Genetic variants in ATP2B2 as risk factors for mortality in patients unrelated but not associated with families with severe COVID-19.

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19). The disease has a wide range of clinical manifestations, from asymptomatic to severe. Ancestral contribution, sex, immune response, and genetic factors influence the presentation of the disease. The objective of the present study was to validate these genetic variants in patients with severe COVID-19 who died and in survivor patients. Methods: Single nucleotide variants (SNVs) in six genes: ATPase plasma membrane Ca2+ transporting 2 (ATP2B2), transmembrane serine protease 2 (TMPRSS2), dedicator of cytokinesis 2 (DOCK2), (interferon alpha and beta receptor subunit 2) IFNAR2, tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), and tumor necrosis factor receptor superfamily, member 1B (TNFRSF1B), were explored in two groups: the first consisted of severe COVID-19-related patients (familial cases from 58 families, n = 130), and the second group of unrelated severe COVID-19 patients (n = 1045). In each study group, death was evaluated as the outcome. Results: In non-related patients with severe COVID-19, carriers of GG genotype (rs2289274) in the ATP2B2 gene showed a high-risk probability of non-surviving (OR = 1.43). Survival analysis to 75 days indicates that carriers of GG have a higher risk than GA or AA genotypes (p = 0.0059). The haplotype GG (rs2289273-rs2289274) in ATP2B2 was found to be associated with a high risk of death in severe non-related COVID-19 patients. No significant associations were found between severe COVID-19-related patients and SNVs in ATP2B2, TMPRSS2, DOCK2, IFNAR2, TNFRSF1A, or TNFRSF1B. Conclusions: Unrelated patients with severe COVID-19 that carry the GG genotype (rs2289274) in ATP2B2 showed a high death risk. Survival analysis to 75 days indicates that carriers of GG have a higher risk of non-survival compared to GA or AA genotypes.

High Expression Levels of miR-21-5p in Younger Hospitalized COVID-19 Patients Are Associated with Mortality and Critical Disease.

In COVID-19, critical disease and invasive mechanical ventilation (IMV) increase the risk of death, mainly in patients over 60 years of age. OBJECTIVES: To find the relationship between miR-21-5p and miR-146a-5p in terms of the severity, IMV, and mortality in hospitalized COVID-19 patients younger than 55 years of age. METHODS: The patients were stratified according to disease severity using the IDSA/WHO criteria for severe and critical COVID-19 and subclassified into critical non-survivors and critical survivors. RESULTS: Ninety-seven severe/critical COVID-19 patients were included; 81.3% of the deceased were male and 18.8% were female. Higher expression miR-21-5p levels were associated as follows: severe vs. critical disease (p = 0.007, FC = 0.498), PaO2/FiO2 index, mild vs. severe (p = 0.027, FC = 0.558), and survivors vs. non-survivors (p = 0.03, FC = 0.463). Moreover, we identified correlations with clinical variables: CRP (rho = -0.54, p < 0.001), D-dimer (rho = -0.47, p < 0.05), related to damage in the kidney (rho = 0.60, p < 0.001), liver (rho = 0.41, p < 0.05), and lung (rho = 0.54, p < 0.001). Finally, miR-21-5p thresholds were calculated according to severity (8.191), IMV (8.191), and mortality (8.237); these values increased the risk of developing a critical disease (OR = 4.19), the need for IMV (OR = 5.63), and death (OR = 6.00). CONCLUSION: Increased expression levels of miR-21-5p are related to worse outcome of COVID-19 in younger hospitalized patients.

SERPINE1 rs6092 Variant Is Related to Plasma Coagulation Proteins in Patients with Severe COVID-19 from a Tertiary Care Hospital.

An impaired coagulation process has been described in patients with severe or critical coronavirus disease (COVID-19). Nevertheless, the implication of coagulation-related genes has not been explored. We aimed to evaluate the impact of F5 rs6025 and SERPINE1 rs6092 on invasive mechanical ventilation (IMV) requirement and the levels of coagulation proteins among patients with severe COVID-19. Four-hundred fifty-five patients with severe COVID-19 were genotyped using TaqMan assays. Coagulation-related proteins (P-Selectin, D-dimer, P-selectin glycoprotein ligand-1, tissue plasminogen activator [tPA], plasminogen activator inhibitor-1, and Factor IX) were assessed by cytometric bead arrays in one- and two-time determinations. Accordingly, SERPINE1 rs6092, P-Selectin (GG 385 pg/mL vs. AG+AA 632 pg/mL, p = 0.0037), and tPA (GG 1858 pg/mL vs. AG+AA 2546 pg/mL, p = 0.0284) levels were different. Patients carrying the CT F5-rs6025 genotype exhibited lower levels of factor IX (CC 17,136 pg/mL vs. CT 10,247 pg/mL, p = 0.0355). Coagulation proteins were also different among IMV patients than non-IMV. PSGL-1 levels were significantly increased in the late stage of COVID-19 (>10 days). The frequencies of F5 rs6025 and SERPINE1 rs6092 variants were not different among IMV and non-IMV. The SERPINE1 rs6092 variant is related to the impaired coagulation process in patients with COVID-19 severe.

Gastropatía hipertrófica por IgG4: reporte del primer caso en Chile / IgG4 related hypertrophic gastropathy: report of one case

IgG4 related disease is a systemic autoimmune disease, which can affect different organs. The most common digestive manifestation is autoimmune pancreatitis (AIP), followed by involvement of bile ducts and the major papilla. The stomach is only rarely involved. We report a 71-year-old diabetic woman consulting for jaundice and weight loss. Abdominal CAT scan, cholangio resonance imaging, endosonography and a serum IgG4 of five times the normal value, lead to the diagnosis of an autoimmune pancreatitis. An upper gastrointestinal endoscopy showed a diffuse thickening of gastric folds. The pathological study confirmed the presence of IgG4 positive plasma cells. The patient was successfully treated with steroids.

Pilot Feasibility Study of a Digital Storytelling Intervention for Immigrant and Refugee Adults With Diabetes.

Purpose The purpose of this pilot feasibility project was to examine the potential effectiveness of a digital storytelling intervention designed through a community-based participatory research (CBPR) approach for immigrants and refugees with type 2 diabetes mellitus (T2DM). Methods The intervention was a 12-minute culturally and linguistically tailored video consisting of an introduction, 4 stories, and a concluding educational message. A structured interview was used to assess the intervention for acceptability, interest level, and usefulness among 25 participants with T2DM (15 Latino, 10 Somali) across 5 primary care clinical sites. After watching the video, participants rated their confidence and motivation about managing T2DM as a result of the intervention. Baseline A1C and follow-up values (up to 6 months) were abstracted from medical records. Results All participants reported that the intervention got their attention, was interesting, and was useful; 96% reported that they were more confident about managing their T2DM than before they watched the video, and 92% reported that the video motivated them to change a specific behavior related to T2DM self-management. The mean baseline A1C level for the intervention participants was 9.3% (78 mmol/mol). The change from baseline to first follow-up A1C level was -0.8% (-10 mmol/mol) ( P < .05). Conclusions Implementation of a digital storytelling intervention for T2DM among immigrant populations in primary care settings is feasible and resulted in self-rated improvement in psychosocial constructs that are associated with healthy T2DM self-management behaviors, and there was some evidence of improvement in glycemic control. A large-scale efficacy trial of the intervention is warranted.

Erratum to: Lessons Learned from Community-Led Recruitment of Immigrants and Refugee Participants for a Randomized, Community-Based Participatory Research Study.

The original version of this article unfortunately contained an error in the author affiliation. The affiliations for the Authors Marcelo M. Hanza, Miriam Goodson, Ahmed Osman, Maria D. Porraz Capetillo, Abdullah Hared, Julie A. Nigon, Mark L. Wieland, and Irene G. Sia were published incorrectly. The correct affiliations are given in this erratum.

Lessons Learned from Community-Led Recruitment of Immigrants and Refugee Participants for a Randomized, Community-Based Participatory Research Study.

Ethnic minorities remain underrepresented in clinical trials despite efforts to increase their enrollment. Although community-based participatory research (CBPR) approaches have been effective for conducting research studies in minority and socially disadvantaged populations, protocols for CBPR recruitment design and implementation among immigrants and refugees have not been well described. We used a community-led and community-implemented CBPR strategy for recruiting 45 Hispanic, Somali, and Sudanese families (160 individuals) to participate in a large, randomized, community-based trial aimed at evaluating a physical activity and nutrition intervention. We achieved 97.7 % of our recruitment goal for families and 94.4 % for individuals. Use of a CBPR approach is an effective strategy for recruiting immigrant and refugee participants for clinical trials. We believe the lessons we learned during the process of participatory recruitment design and implementation will be helpful for others working with these populations.

Healthy immigrant families: Participatory development and baseline characteristics of a community-based physical activity and nutrition intervention.

BACKGROUND: US immigrants often have escalating cardiovascular risk. Barriers to optimal physical activity and diet have a significant role in this risk accumulation. METHODS: We developed a physical activity and nutrition intervention with immigrant and refugee families through a community-based participatory research approach. Work groups of community members and health scientists developed an intervention manual with 12 content modules that were based on social-learning theory. Family health promoters from the participating communities (Hispanic, Somali, Sudanese) were trained to deliver the intervention through 12 home visits during the first 6 months and up to 12 phone calls during the second 6 months. The intervention was tested through a randomized community-based trial with a delayed-intervention control group, with measurements at baseline, 6, 12, and 24 months. Primary measurements included accelerometer-based assessment of physical activity and 24-hour dietary recall. Secondary measures included biometrics and theory-based instruments. RESULTS: One hundred fifty-one individuals (81 adolescents, 70 adults; 44 families) were randomized. At baseline, mean (SD) time spent in moderate-to-vigorous physical activity was 64.7 (30.2) minutes/day for adolescents and 43.1 (35.4) minutes/day for adults. Moderate dietary quality was observed in both age groups. Biometric measures showed that 45.7% of adolescents and 80.0% of adults were overweight or obese. Moderate levels of self-efficacy and social support were reported for physical activity and nutrition. DISCUSSION: Processes and products from this program are relevant to other communities aiming to reduce cardiovascular risk and negative health behaviors among immigrants and refugees. TRIAL REGISTRATION: This trial was registered at Clinicaltrials.gov (NCT01952808).

Sildenafil reverses hypoxic pulmonary hypertension in highland and lowland newborn sheep.

Perinatal exposure to chronic hypoxia induces sustained hypertension and structural and functional changes in the pulmonary vascular bed. We hypothesized that highland newborn lambs (HLNB, 3600 m) have a higher pulmonary arterial pressure (PAP) due in part to a higher activity/expression of phosphodiesterase 5 (PDE5). We administered sildenafil, a PDE5 inhibitor, during basal and hypoxic conditions in the pulmonary hypertensive HLNB and compared them to lowland newborn lambs (LLNB, 580 m). Additionally, we compared the vasodilator responses to sildenafil in isolated small pulmonary arteries and the PDE5 mRNA expression and evaluated the vascular remodeling by histomorphometric analysis in these newborn lambs. Under basal conditions, HLNB had a higher PAP and cardiac output compared with LLNB. Sildenafil decreased the PAP during basal conditions and completely prevented the PAP increase during hypoxia in both groups. HLNB showed a greater contractile capacity and a higher maximal dilation to sildenafil. PDE5 mRNA expression did not show significant differences between HLNB and LLNB. The distal pulmonary arteries showed an increased wall thickness in HLNB. Our results showed that HLNB are more sensitive to sildenafil and therefore could be useful for treatment of pulmonary hypertension in high-altitude neonates.

Effects of tibolone and continuous combined hormone therapy on mammographic breast density and breast histochemical markers in postmenopausal women.

OBJECTIVE: To compare changes in mammographic density and the expression of markers of proliferation (Ki67) and apoptosis (Bcl-2) after 1 year of treatment with tibolone and continuous conjugated equine estrogens combined with medroxyprogesterone acetate (CEE-MPA). DESIGN: Comparative, randomized, evaluator-blinded study. SETTING: City research hospital. PATIENT(S): Thirty-seven postmenopausal women. INTERVENTION(S): Tibolone (2.5 mg; n = 18) or continuous conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (5 mg; n = 19) for 1 year. MAIN OUTCOME MEASURE(S): Mammographic density (BI-RADS density score), expression of immunohistochemical markers Ki67 and Bcl-2. RESULT(S): Mean breast density score decreased significantly from 2.22 to 1.67 in the tibolone group, compared with a significant increase in the CEE-MPA-treated group from 1.84 to 2.63. Ki67 expression decreased in 12 of 15, increased in 2 of 15, and remained unchanged in 1 of 15 subjects in the tibolone group, compared with 1 of 19, 15 of 19, and 3 of 19 subjects, respectively, in the CEE-MPA group. Bcl-2 expression decreased in 12 of 15, increased in 2 of 15, and remained unchanged in 1 of 15 subjects in the tibolone group, compared with 5 of 19, 9 of 19, and 5 of 19 subjects, respectively, in the CEE-MPA group. CONCLUSION(S): One-year treatment with tibolone induced a decrease in breast density, with a reduction in proliferation and a stimulation of apoptosis, whereas 1-year treatment with CEE-MPA induced an increase in breast density, with stimulation of proliferation and inhibition of apoptosis, indicating that tibolone effects on the breast are different from those of CEE-MPA.

Lactancia exclusiva al seno materno: abandono e incidencia de enfermedades / Exclusive breast feeding: desertion and onset of diseases

Para determinar la incidencia de diarrea infecciosa aguda (DIA) e infección respiratoria aguda (IRA) en niños menores de cuatro meses de edad con y sin lactancia exclusiva al seno materno (LESM), así como la frecuencia de abandono de la misma, se diseñó un estudio de cohortes de recién nacidos alimentados con LESM (grupo A) y lactancia mixta o sucedáneos (grupo B). Se determinó peso, talla inicial y final, ocurrencia de DIA o IRA. La ablactación y la lactancia mixta antes de los cuatro meses de edad se consideraron como abandono de LESM. Se incluyeron 32 niños en el grupo A y 25 en el B. Hubo mayor ganancia de peso y talla en el grupo A. En 31.25 por ciento hubo abandono de LESM. La incidencia de enfermedad fue 28 por ciento para el grupo A y 76 por ciento para el B. La causa más frecuente de abandono y no aceptación de LESM fue la información insuficiente sobre sus beneficios.

Daño pulmonar experimental por bleomicina en ratas: alteraciones del lavado broncoalveolar e histopatología / Experimental pulmonary damage by bleomycin in rats: changes in bronchoalveolar lavage and histopathology

Estudios previos han demostrado que la instilación endotraquial de bleomicina en la rata produce edema e inflamación al cabo de 24H y cierto grado de fibrosis luego de 15 días. El objetivo de este trabajo fue evaluar el daño pulmonar inducido a largo plazo (3,7,14,30 y 60 días)por la instilación endotraqueal de 1U de bleomicina por 100g de peso a fin de relacionar las alteraciones del lavado broncoalveolar (LBA) conla histopatología pulmonar. La serie control consistió en ratas instiladas con NaCl 0,9 por ciento vía endotraqueal y sometidas a similares procedimientos. En el LBA se practicó recuento celular y determinaciones de proteínas, fosfolípidos, fosfatasa alcalina gama glutamiltranspeptidasa (GGT). Se observó aumento significativo (p<0,05)de la realción peso pulmonar/peso corporal en las ratas tratadas con bleomicina la histología reveló daño pulmonar temprano (3 a 7 días):aumento de neutrófilos y eosinófilos y hemorragia intra-alveolar. En días ulteriores (14 a 60 días) se observó pérdida de la arquitectura, proliferación de neumocitos tipo II y fibrosis pulmonar. En el LBA de las ratas tratadas con bleomicina se observó aumento significativo (p<0,05)en realción a la serie de control en las siguientes variables: células (3 y 14 días), proteínas (3-7 y 30 días), fosfolípidos, fosfatasa alcalina y GGT (7-14 y 30 días). En el daño pulmonar pr bleomicina existiría relación entre el grado de inflamación de la fase exudativa y las alteraciones del LBA. La determinación de fosfatasa alcalina y GGT en el LBA podría ser potencialmente útil en el seguimiento del daño pulmonar por bleomicina

Actividad de acetilcolinoesterasa en dos casos de demencia por infartos múltiples / Acetylcholinesterase activity in 2 cases of multi-infarct dementia

Se determina la actividad de acetilcolinoesterasa (AchE) en 2 cerebros de pacientes que cumplen los criterios de demencia por infartos múltiples. Se demuestra una disminución de la actividad de AchE en el córtex prefrontal, parietal, hipocampo y núcleo basal de Meynert, la que afecta de manera particular a las fibras, con conservación de la actividad en los somas neuronales. Se postula que la inhibición de los sistemas colinérgicos del telencéfalo basal, tendrían algún rol en la génesis de la demencia por múltiples infartos

Intoxicación experimental por paraquat: correlación entre el recuento celular diferencial del lavado broncoalveolar y la histopatología pulmonar / Paraquat experimental intoxication: correlation between diferential cell count of the bronchoalveolar lavage and pulmonary histopathology

El paraquat es un hervicida ampliamente usado en agricultura. Evidencias clínicas y experimentales han mostrado que el paraquat puede causar daño pulmonar intenso produciendo un síndrome de distress respiratorio del adulto. El grado de alveolitis demostrado por el recuento celular diferencial en el lavado broncoalveolar (LBA) se relacionó con el daño histológico del pulmón, usando un modelo experimental de daño pulmonar agudo inducido por paraquat. El paraquat fue administrado a 34 ratas en una dosis única intraperitoneal de 2 ó 15 mg/Kg. Las ratas se sacrificaron 5 ó 48 h. después y los resultados se compararon con la serie control (ratas inyectadas con Na Cl 0,90%). En todas las series tratadas con paraquat se demostró un aumento significativo de los polimorfonucleares (PMN) y linfocitos y una disminución significativa en el recuento de macrófagos del lavado broncoalveolar (LBA). Sin embargo, el recuento total de células del LBA no demostró diferencias significativas comparado con la serie control

Evaluación diagnóstica de infecciones de cuello uterino asociadas a infección por virus papiloma humano / Diagnostic evaluation of cervix uteri infections associated with infection caused by human papilloma virus

El objetivo de este trabajo es demostrar la presencia de proteínas de virus papilomas humano (HPV) en biopsias de cuello uterino diagnosticadas histológicamente como cervicopatías de origen viral. Se escogieron 38 biopsias cervicales que cumplían con los criterios mencionados por Toki y Yajima para diagnóstico de HPV. Las biopsias provienen de archivos de placas del programa de detección de cáncer cérvico-uterino de las áreas Norte y Oriente de Santiago. Se empleó la técnica de inmunoperoxidasa usando el método ABC (complejo avidina-biotina-peroxidasa), utilizando como anticuerpo primario, uno policlonal diluido a 1:200, que reacciona con todas las variedades de virus papiloma. Veinte de las 38 biopsias (52,9%) presentan antígenos virales en núcleo de las capas superficiales del epitelio escamoso, en cantidad suficiente como para ser reconocidos por la sensibilidad del método. Este porcentaje es comparable a lo descrito en la literatura y que varía entre un 40% y un 62%

Actividad de acetilcolinoesterasa en el cortex cerebral y nucleo de Meynert: estudio en cerebro humano normal / Acetylcholinesterase activity in the cerebral cortex and nucleus basalis of Meynert: study in the normal human brain

La actividad de acetilcolinoesterasa (AchE) es estudiada en 4 cerebros de pacientes sin patología neurológica ni psiquiátrica mediante el método de Karnovsky y Roots modificado. Se definen áreas AchE (+) en el hipocampo, donde se observan bandas de fibras aferentes a las capas piramidal y granulosa, así como somas neuronales AchE (+) en el sector CA1 y el subiculum. En el córtex frontal se reconoce un plexo de fibras AchE (+) relacionado con las capas III y V donde se observan neuronas piramidales con actividad AchE. En el córtex parietal la mayor actividad está relacionada a los somas de la capa III y a un haz de fibras en la capa I. En el núcleo basal de Meynert se aprecia gran cantidad de fibras y neuronas de 30 a 40 micrones AchE (+)

BCG en cancer vesical superficial / BCG in superficial bladder cancer

Presentamos nuestra experiencia de 5 años en el tratamiento con BCG del Ca. vesical superficial. Comparamos un primer grupo de 19 pacientes tratados con un esquema de 2 meses de duración con un segundo grupo de 15 pacientes tratados durante un año. En el grupo 1, tenemos 50% de los enfermos libres de tumor a 4 años de tiempo medio de seguimiento y en el grupo 2, un 80% de los pacientes están sin cáncer a 1,5 años (tiempo 1/2)

Timectomía en miastenia gravis por timoma: experiencia de 11 casos / Thymectomy in myasthenia gravis by thymoma: experience of 11 cases

Estudio retrospectivo de 159 pacientes con MG sometidos a timectomía total en los últimos 16 años. En la serie, 147 casos corresponden a hiperplasia tímica (MG sin timoma) y 11, que motivan este estudio, corresponden a timoma (MG con timoma). De los 11 pacientes com timoma 10 son sólidos y uno quístico. Dos tumores sólidos son malignos. Los 9 timomas benignos curaron de su lesión anatómica; el cuadro de MG regresó parcialmente en 5, no hubo curación o agravamiento en 3 y uno no se controló. Los dos tumores malignos evolucionaron hacia la generalización. El criterio para definir si el tumor es benigno o maligno es prácticamente operatorio, determinado por la influencia macroscópica de estructuras vecinas para el maligno y por el aspecto localizado o encapsulado para el benigno, siendo ambas situaciones cito e histopatológicamente similares. La regresión de la MG con la timectomía en los casos de timoma es muy inferior a la de los casos de hiperplasia tímica (30% conta 70%). La MG por timoma corresponde en nuestra serie al 7%. Creemos que esta cifra puede ser mayor si se efectúan cortes histológicos más numerosos y en toda la glándula, dado que en un caso de nuestra, el hallazgo fue prácticamente casual porque se encontró un timoma de 2 mm inmerso en un timo hiperplásico

Ginecomastias / Gynecomastia

Se estudian 21 varones con ginecomastia, siendo unilaterales el 6,29% y bilaterales el 15,71%; esto se traduce en 36 hipertrofias mamarias en el hombre, entre los cuales se descubren dos carcinomas implantados en ginecomastias (5,5%). La mayoría de las ginecomastias fueron de origen fisiológico, y su aparición ocurrió en la adolescencia, siendo variable el tiempo de latencia para consultar; 72% se descubrieron en la segunda y tercera décadas de la vida, y sólo una después de los 70 años. El mejor método de diagnóstico complementario en la mamografía, la que tiene un altísimo rendimento, descubriendo la bilateralidad por muy pequeña que sea la hipertrofia, y siendo decisiva para el diagnóstico diferencial con el carcinoma mamario masculino. Prácticamente todos los pacientes eran de configuración genotípica y fenotípica masculina, y la mayoría no tenía alteraciones endocrinas de importancia. El patologia mamaria agregada es importante la presencia de dos carcinomas mamarios, presentados en ginecomastias unilaterales y en personas mayores. El tratamiento fue la adenomastectomía subcutánea en todos lo casos. En los carcinomas, el tratamiento se adaptó a la características locales del tumor y generales del paciente. Concluimos que toda patología mamaria en el hombre, especialmente las ginecomastias, debe ser estudiada con acuciosidad, pues en el futuro del paciente puede acechar un carcinoma, que, por lo general, tiene peor pronóstico que en la mujer, considerando igualdad de condiciones