Eliseo Portilla-de Buen

Interleukin-6 Polymorphisms Are Associated with Obesity and Hyperglycemia in Mexican Adolescents

BACKGROUND AND AIMS Interleukin-6 is an inflammatory response mediator used as a metabolic marker of obesity. Polymorphisms IL6 -597C>A, -572G>C, and -174G>C modify the production of this protein. The associations between these haplotypes and obesity or metabolic markers have not been studied in adolescents, so an analysis of these associations was performed. METHODS The cross-sectional study included 745 apparently healthy 14- to 19-year-old adolescents. Obesity, serum glucose, insulin, triglycerides, total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol (HDL-C), and high-sensitivity C-reactive protein (hs-CRP) were evaluated, and IL6 -597G>A, -572G>C and -174G>C polymorphisms determined. The associations were analyzed using multivariate logistic regression models. RESULTS The allele frequencies were 0.15 for -597A and -174C and 0.30 for -572C. Genotypes were in Hardy-Weinberg equilibrium. IL-6(-597/-572/-174) haplotypes GGG, GCG, and AGC comprised 99.74% of the total haplotypes. The associations were significant between genotype GCG/GCG and hyperglycemia (OR = 2.86, 95% CI = 1.02-7.97); between GCG/GCG and high hs-CRP (OR = 6.17, 95% CI = 1.13-33.77); between AGC/AGC and obesity (OR = 4.42, 95% CI = 1.40-14.01); and between GGG/GCG and low HDL-C (OR = 1.53, 95% CI = 1.03-2.28). CONCLUSIONS Genotypes of the IL6(-597/-572/-174) polymorphisms are associated with metabolic risk factors in Mexican adolescents.

Influence of cytokine and intercellular adhesion molecule-1 gene polymorphisms on acute rejection in pediatric renal transplantation

Abstract:  Immune response regulation by cytokines is a key to understanding AGR. The influence of the functional polymorphisms in genes coding for TNF‐α (−308G > A), IL‐10 (−819C > T, and −1082A > G), IFN‐γ [(CA)n], TGF‐β1 (+869T > C), and iCAM‐1 (R241G and E469K), in addition to HLA and gender matching on the presentation of AGR in 51 pediatric renal recipients during a 36‐month post‐transplantation follow‐up were analyzed. Also, donors and a control group were genotyped. All groups were within Hardy‐Weinberg equilibrium for all polymorphisms except IL‐10–819C > T and TNF‐α (p < 0.005 and p < 0.01, respectively) in recipients. Transplants with gender mismatch showed a higher risk for AGR than those between individuals with gender match (OR, 4.227; p = 0.010). Recipients with a high‐production compared with low‐production TNF‐α allele experienced earlier AGR (p = 0.030), and those with high‐production alleles of both TNF‐α and IFN‐γ showed a further increased risk (OR = 11.129, p = 0.024). These findings support the notion that a single genotype cannot by itself explain an event as complex as AGR. The sum or combination of different specific alleles of these genes could better account for the immune response to an allograft.

Contribution of TNF-308A and CCL2-2518A to carotid intima-media thickness in obese mexican children and adolescents.

BACKGROUND Although commonly used in adults to detect early atherosclerosis, the value of the carotid intima-media thickness (CIMT) in children and adolescents is not clear. This marker has an inheritable component that supports the notion of a genetic influence. Among the genes studied as candidates for atherosclerosis development are those for chemokines, cytokines, and adhesion molecules because of their participation in atheroma formation through monocyte recruitment and migration. METHODS We analyzed the relationship between CIMT and functional polymorphic variants in the genes for chemokines and proinflammatory cytokines associated with cardiovascular events in adults in lean and obese but otherwise healthy 6- to 19-year-old subjects. RESULTS In the obese group, systolic blood pressure correlated negatively (r =-0.332; p = 0.008) and the TNF-308A allele correlated positively (r = 0.262; p = 0.040) with CIMT. The mean CIMT was higher in obese individuals with the TNF-308A allele than in those with TNF-308G allele (p = 0.041). In a multiple regression model for the total population, an increase in CIMT was explained by body mass index, systolic and diastolic blood pressure, and the TNF-308A and CCL2-2518A alleles (r(2) = 0.321; p = 0.022). CONCLUSIONS This study contributes to the understanding of the pathophysiology of atherosclerosis and suggests that genetic markers of an increased inflammatory response and its deleterious effects are already present in obese children and adolescents.

Nitric oxide in the commissural nucleus tractus solitarii regulates carotid chemoreception hyperglycemic reflex and c-Fos expression

Carotid body chemoreceptors function as glucose sensors and contribute to glucose homeostasis. The nucleus tractus solitarii (NTS) is the first central nervous system (CNS) nuclei for processing of information arising in the carotid body. Here, we microinjected a nitric oxide (NO) donor sodium nitroprusside (SNP), an NO-independent activator of the soluble guanylyl cyclase (sGC) (YC₁) or an NO-synthase (NOS) inhibitor Nω-nitro-l-arginine methyl ester (L-NAME) into the commissural NTS (cNTS) before carotid chemoreceptor anoxic stimulation and measured arterial glucose and the expression of Fos-like immunoreactivity (Fos-ir). Male Wistar rats (250-300 g) were anesthetized, and the carotid sinus was vascularly isolated. Either artificial cerebrospinal fluid (aCSF), SNP, YC₁ or L-NAME were stereotaxically injected into the cNTS. The SNP and YC₁ infused into the cNTS before carotid chemoreceptor stimulation (SNP-2 and YC₁-2 groups) similarly increased arterial glucose compared to the aCSF-2 group. By contrast, infusion of L-NAME into the cNTS before carotid chemoreceptor stimulation (L-NAME-2 group) decreased arterial glucose concentration. The number of cNTS Fos-ir neurons, determined in all the groups studied except for YC₁ groups, significantly increased in SNP-2 rat when compared to the aCSF-2 or SNP-2 groups. Our findings demonstrate that NO signaling, and the correlative activation of groups of cNTS neurons, plays key roles in the hyperglycemic reflex initiated by carotid chemoreceptor stimulation.

Nitric oxide infused in the solitary tract nucleus blocks brain glucose retention induced by carotid chemoreceptor stimulation

Previous work has shown that the carotid body glomus cells can function as glucose sensors. The activation of these chemoreceptors, and of its afferent nucleus in the brainstem (solitary tract nucleus - STn), induces rapid changes in blood glucose levels and brain glucose retention. Nitric oxide (NO) in STn has been suggested to play a key role in the processing of baroreceptor signaling initiated in the carotid sinus. However, the relationship between changes in NO in STn and carotid body induced glycemic changes has not been studied. Here we investigated in anesthetized rats how changes in brain glucose retention, induced by the local stimulation of carotid body chemoreceptors with sodium cyanide (NaCN), were affected by modulation of NO levels in STn. We found that NO donor sodium nitroprusside (SNP) micro-injected into STn completely blocked the brain glucose retention reflex induced by NaCN chemoreceptor stimulation. In contrast, NOS inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) increased brain glucose retention reflex compared to controls or to SNP rats. Interestingly, carotid body stimulation doubled the expression of nNOS in STn, but had no effect in iNOS. NO in STn could function to terminate brain glucose retention induced by carotid body stimulation. The work indicates that NO and STn play key roles in the regulation of brain glucose retention.

Fibrinogen and thrombin concentrations are critical for fibrin glue adherence in rat high-risk colon anastomoses

OBJECTIVE: Fibrin glues have not been consistently successful in preventing the dehiscence of high-risk colonic anastomoses. Fibrinogen and thrombin concentrations in glues determine their ability to function as sealants, healers, and/or adhesives. The objective of the current study was to compare the effects of different concentrations of fibrinogen and thrombin on bursting pressure, leaks, dehiscence, and morphology of high-risk ischemic colonic anastomoses using fibrin glue in rats. METHODS: Colonic anastomoses in adult female Sprague-Dawley rats (weight, 250-350 g) treated with fibrin glue containing different concentrations of fibrinogen and thrombin were evaluated at post-operative day 5. The interventions were low-risk (normal) or high-risk (ischemic) end-to-end colonic anastomoses using polypropylene sutures and topical application of fibrinogen at high (120 mg/mL) or low (40 mg/mL) concentrations and thrombin at high (1000 IU/mL) or low (500 IU/mL) concentrations. RESULTS: Ischemia alone, anastomosis alone, or both together reduced the bursting pressure. Glues containing a low fibrinogen concentration improved this parameter in all cases. High thrombin in combination with low fibrinogen also improved adherence exclusively in low-risk anastomoses. No differences were detected with respect to macroscopic parameters, histopathology, or hydroxyproline content at 5 days post-anastomosis. CONCLUSIONS: Fibrin glue with a low fibrinogen content normalizes the bursting pressure of high-risk ischemic left-colon anastomoses in rats at day 5 after surgery.

Concomitant Effects of Nitric Oxide and Carotid Chemoreceptor Stimulation on Brain Glucose in Normoglycemic and Hyperglycemic Rats

BACKGROUND AND AIMS Carotid body (CB) sinus perfusion with different glucose concentrations modifies arterial glucose concentration and brain glucose retention, thereby changing the brains threshold to hypoxia. Because nitric oxide (NO) modulates hypoxic chemoreception, we investigated the relationship between NO- and CB-receptor pathways on arterial glucose and brain arteriovenous (a-v) glucose difference after hypoxic stimulation under hyperglycemic conditions. METHODS Normoglycemic and streptozotocin (STZ, 50 mg/kg i.p.)-induced hyperglycemic Sprague Dawley rats were infused with the NO donor, sodium nitroprusside (SNP), or the NOS inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME) into the circulatory isolated carotid sinus after (30 sec) local anoxic CB chemoreceptor stimulation with sodium cyanide (NaCN). RESULTS L-NAME abolished the hyperglycemia and the increase in brain a-v glucose concentration difference induced by CB chemoreceptor stimulation in normoglycemic rats, whereas the same treatment in hyperglycemic rats did not change the glucose variables studied. However, SNP infused under the same conditions induced a bigger rise in arterial glucose and brain a-v glucose concentration difference only in normoglycemic rats, when compared with the results obtained in sham-2-control rats. CB stimulation plus SNP treatment also resulted in an increase in nitrite levels in cephalic venous blood in normoglycemic, but not in hyperglycemic, rats. CONCLUSIONS We showed a clear concomitant effect of SNP infusion into local CB circulation and anoxic cyanide stimulation, enhancing hyperglycemia and brain a-v glucose concentration difference. Importantly, at high glucose levels, nitrergic drugs did not modify glucose variables when compared with the corresponding sham controls.

Analysis of cytokine gene polymorphisms in Mestizo and native populations from Mexico

To determine whether the well‐known genetic structure of the Mexican population observed with other multiallelic markers can be detected by analyzing functional polymorphisms of cytokine and other inflammatory‐response‐related genes.

Metabolic and genetic markers’ associations with elevated levels of alanine aminotransferase in adolescents

Abstract Background: Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in adolescents, is a feature of metabolic syndrome (MetS). Obesity and insulin resistance (IR) are risk factors for NAFLD, as well as inflammation-related genetic markers. The relationship between metabolic or inflammation-related genetic markers and alanine aminotransferase (ALT) is not fully understood. We examined the relationship of MetS, metabolic and inflammation-related genetic markers with elevated ALT in adolescents. Methods: A total of 674 adolescents participated in a cross-sectional study in Guadalajara, Mexico. Elevated ALT (>40 IU/L), a surrogate marker of NAFLD, and MetS (International Diabetes Federation definition) were evaluated. Obesity, IR, lipids, C-reactive protein (CRP) and genetic markers (TNFA-308G>A, CRP+1444C>T, IL1RN and IL6-597/-572/-174 haplotype) were evaluated. Multivariate logistic regression was performed. Results: Elevated ALT was observed in 3% and 14.1% (total and obese, respectively) of the adolescents. Obesity (odds ratio [OR], 5.86; 95% confidence interval [95% CI], 1.16–25.89), insulin (OR, 8.51; 95% CI, 2.61–27.71), IR (OR, 9.10; 95% CI, 2.82–29.38), total cholesterol (TC) (OR, 3.67; 95% CI, 1.25–10.72), low-density lipoprotein-cholesterol (LDL-C) (OR, 3.06; 95% CI, 1.06–8.33), non-high-density lipoprotein-cholesterol (HDL-C) (OR, 3.88; 95% CI, 1.27–11.90) and IL1RN (OR, 4.64; 95% CI, 1.10–19.53) were associated with elevated ALT. Among males, ≥2 MetS criteria were associated with elevated ALT (OR, 4.22; 95% CI, 1.14–15.71). Conclusions: Obesity, insulin, IR, high TC, high LDL-C, high non-HDL-C and IL1RN polymorphism were associated with elevated ALT. Among males, ≥2 MetS criteria were associated with elevated ALT. There is an urgent need to reduce obesity and IR in adolescents to prevent NAFLD.

Alternate Method for Hybrid Fontan Completion

A Fontan completion with a hybrid approach was performed on a 27-month-old girl with a univentricular heart. A large covered stent was placed between the inferior vena cava and the cavopulmonary anastomosis through a pericardial patch in the intracardiac fenestrated tunnel, circumventing the need for an occluder device for baffle closure. The childs progress has been good and she displays normal growth and acceptable clinical, ultrasonographic, and laboratory results.