensory inputs to account for available environmental cues, with bats relying more heavily on echolocation in the absence of adequate scent cues. Our results suggest that C. castanea requires olfactory information and relies almost exclusively on ripe fruit scent to make foraging attempts. Piper sancti-felicis ripe fruit scent is chemically distinct from vegetation scent; it is dominated by 2-heptanol, which is absent from vegetation scent, and has a greater abundance of ß-caryophyllene, ß-ocimene, γ-elemene, and α-cubebene. Although variation in echolocation call parameters was independent of scent cue presence, bats emitted longer and more frequent echolocation calls in trials where fruit scent was absent. Altogether, these results highlight the adaptations and plasticity of the sensory system in neotropical fruit bats.

Los frugívoros han evolucionado adaptaciones sensoriales y conductuales que les permiten encontrar frutos maduros de manera efectiva, pero aún existe una falta de conocimiento sobre la importancia relativa de los diferentes sentidos que los frugívoros utilizan en diferentes escenarios de forrajeo. Dentro de los ecosistemas neotropicales, los murciélagos de cola corta (Carollia: Phyllostomidae) son frugívoros nocturnos abundantes que dependen principalmente de los frutos de Piper como recurso alimentario. Previamente se ha demostrado que Carollia emplea el olfato y la ecolocalización para encontrar frutos de Piper, pero se desconoce cómo su uso sensorial y decisiones de forrajeo están influenciados por la compleja diversidad de señales químicas producidas por las plantas. En este trabajo, utilizamos C. castanea y su especie de frutos preferida, Piper sancti-felicis, para llevar a cabo experimentos conductuales y probar dos hipótesis principales: (1) las decisiones de forrajeo de C. castanea son incitadas principalmente por el aroma del fruto maduro y, en segundo lugar, por el aroma de la vegetación, y (2) C. castanea modula el uso de sus sentidos de acuerdo a las señales ambientales disponibles y utiliza la ecolocalización en mayor grado en ausencia de señales olfativas adecuadas. Nuestros resultados sugieren que C. castanea requiere información olfativa y se basa casi exclusivamente en el aroma del fruto maduro para hacer intentos de forrajeo. El aroma del fruto maduro de P. sancti-felicis es químicamente distinto al aroma de su vegetación; está dominado por 2-heptanol, el cual está ausente del aroma de la vegetación, y tiene una mayor abundancia de ß-cariofileno, ß-ocimeno, γ-elemeno, y α-cubibeno. Aunque encontramos que la variación en los parámetros de llamadas de ecolocalización es independiente de la presencia de diferentes señales aromáticas, los murciélagos emitieron llamadas de ecolocalización más largas y frecuentes en los experimentos donde el aroma de fruto estaba ausente. Conjuntamente, estos resultados destacan las adaptaciones y plasticidad del sistema sensorial de los murciélagos frugívoros neotropicales.

Hipotiroidismo refractario idiopático: un caso clínico / Idiopathic refractory hypothyroidism: case report

Introducción: El hipotiroidismo constituye una patología frecuente, y su tratamiento habitual es el suplemento de levotiroxina (LT4) oral (VO). Sin embargo, existen casos inhabituales donde no es posible corregir esta condición a pesar de la utilización de LT4 en dosis alta. El hipotiroidismo refractario se define como la persistencia del hipotiroidismo a pesar del uso de LT4 > 1,9 ug/kg/día. La prevalencia del hipotiroidismo refractario no ha sido suficientemente documentada hasta ahora. Descripción del caso: Mujer de 53 años con antecedentes de hipotiroidismo, obesidad, dislipidemia, hipertensión arterial e insulinorresistencia. Fue derivada desde APS a nivel terciario por hipotiroidismo persistente a pesar del uso de LT4 800 ug/día y liotironina 80 ug/día. En forma ambulatoria se descartaron distintas causas, como mala adhesión al tratamiento, pseudo-malabsorción, síndromes de malabsorción; interacciones farmacológicas o interacciones alimentarias. Ante esto, y manteniéndose en su condición, se decide hospitalizar. Durante la hospitalización se prueban distintas fórmulas de administración. Finalmente, se logra respuesta adecuada con LT4 por vía rectal 100 ug/día asociado a 100 ug c/12 horas VO. Discusión: A pesar de no contar con herramientas óptimas para enfrentar este caso, se logró aplicar una estrategia sistemática especializada, que permitió un buen manejo de la paciente. Luego de probar distintas formulaciones de hormonas tiroideas, se logró respuesta mediante la administración por vía rectal, lo cual sugiere que esta paciente presentaba algún trastorno celular/bioquímico intestinal alto, que impedía la absorción óptima de LT4 VO. Conclusiones: La principal fortaleza de este trabajo consiste en la demostración de la utilidad práctica, en un contexto de recursos limitados, de una estrategia de estudio y tratamiento sistemático del hipotiroidismo refractario, lo cual ha sido escasamente publicado en la literatura internacional. Además, se recalca la importancia de una intervención especializada oportuna para evitar los riesgos sistémicos asociados a dosis altas de hormonas tiroideas.

Introduction: Hypothyroidism is a common condition, and its usual treatment is the supplement of oral levothyroxine (po). However, there are unusual cases where it is not possible to correct this condition despite the use of high-dose levothyroxine. Refractory hypothyroidism is defined as the persistence of hypothyroidism despite the use of levothyroxine > 1.9 ug/kg/ day. The prevalence of refractory hypothyroidism has not been sufficiently documented so far. Case description: 53 year old woman with a history of hypothyroidism, obesity, dyslipidemia, hypertension and insulin resistance. She was sent from primary care to tertiary level due to persistent hypothyroidism despite the use of 800 ug/day levothyroxine and liothyronine 80 ug/ day. On an outpatient basis, different causes were excluded as poor adherence to treatment, pseudo-malabsorption, malabsorption syndromes; drug interactions or food interactions. Given this, and staying on her condition, it was decided to hospitalize. Different forms of administration were tested during hospitalization. Finally, got adequate response with levothyroxine rectally 100 ug/day associated with 100 ug po bid. Discussion: Despite not having optimum tools to deal with this case, it was succeeded thanks to the implementation of a specialized systematic strategy. After testing different formulations of thyroid hormones, a positive response by rectal administration was achieved, which suggests that this patient presented any high intestinal cell/biochemist disorder that prevented the optimal absorption of levothyroxine po. Conclusions: The main strength of this work consists in demonstrating the practical utility, in a context of limited resources, of a study and systematic treatment strategy of refractory hypothyroidism, which has barely been published in the international literature. It is also highlighted the importance of an early specialized intervention to prevent the systemic risks associated with high doses of thyroid hormones.

Identificación de potenciales biomarcadores de calcificación vascular en pacientes con diabetes mellitus tipo 2 mediante el uso de herramientas bioinformáticas de libre acceso / Using free access bioinformatic tools to identify potential vascular calcification biomarkers in patients with diabetes mellitus type 2

Objetivos: Identificación de potenciales biomarcadores implicados en procesos de calcificación vascular para avanzar en el diagnóstico y tratamiento de esta patología en sus estadíos subclínicos. Métodos: Se trata de un trabajo experimental en el que se incluyeron 5 pacientes con diabetes mellitus tipo 2 (DM2) con enfermedad arterial periférica e isquemia crítica. Se realizó una extracción proteica e identificación del proteoma mediante cromatografía líquida y espectrometría de masas (LC-MS/MS) de secciones de arteria femoral calcificada. Las proteínas identificadas fueron analizadas a través de gene ontology y comparadas con otras proteínas específicas de patologías vasculares relacionadas mediante la base de datos DisGeNET. Mediante el programa informático Cytoscape se analizó la red de funciones biológicas de las proteínas seleccionadas para su clasificación en base a la patología en la que están implicadas. Resultados: Se identificaron 530 proteínas en las muestras analizadas con funciones mayoritariamente de unión a calcio y catalítica. 37 de ellas fueron comunes en otras patologías vasculares relacionadas. La exploración de las redes biológicas de las 37 proteínas identificadas, dio lugar a la identificación de 2 potenciales marcadores específicos de calcificación vascular en procesos ateroscleróticos, como la proteína mitocondrial de choque térmico de 10 kDa, y la subunidad flavoproteica de la succinato deshidrogenasa. Conclusiones: Existe una importante expresión de proteínas implicadas en procesos de mineralización ósea en tejido vascular calcificado, sugiriendo la existencia de mecanismos moleculares comunes entre la regulación ósea y vascular. El uso de herramientas bioinformáticas sugiere la implicación de la proteína de choque térmico de 10 kDa mitocondrial y la subunidad flavoproteica de la succinato deshidrogenasa como posibles biomarcadores de calcificación vascular en pacientes con DM2, aunque son necesarios estudios adicionales que confirmen esta hipótesis

Objectives: Identify potential biomarkers involved in vascular calcification processes to improve DM2 diagnosis and treatment in its subclinical stages. Methods: This experimental study included 5 patients suffering diabetes mellitus type 2 (DM2) with peripheral arterial disease and critical ischemia. Protein extraction and identification of the proteome were carried out using liquid chromatography and mass spectrometry (LC-MS/MS) of calcified femoral artery sections. The identified proteins were analyzed through gene ontology and compared with other specific proteins of related vascular pathologies through the DisGeNET database. Cytoscape software analyzed the network of biological functions of the proteins selected for classification based on the disease in which they are involved. Results: 530 proteins were identified in the analyzed samples with functions mainly of calcium binding and catalytic. 37 of them were common in other related vascular pathologies. The exploration of the biological networks of the 37 proteins identified, led to the identification of 2 potential specific markers of vascular calcification in atherosclerotic processes, such as 10-kDa thermal shock mitochondrial protein, and the flavoprotein subunit of succinate dehydrogenase. Conclusions: There is significant expression of proteins involved in processes of bone mineralization in calcified vascular tissue, suggesting the existence of common molecular mechanisms between bone regulation and vascular. The use of bioinformatics tools suggests the involvement of the mitochondrial 10 kDa heat shock protein and the subunit of the succinate dehydrogenase as potential biomarkers of vascular calcification in patients with DM2, although additional studies are needed to confirm this hypothesis

Serological evidence of widespread exposure of Grenada fruit bats to chikungunya virus.

Antibody detection against selected potentially zoonotic vector-borne alphaviruses and flaviviruses was conducted on sera from bats from all six parishes in Grenada, West Indies. Sera were tested for (i) antibodies to flaviviruses West Nile virus, St. Louis encephalitis virus, Ilhéus virus, Bussuquara virus (BSQV), Rio Bravo virus and all four serotypes of dengue virus (DENV) by plaque reduction neutralization test (PRNT); (ii) antibodies to alphaviruses western equine encephalitis virus, Venezuelan equine encephalitis virus and eastern equine encephalitis virus by epitope-blocking enzyme-linked immunosorbent assay (ELISA); and (iii) antibodies to the alphavirus chikungunya (CHIKV) by PRNT. Two species of fruit bats were sampled, Artibeus jamaicensis and Artibeus lituratus, all roosting in or within 1,000 m of human settlements. Fifteen (36%) of the 42 bats tested for neutralizing antibodies to CHIKV were positive. The CHIKV-seropositive bats lived in localities spanning five of the six parishes. All 43 bats tested for epitope-blocking ELISA antibody to the other alphaviruses were negative, except one positive for Venezuelan equine encephalitis virus. All 50 bats tested for neutralizing antibody to flaviviruses were negative, except one that had a BSQV PRNT80 titre of 20. The CHIKV serology results indicate that bats living close to and within human settlements were exposed to CHIKV in multiple locations. Importantly, bats for this study were trapped a year after the introduction and peak of the human CHIKV epidemic in Grenada. Thus, our data indicate that bats were exposed to CHIKV possibly during a time of marked decline in human cases.

[Candidemia and invasive candidiasis approach in critically ill patients: role of the echinocandins]. / Abordaje de la candidemia y la candidiasis invasiva en el paciente crítico: papel de las equinocandinas.

OBJECTIVE: Invasive infections caused by Candida spp. in critically ill patients may significantly worsen their prognosis, so it is of great importance to establish an early detection and a suitable therapeutic strategy. The objective of this study was to define the differential role of echinocandins in treating certain critical patient profiles. METHODS: A scientific committee of 9 experts in infectious diseases, critical care, microbiology, and hospital pharmacy reviewed the existing evidence on the treatment of candidemia and invasive candidiasis in critically ill patients. After that, a questionnaire with 35 items was elaborated to be agreed by 26 specialists in the aforementioned disciplines using a modified Delphi method. RESULTS: After two rounds of evaluation, a consensus was reached in terms of agreement in 66% of the items. Some of the consensuses achieved included: it is not necessary to adjust the dose of echinocandins during renal replacement therapy; the echinocandins are the empirical and/or directed treatment of choice for candidemia and invasive candidiasis associated with biofilms; these drugs may be used in the antifungal prophylaxis of high-risk liver transplantation. In the absence of additional clinical data, it should be noted that micafungin is the echinocandin with the most available scientific evidence. CONCLUSIONS: The experts consulted showed a high degree of agreement on some of the most controversial aspects regarding the management of candidemia and invasive candidiasis in critical patients, which could inform of practical recommendations for their treatment.

A Bigger Picture: Organismal Function at the Nexus of Development, Ecology, and Evolution: An Introduction to the Symposium.

Over the past 40 years of research, two perspectives have dominated the study of ecomorphology at ontogenetic and evolutionary timescales. For key anatomical complexes (e.g., feeding apparatus, locomotor systems, sensory structures), morphological changes during ontogeny are often interpreted in functional terms and linked to their putative importance for fitness. Across larger timescales, morphological transformations in these complexes are examined through character stability or mutability during cladogenesis. Because the fittest organisms must pass through ontogenetic changes in size and shape, addressing transformations in morphology at different time scales, from life histories to macroevolution, has the potential to illuminate major factors contributing to phenotypic diversity. To date, most studies have relied on the assumption that organismal form is tightly constrained by the adult niche. Although this could be accurate for organisms that rapidly reach and spend a substantial portion of their life history at the adult phenotype (e.g., birds, mammals), it may not always hold true for species that experience substantial growth after one or more major fitness filters during their ontogeny (e.g., some fishes, reptiles). In such circumstances, examining the adult phenotype as the primary result of selective processes may be erroneous as it likely obscures the developmental configuration of morphology that was most critical to early survival. Given this discrepancy-and its potential to mislead interpretations of how selection may shape a taxon's phenotype-this symposium addresses the question: how do we identify such ontogenetic "inertia," and how do we integrate developmental information into our phylogenetic, ecological, and functional interpretations of complex phenotypes?

Dickkopf1 (DKK1), metabolismo óseo y enfermedad ateroesclerótica en pacientes con diabetes mellitus tipo 2 / Serum dickkopf1 (DKK1), bone metabolism and atherosclerotic disease in patients with type 2 diabetes

Objetivos: La diabetes mellitus tipo 2 (DM2) se asocia a un incremento del riesgo de fracturas y de enfermedades cardiovasculares. Los objetivos de nuestro estudio fueron evaluar los niveles séricos de Dickkopf-1 (DKK1) en una cohorte de pacientes con DM2 y analizar su relación con el metabolismo óseo y la enfermedad ateroesclerótica (EA). Pacientes y métodos: Se estudiaron 126 sujetos: 72 pacientes con DM2 (edad media de 58,2±6 años) y 54 sujetos no diabéticos (edad media de 55,4±7 años). Se midió DKK1 mediante ensayo de inmunoabsorción ligado a enzimas (ELISA, Biomedica Gruppe), se determinó la densidad mineral ósea (DMO) mediante absorciometría dual de rayos X (DXA), se registró la presencia de EA (enfermedad cerebrovascular, enfermedad arterial periférica, cardiopatía isquémica) y se evaluó el grosor de la íntima-media (GIM, ultrasonografía doppler) y la calcificación aórtica (radiología simple). Resultados: No se encontraron diferencias significativas en DKK1 entre diabéticos y no diabéticos. Las concentraciones séricas de DKK1 fueron significativamente mayores en las mujeres de la muestra total (24,3±15,2 vs. 19,6±10,2 pmol/L, p=0,046) y del grupo DM2 (27,5±17,2 vs. 19,8±8,9 pmol/L, p=0,025). Hubo una correlación positiva entre DKK1 y DMO lumbar en la muestra total (r=0,183, p=0,048). Sin embargo, no se encontraron diferencias en función del diagnóstico de osteoporosis o presencia de fracturas vertebrales morfométricas. Los valores de DKK1 fueron significativamente mayores en los pacientes con DM2 y EA (26,4±14,5 pmol/L vs. 19,1±11,6 pmol/L, p=0,026) y también en pacientes con GIM anormal (26,4±15,1 pmol/L vs. 19,8±11,3 pmol/L, p=0,038). En el análisis de la curva ROC para evaluar la utilidad de DKK1 como un marcador de alto riesgo de EA, el área bajo la curva fue de 0,667 (intervalo de confianza -IC- del 95%: 0,538-0,795; p=0,016). Una concentración de 17,3 pmol/L o superior mostró una sensibilidad del 71,4% y una especificidad del 60% para identificar un mayor riesgo de EA. Conclusiones: Los niveles circulantes DKK1 son más altos en los diabéticos con EA y se asocian con un GIM patológico. Por tanto, consideramos que DKK1 puede estar implicado en la enfermedad vascular de los pacientes con DM2 (AU)

Background and objectives: Type 2 diabetes (T2DM) is a risk factor for osteoporotic fractures and cardiovascular disease. The aims of our study were to evaluate serum Dickkopf-1(DKK1) levels in a cohort of T2DM patients and to analyze its relationships with bone metabolism and atheroesclerotic disease (AD). Patients and methods: We studied 126 subjects: T2DM patients (n: 72, mean age 58,2±6 years) and non-diabetic subjects (n: 54, mean age 55,4±7 years). DKK-1 was measured by enzyme-linked immunosorbent assay (ELISA, Biomedica Gruppe). Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA). The presence of AD (cerebrovascular disease, peripheral arterial disease, ischemic heart disease) was recorded. Intima-media thickness (IMT) was determined by doppler ultra- sonography and aortic calcification by evaluation of lateral view conventional X-rays. Results: We did not find significant differences in DKK1 between groups. Serum DKK1 concentrations were significantly higher in females in total sample (24,3±15,2 vs 19,6±10,2 pmol/L, p=0,046) and in T2DM group (27,5±17,2 vs 19,8±8,9 pmol/L, p=0,025). There was a positive correlation between serum DKK1 and LS BMD in total sample (r=0,183, p=0,048). However, we did not find a significant relationship with osteoporosis diagnosis or morphometric vertebral fractures. Serum DKK1 was significantly higher in T2DM patients with AD (26,4±14,5 pmol/L vs 19,1±11,6 pmol/L, p=0,026) and also in patients with abnormal IMT (26,4±15,1 pmol/L vs 19,8±11,3 pmol/L, p=0,038). In the ROC curve analysis to evaluate the usefulness of DKK-1 as a marker for high risk of AD, the area under the curve was 0,667 (95% confidence interval: 0,538-0,795; p=0,016). A concentration of 17,3 pmol/L or higher showed a sensitivity of 71,4% and a specificity of 60% to identify an increased risk of AD. Conclusions: Circulating DKK1 levels are higher in T2DM with AD and are associated with an abnormal IMT in this cross-sectional study. DKK1 may be involved in vascular disease of T2DM patients (AU)