Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile.

BACKGROUND: In mice, GPR146 (G-protein-coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown. METHODS: Common and rare genetic variants in the GPR146 gene locus were used as research instruments in the UK Biobank. The Lifelines, The Copenhagen-City Heart Study, and a cohort of individuals with familial hypobetalipoproteinemia were used to find and study rare GPR146 variants. RESULTS: In the UK Biobank, carriers of the common rs2362529-C allele present with lower low-density lipoprotein cholesterol, apo (apolipoprotein) B, high-density lipoprotein cholesterol, apoAI, CRP (C-reactive protein), and plasma liver enzymes compared with noncarriers. Carriers of the common rs1997243-G allele, associated with higher GPR146 expression, present with the exact opposite phenotype. The associations with plasma lipids of the above alleles are allele dose-dependent. Heterozygote carriers of a rare coding variant (p.Pro62Leu; n=2615), predicted to be damaging, show a stronger reductions in the above parameters compared with carriers of the common rs2362529-C allele. The p.Pro62Leu variant is furthermore shown to segregate with low low-density lipoprotein cholesterol in a family with familial hypobetalipoproteinemia. Compared with controls, carriers of the common rs2362529-C allele show a marginally reduced risk of coronary artery disease (P=0.03) concomitant with a small effect size on low-density lipoprotein cholesterol (average decrease of 2.24 mg/dL in homozygotes) of this variant. Finally, mendelian randomization analyses suggest a causal relationship between GPR146 gene expression and plasma lipid and liver enzyme levels. CONCLUSIONS: This study shows that carriers of new genetic GPR146 variants have a beneficial cardiometabolic risk profile, but it remains to be shown whether genetic or pharmaceutical inhibition of GPR146 protects against atherosclerosis in humans.

A novel role for GalNAc-T2 dependent glycosylation in energy homeostasis.

OBJECTIVE: GALNT2, encoding polypeptide N-acetylgalactosaminyltransferase 2 (GalNAc-T2), was initially discovered as a regulator of high-density lipoprotein metabolism. GalNAc-T2 is known to exert these effects through post-translational modification, i.e., O-linked glycosylation of secreted proteins with established roles in plasma lipid metabolism. It has recently become clear that loss of GALNT2 in rodents, cattle, nonhuman primates, and humans should be regarded as a novel congenital disorder of glycosylation that affects development and body weight. The role of GALNT2 in metabolic abnormalities other than plasma lipids, including insulin sensitivity and energy homeostasis, is poorly understood. METHODS: GWAS data from the UK Biobank was used to study variation in the GALNT2 locus beyond changes in high-density lipoprotein metabolism. Experimental data were obtained through studies in Galnt2-/- mice and wild-type littermates on both control and high-fat diet. RESULTS: First, we uncovered associations between GALNT2 gene variation, adiposity, and body mass index in humans. In mice, we identify the insulin receptor as a novel substrate of GalNAc-T2 and demonstrate that Galnt2-/- mice exhibit decreased adiposity, alterations in insulin signaling and a shift in energy substrate utilization in the inactive phase. CONCLUSIONS: This study identifies a novel role for GALNT2 in energy homeostasis, and our findings suggest that the local effects of GalNAc-T2 are mediated through posttranslational modification of the insulin receptor.

Taking One Step Back in Familial Hypercholesterolemia: STAP1 Does Not Alter Plasma LDL (Low-Density Lipoprotein) Cholesterol in Mice and Humans.

OBJECTIVE: STAP1, encoding for STAP1 (signal transducing adaptor family member 1), has been reported as a candidate gene associated with familial hypercholesterolemia. Unlike established familial hypercholesterolemia genes, expression of STAP1 is absent in liver but mainly observed in immune cells. In this study, we set out to validate STAP1 as a familial hypercholesterolemia gene. Approach and Results: A whole-body Stap1 knockout mouse model (Stap1-/-) was generated and characterized, without showing changes in plasma lipid levels compared with controls. In follow-up studies, bone marrow from Stap1-/- mice was transplanted to Ldlr-/- mice, which did not show significant changes in plasma lipid levels or atherosclerotic lesions. To functionally assess whether STAP1 expression in B cells can affect hepatic function, HepG2 cells were cocultured with peripheral blood mononuclear cells isolated from heterozygotes carriers of STAP1 variants and controls. The peripheral blood mononuclear cells from STAP1 variant carriers and controls showed similar LDLR mRNA and protein levels. Also, LDL (low-density lipoprotein) uptake by HepG2 cells did not differ upon coculturing with peripheral blood mononuclear cells isolated from either STAP1 variant carriers or controls. In addition, plasma lipid profiles of 39 carriers and 71 family controls showed no differences in plasma LDL cholesterol, HDL (high-density lipoprotein) cholesterol, triglycerides, and lipoprotein(a) levels. Similarly, B-cell populations did not differ in a group of 10 STAP1 variant carriers and 10 age- and sex-matched controls. Furthermore, recent data from the UK Biobank do not show association between STAP1 rare gene variants and LDL cholesterol. CONCLUSIONS: Our combined studies in mouse models and carriers of STAP1 variants indicate that STAP1 is not a familial hypercholesterolemia gene.

GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis.

Although human genetic studies have implicated many susceptible genes associated with plasma lipid levels, their physiological and molecular functions are not fully characterized. Here we demonstrate that orphan G protein-coupled receptor 146 (GPR146) promotes activity of hepatic sterol regulatory element binding protein 2 (SREBP2) through activation of the extracellular signal-regulated kinase (ERK) signaling pathway, thereby regulating hepatic very low-density lipoprotein (VLDL) secretion, and subsequently circulating low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels. Remarkably, GPR146 deficiency reduces plasma cholesterol levels substantially in both wild-type and LDL receptor (LDLR)-deficient mice. Finally, aortic atherosclerotic lesions are reduced by 90% and 70%, respectively, in male and female LDLR-deficient mice upon GPR146 depletion. Taken together, these findings outline a regulatory role for the GPR146/ERK axis in systemic cholesterol metabolism and suggest that GPR146 inhibition could be an effective strategy to reduce plasma cholesterol levels and atherosclerosis.

Novel regulators of plasma lipid levels.

PURPOSE OF REVIEW: To highlight very recent studies identifying novel regulatory molecules and mechanisms in plasma lipid metabolism. RECENT FINDINGS: Two novel regulatory mechanisms of LDL receptor (LDLR) intracellular trafficking have been described. The "COMMD/CCDC22/CCDC93" and "Wiskott-Aldrich syndrome protein and SCAR homologue" complexes were found to be involved in LDLR endosomal sorting and recycling, whereas the GRP94 was shown to protect LDLR from early degradation within the hepatocyte secretory pathway. Additionally, the transcription factors PHD1 and Bmal1 were identified to regulate LDL-C levels in mice by modulating cholesterol excretion. Important advances are reported on the relevance of two Genome Wide Association Studies hits: Reassessment of GALNT2 showed, in contrast to previous reports, that loss of GALNT2 reduces HDL-cholesterol in humans and other mammalian species, while phospholipid transfer protein was identified as an additional target of GALNT2. Tetratricopeptide repeat domain protein 39B was found to promote ubiquitination and degradation of Liver X receptor, and its deficiency increased HDL-cholesterol and cholesterol removal while also inhibiting lipogenesis in mice. SUMMARY: The unraveling of mechanisms how new factors modulate plasma lipid levels keep providing interesting opportunities to rationally design novel therapies to treat cardiovascular disease but also metabolic disorders.

Cellular senescence and tumor promotion: Is aging the key?

The senescence response is a potent tumor suppressor mechanism characterized by an irreversible growth arrest in response to potentially oncogenic signals to prevent the proliferation of damaged cells. Late in life, some of the features of senescent cells seem to mediate the development of age-related pathologies, including cancer. In the present review, we present a summary of the current knowledge regarding the causes, effector pathways and cellular features of senescence. We also discuss how the senescence response, initially a tumor suppressor mechanism, turns into a tumor promoter apparently as a consequence of aging. We argue that three age-related phenomena--senescence-associated secretory phenotype (SASP) dysregulation, decline in the immune system function and genomic instability--could contribute, independently or synergistically, to deteriorate the efficacy of the senescence response in stopping cancer. As a consequence, senescent cells could be considered premalignant cells, and targeting senescent cells could be a preventive and therapeutic strategy against cancer.

Caracterización de las gestantes tamizadas para Streptococcus agalactiae y su relación con sepsis neonatal temprana, en la Clínica del Prado de Medellín (Colombia), año 2010 / Characterization of pregnant women screened for Streptococcus agalactiae and its relationship with early neonatal sepsis, at the Clínica del Prado de Medellín (Colombia), 2010

Streptococcus agalactiae (S. agalactiae) es el principal microorganismo causante de sepsis neonatal temprana (SNT) en el mundo. La profilaxis basada en la tamización rectovaginal de las gestantes es una estrategia eficaz para prevenir la SNT. Objetivo: Describir la prevalencia de colonización rectovaginal por S. agalactiae en gestantes tamizadas en la Clínica del Prado de Medellín durante 2010 y establecer la relación entre colonización materna y SNT. Materiales y métodos: Estudio observacional, descriptivo y de corte transversal, para determinar la prevalencia de colonización rectovaginal por S. agalactiae , mediante revisión de historias clínicas y resultados de laboratorio. Se incluyó aleatoriamente a 182 gestantes de 540 tamizadas. Resultados: La prevalencia de colonización rectovaginal por S. agalactiae determinada fue de 17,6%. La edad promedio de las gestantes fue 25 años (14-44), la edad gestacional promedio fue 35,4 semanas. Se suministró profilaxis con penicilina cristalina en 21,4% de las mujeres tamizadas y en 44% de las colonizadas, entre las que el 17% tuvieron el parto por cesárea y recibieron profilaxis con cefazolina. En el 48,9% no se suministró profilaxis. Ninguno de los hijos de las madres incluidas desarrolló SNT. Entre los nacidos en 2010 la prevalencia de esta entidad fue 0,14%. No se encontró asociación estadística (p = 0,062) entre el tamización rectovaginal y la administración de profilaxis antibiótica. Conclusión: La prevalencia de colonización rectovaginal por S. agalactiae hallada apoya la recomendación de adoptar la tamización sistemática de las gestantes para conocer su estado de portador y tomar medidas oportunas que disminuyan la incidencia de SNT.

Streptococcus agalactiae (S. agalactiae) is the main worldwide cause of early onset neonatal sepsis (EONS). Antibiotic prophylaxis based on vaginal-rectum screening of pregnant women is an effective strategy to prevent EONS. Objective: To describe the prevalence of vaginal-rectum S. agalactiae colonization in pregnant women screened at the Clinica del Prado in Medellin during 2010 and to establish a relationship between maternal colonization and EONS. Materials and methods: This was an observational, descriptive and, cross-sectional study to determine the prevalence of vaginal-rectum colonization by S. agalactiae , through a review of medical records and laboratory test results. A total of 182 pregnant women out of 540 screened were randomly included. Results: The prevalence of vaginal-rectum S. agalactiae colonization was 17.6%. The average age of the women was 25 years (14-44 range); the mean gestational age was 35.4 weeks. Prophylaxis with crystalline penicillin was given to 21.4% of the screened women and to 44% of those colonized. A total of 17% had cesarean deliveries and cephazolin prophylaxis was given. A total of 48.9% did not receive prophylaxis. None of the children of mothers included in the treatment developed EONS. The prevalence of EONS among the children born in 2010 was 0.14%. There was no statistical association (P =0,062) between vaginal-rectum screening and antibiotic prophylaxis. Conclusions: The prevalence of vaginal-rectum S. agalactiae colonization found supports a universal screening strategy in pregnant women, to know their carrier status and to take appropriate actions to minimize the incidence of EONS.

Principales hallazgos prenatales y postnatales en mujeres embarazadas adolescentes y adultas, cuyos partos fueron atendidos en la clínica San Cayetano de ASSBASALUD E. S. E Manizales (Colombia), 2009-2010 / Key findings, prenatal and postnatal, in pregnant women under and above age 19, whose births were attended at the health center San Cayetano ASSBASALUD ESE Manizales (Colombia), 2009-2010

Objetivo: Evaluar los factores relacionados con la maternidad adolescente, con relación a un grupo de gestantes adultas y las particularidades potenciales que pueden repercutir en la salud de la madre y el neonato. Materiales y métodos: Estudio de corte transversal. Se incluyeron todas aquellas gestantes cuyos partos fueron atendidos en el centro de salud San Cayetano de ASSBASALUD E.S.E (Manizales, Colombia) entre los años 2009 y 2010. Resultados: Se analizaron 900 historias, el 99% de los partos fue vaginal, 64,2% de las gestantes <19 años presentó complicaciones en el parto, siendo la necesidad de episiotomía la más frecuente, 33,3%. El promedio de peso neonatal fue 3063 gr con 4,3% de bajo peso, el 49,6% de las gestantes >19 años tuvieron complicaciones en el parto siendo el desgarro grado II la más frecuente, promedio de peso neonatal 3163 con 3,1% de bajo peso. No hubo diferencias significativas entre ambos grupos en mortalidad materna, neonatal, malformación fetal, índice apgar al minuto, a los 5 minutos, talla neonatal, número de controles prenatales, etc. Además entre ambos grupos hubo diferencias significativas en consumo de sustancias, planeación del embarazo, escolaridad, empleo de anticonceptivos, peso materno, edad de inicio de relaciones sexuales, número de gravideces, y de partos, entre otras. Conclusiones: Si bien en esta población hay diferencias significativas entre adolescentes y adultas en peso del recién nacido, y complicaciones en el parto, estas asimetrías no son suficientes para producir diferencias de morbimortalidad entre los neonatos de gestantes adolescentes y adultas...

Diabetes mellitus en pacientes con infarto agudo de miocardio en un hospital de alto nivel de complejidad de la ciudad de Medellín / Diabetes mellitus in patients with acute myocardial infarction in a high-complexity hospital of Medellin

Objetivo: describir las características clínicas y epidemiológicas de los pacientes con Infarto Agudo de Miocardio que tenían antecedente de Diabetes Mellitus. Metodología: estudio observacional, descriptivo y retrospectivo en el que se estudiaron 347 historias de pacientes mayoresde 18 años que presentaron infarto agudo de miocardio y que tenían antecedente confirmado de Diabetes Mellitus. Resultados: 52 pacientes fueron estudiados (23 mujeres y 29 hombres. 60% tenían 61 y más años. Solo tres de los 52 pacientes tenían medición de HbA1c, además en 33 pacientes (63.5%) no se conocía el tiempo de evolución de la diabetes. El 25% de los pacientes reingresó, de éstos, el 61.5% fue por reinfarto. Las personas tratadas con hipoglicemiantes orales y con insulina tuvieron mayor proporción de reingreso (34.7% y 30.0%, respectivamente) con respecto a los otros tratamientos. Conclusión: teniendo en cuenta los resultados encontrados, podemos inferir que la falta de control de la diabetes, sumadaa la edad del paciente, hace que esta enfermedad sea más deletérea, y que se requiere mejor seguimiento clínico y control terapéutico de la diabetes para prevenir las complicaciones como síndromes coronarios agudos.

Objective: to describe the clinical and epidemiological characteristics of patients with Acute Myocardial Infarction who have a history of Diabetes Mellitus. Methods: observational, descriptive and retrospective study in which were read 347 medical histories from patients aged 18 or older with Acute Myocardial Infarction and comfirmed antecedent of Diabetes Mellitus. Results: 52 patients were studied (23 female and 29 male). 60% were aged 61 or older. Only 3 of the 52 patients had HbA1cmeasurement, additionally, in 33 patients (63.5%) the time of evolution of diabetes could not be ascertained. 25% of the patients were readmitted, of these, 61.5% were readmitted for reinfarction. The patients treated with oral hypoglycemic agents andinsulin had greater proportion of readmission (34.7% y 30.0%, respectively) with respect to the others therapies. Conclusion: taking into account the results we found, we can conclude that poor Diabetes Mellitus control as well as the age of patients makes this disease more devastating, requiring better clinical follow-up and therapeutic control for diabetes in orderto prevent complications such as acute coronary syndrome.

[A comparative study of direct immunofluorescence, enzyme immunoassay, and culture for diagnosing metapneumovirus infection]. / Estudio comparativo de inmunofluorescencia directa, enzimoinmunoanálisis y cultivo para el diagnóstico de las infecciones por metapneumovirus humano.

INTRODUCTION: Human metapneumovirus (hMPV) is an important cause of lower respiratory tract infections in children, accounting for 14% to 24% of all viral respiratory infections with an etiological diagnosis. This study compares a direct fluorescent antibody (DFA) test, enzyme immunoassay (EIA), and shell-vial culture for diagnosing acute bronchiolitis in infants. METHODS: A total of 124 nasopharyngeal aspirates from 108 infants with lower respiratory tract infection were analyzed. Incoming samples were processed for DFA using a commercial anti-hMPV antibody (Diagnostic Hybrids Inc.); 76 were inoculated in an LLC-MK2 cell line, and after an incubation period of 48 h, were stained and fixed with the aforementioned serum. The remaining sample was processed according to the routine diagnostic procedure and aliquots were frozen for EIA analysis (Biotrin). RESULTS: Twenty (16.12%) samples were positive for hMPV by DFA, 27 (21.77%) by EIA, and 15 (19.73%) by culture. DFA and EIA results were consistent in 92.73% of the 124 samples. Considering the 3 techniques, the same results were obtained in 90.78% of the 76 specimens. Considering only the first specimen from each patient (acute phase), the sensitivity, predictive values, and Kappa index for DFA improved and were very close to the EIA values. CONCLUSION: DFA and EIA are useful for antigen detection in the diagnosis of acute hMPV infection, particularly in pediatric hospitals that do not have amplification techniques for this virus, and when a rapid diagnosis is required. It should be kept in mind that DFA analysis is a suitable test for this purpose only in the acute phase of the infection.

Evaluación de la concordancia entre dos métodos de lavado broncoalveolar para el diagnóstico microbiológico de la neumonía en pacientes con asistencia respiratoria mecánica / Concordance between two methods of bronchoalveolar lavage for the microbiological diagnosis of pneumonia in mechanically ventilated patients

Introducción. El diagnóstico microbiológico de la neumonía permite optimizar el uso de antibióticos en pacientes con asistencia respiratoria mecánica. Para ello se han cultivado cuantitativamente las muestras del lavado broncoalveolar broncoscópico, procedimiento que no siempre es posible. Objetivo. Evaluar la concordancia microbiológica entre muestras respiratorias tomadas porlavado broncoalveolar broncoscópico y no broncoscópico, y establecer si el uso previo de antibióticos y el momento de presentación de la neumonía pueden afectarla. Materiales y métodos. Estudio prospectivo realizado en el Hospital Universitario San Vicente de Paúl, en 38 pacientes con sospecha de neumonía y con asistencia respiratoria mecánica. En todos se practicó el lavado broncoalveolar por fibrobroncoscopia y el lavado nobroncoscópico usando un catéter telescopado de punta preformada (Balcatho). Todas las muestras fueron procesadas siguiendo protocolos microbiológicos convencionales. Resultados. Considerando el lavado broncoalveolar por fibrobroncoscopia como patrón dereferencia, los cultivos permitieron identificar el agente en 60,5 por ciento de los casos. El acuerdo diagnóstico se logró en 82 por ciento de los pacientes y 79 por ciento de los aislamientos. Utilizando el índice kappa de Cohen, la concordancia general entre los dos métodos fue 0,76 [0,60-0,93]; pero en quienes habían recibido antibióticos previos fue 0,26 [0,05-0,48], versus 1,0 en quienes no lo habían hecho (p<0,0001). La concordancia no difirió significativamente cuando se compararon los casos de neumonía temprana y tardía. Conclusiones. La concordancia general entre los dos métodos de lavado broncoalveolar es buena en pacientes con neumonía y respiración asistida mecánicamente. Sin embargo, el uso previo de antibióticos y no el momento de aparición de la neumonía, disminuye ésta significativamente.

[Concordance between two methods of bronchoalveolar lavage for the microbiological diagnosis of pneumonia in mechanically ventilated patients]. / Evaluación de la concordancia entre dos métodos de lavado broncoalveolar para el diagnóstico microbiológico de la neumonía en pacientes con asistencia respiratoria mecánica.

INTRODUCTION: Microbiological diagnosis of pneumonia allows the optimal use of antibiotics in mechanically ventilated patients. That is why samples of bronchoscopic bronchoalveolar lavage had been quantitatively cultivated, but this procedure is not always possible. OBJECTIVE: To evaluate the microbiological concordance between respiratory samples obtained by non-bronchoscopic protected bronchoalveolar lavage compared to the bronchoscopic ones, and to find out whether concordance was affected by previous use of antibiotics or the time of pneumonia onset. MATERIALS AND METHODS: Prospective study conducted at Hospital Universitario San Vicente de Paúl, in 38 patients with suspected pneumonia in mechanical ventilation. Bronchoalveolar lavage specimens were taken by two methods, the traditional one and non-bronchoscopic bronchoalveolar lavage, using a telescoping preformed tip catheter (Balcath). All samples were processed using conventional microbiologic protocols. RESULTS: Considering flexible bronchoscopy with bronchoalveolar lavage as the gold standard, cultures allowed the identification of at least one respiratory pathogen in 60.5% of cases. Diagnostic agreement was achieved in 82% of patients and 79% of microbiologic isolates. Using the Cohen's kappa coefficient, general concordance between both methods was 0.76 [0.60-0.93]; but in those who received previously antibiotics was 0.26 [0.05-0.48], versus 1.0 in those who did not (p<0.0001). Concordance did not differ significantly when cases of early or late pneumonia were compared. CONCLUSIONS: Concordance between non-bronchoscopic and bronchoscopic bronchoalveolar lavage is good in mechanically ventilated patients with pneumonia. However, the use of antibiotics previously, but not the time of pneumonia presentation, significantly decreases that concordance.