Revista De Investigacion Clinica-Clinical and Translational Investigation最新文献

Abstract: Cushing's disease (CD) is the most common cause of endogenous hypercortisolemia. The clinical management of this condition is complex and entails multiple therapeutic strategies, treatment of chronic comorbidities, and lifelong surveillance for recurrences and complications. The identification of robust, practical, and reliable markers of disease behavior and prognosis could potentially allow for a tailored and cost-efficient management of each patient, as well as for a reduction of the medical procedure-associated stress. For this purpose, multiple clinical, biochemical, imaging, histopathological, molecular, and genetic features have been evaluated over the years. Only a handful of them, however, have been sufficiently validated for their application in the routine care of patients with CD. This review summarizes the current status of the established and potential biomarkers of CD, bases for their use, proposed and/or established utility, as well as advantages and barriers for their implementation in the clinic. (Rev Invest Clin. 2022;74(5):244-57).

Background: Genetic eye disorders, affecting around one in 1000 people, encompass a diverse group of diseases causing severe visual deficiency. The recent adoption of next-generation sequencing techniques, including whole-exome sequencing (WES), in medicine has greatly enhanced diagnostic rates of genetically heterogeneous diseases.

Objectives: The objectives of the study were to assess the diagnostic yield of WES in a cohort of Mexican individuals with suspected genetic eye disorders and to evaluate the improvement of diagnostic rates by reanalysis of WES data in patients without an initial molecular diagnosis.

Methods: A total of 90 probands with ocular anomalies of suspected genetic origin were ascertained. Patients underwent WES in leukocytic DNA. Bioinformatics analysis and Sanger sequencing were used to confirm the disease-causing variants. Only variants identified as pathogenic or likely pathogenic were considered as causal.

Results: Initial analysis revealed causal mutations in 46 cases (51%). Reanalysis of WES data 12 months after first analysis resulted in the identification of additional causal variants in 6 patients (7%), increasing the molecular diagnostic yield to 58%. The highest diagnostic rates by disease categories corresponded to hereditary retinal dystrophies (77%) and to anomalies of the anterior segment of the eye (47%).

Conclusions: Our study demonstrates that WES is an effective approach for genetic diagnosis of genetic ocular diseases and that reanalysis of WES data can improve the diagnostic yield.

Background: The coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus and is responsible for nearly 6 million deaths worldwide in the past 2 years. Machine learning (ML) models could help physicians in identifying high-risk individuals.

Objectives: To study the use of ML models for COVID-19 prediction outcomes using clinical data and a combination of clinical and metabolic data, measured in a metabolomics facility from a public university.

Methods: A total of 154 patients were included in the study. "Basic profile" was considered with clinical and demographic variables (33 variables), whereas in the "extended profile," metabolomic and immunological variables were also considered (156 characteristics). A selection of features was carried out for each of the profiles with a genetic algorithm (GA) and random forest models were trained and tested to predict each of the stages of COVID-19.

Results: The model based on extended profile was more useful in early stages of the disease. Models based on clinical data were preferred for predicting severe and critical illness and death. ML detected trimethylamine N-oxide, lipid mediators, and neutrophil/lymphocyte ratio as important variables.

Conclusions: ML and GAs provided adequate models to predict COVID-19 outcomes in patients with different severity grades.

Background: Low-grade inflammation is known to facilitate the development of hypertensive organ damage. The systemic immune-inflammation index (SII) is a new inflammatory index based on circulating immune-inflammatory cells.

Objectives: The objectives of this study were to investigate the relationship between the SII and asymptomatic organ damage (AOD) in patients with newly diagnosed treatment-naive hypertension (HTN).

Methods: A total of 500 participants (≥ 18 years) were enrolled in the study, including 250 patients and 250 healthy volunteers. Microalbuminuria of > 30 mg/day or proteinuria of > 150 mg/day, left ventricular mass index of > 95 g/m² in women and > 115 g/m² in men, and carotid intima-media thickness of > 0.9 mm or the presence of plaque in the carotid were evaluated as AOD indicators. AOD grade was classified as follows: Grade I - One organ involved, Grade II - Two organs involved, Grade III - Three organs involved, and Grade IV - Four organs involved.

Results: SII values were higher among patients with HTN than in the control group. Positive correlations were found between the SII and AOD indicators and C-reactive protein levels. Increasing SII values were a common independent predictor of the presence and severity of AOD. The gradually increasing threshold values of the SII from no AOD to Grade III-IV exhibited high diagnostic performance.

Conclusions: High SII values were independent predictors of the presence and severity of AOD in patients with newly diagnosed treatment-naive HTN. Considering the role of inflammation in HTN, the SII, which can be easily evaluated using blood parameters, can be an effective prognostic screening tool. (Rev Invest Clin. 2022;74(5):258-67).

Background: Cervical cancer (CC), as a serious menace to the health of women, has long been one of the most lethal gynecologic neoplasms throughout the world. Long non-coding RNA (LncRNA) NR2F1-AS1 has been documented to exert crucial functions in many malignant tumors. Nonetheless, the function and molecular mechanism of NR2F1-AS1 in CC remain completely unknown.

Objectives: This study aimed to explore the function and molecular mechanism of NR2F1-AS1 in CC.

Methods: The expression levels of NR2F1-AS1, miR-642a-3p, NR2F1 in CC tissues, and cell lines were examined by reverse transcription real-time quantitative polymerase chain reaction. Cell viability, proliferation, migration, and invasion were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, colony formation and Transwell assays. The protein levels of epithelial-mesenchymal transition markers and NR2F1 in CC cells were assessed by Western blot analysis. The correlations among NR2F1-AS1, miR-642a-3p, and NR2F1 were estimated through luciferase reporter and RNA immunoprecipitation assays.

Results: NR2F1-AS1 expression was clearly downregulated in CC tissues and cell lines. Molecular mechanistic experiments showed that NR2F1-AS1 overexpression upregulated NR2F1 expression in CC cells by directly binding to miR-642a-3p, and inhibiting by this way cell viability, proliferation, migration, and invasion in CC. Rescue assays showed that NR2F1 knockdown or miR-642a-3p overexpression offset NR2F1-AS1 upregulation-induced inhibition on CC cell malignant phenotypes.

Conclusions: These findings revealed that NR2F1-AS1 played a tumor suppressor role in CC by mediating the miR-642a-3p/NR2F1 axis.

Abstract: Recent investigations highlight the importance of the gut microbiota and bacteria-derived metabolites as key components in obesity and metabolic health. The microbiota-gut-brain axis presents promising targets for future obesity treatments and prevention. However, the current state of evidence and existing clinical applications of the microbiota-gut-brain axis have yet to be summarized in a thorough review. Therefore, we sought to examine current evidence on the effect of lifestyle, dietary, pharmacological, and surgical interventions on the microbiota-gut-brain axis. In addition, this review highlights potential next steps in research toward characterizing the role of the microbiota-gut-brain axis in metabolic health, along with possible interventions to address obesity.

Background: A high incidence of acute kidney injury (AKI) has been reported in coronavirus disease 2019 (COVID-19) patients in critical care units and those undergoing invasive mechanical ventilation (IMV). The introduction of dexamethasone (DXM) as treatment for severe COVID-19 has improved mortality, but its effects in other organs remain under study.

Objective: The objective of this study was to evaluate the association between DXM and AKI in COVID-19.

Methods: In this prospective observational cohort study, we evaluated the incidence of AKI in critically ill COVID-19 patients undergoing mechanical ventilation, and the association of DXM treatment with the incidence, severity, and outcomes of AKI. The association between DXM treatment and AKI was evaluated by multivariable logistic regression. The association of the combination of DXM treatment and AKI on mortality was evaluated by Cox-regression analysis. Results: We included 552 patients. AKI was diagnosed in 311 (56%), of which 196 (63%) corresponded to severe (stage 2 or 3) AKI, and 46 (14.8%) received kidney replacement therapy. Two hundred and sixty-seven (48%) patients were treated with DXM. This treatment was associated to lower incidence of AKI (Odds Radio 0.34, 95% Confidence intervals [CI] 0.22-0.52, p < 0.001) after adjusting for age, body mass index, laboratory parameters, SOFA score, and vasopressor use. DXM treatment significantly reduced mortality in patients with severe AKI (HR 0.63, 95%CI 0.41-0.96, p = 0.032).

Conclusions: The incidence of AKI is high in COVID-19 patients under IMV. DXM treatment is associated with a lower incidence of AKI and a lower mortality in the group with severe AKI.

Background: The state of Aguascalientes, Mexico, has been recognized as a chronic kidney disease hotspot. Screening studies have revealed a high prevalence of persistent albuminuria (pA), histologically characterized by glomerulomegaly, and incomplete podocyte fusion, probably associated with oligonephrony. To date, urinary biomarkers have not been explored in this population.

Objective: The aim of the study was to identify the presence of potential biomarkers of early renal injury in patients with pA (pACR) and that correspond with the characteristic nephropathy profile that prevails in this entity.

Methods: This is a cross-sectional, analytical, and comparative study. Four groups were recruited: adolescents aged 10-17 years with pACR, isolated albuminuria (iACR), no albuminuria (negative control), and adults with biopsy-confirmed glomerulopathy (positive control). Urinary excretion of SerpinA3, heat-shock protein-72 (HSP-72), podocalyxin (PCX), and nephrin was evaluated in urine samples. SerpinA3 and HSP-72 were analyzed by Western blot, and PCX and nephrin were quantified by enzyme-linked immunosorbent assay.

Results: The mean GFR in the pACR group was 113.4 mL/min/1.73m2 and differed significantly only from that of the positive control group (65.1 mL/min/1.73m2). The mean albuminuria value in the pACR group was 48.9 mg/g. SerpinA3 concentration differed between groups (0.08 vs. 0.25 ng/mL, p < 0.001): it was significantly higher in the pACR group compared to the negative controls (p = 0.037).

Conclusion: SerpinA3 was significantly associated with pA and could become a biomarker of early kidney injury. Further investigations are required to determine whether SerpinA3 precedes the development of albuminuria and its pathogenic role.

Background: Severe congenital neutropenia type 4 (SCN4) is a rare autosomal recessive granulopoiesis disorder caused by G6PC3 gene pathogenic variants. The estimated prevalence is 1/10,000,000 people. Over 90% of patients present a syndromic form with variable multisystemic involvement, including congenital heart defects, increased visibility of superficial veins (IVSV), inflammatory bowel disease, and congenital urogenital defects as prominent symptoms.

Objectives: The objective of the study was to study non-hematological phenotypic findings that suggest a clinical diagnosis of SCN4.

Methods: We examined medical records of patients diagnosed with neutropenia from January 2000 to December 2020, selecting cases with non-hematologic manifestations for phenotypic description and G6PC3 gene sequencing.

Results: We found 11 cases with non-hematologic features: congenital heart defects in 8, IVSV in 6, inflammatory bowel disease in 4, urogenital defects in 4, and similar facial appearance. In addition, Sanger sequencing confirmed 3 homozygous cases for the c.210delC variant, a compound heterozygous harboring this variant, and a c.199_218+1 deletion.

Conclusions: Our findings of the c.210delC variant in very close geographical settings, to date, have only been reported among Mexicans, and a mutual uncommon surname in two families strongly supports a founder effect for the variant in the studied population. Furthermore, the described non-hematologic symptoms in patients with severe primary neutropenia should be explored, confirming SCN4 by investigating G6PC3 gene mutations.