Bilateral Variation of the Vertebral Artery: Report of a Case and its Clinical Implication / Variación Bilateral de la Arteria Vertebral; Reporte de un Caso y su Implicancia Clínica

SUMMARY: There are many reports on anatomical variations of the vertebral arteries, which may be related to origin, trajectory, caliber, and side. Bilateral variations are less frequent, however, and less common are bilateral variants that differ from each other. The aim of this work was to report the presence of a bilateral variation of the vertebral artery and its functional and clinical implications. Dissection of a female cadaver, fixed in 10 % buffered formaldehyde, which had not undergone any previous surgeries in the study area and had anatomical variations in both vertebral arteries. In each one, follow-up was done from its origin to its end, determining its trajectory, diameters, branching, and anatomical relations. A left vertebral artery was found, starting in the aortic arch and making a sinuous trajectory of 4 curvatures to enter the transverse foramen of C4. The right vertebral artery began as the first branch of the subclavian artery. Its initial trajectory was rectilinear, followed by a right concave curve, a 360° loop that included a second ascending curve, and ended straight before entering the transverse foramen of C6. The coexistence of bilateral variations in the vertebral arteries is possible. This atypical situation can potentially generate vascular and neurological pathologies, but with different symptoms and causes. Knowing these variations and deliberately searching for them will enable the specialist to make a suitable differential diagnosis.

Existen múltiples reportes sobre variaciones anatómicas de las arterias vertebrales, las que se pueden relacionar con origen, trayecto, calibre y lateralidad. Sin embargo, las variaciones bilaterales son menos frecuentes, y menos común es que las variantes bilaterales sean diferentes entre ellas. El objetivo de este trabajo fue reportar la presencia de una variación bilateral de la arteria vertebral y su implicancia funcional y clínica. Disección en un cadáver de sexo femenino, fijado en formaldehido tamponado al 10 %, el cual no presentaba intervenciones quirúrgicas previas en la región de estudio y que tenía variaciones anatómicas en ambas arterias vertebrales. En cada una se realizó seguimiento desde su origen hasta su terminación, pudiendo determinar su trayecto, diámetros, ramificaciones y relaciones anatómicas. Se encontró una arteria vertebral izquierda originada en el arco aórtico, que realizaba un trayecto sinuoso de 4 curvaturas e ingresaba al foramen transverso de C4. La arteria vertebral derecha se originaba como primera rama de la arteria subclavia. Su trayecto inicial era rectilíneo seguido por una curva de concavidad derecha, un loop (giro) de 360° que incluía una segunda curva ascendente y terminaba en dirección recta antes de ingresar al foramen transverso de C6. La coexistencia de variaciones bilaterales en las arterias vertebrales es posible. Esta situación atípica, potencialmente puede generar en la persona patologías neurológicas de origen vascular, pero con sintomatología y causas diferentes. Conocer estas variaciones y realizar una búsqueda intencionada de ellas permitirá el especialista realizar un adecuado diagnóstico diferencial.

Intervenciones efectivas para aumentar la duración y la exclusividad de la lactancia materna: una revisión sistemática / Effective interventions to increase the duration and exclusivity of breastfeeding: a systematic review

INTRODUCCIÓN: La lactancia materna según las recomendaciones de la Organización Mundial de la Salud, debería ser exclusiva por al menos los primeros 6 meses de vida del lactante. OBJETIVO: Evaluar la efectividad de las estrategias e intervenciones disponibles en la literatura científica actual, para aumentar la duración y exclusividad de la lactancia materna durante los primeros seis meses de vida del lactante. MÉTODO: Se realizó una revisión sistemática en las bases bibliografías CINAHL, Medline y Clinical Key, utilizando la estrategia de búsqueda "Mother-child relations" OR "Infant" OR "Newborn" AND "Lactation" AND "Breast feeding" OR "Breastfeeding duration" OR "Breastfeeding exclusive" OR "Interventions" AND "Best practices" OR "Evidence-based practice" OR "Evaluation of results of therapeutic interventions". RESULTADOS: De los 749 artículos localizados, 22 fueron incluidos en el análisis. Las estrategias identificadas para promover la lactancia materna se dividieron en 3 categorías según su entorno: las realizadas en los sistemas de salud, entornos domésticos o comunitarios y entornos múltiples. CONCLUSIÓN: Las estrategias e intervenciones que demostraron ser efectivas para aumentar la duración y exclusividad de la lactancia materna fueron las intervenciones multicomponentes, las iniciativas para capacitación de los profesionales de la salud y la estrategia "Hospital Amigo".

INTRODUCTION: Breastfeeding according to the recommendations of the World Health Organization, should be exclusive for at least the first 6 months of the nursling. OBJECTIVE: to evaluate the effectiveness of the strategies and interventions available in the current scientific literature, to increase the duration and exclusivity of breastfeeding during the first six months of the nursling. METHOD: A systematic review was carried out in the CINAHL, Medline and Clinical Key bibliography databases, using the search strategy "Mother-child relations" OR "Infant" OR "Newborn" AND "Lactation" AND "Breast feeding" OR "Breastfeeding duration" OR "Breastfeeding exclusive" OR "Interventions" AND "Best practices" OR "Evidence-based practice" OR "Evaluation of results of therapeutic interventions". RESULTS: Of the 749 articles found, 22 were included in the analysis. The strategies identified to promote breastfeeding were divided into 3 categories according to their setting: those carried out in health systems, home or community settings, and multiple settings. CONCLUSION: The strategies and interventions that proved to be effective in increasing the duration and exclusivity of breastfeeding were the multicomponent interventions, the initiatives for training health professionals and the "Friendly Hospital" strategy.

Pattern recognition receptors and their roles in the host response to Helicobacter pylori infection.

Helicobacter pylori (H. pylori) infection is highly prevalent, affecting 4.4 billion people globally. This pathogen is a risk factor in the pathogenesis of more than 75% of worldwide cases of gastric cancer. Pattern recognition receptors are essential in the innate immune response to H. pylori infection. They recognize conserved pathogen structures and myriad alarmins released by host cells in response to microbial components, cytokines or cellular stress, thus triggering a robust proinflammatory response, which is crucial in H. pylori-induced gastric carcinogenesis. In this review, we intend to highlight the main pattern recognition receptors involved in the recognition and host response to H. pylori, as well as the main structures recognized and the subsequent inflammatory response.

Diabetes mellitus contribution to the remodeling of the tumor microenvironment in gastric cancer.

Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial contribution of diabetes mellitus (DM) as a risk factor associated with increased cancer incidence and mortality in many human neoplasms, including gastric cancer (GC). DM is considered a systemic inflammatory disease and therefore, this inflammatory status may have profound effects on the tumor microenvironment (TME), particularly by driving many molecular mechanisms to generate a more aggressive TME. DM is an active driver in the modification of the behavior of many cell components of the TME as well as altering the mechanical properties of the extracellular matrix (ECM), leading to an increased ECM stiffening. Additionally, DM can alter many cellular signaling mechanisms and thus favoring tumor growth, invasion, and metastatic potential, as well as key elements in regulating cellular functions and cross-talks, such as the microRNAs network, the production, and cargo of exosomes, the metabolism of cell stroma and resistance to hypoxia. In the present review, we intend to highlight the mechanistic contributions of DM to the remodeling of TME in GC.

Gastric Tumor Microenvironment.

A compelling body of evidence has demonstrated that gastric cancer has a very particular tumor microenvironment, a signature very suitable to promote tumor progression and metastasis. Recent investigations have provided new insights into the multiple molecular mechanisms, defined by genetic and epigenetic mechanisms, supporting a very active cross talk between the components of the tumor microenvironment and thus defining the fate of tumor progression. In this review, we intend to highlight the role of very active contributors at gastric cancer TME, particularly cancer-associated fibroblasts, bone marrow-derived cells, tumor-associated macrophages, and tumor-infiltrating neutrophils, all of them surrounded by an overtime changing extracellular matrix. In addition, the very active cross talk between the components of the tumor microenvironment, defined by genetic and epigenetic mechanisms, thus defining the fate of tumor progression, is also reviewed.

HMGB1 decreases CCR-2 expression and migration of M2 macrophages under hypoxia.

OBJECTIVE: The hypoxic milieu at tumor microenvironment is able to drive the behavior of infiltrating tumor cells. Considering that hypoxia-mediated HMGB1 release is known to promote tumor growth, as well to enhance the pro-tumoral profile of M2 macrophages by a RAGE-dependent mechanism, it is tempting to evaluate the potential contribution of HMGB1 under hypoxia to restrain M2 macrophages mobility. METHODS: CCR-2 expression was evaluated in M2 polarized macrophages by western blotting and immunocytochemistry. The secreted levels of CCL-2 and the migration capability were evaluated using an ELISA and a chemotaxis assay, respectively. RESULTS: HMGB1, under hypoxic conditions, markedly reduce both the production of CCL-2 and the expression of its receptor CCR-2; and reduced the migration capacity of M2 macrophages. CONCLUSIONS: These results provided new insights into the mechanisms that regulate M2 macrophages mobility at the tumor microenvironment.

Inhibition of RAGE Axis Signaling: A Pharmacological Challenge.

The Receptor for Advanced Glycation End Products (RAGE) is an important cell surface receptor, which belongs to the IgG super family and is now considered as a pattern recognition receptor. Because of its relevance in many human clinical settings, it is now pursued as a very attractive therapeutic target. However, particular features of this receptor such as a wide repertoire of ligands with different binding domains, the existence of many RAGE variants as well as the presence of cytoplasmatic adaptors leading a diverse signaling, are important limitations in the search for successful pharmacological approaches to inhibit RAGE signaling. Therefore, the present review aimed to display the most promising approaches to inhibit RAGE signaling, and provide an up to date review of progress in this area.

Helicobacter Pylori Infection and Lung Cancer: 
New Insights and Future Challenges.

Helicobacter pylori (H. pylori) is the causative agent of chronic gastritis and peptic ulcer diseases and is an important risk factor for the development functional dyspepsia, peptic ulceration, gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. H. pylori has very high rates of infection in human populations, and it is estimated that over 50% of the world population is infected. Recently, certain extra-gastric manifestations, linked to H. pylori infection, have been widely investigated. Noteworthy, a growing body of evidences supports an association between H. pylori infection with lung cancer. The present review intend to highlight not only the most recent evidences supporting this association, but also some missed points, which must be considered to validate this emerging association.

Skewed Signaling through the Receptor for Advanced Glycation End-Products Alters the Proinflammatory Profile of Tumor-Associated Macrophages.

Tumors are complex tissues composed of variable amounts of both non-cellular components (matrix proteins) and a multitude of stromal cell types, which are under an active cross-talk with tumor cells. Tumor-associated macrophages (TAMs) are the major leukocyte population among the tumor-infiltrating immune cells. Once they are infiltrated into tumor stroma they undergo a polarized activation, where the M1 and M2 phenotypes represent the two extreme of the polarization heterogeneity spectrum. It is known that TAMs acquire a specific phenotype (M2), oriented toward tumor growth, angiogenesis and immune-suppression. A growing body of evidences supports the presence of tuning mechanisms in order to skew or restraint the inflammatory response of TAMs and thus forces them to function as active tumor-promoting immune cells. The receptor of advanced glycation end-products (RAGE) is a member of the immunoglobulin protein family of cell surface molecules, being activated by several danger signals and thus signaling to promote the production of many pro-inflammatory molecules. Interestingly, this receptor is paradoxically expressed in both M1 and M2 macrophages phenotypes. This review addresses how RAGE signaling has been drifted away in M2 macrophages, and thus taking advantage of the abundance of RAGE ligands at tumor microenvironment, particularly HMGB1, to reinforce the supportive M2 macrophages strategy to support tumor growth.

Extracellular matrix glycation and receptor for advanced glycation end-products activation: a missing piece in the puzzle of the association between diabetes and cancer.

A growing body of epidemiologic evidence suggests that people with diabetes are at a significantly higher risk of many forms of cancer. However, the molecular mechanisms underlying this association are not fully understood. Cancer cells are surrounded by a complex milieu, also known as tumor microenvironment, which contributes to the development and metastasis of tumors. Of note, one of the major components of this niche is the extracellular matrix (ECM), which becomes highly disorganized during neoplastic progression, thereby stimulating cancer cell transformation, growth and spread. One of the consequences of chronic hyperglycemia, the most frequently observed sign of diabetes and the etiological source of diabetes complications, is the irreversible glycation and oxidation of proteins and lipids leading to the formation of the advanced glycation end-products (AGEs). These compounds may covalently crosslink and biochemically modify structure and functions of many proteins, and AGEs accumulation is particularly high in long-living proteins with low biological turnover, features that are shared by most, if not all, ECM proteins. AGEs-modified proteins are recognized by AGE-binding proteins, and thus glycated ECM components have the potential to trigger Receptor for advanced glycation end-products-dependent mechanisms. The biological consequence of receptor for advanced glycation end-products activation mechanisms seems to be connected, in different ways, to drive some hallmarks of cancer onset and tumor growth. The present review intends to highlight the potential impact of ECM glycation on tumor progression by triggering receptor for advanced glycation end-products-mediated mechanisms.

Presentación atípica de síndrome infrecuente: absceso como inicio de síndrome de May-Thurner / Atypical presentation in an uncommon syndrome: abscess as debut of May-Thurner syndrome

Resumen Objetivo Presentar un caso de inicio atípico de síndrome de May-Thurner, enfermedad vascular poco frecuente. Caso clínico Se reporta el caso de una paciente de 23 años con absceso de pie izquierdo y extenso edema de dicha extremidad. El dímero D y la ecotomografía doppler color venosa descartan evento trombótico agudo. El estudio complementario con angioTC objetiva compresión del origen de la vena ilíaca común izquierda, presencia de venas colaterales y diferente grado de insuficiencia venosa en dicha extremidad, hallazgos compatibles con el síndrome de May-Thurner. Conclusión El síndrome de May-Thurner representa una causa inusual y de presentación variable en enfermedad venosa de extremidad inferior izquierda en mujeres jóvenes.

ABSTRACT Aim To present a case of an atypical debut of May-Thurner syndrome, uncommon vascular disease. Case report We report a case of a 23 year old female with an abscess of the left foot and extensive edema of the left lower limb. D-Dimmer test and Venous Doppler ultrasound discards an acute trombotic event. Further studies with CT angiogram concludes the compression in the origin of the left common iliac vein compatible with May-Thurner syndrome. Conclusion May-Thurner syndrome represent an uncommon and variable cause of venous disease of the left lower limb in young female patients.

M2 macrophages do not fly into a "RAGE".

Tumor-associated macrophages (TAMs) are key elements in orchestrating host responses inside tumor stroma. This population may undergo a polarized activation process, thus rendering a heterogeneous spectrum of phenotypes, where the classically activated type 1 macrophages (M1) and the alternative activated type 2 macrophages (M2) represent two extreme phenotypes. In this commentary, based on very recent research findings, we intend to highlight how complex could be the crosstalk among all components of tumor stroma, where the coexistence of non-natural partners may even skew the canonical responses that we can expect.

Lysyl oxidase isoforms in gastric cancer.

Gastric cancer (GC) is the fifth most frequent cancer in the world and shows the highest incidence in Latin America and Asia. An increasing amount of evidence demonstrates that lysyl oxidase isoforms, a group of extracellular matrix crosslinking enzymes, should be considered as potential biomarkers and therapeutic targets in GC. In this review, we focus on the expression levels of lysyl oxidase isoforms, its functions and the clinical implications in GC. Finding novel proteins related to the processing of these extracellular matrix enzymes might be helpful in the design of new therapies, which, in combination with classic pharmacology, could be used to delay the progress of this aggressive cancer and offer a wider temporal window for clinical intervention.

HMGB1 enhances the protumoral activities of M2 macrophages by a RAGE-dependent mechanism.

The monocyte-macrophage lineage shows a high degree of diversity and plasticity. Once they infiltrate tissues, they may acquire two main functional phenotypes, being known as the classically activated type 1 macrophages (M1) and the alternative activated type 2 macrophages (M2). The M1 phenotype can be induced by bacterial products and interferon-γ and exerts a cytotoxic effect on cancer cells. Conversely, the alternatively activated M2 phenotype is induced by Il-4/IL13 and promotes tumor cell growth and vascularization. Although receptor for advanced glycation end-products (RAGE) engagement in M1 macrophages has been reported by several groups to promote inflammation, nothing is known about the functionality of RAGE in M2 macrophages. In the current study, we demonstrate that RAGE is equally expressed in both macrophage phenotypes and that RAGE activation by high-mobility group protein box1 (HMGB1) promotes protumoral activities of M2 macrophages. MKN45 cells co-cultured with M2 macrophages treated with HMGB1 at different times displayed higher invasive abilities. Additionally, conditioned medium from HMGB1-treated M2 macrophages promotes angiogenesis in vitro. RAGE-targeting knockdown abrogates these activities. Overall, the present findings suggest that HMGB1 may contribute, by a RAGE-dependent mechanism, to the protumoral activities of the M2 phenotype.

Inflammatory and neurodegeneration markers during asymptomatic HSV-1 reactivation.

BACKGROUND: Currently, it is unclear whether asymptomatic recurrent reactivations of herpes simplex virus type 1 (HSV-1) occur in the central nervous systems of infected people, and if these events could lead to a progressive deterioration of neuronal function. In this context, HSV-1 constitutes an important candidate to be included among the risk factors for the development of neuropathies associated with chronic neuroinflammation. OBJECTIVE: The aim of this study was to assess in vivo inflammatory and neurodegenerative markers in the brain during productive and latent HSV-1 infection using a mouse model of herpes simplex encephalitis. METHODS: Neuroinflammation and neurodegeneration markers were evaluated in mice trigeminal ganglia and cerebral cortex during HSV-1 infection, by immunohistochemistry, western blot, and RT-PCR. RESULTS: Neuronal ICP4 viral antigen expression indicative of a reactivation episode during asymptomatic latency of HSV-1 infection in mice was accompanied by upregulation of neuroinflammatory (toll-like receptor-4, interferon α/ß, and p-IRF3) and early neurodegenerative markers (phospho-tau and TauC3). CONCLUSIONS: HSV-1 reactivation from latency induced neuroinflammatory and neurodegenerative markers in the brain of asymptomatic mice suggesting that recurrent reactivations could be associated with cumulative neuronal dysfunctions.