Diagnóstico oftalmológico del síndrome de linfedema-distiquiasis a través de la mutación FOXC2 / Ophthalmologic diagnosis of lymphedema-distichiasis syndrome through the FOXC2 mutation

El síndrome de linfedema-distiquiasis es uno de los fenotipos más frecuentes de aparición de linfedema primario; aun así, su prevalencia es baja.Este síndrome cursa con la aparición en la infancia o en la pubertad de pestañas aberrantes y otras formas de distiquiasis que pueden disminuir la calidad de vida, especialmente en pacientes en edades tan tempranas. La valoración clínica de este tipo de signos debe hacernos tener en mente este grupo de síndromes, ya que contamos, en este caso, con el diagnóstico de certeza gracias al análisis genético en suero del gen FOXC2, como ocurre en el caso que presentamos.De esta manera podemos prevenir, diagnosticar y tratar tanto los síntomas oftalmológicos como el resto de los síntomas sistémicos de forma precoz y más efectiva, aumentando así la calidad de vida de nuestros pacientes. (AU)

Lymphedema-distichiasis syndrome is one of the most frequent phenotypes of primary lymphedema, even so, its prevalence is still low.This syndrome courses with the appearance of abnormal eyelashes and distichiasis during childhood or puberty. This can cause a notable discomfort on our patients, especially at such an early age. The clinic evaluation of this signs must make us have in mind this group of syndromes, because in the case of lymphedema distichiasis syndrome, we can certainly diagnose it with the genetic analysis of the FOXC2 gen on patient's serum.With this we could prevent, diagnose and treat the ophthalmologic syndrome alongside the rest of systemic symptoms of this syndrome in a more effective way, giving our patients a higher quality of life. (AU)

MSH3-related adenomatous polyposis in a patient with the negative family history of colorectal polyps / Poliposis adenomatosa relacionada con MSH3 en un paciente con antecedentes familiares negativos de pólipos colorrectales

Recently, biallelic MSH3 germline pathogenic/likely pathogenic variants have been recognized as a rare cause of adenomatous polyposis. We present a 49-year-old woman who was admitted to our high-risk colorectal cancer clinic after incidental detection of a biallelic MSH3 (likely) pathogenic variant when tested for the germline (likely) pathogenic variants in hereditary breast and ovarian cancer related genes. The focus of this case report is to describe the genotype and phenotype of our patient with MSH3-related adenomatous polyposis. More than half of the polyps (13/19) were located in the right colon. In addition, benign and malignant extraintestinal lesions may be common as our patient had simple liver and kidney cysts and two basal cell skin carcinomas.(AU)

Recientemente, las variantes patogénicas/probablemente patogénicas de la línea germinal bialélica de MSH3 han sido reconocidas como una causa rara de poliposis adenomatosa. Presentamos a una mujer de 49 años que ingresó en nuestra clínica de cáncer colorrectal de alto riesgo después de la detección incidental de una variante patógena probable de la línea germinal MSH3 bialélica cuando se analizó la línea germinal variantes patogénicas/probablemente patogénicas en genes hereditarios relacionados con el cáncer de mama y de ovario. El objetivo de este informe de caso es describir el genotipo y el fenotipo de nuestro paciente con poliposis adenomatosa relacionada con MSH3. Más de la mitad de los pólipos (13/19) se localizaron en el colon derecho. Además, las lesiones extraintestinales benignas y malignas pueden ser comunes, ya que nuestra paciente tenía quistes hepáticos y renales simples y dos carcinomas cutáneos de células basales.(AU)

The Influence of BMI in Asthma: Which Traits Are due to Obesity and Which to the Asthma and Obesity Phenotype?

Background: The characteristics of the asthma and obesity phenotype have been described in cluster studies but have not been subsequently confirmed. Specific characteristics of this phenotype have not been differentiated from those inherent to the patient’s body mass index (BMI). Objectives: This study aims to assess the effect of BMI on asthma in order to identify which traits could define the asthma and obesity phenotype and which are inherent to the patient's BMI. Methods: A real-life retrospective observational study was conducted based on data from 2514 patients with suspected asthma collected at the first visit to the allergy clinic between November 2014 and November 2017. All patients had to perform an appropriate spirometry maneuver. All BMI, sex, and age groups were represented. Results: The influence of BMI on asthma differed according to age group and sex. All spirometry results and FeNO were influenced by BMI. The only notable asthma characteristics were later onset of asthma with higher BMI values. No other differences were found between the BMI groups. Conclusions: The effect of BMI on asthma is age-dependent; therefore, it should be corrected for age. The most important variations are in FeNO and spirometry results. The specific characteristics of the asthma and obesity phenotype are a greater perception of symptoms with fewer alterations in respiratory function tests and a lower prevalence of atopy, rhinitis, and allergy, including allergic asthma. Other characteristics of this phenotype, such as a higher female prevalence or late-onset or noneosinophilic asthma, are nonspecific for this phenotype

Antecedentes : las características del fenotipo del asma y la obesidad se han descrito en estudios grupales, pero no se han confirmado posteriormente. Las características específicas de este fenotipo no se han diferenciado de las inherentes al índice de masa corporal (IMC) del paciente. Objetivos : Este estudio tiene como objetivo evaluar el efecto del IMC sobre el asma para identificar qué rasgos podrían definir el fenotipo del asma y la obesidad y cuáles son inherentes al IMC del paciente. Métodos : Se realizó un estudio observacional retrospectivo de la vida real basado en datos de 2514 pacientes con sospecha de asma recopilados en la primera visita a la clínica de alergia entre noviembre de 2014 y noviembre de 2017. Todos los pacientes tuvieron que realizar una maniobra de espirometría adecuada. Estuvieron representados todos los grupos de IMC, sexo y edad. Resultados : La influencia del IMC sobre el asma difirió según grupo de edad y sexo. Todos los resultados de la espirometría y el FeNO estuvieron influenciados por el IMC. Las únicas características notables del asma fueron la aparición tardía del asma con valores de IMC más altos. No se encontraron otras diferencias entre los grupos de IMC. Conclusiones : El efecto del IMC sobre el asma depende de la edad; por lo tanto, debe corregirse según la edad. Las variaciones más importantes se encuentran en los resultados de FeNO y espirometría. Las características específicas del fenotipo de asma y obesidad son una mayor percepción de los síntomas con menos alteraciones en las pruebas de función respiratoria y una menor prevalencia de atopia, rinitis y alergia, incluido el asma alérgica. Otras características de este fenotipo, como una mayor prevalencia femenina o asma de aparición tardía o no eosinofílica, no son específicas de este fenotipo (AU)

Influence of enlarged waist circumference and hypertriglyceridemia in the severity of acute pancreatitis: A retrospective study / Influencia del aumento de la circunferencia de la cintura y la hipertrigliceridemia en la gravedad de la pancreatitis aguda: un estudio retrospectivo

Introduction: Acute pancreatitis is a frequent inflammatory gastrointestinal disorder with high mortality rates in severe forms. An early evaluation of its severity is key to identify high-risk patients. This study assessed the influence of waist circumference together with hypertriglyceridemia on the severity of acute pancreatitis. Methods: A retrospective study was performed, which included patients admitted with acute pancreatitis from March 2014 to March 2021. Patients were classified into four phenotype groups according to their waist circumference and triglyceride levels: normal waist circumference and normal triglycerides; normal waist circumference and elevated triglycerides; enlarged waist circumference and normal triglycerides; and enlarged waist circumference and triglycerides, namely hypertriglyceridemic waist (HTGW) phenotype. Clinical outcomes were compared among the groups. Results: 407 patients were included. Systemic inflammatory response syndrome (SIRS) and intensive care unit admission were most frequent among patients in the HTGW phenotype group, at 44.9% and 8.2%, respectively. The incidence of local complications was higher in the normal waist circumference with elevated triglycerides group (27%). On multivariable analysis, an enlarged waist circumference was related to an increase of 4% and 2% in the likelihood of developing organ failure and SIRS, respectively. Hypertriglyceridemia was an independent risk factor for both organ failure and local complications. Conclusions: HTGW phenotype was significant related to developing of SIRS. It seems that an enlarged waist circumference has a greater role than hypertriglyceridemia in the development of SIRS. Obesity and hypertriglyceridemia were both independent risk factors for organ failure. Patients with hypertriglyceridemia were more likely to develop local complications. (AU)

Introducción: La pancreatitis aguda es una patología frecuente con altas tasas de mortalidad en sus formas graves. Este estudio evaluó la influencia de la circunferencia de la cintura (CC) junto con la hipertrigliceridemia en la gravedad de la pancreatitis aguda. Métodos: Se realizó un estudio retrospectivo que incluyó pacientes con pancreatitis aguda desde 2014 hasta 2021. Los pacientes se clasificaron en cuatro grupos fenotípicos según su CC y los niveles de triglicéridos: CC normal y triglicéridos normales, CC normal y triglicéridos elevados, CC aumentada y triglicéridos normales, y CC aumentada y triglicéridos elevados, es decir, el fenotipo cintura hipertrigliceridémica (HTGW). Resultados: Se incluyeron 407 pacientes. El síndrome de respuesta inflamatoria sistémica (SIRS) y la admisión a la unidad de cuidados intensivos fueron más frecuentes entre los pacientes con fenotipo HTGW, en 44,9 y 8,2%, respectivamente. La incidencia de complicaciones locales fue mayor en el grupo de CC normal con triglicéridos elevados (27%). En el análisis multivariable, una CC aumentada se relacionó con un aumento de 4 y 2% en la probabilidad de desarrollar fallo orgánico y SIRS, respectivamente. La hipertrigliceridemia fue un factor de riesgo tanto para el fallo orgánico como para las complicaciones locales. Conclusiones: El fenotipo HTGW se relacionó con el desarrollo de SIRS. Parece que una CC aumentada tiene un papel más importante que la hipertrigliceridemia en el desarrollo de SIRS. La obesidad y la hipertrigliceridemia fueron factores de riesgo independientes para el fallo orgánico. Los pacientes con hipertrigliceridemia tenían más probabilidades de desarrollar complicaciones locales. (AU)

Evaluación de dos técnicas fenotípicas y un panel molecular multiplex comercial para la detección de diferentes carbapenemasas / Evaluation of two phenotypic techniques and a commercial multiplex molecular panel for the detection of different carbapenemases

ras de carbapenemasas ha aumentado en los últimos años, considerándose un importante problema de salud pública. Material y métodos. Se analizaron 106 muestras por distintas técnicas de detección de carbapenemasas: discos de inhibición (DI), test inmunocromatográfico (TIC) y una técnica genotípica, frente a una RT-PCR multiplex como método de referencia. Resultados. Globalmente, las 3 técnicas superaron el 90% de sensibilidad, aunque con diferencias en el rendimiento de algunas de ellas por tipos de carbapenemasa. Los DI presenta ron baja especificidad (62%) para OXA-48, mientras que con el TIC la sensibilidad para metalobetalactamasas tipo NDM (93%) fue ligeramente inferior que para OXA-48 (95%). Los mejores resultados se obtuvieron con la técnica genotípica (rendimien to global del 100%). Conclusiones. A pesar de la menor sensibilidad de los TIC respecto a las técnicas moleculares, especialmente en carba penemasas tipo NDM, con la modificación del protocolo con seguimos aumentar esta sensibilidad, y junto al menor precio, sencillez y rapidez convierte a esta técnica en una buena op ción de screening (AU)

Introduction. The prevalence of carbapenemase-produc ing Enterobacterales has increased in recent years and is con sidered an important public health problem. Material and methods. A total of 106 clinical samples were analyzed by different carbapenemase detection tech niques: inhibition discs (ID), immunochromatographic test (ICT) and a genotypic method, comparing them with a multi plex RT-PCR as a reference method. Results. Overall, all 3 techniques exceeded 90% sensitiv ity, although with differences in the performance of some of them by carbapenemase type. DI had low specificity (62%) for OXA-48, while with TIC the sensitivity for NDM-type metal lo-beta-lactamase (93%) was slightly lower than for OXA-48 (95%). The best results were obtained with the genotypic tech nique (100% overall performance). Conclusions. Despite the lower sensitivity of TICs (espe cially in NDM carbapenemases) compared to molecular tech niques, with the modification of the protocol we managed to increase this sensitivity and, together with the lower price, simplicity and speed, it makes this technique a good screening option (AU)

Enfermedad neurológica asociada al gen KIF1A: correlación genotipo/fenotipo / KIF1A gene-associated neurological disease: the correlation between genotype and phenotype

Introducción: La encefalopatía KIF1A-associated-neurological-disorder (KAND) es un grupo de patologías neurodegenerativas progresivas de diversa gravedad ocasionadas por mutaciones en el gen KIF1A (kinesin family member 1A) situado en el cromosoma 2q37.3. Dicho gen codifica una proteína de la familia de las cinesinas 3 que participa en el transporte anterógrado de las vesículas presinápticas dependientes del trifosfato de adenosina a través de microtúbulos neuronales. Casos clínicos: Se describen cuatro pacientes, con edades entre 1 y 13 años, con mediana de inicio de los síntomas de cinco meses (rango intercuartílico: 0-11 meses), lo que supone una prevalencia aproximada de 1 de cada 64.000 menores de 14 años para nuestra población pediátrica. Clínicamente, destacaron discapacidad intelectual, hipotonía axial y paraparesia espástica en 4/4, y síntomas cerebelosos en 2/4. Otras manifestaciones fueron incontinencia urinaria, polineuropatía sensitivomotora y alteración conductual. Destaca, en el caso 2, la alteración en el videoelectroencefalograma, que mostraba epilepsia focal con generalización secundaria y focalidad paroxística occipitoparietal posterior derecha con transmisión contralateral. También mostraba crisis oculógiras en supraversión instantáneas pluricotidianas sin correlato electroencefalográfico. Conclusiones: En nuestra serie, la encefalopatía KAND, fenotipo trastorno neurodegenerativo con retraso global del desarrollo, de la marcha y espasticidad progresiva de los miembros inferiores, atrofia cerebelosa y/o afectación de la corteza visual, fue predominante, y en uno de los casos asoció polineuropatía sensitivomotora. La mutación de novo missense fue más frecuente y en tres casos es la primera descripción conocida. Un caso mostraba epilepsia focal y crisis oculógiras no epilépticas.(AU)

Introduction: KIF1A-associated-neurological-disorder (KAND) encephalopathy is a group of progressive neurodegenerative pathologies of varying severity caused by mutations in the KIF1A gene (Kinesin family member 1A) located on chromosome 2q37.3. This gene encodes a protein of the kinesin-3 family that participates in the ATP-dependent anterograde transport of presynaptic vesicles through neuronal microtubules. Case report: Four patients are described, aged 1-13 years, with a median onset of symptoms of 5 months (IQR 0-11 months), which represents an approximate prevalence of 1 per 64,000 children under 14 years of age for our pediatric population. Clinically, intellectual disability (ID), axial hypotonia and spastic paraparesis stood out in 4/4 and cerebellar symptoms in 2/4. Other manifestations were urinary incontinence, sensory-motor polyneuropathy, and behavioral alteration. In case 2, the alteration in the video-EEG stands out, which showed focal epilepsy with secondary generalization and right posterior occipito-parietal paroxysmal focality with contralateral transmission. She also showed instantaneous pluricotidian supraversion oculogyric seizures without EEG correlates. Conclusions: In our series, KAND encephalopathy had a predominant neurodegenerative disorder phenotype with global developmental delay, gait delay, and progressive spasticity of the lower limbs, cerebellar atrophy, and/or involvement of the visual cortex, which in one case was associated with sensory-motor polyneuropathy. The de novo missense mutation was more frequent and in three cases it is the first known description. One case showed focal epilepsy and nonepileptic oculogyric seizures.(AU)

Diminished emotion recognition with reduced face gaze in complex situation in individuals with broad autism phenotype / Disminución del reconocimiento de emociones en situaciones complejas debido a la reducción de la mirada a la cara en individuos con fenotipo de autismo amplio

Background/objective: Individuals with broad autism phenotype (BAP) showed a diminished ability to recognize emotion. This study aims to examine whether their decline in emotion recognition ability could be more clearly identified as task complexity increased and whether their decline could be influenced by their eye-gaze patterns. Method: 41 individuals with BAP and 40 healthy controls performed two types of emotion recognition tasks. After confirming conditions wherein the BAP group did not perform well compared to the control group, we compared gaze proportion on faces and context between groups when performing the conditions. Results: The more difficult the task, the clearer the significant relationships between the level of autistic traits and emotion recognition ability. The BAP group showed lower accuracy compared to the control group when a face with mild emotional intensity was presented with context. In terms of gaze proportion, the BAP group looked less at faces when recognizing emotions compared to the control group. Conclusion: These findings indicate that diminished emotion recognition ability in individuals with BAP may be influenced by face gaze. (AU)

AKAP12 promotes cancer stem cell-like phenotypes and activates STAT3 in colorectal cancer

Background Cancer stem cells (CSCs) have unique biological characteristics, including tumorigenicity, immortality, and chemoresistance. Colorectal CSCs have been identified and isolated from colorectal cancers by various methods. AKAP12, a scaffolding protein, is considered to act as a potential suppressor in colorectal cancer, but its role in CSCs remains unknown. In this study, we investigated the function of AKAP12 in Colorectal CSCs. Methods Herein, Colorectal CSCs were enriched by cell culture with a serum-free medium. CSC-associated characteristics were evaluated by Flow cytometry assay and qPCR. AKAP12 gene expression was regulated by lentiviral transfection assay. The tumorigenicity of AKAP12 in vivo by constructing a tumor xenograft model. The related pathways were explored by qPCR and Western blot. Results The depletion of AKAP12 reduced colony formation, sphere formation, and expression of stem cell markers in colorectal cancer cells, while its knockdown decreased the volume and weight of tumor xenografts in vivo. AKAP12 expression levels also affected the expression of stemness markers associated with STAT3, potentially via regulating the expression of protein kinase C. Conclusion This study suggests Colorectal CSCs overexpress AKAP12 and maintain stem cell characteristics through the AKAP12/PKC/STAT3 pathway. AKAP12 may be an important therapeutic target for blocking the development of colorectal cancer in the field of cancer stem cells (AU)

The Role of Inflammatory Phenotype in Patients With Exacerbation-prone Asthma and Ongoing Therapy

Introduction: The risk factors for having frequent exacerbations are not well documented in cohort studies of patients with asthma on existing therapy. The objective of the present study was to compare the clinical and inflammatory characteristics of patients with exacerbation-prone asthma (EPA) with a history of two or more exacerbations in the previous year with those who had presented just one or no exacerbation. Methods: An ambispective observational study was conducted in a tertiary hospital. Patients diagnosed with moderate or severe asthma and ongoing therapy, whose inflammatory profile was determined by means of allergy and atopy status, blood eosinophilia and induced sputum were included. Patients were classified according to the number of asthma exacerbations in EPA (≥2 exacerbations in the previous year) vs. non-exacerbators (≤1 exacerbation in the previous year). Clinical, lung function and inflammatory characteristics of the two groups were compared. Results: Three hundred ten patients were visited in the Asthma Unit in 2018 and the combination of atopy and allergy status, blood eosinophilia and induced sputum was obtained in 96 (31%) patients. Of this latter group, 46 patients (47%) presented EPA compared to 50 (53%) non-exacerbators. Airway and blood eosinophilic inflammation did not differ between EPA and non-exacerbators in patients with asthma and ongoing therapy, and it was not a risk factor for EPA in our cohort. Conclusion: Airway or blood type 2 inflammation status is not a valid tool for recognizing EPA or predicting asthma exacerbations in asthma patients following controller therapy. (AU)

The phenotypes and genotypes associated with biofilm formation among methicillin-susceptible Staphylococcus aureus (MSSA) isolates collected from a tertiary hospital in Terengganu, Malaysia / Los fenotipos y genotipos asociados con la formación de biopelículas entre aislados de Staphylococcus aureus susceptibles a meticilina (MSSA) recolectados en un hospital terciario en Terengganu, Malasia

Methicillin-susceptible Staphylococcus aureus (MSSA) is an important nosocomial pathogen worldwide. This study aims to investigate the in vitro biofilm-forming ability of clinical MSSA isolated from various sources in the main public tertiary referral hospital in Terengganu, Malaysia and to detect the presence of biofilm-associated and regulatory genes among these isolates. A total of 104 MSSA isolates [pus (n = 75), blood (n = 24), respiratory secretions (n = 2), eye (n = 2), and urine (n = 1)] were investigated for slime production and biofilm formation using Congo red agar and crystal violet microtitre plate, respectively. Fifteen MSSA isolates with varying degrees of biofilm formation were selected for validation via a real-time cell analyser. All isolates were screened for microbial surface components recognising adhesive matrix molecules (MSCRAMM) and accessory gene regulator (agr) using polymerase chain reaction assay. A total of 76.0% (79/104) isolates produced slime layer, while all isolates developed biofilm as follows: 52.8% (55/104) strong biofilm producers, 40.4% (42/104) intermediate biofilm producers, and 6.7% (7/104) weak biofilm producers. A total of 98.1% (102/104) isolates carried at least one of the screened MSCRAMM gene(s) with the eno gene detected at the highest rate (87.5%, 91/104), while the sasG gene was significantly associated with strong biofilm production (p = 0.015). Three agr groups, 1, 2, and 3, were detected among the MSSA isolates with a predominance of agr-3 (32.7%, 34/104). In conclusion, biofilm formation varied greatly among clinical MSSA isolates, and the presence of sasG gene and agr-1 may play important role in initiating MSSA infections via biofilm formation.(AU)

Oncogenic roles of GPR176 in breast cancer: a potential marker of aggressiveness and a potential target of gene therapy

Background Belonging to the G-protein coupled receptor 1 family, G protein-coupled receptor 176 (GPR176) is associated with the Gz/Gx G-protein subclass and is capable of decreasing cAMP production. Methods GPR176 expression was detected by qRT-PCR, bioinformatics analysis, Western blot and immunohistochemistry, and compared with clinicopathological characteristics of breast cancer. GPR176-related genes and pathways were subjected to bioinformatic analysis. We also explored the effects of GPR176 on the phenotypes of breast cancer cells. Results Lower expression of GPR176 mRNA was seen in breast cancer than in normal tissues, but the opposite pattern was found for its protein (p < 0.05). GPR176 mRNA was associated with female sex, low T staging, non-Her-2+ subtypes, non-mutant p53 status in breast cancer (p < 0.05). GPR176 methylation was negatively correlated with its mRNA level and T staging in breast cancer, and was higher in breast cancer than normal tissues (p < 0.05). GPR176 protein expression was positively correlated with older age, small tumor size, and non-luminal-B subtype of breast cancers (p < 0.05). The differential genes of GPR176 were involved in receptor-ligand interaction, RNA maturation, and so forth (p < 0.05). GPR176-related genes were categorized into cell mobility, membrane structure, and so on (p < 0.05). GPR176 knockdown weakened the proliferation, glucose catabolism, anti-apoptosis, anti-pyroptosis, migration, invasion, and epithelial-mesenchymal transition of breast cancer cells. Conclusion These results indicate that GPR176 might be involved in the tumorigenesis and subsequent progression of breast cancer by deteriorating aggressive phenotypes. It might be utilized as a potential biomarker to indicate the aggressive behaviors and poor prognosis of breast cancer and a potential target of genetic therapy (AU)

Polysomnographic Phenotypes of Obstructive Sleep Apnea in a Real-Life Cohort: A Pathophysiological Approach

Introduction: Obstructive sleep apnea (OSA) is heterogeneous and complex, but its severity is still based on the apnea–hypoapnea index (AHI). The present study explores using cluster analysis (CA), the additional information provided from routine polysomnography (PSG) to optimize OSA categorization. Methods: Cross-sectional study of OSA subjects diagnosed by PSG in a tertiary hospital sleep unit during 2016–2020. PSG, demographical, clinical variables, and comorbidities were recorded. Phenotypes were constructed from PSG variables using CA. Results are shown as median (interquartile range). Results: 981 subjects were studied: 41% females, age 56 years (45–66), overall AHI 23events/h (13–42) and body mass index (BMI) 30kg/m2 (27–34). Three PSG clusters were identified: Cluster 1: “Supine and obstructive apnea predominance” (433 patients, 44%). Cluster 2: “Central, REM and shorter-hypopnea predominance” (374 patients, 38%). Cluster 3: “Severe hypoxemic burden and higher wake after sleep onset” (174 patients, 18%). Based on classical OSA severity classification, subjects are distributed among the PSG clusters as severe OSA patients (AHI≥30events/h): 46% in cluster 1, 17% in cluster 2 and 36% in cluster 3; moderate OSA (15≤AHI<30events/h): 57% in cluster 1, 34% in cluster 2 and 9% in cluster 3; mild OSA (5≤AHI<15events/h): 28% in cluster 1, 68% in cluster 2 and 4% in cluster 3. Conclusions: The CA identifies three specific PSG phenotypes that do not completely agree with classical OSA severity classification. This emphasized that using a simplistic AHI approach, the OSA severity is assessed by an incorrect or incomplete analysis of the heterogeneity of the disorder. (AU)

Characteristics of the metabolically unhealthy phenotype in menopausal resistance training practitioners / Características del fenotipo metabólicamente no saludable en practicantes de entrenamiento deresistencia en la menopausia

Objective: to evaluate clinical, metabolic and body characteristics related to the metabolically unhealthy phenotype (MUH) in menopausal womenwho practice resistance training (RT).Methods: cross-sectional study with a sample of 31 women. Clinical and metabolic variables were measured. Body adiposity was assessedby body mass index, waist circumference, visceral adiposity index (VAI) and lipid accumulation product (LAP). Body composition analysis wasperformed by DEXA.Results: the prevalence of the MH phenotype was 74.2 %. Metabolically healthy (MH) women were younger, had more years of RT practice,higher HDL-c levels and lower VAI and android/gynoid ratio (A/G) than the MUH women. Women with inadequacy of HDL-c, TG, A/G and VAI had12.50 (95 % CI: 3.30-47.23), 4.83 (95 % CI: 2.37-9.85), 5.20 (95 % CI: 1.90-14.16) and 3.12 (95 % CI: 1.07-9.04) times greater prevalenceof the MUH phenotype, respectively, than those with adequacy of these parameters. Binary logistic regression analysis demonstrated that age isa predictor of the MUH phenotype (OR = 1.254; 95 % CI: 1.00-1.56) and this variable showed correlation with TG, VAI and A/G. There was noassociation between thyrotropin and MUH phenotype in the present sample.Conclusion: age and visceral adiposity are predictors for the MUH phenotype in RT practitioners in menopause, which may initially be characterized by alterations in serum lipid profile. (AU)

Objetivo: evaluar las características clínicas, metabólicas y corporales relacionadas con el fenotipo metabólicamente no saludable (MNS) enmujeres menopáusicas que practican entrenamiento de resistencia (ER).Métodos: estudio transversal con 31 mujeres. Se midieron variables clínicas y metabólicas. La adiposidad corporal se evaluó mediante el índicede masa corporal, la circunferencia de la cintura, el índice de adiposidad visceral (IAV) y el producto de acumulación de lípidos (PAL). El análisisde composición corporal fue realizado por DEXA.Resultados: la prevalencia del fenotipo metabólicamente saludable (MS) fue del 74,2 %. Las mujeres metabólicamente saludables (MS) eranmás jóvenes, tenían más años de práctica de ER, niveles más altos de HDL-c y menor IAV y relación androide/ginoide (A/G) que las mujeresMNS. Hubo asociación del fenotipo MNS con los niveles de HDL-c y A/G. Las mujeres con insuficiencia de HDL-c, TG, A/G y IAV tuvieron 12,50(IC 95 %: 3,30-47,23), 4,83 (IC 95 %: 2,37-9,85), 5,20 (IC 95 %: 1,90-14,16) y 3,12 (IC 95 %: 1,07-9,04) veces mayor prevalencia del fenotipoMNS, respectivamente, que aquellas con adecuación de estos parámetros. El análisis de regresión logística binaria demostró que la edad es unpredictor del fenotipo MUH (OR = 1,254; IC 95 %: 1,00-1,56) y esta variable mostró correlación con TG, VAI and A/G. No hubo asociación entrela tirotropina y el fenotipo MUH en la presente muestra.Conclusión: la edad y la adiposidad visceral son predictores del fenotipo MUH en practicantes de ER en la menopausia, que puede caracterizarseinicialmente alteraciones en el perfil plasmático de insípidos. (AU)

Study of hydrogen sulfide biosynthesis in synovial tissue from diabetes-associated osteoarthritis and its influence on macrophage phenotype and abundance

Type 2 diabetes (DB) is an independent risk factor for osteoarthritis (OA). However, the mechanisms underlying the connection between both diseases remain unclear. Synovial macrophages from OA patients with DB present a marked pro-inflammatory phenotype. Since hydrogen sulphide (H2S) has been previously described to be involved in macrophage polarization, in this study we examined H2S biosynthesis in synovial tissue from OA patients with DB, observing a reduction of H2S-synthetizing enzymes in this subset of individuals. To elucidate these findings, we detected that differentiated TPH-1 cells to macrophages exposed to high levels of glucose presented a lower expression of H2S-synthetizing enzymes and an increased inflammatory response to LPS, showing upregulated expression of markers associated with M1 phenotype (i.e., CD11c, CD86, iNOS, and IL-6) and reduced levels of those related to M2 fate (CD206 and CD163). The co-treatment of the cells with a slow-releasing H2S donor, GYY-4137, attenuated the expression of M1 markers, but failed to modulate the levels of M2 indicators. GYY-4137 also reduced HIF-1α expression and upregulated the protein levels of HO-1, suggesting their involvement in the anti-inflammatory effects of H2S induction. In addition, we observed that intraarticular administration of H2S donor attenuated synovial abundance of CD68+ cells, mainly macrophages, in an in vivo model of OA. Taken together, the findings of this study seem to reinforce the key role of H2S in the M1-like polarization of synovial macrophages associated to OA and specifically its metabolic phenotype, opening new therapeutic perspectives in the management of this pathology. (AU)

Hypoxia promotes conversion to a stem cell phenotype in prostate cancer cells by activating HIF-1a/Notch1 signaling pathway

Purpose The hypoxic tumor microenvironment and the maintenance of stem cells are relevant to the malignancy of prostate cancer (PCa). However, whether HIF-1α in the hypoxic microenvironment mediates the transformation of prostate cancer to a stem cell phenotype and the mechanism have not been elucidated.Materials and methods Prostate cancer stem cells (PCSCs) from PC-3 cell lines were examined for the expression of CD44, CD133, ALDH1, HIF-1α, Notch1, and HES1. We observed the effect of knockdown HIF-1α in vitro and mice models and evaluated the impact of HIF-1α on the Notch1 pathway as well as stem cell dedifferentiation. The effects on sphere formation, cell proliferation, apoptosis, cell cycle, and invasive metastasis were evaluated. Results In our study, hypoxia upregulated HIF-1α expression and induced a stem cell phenotype through activation of the Notch1 pathway, leading to enhanced proliferation, invasion, and migration of PCa PC-3 cells. The knockdown of HIF-1α significantly inhibited cell dedifferentiation and the ability to proliferate, invade and metastasize. However, the inhibitory effect of knocking down HIF-1α was reversed by Jagged1, an activator of the Notch1 pathway. These findings were further confirmed in vivo, where hypoxia could enhance the tumorigenicity of xenograft tumors by upregulating the expression of HIF-1α to activate the Notch1 pathway. In addition, the expression of HIF-1α and Notch1 was significantly increased in human PCa tissues, and high expression of HIF-1α correlated with the malignancy of PCa. Conclusion In a hypoxic environment, HIF-1α promotes PCa cell dedifferentiation to stem-like cell phenotypes by activating the Notch1 pathway and enhancing the proliferation and invasive capacity of PC-3 cells (AU)