SELECTED ORIGINAL PAPERS

Hepatitis C screening in the general population

Clara Corona-Lau, Linda Muñoz, Enrique Wolpert, Luz Ma. Aguilar, Margarita Dehesa, Concepción Gutiérrez, David Kershenobich. Rev Invest Clin 2015;67:104-108.

Given that Hepatitis C is a silent disease, patients infected with the hepatitis C virus are usually poorly aware for many years of having the disease. In this study, Corona-Lau et al.³ reported the results from the screening of 32,945 volunteers (75% belonging to the group of 21-50 years of age) during the period of 2000-2014, employing a chemiluminescence enzyme immunoassay. Anti-hepatitis C virus was positive in 0.58% of the subjects (194 patients), of which 129 were confirmed by polymerase chain reaction (PCR), yielding an overall prevalence of 0.39% in the sample analyzed. Although the data need to be updated to search for trends in the prevalence of positive cases, the study is of great value considering the number of individuals tested as well as the laboratory procedures employed in the analysis. Determining the prevalence of hepatitis C viremia in the general population is important since this infection may lead to chronic liver disease. The authors conclude that their findings are of relevance when deciding the allocation of resources in the era of new pharmacological approaches to treat this disease, starting treatment earlier to prevent advanced liver disease.

Distinguishing intracerebral hemorrhage from acute cerebral infarction through metabolomics

Xuxin Zhang, Yanzhao Li, Yan Liang, Pitong Sun, Xue Wu, Jinhui Song, Xiaoyu Sun, Mo Hong, Peng Gao, Dongfeng Deng. Rev Invest Clin 2017;69:319-328.

Stroke is the major leading cause of death in adults worldwide. Essentially, stroke can be ischemic or hemorrhagic. Typically, diagnosis is made by neuroimaging⁴. Both conditions share common clinical manifestations in the acute, bedside setting, but require opposite therapeutic strategies. In this study, Zhang et al.⁵ enrolled 129 patients with ischemic stroke and 128 with hemorrhagic stroke diagnosed by computed tomography and/or magnetic resonance imaging, and 65 healthy controls. The authors compared changes in metabolites between both conditions and controls, using dried blood spot-based direct infusion mass spectrometry technology, and found 11 clinically relevant biomarkers based on multivariate analysis. An artificial neural network model was constructed based on these biomarkers and the authors describe an external validation of this model, stating a diagnostic sensitivity of 0.84 (95% Confidence Interval [CI] 0.74-0.94) and specificity of 0.77 (95% CI 0.65-0.88). This study is relevant because it suggests that, besides high-technology imaging, metabolomic analysis is a promising tool for fast differentiation between ischemic or hemorrhagic stroke. However, the results from this study should be taken with caution since the search for these metabolites was empirical, without a clear pathophysiological basis. Furthermore, it should be considered that the levels of the metabolites investigated may vary depending on gender, age, prevalence of diabetes, obesity or hypertension, and drugs administered or timing of their administration⁶.

The role of stents as bridge to surgery for acute left-sided obstructive colorectal cancer: eta-analysis of randomized controlled trials

Ping Yang, Xiu-Feng Lin, Kai Lin, Wei Li. Rev Invest Clin 2018;70:269-278.

Colorectal cancer is a major health problem worldwide. Left-sided neoplasms are frequently diagnosed as colonic occlusion and, in selected cases, the role of self-expanding metallic stents to permit resolution of the occlusion and to prepare the patient to definitive surgery is a matter of controversy⁷. In this meta-analysis⁸, the authors included eight randomized trials comprising patients who received a colonic stent or directly underwent surgery; 497 individuals were studied. Patients who underwent resolution by stent received a colonic stoma less frequently and a primary anastomosis more frequently than those who went directly to surgery. The frequency of surgical complications was lower in the group who underwent colonic stents as well. However, the frequency of cancer recurrence was higher in this latter group. Considering the heterogeneity of surgical randomized clinical trials, the absence of blinding, and different inclusion criteria, the authors concluded that the resolution of colonic occlusion by the use of stents increases the frequency of primary anastomosis as well as the risk of cancer recurrence. Probably, the pre-operative use of metal stents to decompress colonic occlusion must be considered with caution, selecting patients with clear risk factors for surgical morbidity and increased probability of having a definitive stoma, and selecting the best pre-operative chemotherapy for each case⁹.

The effect of single-dose intraperitoneal bevacizumab on peritoneal adhesion formation

Gokce Acun, Hakan Ozdemir, Oguzhan Sunamak, Zehra Unal Ozdemir, Emel Baskan, Mete Yazi, Berna Zavas, Ugur Berberoglu. Rev Invest Clin 2018;70:279-284.

Intestinal occlusion caused by surgical adhesions is a leading cause of abdominal surgical emergencies, and a major cause of morbidity, mortality, and costs at the emergency room¹⁰. Therefore, various treatments that aim to reduce the formation of surgical adhesions are being investigated, and it is a quite controversial matter. Angiogenesis and adhesion can be blocked by inhibiting vascular endothelial growth factor (VEGF). In this study by Acun et al.¹¹ an experimental model in rats is presented, employing bevacizumab to reduce adhesion formation in a cecum abrasion model, pretending to demonstrate the effect of VEGF blockade. The authors randomly assigned 32 Wistar rats into two groups, the first was treated with intraperitoneal bevacizumab and the second with placebo. Two weeks after surgery, adhesion formation was evaluated and found to be lower in the treated group. The authors concluded that bevacizumab was effective in preventing the development of intraperitoneal adhesion in rats. However, its role in the prophylaxis of adhesion formation could be limited by costs and adverse effects, factors that should be anticipated in clinical trials in humans. This study is an Editors’ choice because of its seminal approach to a major surgical problem that can stimulate further clinical research on this important issue¹².

Factors influencing achievement of low-density lipoprotein cholesterol (LDL-C) goals in mexico: The International Cholesterol Management Study

Omar Y. Bello-Chavolla, Carlos A. Aguilar-Salinas. Rev Invest Clin. 2019;71:408-416.

High LDL-C level, a strong risk factor for cardiovascular disease¹³, is among the most common forms of dyslipidemia in Mexicans, although remains usually underdiagnosed and untreated. In this cross-sectional observational study¹⁴ that included 623 patients receiving stable lipid-lowering therapy (statins), the authors evaluated the achievement of LDL-C goals in Mexico in the real life. The results showed that only around 25% of the patients with very-high or high cardiovascular risk, and half of the patients with moderate risk achieved their LDL-C level goals. A number of factors associated to the lack of accomplishment were identified, including statin intolerance, obesity, metabolic syndrome, type 2 diabetes, female gender, and use of public health-care service. These findings indicate that achievement of LDL-C goals is suboptimal in Mexico, unveiling several gaps in the application of this therapy, and suggesting that their implementation should be adapted to the patient´s needs and profile.

Clinical and epidemiological characteristics of patients diagnosed with COVID-19 in a tertiary care center in mexico city: a prospective cohort study

Edgar Ortiz-Brizuela, Marco Villanueva-Reza, María F. González-Lara MF, Karla M. Tamez-Torres, Carla M. Román-Montes, Bruno A. Díaz-Mejía, et al. Rev Invest Clin. 2020;72:252-258.

The COVID-19 pandemic triggered an unprecedented clinical challenge for scientists, clinicians, epidemiologists, and health-care systems¹⁵,¹⁶. It was soon demonstrated that the severity of symptoms varies considerably from being asymptomatic to manifest as a critical disease with lethal complications. This pioneer, multi-author study¹⁷ examined, at the beginning of the first wave of the pandemic in Mexico, the clinical features of 309 COVID-19 patients searching for differences between outpatients and hospitalized patients, both those who required intensive care unit (ICU) and those who did not. The results showed that hospitalization was more frequent in middle-age obese or overweight men and in older individuals with different comorbidities. Patients requiring intensive care, primarily due to respiratory failure demanding mechanical ventilation, presented several laboratory parameters suggestive of a more intense inflammatory response, a more severe pro-thrombotic state, and a higher frequency of cardiac and liver involvement. This study identified in the population attended in a third level hospital in Mexico City, several clinical, demographic, and laboratory differences between ambulatory and hospitalized COVID-19 patients, including those who needed intensive care treatment.

Coronary artery calcium is associated with lpa gene variant RS7765803-C in Mexican mestizo population. The GEA Project

Guillermo C. Cardoso-Saldaña, Rosalinda Posadas-Sánchez, María del C. González-Salazar, José M. Fragoso-Lona, Gilberto Vargas-Alarcón. Rev Invest Clin. 2020;72:61-68.

Strong evidence supports the notion that high serum levels of lipotrotein(a) [Lp(a)] is an independent and important risk factor for atherosclerotic disease¹⁸ and that some single-nucleotide polymorphisms (SNPs) are associated with their serum concentrations. However, the association between LPA gene variants and coronary artery calcification (CAC), an atherosclerosis marker that predicts cardiovascular events, is unclear. In this study, that included 1594 individuals, six SNPs were examined and related to Lp(a) levels and the presence of CAC¹⁹. Three polymorphisms were associated with high levels of Lp(a) with strong association with rs7765803-C. Importantly, this polymorphism conferred a 1.7-fold increase in the risk for coronary artery disease. These findings demonstrate for the 1^st time and in a well-characterized Mexican- Mestizo population, that the rs7765803-C allele of LPA is significantly associated with high concentrations of Lp(a) as well as with the presence of subclinical atherosclerosis (CAC).

Analysis of the endometrial transcriptome at the time of implantation in women receiving a single post-ovulatory dose of levonorgestrel (LNG) or mifepristone

Ana E. Barrios-Hernández AE, Marta Durand-Carbajal, Claudia C. Vega, Fernando Larrea. Rev Invest Clin 2020; 72:363-371.

Levonorgestrel (LNG) is a progesterone receptor agonist widely used as a contraceptive, including its post-coital administration as an emergency contraceptive. In this study, Barrios-Hernández et al.²⁰ assessed the effects of LNG on implantation. To this end, they applied a microarray expression approach to study gene expression in endometrial samples taken during the luteal phase of the menstrual cycle from women treated with LNG after ovulation. Post-ovulatory administration of LNG or mifepristone (a progesterone receptor antagonist) caused changes in gene expression compared to those in the control group. Nevertheless, bioinformatics analysis of differentially expressed genes found that LNG did not significantly alter the molecular activity of the biofunctions related to decidualization and embryo implantation as seen with mifepristone. These results contribute with evidence to the concept that LNG has no effects on endometrial receptivity when administered after ovulation as an emergency contraceptive, and that its mechanism of action rather resides in inhibiting or delaying ovulation when administered before the ovulatory peak of luteinizing hormone²¹ without effects when administered after ovulation has occurred. This information is important for the acceptance and use of LNG as an approach for emergency contraception, particularly in some conservative communities of the society.

Impact of the RT-PCR test false-negative results for SARS-CoV-2 surveillance in Mexico

Isaac Núñez, Pablo F. Belaunzarán, Yanink Caro-Vega. Rev Invest Clin 2021;73:120-126.

Underestimation of the number of cases during the COVID-19 pandemic is a constant concern worldwide, particularly because of the suboptimal sensitivity of detection of viral RNA using RT-PCR, which is the most common technique to confirm a case. In this study, Núñez et al.²² applied mathematical modeling strategies to provide corrected estimates of the number of cases, hospitalizations in Intensive Care Units (ICU), and deaths among people tested for SARS-CoV-2 in Mexico in a period of 6 months, considering the probability of RT-PCR false negative test results. They found that the number of cases reported in the publicly available national databases during that period was underestimated by 28%, the number of patients at the ICU by 15%, and the number of deaths by 8%. Considering that only a small proportion of symptomatic cases seeking healthcare are tested, the true underestimation of COVID-19 cases may be much higher. This study represents a call of attention to the official health authorities in Mexico to take into account these underestimating figures when establishing health policies on the SARS-CoV-2 pandemic, and to consider expanding the testing capacity in order to make safe progressive reopening. This is important to prevent a new outbreak of the disease and further confinement, which may be disastrous for the economy of the country.

Methylene blue (MB) for treatment of hospitalized COVID-19 patients: a randomized, controlled, open-label clinical trial, and phase 2

Daryoush Hamidi-Alamdari, Saied Hafizi-Lotfabadi, Ahmad Bagheri-Moghaddam, Hossin Safari, Mahnaz Mozdourian, Zahra Javidarabshahi Z., et al. Rev Invest Clin 2021;73:190-198.

COVID-19 has spread rapidly worldwide, and it is urgent to explore effective treatments to protect patients from developing severe illness. In this context, it was recently reported that methylene blue (MB) inhibited the entry of a SARS-CoV-2 spike bearing pseudovirus into ACE2-expressing cells, suggesting a possible therapeutic option²³. Thus, in this multi-author study, the effect of MB was explored in 80 hospitalized patients with severe COVID-19 that were randomly selected to receive either oral MB along with standard of care (SOC) or SOC only²⁴. MB syrup was administered orally during 2 weeks. The results showed that the addition of MB to the treatment protocol significantly improved oxygen saturation and clinical respiratory distress, without serious adverse events, decreasing hospital stay, and mortality. This finding suggests that MB may be useful as a complementary therapy in patients with COVID-19 and severe respiratory disease, although studies with larger cohorts still are necessary.

SELECTED REVIEWS

Aging and pulmonary fibrosis

Moisés Selman, Ivette Buendía-Roldán, Annie Pardo. Rev Invest Clin. 2016;68:75-83.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of unknown etiology, and by far the most aggressive of the fibrotic lung disorders. Aging is a driving force of the disease, although the mechanisms linking age with IPF are unclear. In this review included in the thematic issue Aging and Disease, Selman et al.²⁵ explore the contribution of the main hallmarks of aging in the development of IPF, dissecting the putative role of genomic instability, cellular senescence, mitochondrial dysfunction, telomere shortening, loss of proteostasis, stem-cell exhaustion, deregulated nutrient sensing, and epigenetic alterations, including modifications in DNA methylation and non-coding RNA. The authors demonstrated that most of these aging-associated characteristics are occurring prematurely or excessively in the IPF lungs affecting primarily the lung epithelium, additionally confirming that this is an epithelial-driven disease²⁶.

Genetic risk assessment for breast cancer (BC) in Latin America (LA)

Yanin Chavarri-Guerra Y, Kathleen Reilly Blazer K, Jeffrey Nelson Weitzel. Rev Invest Clin 2017;69:94-102.

Breast cancer (BC) is the most prevalent malignancy in women from Latin America (LA), and it is becoming even more frequent among young women living in this region. In this article, included in the thematic issue BC in Young Women, Chavarri-Guerra et al.,²⁷ a group of experts in BC, review an important aspect of this neoplasia, the genetic issue problem in LA, emphasizing on the marked barriers for access to genetic care, particularly in limited-resource settings. They nicely review the BRCA mutations (which are responsible for around 40% of hereditary breast and ovarian cancer cases) and other BC-associated genes detected in LA, and also summarize the access to genetic cancer risk assessment, availability of genetic testing, and genetic cancer risk assessment programs in LA at the time of publication of this review. The authors conclude that there is an urgent need for the development and implementation of genetic cancer risk assessment programs in LA as well as for improving the education of health-care personnel and allocation of existing resources to provide genetic testing at reasonable costs. Although some progress in this important issue has been achieved, those needs are still not being met²⁸. Preventing and decreasing the burden of BC in the region, mostly represented by underdeveloped countries, should be a health priority.

Non-nutritive sweeteners (NNS): Evidence on their association with metabolic diseases and potential effects on glucose metabolism and appetite

Alfonso Romo-Romo, Carlos A. Aguilar-Salinas, Rita A. Gómez-Díaz, Griselda X. Brito-Córdova, Donají V. Gómez-Velasco, María J. López-Rocha, Paloma Almeda-Valdez. Rev Invest Clin 2017;69:129-138.

NNS have frequently been used all over the world for decades and, in fact, many health-care providers generally recommend their use to replace regular sugar consumption to get a sweet taste in patients without obesity or diabetes mellitus or any other metabolic disease, in whom the indication for its therapeutic use may be medically justified²⁹. In this review by Romo-Romo et al.³⁰, the authors analyzed and discuss several aspects related to this important issue, including the evidence on the metabolic effects of sweeteners, their safety aspects as well as the scientific evidence from observational and clinical trials in humans that question that these types of sweeteners are innocuous for general health. The literature review on this particular topic is quite complete and critically analyzed by the authors, and concludes that NNS should be advised only in the specific conditions mentioned above; in fact, both the American Diabetes Association and the American Heart Association²⁹ suggest that the NNS can be useful when complemented with a well-structured diet. Nevertheless, the authors also conclude that convincing evidence of the effects on the metabolic and appetite hormones of NSS is not available yet, emphasizing on the need of adequately designed, well-controlled studies to solve definitively the controversial issues on the negative effects on health provoked by longstanding NNS use. If so, then should some NNS be considered as endocrine disruptors as suggested by in vitro studies³¹

Integrative view of the mechanisms that induce acute kidney injury (AKI) and its transition to chronic kidney disease (CKD)

Luis Enrique García-Ortuño, Norma A. Bobadilla. Rev Invest Clin 2018;70:261-268.

In this interesting review, García-Ortuño and Bobadilla³² nicely discuss the mechanisms subserving the transition from AKI to CKD, a relatively frequent condition that in any stage affects 7-12% of the population in diverse regions of the world (e.g., in Mexico) and that lead to systemic complications including accelerated cardiovascular disease and death³³. The authors briefly address different recently published evidence unveiling the physiopathogenic mechanisms involved in the transition from AKI to CKD. These mechanisms include endothelial and proximal tubular epithelium injury and the concurrent activation of inflammatory processes triggering different signaling pathways that eventually lead to tubulointerstitial fibrosis, chronic hypoxia, and deterioration of functional tissue. They also discuss the role of sexual dimorphism in this transition, briefly describing experimental data from their own laboratory suggesting that a male hormonal milieu favors the development of CKD after AKI. Early identification of AKI, particularly in hospitalized patients, is important to prevent progression to CKD and reduce the high costs of the long-term effects of this condition.

Respiratory impact of electronic cigarettes and low-risk tobacco

Ireri Thirión-Romero I., Rogelio Pérez-Padilla, Gustavo Zabert, Inti Barrientos-Gutiérrez. Rev Invest Clin 2019; 71:17-27.

Electronic cigarettes or e-cigarettes, also known as electronic nicotine dispensing systems (ENDS), appeared in the market more than a decade ago and gained popularity because they were considered a less harmful alternative to conventional cigarette smoking³⁴. In this review, included in the thematic issue Chronic Obstructive Pulmonary Disease, the authors demystify this concept giving evidence that exposure to e-cigarettes provokes a variety of abnormalities in vitro, in animal models, and in humans, including airway inflammation, decrease in the immune response, and increase of oxidative stress and endothelial/vascular dysfunction, among others³⁵. Moreover, they cast doubt about the role of e-cigarettes as an option for reducing cigarette consumption or for smoking cessation as it was proposed. Actually, e-cigarette initiation in a never-smoke youth may not only cause harm but also may stimulate to smoke regular cigarettes.

CONCLUSIONS

We have presented here the summaries from original and review articles published in the RIC –Clinical and Translational Investigation– in the last 6 years that were carefully selected by the Editors on the basis of their translational implications. It is expected that as the IF of the journal increases, more studies containing novel information with a translational character will be considered for publication, making the journal more competitive and attractive not only for national but also for international authors. Meanwhile, we should continue selecting for peer review and publication the best articles based on the expert opinion of the editors and reviewers, considering originality, study design, application of new technologies, validation, and meaningful scientific conclusions. In addition to selecting for publication those manuscripts that meet these characteristics, the new version of the RIC will also continue promoting the publication of results from interdisciplinary research on emerging and important clinical problems of interest to both the national and international community of physicians, scientists, and health providers. This is the challenge that we, the Editors and the Editorial Committee of the current version of the RIC must accomplish with passion and devotion as the journal’s founders did.