The Purinergic Landscape of Type 2 Diabetes Mellitus.

Adenosine triphosphate (ATP) is the key energy intermediate of cellular metabolic processes and a ubiquitous extracellular messenger. As an extracellular messenger, ATP acts at plasma membrane P2 receptors (P2Rs). The levels of extracellular ATP (eATP) are set by both passive and active release mechanisms and degradation processes. Under physiological conditions, eATP concentration is in the low nanomolar range but can rise to tens or even hundreds of micromoles/L at inflammatory sites. A dysregulated eATP homeostasis is a pathogenic factor in several chronic inflammatory diseases, including type 2 diabetes mellitus (T2DM). T2DM is characterized by peripheral insulin resistance and impairment of insulin production from pancreatic ß-cells in a landscape of systemic inflammation. Although various hypoglycemic drugs are currently available, an effective treatment for T2DM and its complications is not available. However, counteracting systemic inflammation is anticipated to be beneficial. The postulated eATP increase in T2DM is understood to be a driver of inflammation via P2X7 receptor (P2X7R) activation and the release of inflammatory cytokines. Furthermore, P2X7R stimulation is thought to trigger apoptosis of pancreatic ß-cells, thus further aggravating hyperglycemia. Targeting eATP and the P2X7R might be an appealing novel approach to T2DM therapy.

B regulatory cells associated with changes in biochemical and inflammatory parameters in normal-glycemic individuals, pre-diabetes and T2DM patients.

AIM: To determine the percentages of (CD19 + CD24 + CD38+, CD19 + CD24 + CD27+, CD19 + IL-10+)-Breg cells, IL-17 single and IL-17+/IFN-γ double producers T cells and IFN-γ+ T cells, in normal-glycemic individuals, prediabetes and T2DM patients, and to analyze the association of Breg cells with metabolic parameters of T2DM. METHODS: percentages of Breg cells, IL-17+ and IL-17 + IFN-γ+ T cells, IFN-γ+ T cells and IL-10 were determined by flow cytometry. IL-6 levels were evaluated by ELISA assay. RESULTS: increased IL-6 levels, IL-17+ and IL-17 + IFN-γ+ T cells and a diminution of IL-10 levels and CD19 + IL-10+ cells in T2DM patients were observed. We found that CD19 + CD24 + CD27+ cells and CD19 + CD24 + CD38+ cells were increased in T2DM patients. The percentages of CD19 + CD24 + CD38+ cells were associated with HOMA-B, TyG index, HDL and cholesterol values. In normal-glycemic individuals, CD19 + CD24 + CD27+ cells were inversely associated to triglycerides and TyG index. In prediabetes patients, CD19 + CD24 + CD38+ cells were inversely related with cholesterol and LDL. Finally, CD19 + CD24 + CD38+ cells were inversely related with HDL values in T2DM patients. CONCLUSION: Our results suggest that increased percentages of IL-17 single and IL-17/IFN-γ double producers T cells in T2DM patients may be a consequence of the initial CD19 + IL-10+ cells reduction. Furthermore, dyslipidemia could play an important role in percentages and activity of B regulatory cells.

On the importance of tunica intima in the aging aorta: a three-layered in silico model for computing wall stresses in abdominal aortic aneurysms.

Layer-specific experimental data for human aortic tissue suggest that, in aged arteries and arteries with non-atherosclerotic intimal thickening, the innermost layer of the aorta increases significantly its stiffness and thickness, becoming load-bearing. However, there are very few computational studies of abdominal aortic aneurysms (AAAs) that take into account the mechanical contribution of the three layers that comprise the aneurysmal tissue. In this paper, a three-layered finite element model is proposed from the simplest uniaxial stress state to geometrically parametrized models of AAAs with different asymmetry values. Comparisons are made between a three-layered artery wall and a mono-layered intact artery, which represents the complex behavior of the aggregate adventitia-media-intima in a single layer with averaged mechanical properties. Likewise, the response of our idealized geometries is compared with similar experimental and numerical models. Finally, the mechanical contributions of adventitia, media and intima are analyzed for the three-layered aneurysms through the evaluation of the mean stress absorption percentage. Results show the relevance and necessity of considering the inclusion of tunica intima in multi-layered models of AAAs for getting accurate results in terms of peak wall stresses and displacements.

Cirugía abdominal en prematuros con persistencia de ductus arterioso / Abdominal surgery in premature infants with patent ductus arteriosus

Introducción: La persistencia de ductus arterioso (PDA), se considera un factor de riesgo para enterocolitis necrosante (ECN) y otras complicaciones digestivas en prematuros. El objetivo del presente trabajo es analizar si existe un mayor riesgo de cirugía abdominal y morbimortalidad asociada en prematuros que precisaron tratamiento debido a una PDA significativa. Metodología: Estudio observacional, analítico y retrospectivo incluyendo prematuros menores de 37 semanas de gestación, con diagnóstico de PDA en los últimos 10 años. En función del tratamiento recibido, los pacientes fueron divididos en 3 grupos: tratamiento médico (A), tratamiento médico y quirúrgico (B) y sin tratamiento (C). Se analizaron variables pre y perinatales, incidencia de complicaciones digestivas (ECN y necesidad de cirugía por este motivo) y mortalidad global. Resultados: Se obtuvo una muestra de 144 pacientes: 91 se asignaron al grupo A, 16 al B y 37 al C. La edad gestacional media por grupos fue de 28, 26,7 y 30,1 semanas. El peso medio al nacer fue de 1.083,9, 909,3 y 1471,2g, respectivamente. En cuanto a la incidencia de ECN, se encontraron un total de 21, 5 y 5 casos en cada grupo, precisando cirugía abdominal un 43, 60 y 35%, respectivamente. La mortalidad por grupos fue del 12, 19 y 3%. Conclusiones: Los pacientes que precisaron tratamiento por PDA, presentaron una mayor incidencia de complicaciones digestivas y una mayor mortalidad que los pacientes no tratados, sin embargo, no encontramos diferencias estadísticamente significativas. En el grupo de pacientes que requirieron tratamiento, la menor edad gestacional y peso al nacer, podrían explicar el incremento de la morbimortalidad encontrada en estos pacientes

Introduction: Patent ductus arteriosus (PDA) is considered a risk factor for necrotising enterocolitis (NEC) and other gastrointestinal complications in preterm infants. The aim of this study is to determine whether there is a higher incidence of abdominal surgery and the associated morbidity and mortality in preterm infants who require treatment due to a significant PDA. Methods: An observational study was conducted that included preterm infants with <37 weeks of gestational age, and a diagnosis of PDA in the last 10 years. Depending on the treatment received, the patients were divided into 3 groups: medical (A), medical and surgical (B), and no treatment (C). An analysis was performed on the pre- and peri-natal variables, as well as the incidence of gastrointestinal complications (NEC, and need for surgery for this reason), and overall mortality. Results: The study included a sample of 144 patients, of whom 91 were assigned to group A, 16 to B, and 37 to C. The mean gestational age by groups was 28, 26.7, and 30.1 weeks, respectively. The mean birth weight was 1083.9 gr, 909.3 gr, and 1471.2 gr, respectively. As regards the incidence of NEC, a total of 21, 5, and 5 cases, respectively, were found in each group, with 43%, 60% and 35%, respectively requiring abdominal surgery. Mortality by groups was 12%, 19%, and 3%, respectively Conclusion: Patients who required treatment for a significant PDA had a higher incidence of gastrointestinal complications and higher mortality than untreated patients, with no statistically significant differences being found. In the group of patients that required treatment, lower gestational age and birth weight, could explain the increase in morbidity and mortality found in these patients

Circulating miR-146a, miR-34a and miR-375 in type 2 diabetes patients, pre-diabetic and normal-glycaemic individuals in relation to ß-cell function, insulin resistance and metabolic parameters.

The pathogenesis of type 2 diabetes (T2D) is associated with a progressive loss of pancreatic ß-cell mass. It is known that miR-146a, miR-34a, and miR-375 are involved in ß-cell functionality. In this work, we evaluated the levels of these miRNAs in normal-glycaemic individuals, pre-diabetic, and T2D patients in relation to ß-cell functionality, insulin resistance, and metabolic parameters. The relative expression of the miRNAs was evaluated in serum samples by real-time polymerase chain reaction. In a principal component analysis, we observed that T2D patients and pre-diabetic individuals were not associated with ß-cell functionality. However, in a correlation matrix analysis, we detected that miR-34a was related to miR-146a and insulin resistance. The relative expression of miR-375 was correlated with cholesterol and low-density lipoprotein levels. A decrease of ß-cell function in pre-diabetic individuals and T2D patients was observed. The insulin resistance was higher in pre-diabetic individuals and T2D patients. The relative expression of miR-146a in pre-diabetic individuals, T2D patients with insulin treatment, and T2D patients with nephropathy and diabetic foot was decreased. In addition, miR-34a was increased in T2D patients who were overweight and obese. The relative expression of miR-375 was increased in T2D patients with poor glycaemic control, while a decrease was seen in T2D patients with nephropathy and diabetic foot. Circulating miR-375, miR-34a, and miR-146a were not associated with ß-cell functionality, but their expression was differentially affected by glycaemia, obesity, insulin treatment, and the presence of nephropathy and diabetic foot.

[Abdominal surgery in premature infants with patent ductus arteriosus]. / Cirugía abdominal en prematuros con persistencia de ductus arterioso.

INTRODUCTION: Patent ductus arteriosus (PDA) is considered a risk factor for necrotising enterocolitis (NEC) and other gastrointestinal complications in preterm infants. The aim of this study is to determine whether there is a higher incidence of abdominal surgery and the associated morbidity and mortality in preterm infants who require treatment due to a significant PDA. METHODS: An observational study was conducted that included preterm infants with <37 weeks of gestational age, and a diagnosis of PDA in the last 10 years. Depending on the treatment received, the patients were divided into 3 groups: medical (A), medical and surgical (B), and no treatment (C). An analysis was performed on the pre- and peri-natal variables, as well as the incidence of gastrointestinal complications (NEC, and need for surgery for this reason), and overall mortality. RESULTS: The study included a sample of 144 patients, of whom 91 were assigned to group A, 16 to B, and 37 to C. The mean gestational age by groups was 28, 26.7, and 30.1 weeks, respectively. The mean birth weight was 1083.9 gr, 909.3 gr, and 1471.2 gr, respectively. As regards the incidence of NEC, a total of 21, 5, and 5 cases, respectively, were found in each group, with 43%, 60% and 35%, respectively requiring abdominal surgery. Mortality by groups was 12%, 19%, and 3%, respectively CONCLUSION: Patients who required treatment for a significant PDA had a higher incidence of gastrointestinal complications and higher mortality than untreated patients, with no statistically significant differences being found. In the group of patients that required treatment, lower gestational age and birth weight, could explain the increase in morbidity and mortality found in these patients.

Mesomorphic Behavior in Silver(I) N-(4-Pyridyl) Benzamide with Aromatic π⁻π Stacking Counterions.

Organic semiconductor materials composed of π⁻π stacking aromatic compounds have been under intense investigation for their potential uses in flexible electronics and other advanced technologies. Herein we report a new family of seven π⁻π stacking compounds of silver(I) bis-N-(4-pyridyl) benzamide with varying counterions, namely [Ag(NPBA)2]X, where NPBA is N-(4-pyridyl) benzamine, X = NO3- (1), ClO4- (2), CF3SO3- (3), PF6- (4), BF4- (5), CH3PhSO3- (6), and PhSO3- (7), which form extended π-π stacking networks in one-dimensional (1D), 2D and 3D directions in the crystalline solid-state via the phenyl moiety, with average inter-ring distances of 3.823 Å. Interestingly, the counterions that contain π⁻π stacking-capable groups, such as in 6 and 7, can induce the formation of mesomorphic phases at 130 °C in dimethylformamide (DMF), and can generate highly branched networks at the mesoscale. Atomic force microscopy studies showed that 2D interconnected fibers form right after nucleation, and they extend from ~30 nm in diameter grow to reach the micron scale, which suggests that it may be possible to stop the process in order to obtain nanofibers. Differential scanning calorimetry studies showed no remarkable thermal behavior in the complexes in the solid state, which suggests that the mesomorphic phases originate from the mechanisms that occur in the DMF solution at high temperatures. An all-electron level simulation of the band gaps using NRLMOL (Naval Research Laboratory Molecular Research Library) on the crystals gave 3.25 eV for (1), 3.68 eV for (2), 1.48 eV for (3), 5.08 eV for (4), 1.53 eV for (5), and 3.55 eV for (6). Mesomorphic behavior in materials containing π⁻π stacking aromatic interactions that also exhibit low-band gap properties may pave the way to a new generation of highly branched organic semiconductors.

Frequency of regulatory B cells in adipose tissue and peripheral blood from individuals with overweight, obesity and normal-weight.

STATEMENTS OF THE PROBLEM: Regulatory B (Breg) cells have a critical role in adipose tissue homeostasis, and although subtypes of Breg cells have been described, their contribution during obesity is unclear. Therefore, the levels of regulatory B cells in adipose tissue and peripheral blood samples drawn from individuals with overweight, obesity, and normal-weight were evaluated. METHODS: The percentages of Breg cells were analyzed by flow cytometry. The activity of Breg cells was assessed by measuring the release of IFN-γ in the supernatants of co-cultures of CD4+ T and regulatory B cells with an ELISA assay. The levels of IL-17 and IFN-γ produced by the CD4+ T cells were assessed using an ELISA assay. RESULTS: Diminished frequencies of Breg cells with phenotypes CD19+CD27+CD38High, CD19+CD24HighCD38High, and CD19+CD24HighCD38HighIL-10+ cells were observed in the blood samples from the individuals with overweight and obesity but not in the individuals with normal-weight. The production of IFN-γ in CD4+ T-cell cultures showed a decrease in the presence of Breg cells in individuals with obesity and normal-weight. We found fewer percentages of CD19+CD27+CD38High cells in the adipose tissue samples from individuals with overweight and obesity compared to individuals with normal-weight. In addition, elevated levels of IL-17 and IFN-γ in the supernatants of the cultures of CD4+ T cells from the individuals with obesity compared to the individuals with normal-weight were observed. CONCLUSIONS: The results suggest that individuals with obesity show increased levels of Th1/Th17 cytokines, which might be caused by the decreased frequency of regulatory B cells.

Increased Levels of AIM2 and Circulating Mitochondrial DNA in Type 2 Diabetes.

BACKGROUND: Chronic inflammation has critical role in Type 2 diabetes (T2D), in which IL-1ß contributes in insulin resistance and beta cell dysfunction. The activation of NLRP3 and AIM2 by endogens ligands, such as mtDNA can lead to the release of active form of IL-1ß. OBJECTIVE: To evaluate AIM2 expression and activation as well as circulating mtDNA levels in T2D patients. METHODS: AIM2 expression was analyzed by flow cytometry, it's activity was assessed by measuring in vitro release of IL-1ß induced by Poly (dA:dT), and mtDNA copy number was determined by quantitative real-time polymerase chain reaction. RESULTS: Increased percent of AIM2+ cells were detected in monocytes from patients with T2D. Moreover, increased levels of IL-1ß in monocytes cultures from T2D patients compared to healthy controls were observed. Also, association between AIM2+ cells and hyperglycemia (r=0.4385, P=0.0095) and triglycerides levels (r=0.5112, P=0.002) and waist-hip ratio (r=0.4710, P=0.0049) were detected. Likewise, the mtDNA copy number was augmented in T2D patients compared to control group. The mtDNA copies number was associated with body mass index (r=0.4231, P=0.0008) and TNF-α levels (r=0.5231, P=0.0005). In addition, increased levels of IL-12p70, TNF-a, IL-10, IL-6, IL-8 and IL-1ß were detected in a serum from T2D patients. CONCLUSION: These results suggest the involvement of AIM2 and mtDNA in the inflammatory process seen in T2D.

The presence of the 1068 G>A variant of P2X7 receptors is associated to an increase in IL-1Ra levels, insulin secretion and pancreatic ß-cell function but not with glycemic control in type 2 diabetes patients.

It has been reported that an increased function of the P2X7 purinergic receptor is associated with an increase in both insulin sensitivity and secretion. Accordingly, we explored the possible effect of the 1068 G>A polymorphism of the gene P2RX7 on glucose homeostasis and the levels of the anti-inflammatory cytokine IL-1Ra in T2D patients. The presence of the 1068 G>A polymorphism in T2D patients (n = 100) and healthy subjects (n = 100) was determined by DNA sequencing, and serum levels of IL-1Ra were measured by ELISA. Pancreatic ß-cell function, insulin resistance, blood glucose levels and glycated hemoglobin (HbA1c) were also analyzed. We detected a significant negative association between T2D and the 1068 G>A SNP (Odds ratio 0.3916, p = 0.0045). In addition, we observed that T2D patients bearing the 1068 G>A variant showed higher serum levels of IL-1Ra compared to both, patients with the GG genotype or healthy individuals (GG or G>A). Moreover, T2D patients bearing the 1068 G>A SNP showed increased insulin levels and a better pancreatic ß-cell function (p < 0.05 in both cases) compared to patients with the wild type genotype. However, the HbA1c levels, fasting glucose levels and the degree of insulin resistance were similar in T2D patients carrying or not the G>A SNP. Our results suggest that although the 1068 G>A polymorphism of the P2RX7 gene is associated with an increased ß-cell function and IL-1Ra release in T2D patients, the glycemic control is not significantly affected by the presence of this SNP.

Detection of anti-HspX antibodies and HspX protein in patient sera for the identification of recent latent infection by Mycobacterium tuberculosis.

Mycobacterium tuberculosis is a pathogen causing tuberculosis (TB) a spectrum of disease including acute and asymptomatic latent stages. Identifying and treating latently-infected patients constitutes one of the most important impediments to TB control efforts. Those individuals can remain undiagnosed for decades serving as potential reservoirs for disease reactivation. Tests for the accurate diagnosis of latent infection currently are unavailable. HspX protein (α-crystallin), encoded by Rv2031c gene, is produced in vitro by M. tuberculosis during stationary growth phase and hypoxic or acidic culture conditions. In this study, using standard, and Luminex xMAP® bead capture ELISA, respectively, we report on detection of anti-HspX IgG and IgM antibodies and HspX protein in sera from acute and latent TB patients. For the antibody screen, levels of IgG and IgM antibodies were similar between non-infected and active TB patients; however, individuals classified into the group with latent TB showed higher values of anti-HspX IgM (p = 0.003) compared to active TB patients. Using the bead capture antigen detection assay, HspX protein was detected in sera from 56.5% of putative latent cases (p< 0.050) compared to the background median with an average of 9,900 pg/ml and a range of 1,000 to 36,000 pg/ml. Thus, presence of anti-HspX IgM antibodies and HspX protein in sera may be markers of latent TB.

Analysis of Th1, Th17 and regulatory T cells in tuberculosis case contacts.

We have hypothesized that individuals infected with Mycobacteriumtuberculosis that exhibit different patterns of immune reactivity in serial interferon (IFN)-γ release assays (IGRA's) correspond to different status within the immune spectrum of latent tuberculosis (TB). Accordingly, we analyzed the possible association between the consistent results (negative or positive) in an IGRA test and relevant immune parameters, mainly the levels of Th1 and Th17 lymphocytes and T regulatory (Treg) cells in the peripheral blood of TB case contacts. We found that individuals with a persistently positive IGRA showed increased levels of Th1 and Th17 lymphocytes upon in vitro stimulation with MTB antigens. In addition, a significant increase in the proportion of CD4+CTLA-4+ and CD4+Foxp3+ cells was detected in assays with blood samples from these individuals. Our data support that different immune phenotypes can be identified into the spectrum of latent TB, by combining different parameters of immune reactivity against MTB.

[Ankle-brachial index assessed in a Mexican population with vascular risk. The INDAGA study]. / Estudio multicéntrico INDAGA. Índice tobillo-brazo anormal en población mexicana con riesgo vascular.

OBJECTIVE: to know the peripheral arterial disease (PAD) prevalence and its determinants in a nationwide survey in Mexican population. METHODS: baseline ankle brachial index (ABI) measured by Doppler was performed in patients at high vascular risk for PAD. ABI between 1 and 1.3 was regarded as normal. ABI ≤ 0.9 (a low ABI) was considered to be an indicator of PAD. ABI > 1.3 (a high ABI) was also considered abnormal, as an indirect index of artery calcification and stiffness. RESULTS: a total of 5 101 patients were evaluated: 1,212 patients (23.8 %) had ABI ≤ 0.9, and 431 (8.4 %) > 1.3 (including 1 % with incompressible vessels). ABI ≤ 0.9 was associated with age, arterial hypertension, diabetes, current smoking, dyslipidemia and previous vascular events. On the other hand, ABI > 1.3 was associated with male gender, diabetes, previous smoking habit and history of vascular events. A high proportion of patients (62.5 %) with established PAD, identified by a low ABI (≤ 0.9) were asymptomatic or with minimum symptoms at the time of their assessment. CONCLUSION: a significant prevalence of abnormal ABI was identified. ABI measurement by Doppler can help to identify patients who need intense secondary prevention and more aggressive treatment of vascular risk factors.

Expression of DC-SIGN in peripheral blood dendritic cells of patients with typical, slow, and rapid progression to AIDS.

The main access route for human immunodeficiency virus (HIV) into the lymph nodes is through the mucosa. Once there, dendritic cells (DCs) are the first cells to interact with the virus. Then, DCs can uptake and transport to the lymph nodes, beginning a disseminated infection. Interaction between the virus and DCs is mediated by the receptor DC-SIGN. This study seeks to determine any relationship between HIV-AIDS immunopathology and DC-SIGN expression levels in DCs from typical, rapid, and slow progressors. A DC separation system was implemented using peripheral blood mononuclear cells from infected subjects. The study included 27 patients classified as typical, rapid, and slow progressors according to their clinical and epidemiological files. Finally, quantification of DC-SIGN was achieved by real-time PCR and by applying the Relative Quantification Scheme (DeltaDeltaCt). We isolated DCs from peripheral blood of 27 HIV-infected patients. Nineteen were considered as typical progressors, five as slow progressors, and three as rapid progressors. No significant differences were observed on the expression levels of DC-SIGN among the three groups of patients. Even if there are differences in expression levels among the analyzed patients, we did not find any significant differences in DC-SIGN expression among the three included groups. We therefore cannot conclude that the expression level of the receptor is related with the progression to AIDS.

[Medico-surgical consensus for management of children with gastroesophageal reflux Acapulco, Mexico 2002]. / Consenso médico quirúrgico para el manejo de niños con reflujo gastroesofágico--Acapulco, México 2002.

UNLABELLED: Gastroesophageal reflux (GER) is a common disease in children less one year old. It is present around 10% of unselected infant population. 40-50% have abnormal 24 h pH monitoring. An early diagnosis and treatment should be done in order to avoid complications. AIM: To establish the consensus for the diagnosis and treatment of children with GER, to rule out similar diseases avoid the use of unnecessary drugs and the secondary side effects as well as unnecessary surgery. METHOD: The consensus was done with the participation of general pediatricians, pediatrics gastroenterologist, pediatric surgeons, radiologist and endoscopist. An initial paper was done by pediatric surgeon and pediatric gastroenterologist who submitted to the rest of participants. Second stage: the paper was review through E-mail for all participants who send their suggestions and modifications. A new paper was done and discussed by medical and surgery area. During the Congress of Pediatric Surgery, in an open session was discuss again with the participation of the main authors and all the audience present. Finally, a paper was done and review for the main authors.

Síndrome de Peutz-Jeghers: presentación de 12 casos / Peutz-Jeghers: presentation of 12 cases

Se presentan 12 pacientes con síndrome de Peutz-Jeghers, cuyas manifestaciones gastrointestinales fueron el motivo principal de consulta a este Instituto. El sexo femenino fue el más frecuentemente afectado. En todos ellos los pólipos fueron de naturaleza hamartomatosa y se encontraron distribuidos prácaticamente en todo el tracto gastrointestinal, excepto boca y esófago. Se encontró una buena correlación radiológica y endoscópica para el diagnóstico de los mismos. La polipectomía transendoscópica es importante, tanto para el diagnóstico como para el tratamiento.