Portal Angiogenesis in Chronic Liver Disease Patients Correlates with Portal Pressure and Collateral Formation.

BACKGROUND/AIMS: One hallmark of chronic liver disease in patients with portal hypertension is the formation of portal-systemic collaterals in which angiogenesis has a fundamental role. We studied patients with chronic liver disease undergoing liver transplantation to correlate levels of circulating angiogenic factors in portal and peripheral circulation with portal pressure and portal-systemic collaterals. METHODS: Sixteen patients who underwent liver transplantation were enrolled. During transplant surgery, we determined portal venous pressure and portal-systemic collateral formation. We determined angiogenics mediator levels in systemic and portal plasma. Peripheral plasma from healthy donors was measured as controls. RESULTS: Vascular endothelial growth factor (VEGF)-R1 and 2, Ang-1 and 2, Tie2, FGF- 1 and 2, CD163, PDGFR-ß, PDGFsRα, PDGF-AB and BB, CD163, TGF-ß VASH-1 levels were significantly different in the controls in comparison to cases. Significantly decreased portal venous levels of Ang-1, FGF-1, PDGF-AB/BB, and CC were observed in patients with higher portal pressure. Peripheral VEGF, Ang-1, pPDGF-AB, BB, and CC were significantly decreased in patients with more severe collateral formation. While peripheral VEGF-R1 was higher in patients with severe collateral formation. For portal circulation, VEGF, Ang-1, -pPDGF-AB, BB, and CC were significantly decreased in patients with more severe collateral formation Conclusions: Angiogenesis factors correlated with portal pressure and collateral formation and different patterns of circulating angiogenesis mediators were found in peripheral and portal blood of patients with chronic liver disease. These results support the importance of angiogenic pathways in cirrhosis and portal hypertension and highlight areas for further study to identify clinically useful noninvasive markers of portal pressure and collateral formation.

Iron Deficiency and IL1ß Polymorphisms in Helicobacter pylori-infected Children.

BACKGROUND: Helicobacter pylori infection has been associated with an imbalance of iron homeostasis. IL-1ß has been related with iron absorption disturbances through a variety of mechanisms. The aim of this study was to evaluate the presence of polymorphic variants for IL-1ß cluster and gastric IL1ß mRNA expression in H. pylori-infected children and their relationship with hypochlorhydria and iron deficiency (ID). PATIENTS AND METHODS: Prospective study of 123 symptomatic children. At endoscopy, antral biopsies were taken for urease test, pathology and culture and blood for analysis of ferritin, transferrin, serum iron, and total iron-binding capacity. Polymorphisms in the IL-1ß cluster (positions -511, -31, +3954, ILRN) were determined by PCR-RFLP. Gastric mucosal expression of IL-1ß mRNA was determined by RT-PCR. RESULTS: After exclusions, of 105 patients, 33 (31.4%) were H. pylori positive. Nine (8.6%) children were classified as iron deficient (ID). Helicobacter pylori positivity was associated with ID (OR: 5.1; 95% CI: 1.2-21.9) (p = .04). No significant differences were found in allele frequency for IL1ß gene cluster polymorphisms between infected and uninfected children. Helicobacter pylori-infected children with ID had significantly increased gastric IL1ß mRNA in comparison with infected children without ID. In addition, a significant positive correlation was observed between mucosal IL-1ß mRNA and fasting gastric juice pH. Gastric pH values were significantly increased in H. pylori-infected patients with ID compared to uninfected children. CONCLUSIONS: The established association between H. pylori infection and ID in children may be mediated by increased gastric mucosal IL-1ß.

[Maternal infection due to Helicobacter pylori does not increase the risk of the infection in the first trimester of the life of their infants]. / La infección materna por Helicobacter pylori no aumenta el riesgo de contraer la bacteria en el primer trimestre de vida de sus lactantes.

INTRODUCTION: H. pylori infection is acquired early in childhood. However, there is little information available regarding the role of breastfeeding and neonatal acquisition of the infection. OBJECTIVE: To evaluate factors affecting the acquisition of H. pylori in newborns and infants from infected mothers. PATIENTS AND METHOD: Consecutive mothers and their newborns were recruited into the study from the maternity unit, immediately after delivery. After signing informed consent, one stool sample from the mother was obtained before hospital discharge. Three stool samples of the newborns were then collected at home at 15, 60, and 90 days of life, for the detection of H. pylori antigen (Monoclonal HpSAg, sensitivity 94% and specificity 97%). The socio-epidemiological and biomedical variables were also analysed using a questionnaire. RESULTS: A total of 32 mother-child pairs (64 subjects) were enrolled. The mean maternal age was 30.1±5.1 years, with 53% vaginal delivery, and 85% exclusively breastfed. There were 13 (40%) infected mothers. No H. pylori infection was detected in newborns and infants up to 3 months of follow-up. No significant differences were found in socioeconomic level between infected versus non-infected mothers (both groups mostly in the very high socioeconomic category: 28% and 32%, respectively, P=.15) and in the number of family members between infected versus non-infected mothers (3.8±0.8 vs 4.2±1.8 persons, P=.18). CONCLUSION: Despite having a significant percentage of H. pylori-infected mothers, no newborn was infected at the third month of life. The protective role of breastfeeding cannot be ruled out.

Peptic ulcer disease in Helicobacter pylori-infected children: clinical findings and mucosal immune response.

OBJECTIVES: Peptic ulcer disease (PUD) is highly prevalent among adults but less common in children. Helicobacter pylori infection, the main cause of PUD, is, however, acquired extremely early in life. The aim of the study was to analyze clinical characteristics of children with PUD in a country with a high prevalence of the disease and to evaluate which host factors could determine this clinical outcome. METHODS: Children referred for upper gastrointestinal (GI) endoscopy with suspicion of peptic diseases were included prospectively during an 8-year period. Antral biopsies were performed to determine H pylori presence and mucosal cytokines profile. RESULTS: A total of 307 children between 3 and 18 years old were enrolled. Of the total, 237 children (46% boys) with complete data were included. H pylori infection was confirmed in 133 (56.1%) participants. Duodenal ulcer (DU) was diagnosed in 32 patients (13.5%); among them 29 were infected with H pylori (90.6%). Infected children had a nodular appearance of the gastric mucosa more often than noninfected children. Noninfected children had fewer lymphoid follicles and less inflammatory infiltrate than infected children. Only mucosal polymorphonuclear cell infiltration was more intense in DU-infected children as compared with non-DU-infected children. DU-infected children had higher levels of mucosal interferon-γ than noninfected and non-DU-infected patients. Non-DU-infected children had also higher levels of mucosal interleukin-10 than noninfected patients (P < 0.05). CONCLUSIONS: PUD in children, especially DU, is strongly associated with H pylori infection in developing countries. There is no distinctive clinical presentation of children with PUD. T-helper cytokine balance may influence clinical outcomes in children.

[Frequency of Helicobacter pylori infection in 144 school age Chilean children]. / Prevalencia de la infección por Helicobacter pylori en niños: estimando la edad de adquisición.

BACKGROUND: A 73% prevalence of Helicobacter pylori infection was estimated in adults in the 2003 Chilean National Health Survey. However, this infection is usually acquired during childhood. AIM: To determine the frequency of H. pylori infection in healthy Chilean children from a school in Santiago. MATERIAL AND METHODS: A cross sectional study in a private/ subsidized school in Santiago. Children aged less than 18 years were invited to participate. The parents of those who accepted answered a demographic survey and a stool sample was obtained from participants to detect H. pylori antigen using a monoclonal antibody ELISA kit. RESULTS: We studied 144 students aged 10.6 ± 3.1 years (54% females). Twenty six participants (18.1%, 95% CI: 12.4-24.9%) had a positive test. Children from higher socioeconomic levels had a non-significant lower frequency of infection. No differences in the frequency of infection were observed by age, gender, household type or number of people living in it or history of breastfeeding. CONCLUSIONS: In this sample of children, an 18.1% frequency of H. pylori infection was observed.

Plasminogen activator inhibitor type 1 serum levels and 4G/5G gene polymorphism in morbidly obese Hispanic patients with non-alcoholic fatty liver disease.

BACKGROUND: The plasminogen activator inhibitor type-1 (PAI-1) has been implicated in the regulation of fibrinolysis and extracellular matrix components. The single base pair guanine insertion/deletion polymorphism (4G/5G) within the promoter region of the PAI-1 gene influences PAI-1 synthesis and may modulate hepatic fibrogenesis. AIM: To evaluate the influence of PAI-1 serum levels and 4G/5G polymorphism on the risk of liver fibrosis associated to non-alcoholic fatty liver disease (NAFLD) in morbidly obese patients. MATERIAL AND METHODS: Case-control study of 50 obese patients undergoing bariatric surgery and 71 non-obese subjects matched by age and sex. Anthropometric and biochemical measurements were performed, including PAI-1 serum levels. Genomic DNA was obtained to assess the presence of 4G/5G polymorphism. RESULTS: BMI, insulinemia, triglycerides, HOMA-IR, hypertension and diabetes were significantly higher in obese patients compared to control subjects. PAI-1 serum levels observed in obese patients were significantly lower (10.63 ± 4.82) compared to controls (14.26 ± 11.4; p < 0.05). No differences were observed in the PAI-1 4G/5G promoter genotypes frequencies (p = 0.12). No differences were observed in PAI-1 plasma levels among obese patients with liver fibrosis (10.64 ± 4.35) compared to patients without liver fibrosis (10.61 ± 5.2; p = 0.985). PAI-1 4G/5G promoter genotypes frequencies were similar in patients with or without liver fibrosis associated to NASH (p = 0.6). CONCLUSIONS: Morbidly obese patients had significantly lower PAI-1 serum levels with similar PAI-1 4G/5G genotypes frequencies compared to non-obese subjects. The frequency of 4G/5G genotypes in Chilean Hispanic healthy subjects was similar to that described in other populations. No association was found between PAI-1 serum levels or 4G/5G genotype with liver fibrosis in obese patients.

[Normal values of eosinophils in gastric and duodenal mucosa of children referred to upper gastrointestinal endoscopy]. / Valores de normalidad de eosinófilos en mucosa gástrica y duodenal de niños referidos a endoscopía digestiva alta.

INTRODUCTION: With the increasing incidence of food allergies, the presence of eosinophils (Eos) in the gastrointes tinal mucosa has received increased attention, particularly in the esophagus and colon. However, normal values for the Eos count in the stomach and duodenum in pediatric patients are still limited. THE OBJECTIVE: of this study was to estimate Eos reference values in stomach and duodenal biopsies of children referred to upper gastrointestinal endoscopy. PATIENTS AND METHODS: Cross-sectional study of biopsies from symptomatic children referred to upper gastrointestinal endoscopy. The endoscopic report, Rapid Urease Test for the presence of H. pylori, and the quantitative histological evaluation (number of cells/HFP, high power field) were analyzed. The Eos distribution is described as mean and standard deviation, and also as percentiles since the counts did not have a normal distribution. Statistical analysis included x2 test, Wilcoxon test, analysis of variance, and linear regression curves were evaluated as appropriate. RESULTS: Of the 170 patients referred to endoscopy, 72 met "normal" criteria (normal endoscopy in macroscopic analysis, negative Rapid Urease Test, and normal biop sy). The median age was 11 years (range 4-16), and 68% were girls. The Eos count (mean ± 1SD) in gastric antrum (n = 72) was 1.13 ± 1.79 Eos/HPF; in gastric body (n = 27), 1.06 ± 1.79 Eos/HPF; and in duodenum (n = 30), 10.44 ± 7.09 Eos/HPF. There were no significant differences by age and sex, or by H. pylori infection (p = 0.095). CONCLUSIONS: We propose an Eos count of 0-3 Eos/HPF for the gastric body, 0-3 Eos/HPF in the antrum, and 3-17 Eos/HPF in the duodenum as a normal range for gastric mucosa in children. This study suggests that in areas with a high prevalence of H. pylori infec tion, the count of Eos does not seem to be a distinctive element and that Eos are commonly present in the gastroduodenal mucosa.

Maternal H. pylori is associated with differential fecal microbiota in infants born by vaginal delivery.

Helicobacter pylori colonization may affect the mucosal immune system through modification of microbiota composition and their interactions with the host. We hypothesized that maternal H. pylori status affects the maternal intestinal microbiota of both mother and newborn. In this study, we determine the structure of the fecal microbiota in mothers and neonates according to maternal H. pylori status and delivery mode. We included 22 mothers and H. pylori infection was determined by fecal antigen test. Eleven mothers (50%) were H. pylori-positive (7 delivering vaginally and 4 by C-section), and 11 were negative (6 delivering vaginally and 5 by C-section). Stool samples were obtained from mothers and infants and the fecal DNA was sequenced. The fecal microbiota from mothers and their babies differed by the maternal H. pylori status, only in vaginal birth, not in C-section delivery. All 22 infants tested negative for fecal H. pylori at 15 days of age, but those born vaginally -and not those by C-section- showed differences in the infant microbiota by maternal H. pylori status (PERMANOVA, p = 0.01), with higher abundance of Enterobacteriaceae and Veillonella, in those born to H. pylori-positive mothers. In conclusion, the structure of the infant fecal microbiota is affected by the maternal H. pylori status only in infants born vaginally, suggesting that the effect could be mediated by labor and birth exposures.

Helicobacter pylori-associated hypochlorhydria in children, and development of iron deficiency.

AIMS: Acute Helicobacter pylori infection is associated with transient hypochlorhydria. In H pylori-associated atrophy, hypochlorhydria has a role in iron deficiency (ID) through changes in the physiology of iron-complex absorption. The aims were to evaluate the association between H pylori-associated hypochlorhydria and ID in children. METHODS: Symptomatic children (n=123) were prospectively enrolled. Blood, gastric juice and gastric biopsies were taken, respectively, for haematological analyses, pH assessment and H pylori determination, and duodenal biopsies for exclusion of coeliac disease. Stool samples were collected for parasitology/microbiology. Thirteen children were excluded following parasitology and duodenal histopathology, and five due to impaired blood analysis. RESULTS: Ten children were hypochlorhydric (pH>4) and 33 were H pylori positive. In H pylori-positive children with pH>4 (n=6) serum iron and transferrin saturation levels % were significantly lower (p<0.01) than H pylori-positive children with pH≤4. No differences in ferritin, or total iron binding capacity, were observed. In H pylori-negative children with pH>4, iron and transferrin saturation were not significantly different from children with pH≤4. CONCLUSIONS: Low serum iron and transferrin in childhood H pylori infection is associated with hypochlorhydria. In uninfected children, hypochlorhydria was not associated with altered serum iron parameters, indicating a combination of H pylori infection and/or inflammation, and hypochlorhydria has a role in the aetiology of ID. Although H pylori-associated hypochlorhydria is transient during acute gastritis, this alters iron homeostasis with clinical impact in developing countries with a high H pylori prevalence.

Iron status and Helicobacter pylori infection in symptomatic children: an international multi-centered study.

OBJECTIVE: Iron deficiency (ID) and iron deficiency anaemia (IDA) are global major public health problems, particularly in developing countries. Whilst an association between H. pylori infection and ID/IDA has been proposed in the literature, currently there is no consensus. We studied the effects of H. pylori infection on ID/IDA in a cohort of children undergoing upper gastrointestinal endoscopy for upper abdominal pain in two developing and one developed country. METHODS: In total 311 children (mean age 10.7±3.2 years) from Latin America--Belo Horizonte/Brazil (n = 125), Santiago/Chile (n = 105)--and London/UK (n = 81), were studied. Gastric and duodenal biopsies were obtained for evaluation of histology and H. pylori status and blood samples for parameters of ID/IDA. RESULTS: The prevalence of H. pylori infection was 27.7% being significantly higher (p<0.001) in Latin America (35%) than in UK (7%). Multiple linear regression models revealed H. pylori infection as a significant predictor of low ferritin and haemoglobin concentrations in children from Latin-America. A negative correlation was observed between MCV (r = -0.26; p = 0.01) and MCH (r = -0.27; p = 0.01) values and the degree of antral chronic inflammation, and between MCH and the degree of corpus chronic (r = -0.29, p = 0.008) and active (r = -0.27, p = 0.002) inflammation. CONCLUSIONS: This study demonstrates that H. pylori infection in children influences the serum ferritin and haemoglobin concentrations, markers of early depletion of iron stores and anaemia respectively.

La infección materna por Helicobacter pylori no aumenta el riesgo de contraer la bacteria en el primer trimestre de vida de sus lactantes / Maternal infection due to Helicobacter pylori does not increase the risk of the infection in the first trimester of the life of their infants

Introducción: La infección por H. pylori se adquiere tempranamente en la infancia. Sin embargo, existe escasa información acerca del rol de la lactancia materna y la adquisición de la bacteria en la etapa neonatal/lactante. Objetivo: Evaluar algunos factores que afectan la adquisición de H. pylori en recién nacidos y lactantes hijos de madres infectadas. Pacientes y método: Reclutamiento consecutivo de binomios madre-hijo en maternidad, inmediatamente posparto. Luego de la firma de consentimiento informado, se obtuvo una muestra de deposición de la madre, previo al alta. Posteriormente se obtuvieron 3 muestras de deposición de los recién nacidos/lactantes a los 15, 60 y 90 días de vida, para la detección de antígeno en deposición de H. pylori (HpSAg monoclonal, sensibilidad 94% y especificidad 97%). Además se registraron variables socio-epidemiológicas y biomédicas. Resultados: Se reclutaron 32 binomios madre-hijo, 64 sujetos. Promedio de edad materna de 30,1 ± 5,1 años, 53% parto eutócico, 85% con lactancia materna exclusiva al final del seguimiento. Se encontró 13 madres (40%) infectadas por H. pylori. No hubo infección por H. pylori en los recién nacidos y lactantes a los 3 meses de seguimiento. No hubo diferencia significativa en el nivel socioeconómico entre madres infectadas versus no infectadas (ambos grupos en nivel socioeconómico muy alto: 28% y 32% respectivamente, p = 0,15), ni en el número de habitantes por domicilio entre madres infectadas y no infectadas (3,8 ± 0,8 vs 4,2 ± 1,8 personas, p = 0,18). Conclusión: A pesar de tener un alto porcentaje de madres infectadas por H. pylori, no hubo recién nacidos/lactantes infectados al tercer mes de vida. El rol protector de la lactancia maternal no se puede descartar.

Introduction: H. pylori infection is acquired early in childhood. However, there is little information available regarding the role of breastfeeding and neonatal acquisition of the infection. Objective: To evaluate factors affecting the acquisition of H. pylori in newborns and infants from infected mothers. Patients and method: Consecutive mothers and their newborns were recruited into the study from the maternity unit, immediately after delivery. After signing informed consent, one stool sample from the mother was obtained before hospital discharge. Three stool samples of the newborns were then collected at home at 15, 60, and 90 days of life, for the detection of H. pylori antigen (Monoclonal HpSAg, sensitivity 94% and specificity 97%). The socio-epidemiological and biomedical variables were also analysed using a questionnaire. Results: A total of 32 mother-child pairs (64 subjects) were enrolled. The mean maternal age was 30.1 ± 5.1 years, with 53% vaginal delivery, and 85% exclusively breastfed. There were 13 (40%) infected mothers. No H. pylori infection was detected in newborns and infants up to 3 months of follow-up. No significant differences were found in socioeconomic level between infected versus non-infected mothers (both groups mostly in the very high socioeconomic category: 28% and 32%, respectively, P = .15) and in the number of family members between infected versus non-infected mothers (3.8 ± 0.8 vs 4.2 ± 1.8 persons, P = .18). Conclusion: Despite having a significant percentage of H. pylori-infected mothers, no newborn was infected at the third month of life. The protective role of breastfeeding cannot be ruled out.

Differences in lung glutathione metabolism may account for rodent susceptibility in elastase-induced emphysema development.

Syrian Golden hamsters develop more severe emphysema than Sprague-Dawley rats after intratracheal instillation of the same dose of elastase/body weight. Although species variations in antielastase defenses may largely explain these results, other variables, such as differences in lung antioxidants, cannot be overlooked since oxidative stress modulates antiprotease activity. We propose that elastase instillation might affect lung glutathione (GSH) metabolism differently in these species. Our aim was to study in hamsters and rats, lung glutathione metabolism at different times, from the stage of diffuse alveolar damage to advanced emphysema. We measured total and oxidized glutathione content as well as activity and expression of enzymes related to GSH synthesis and redox cycling: gamma-glutamylcysteine synthetase, glutathione peroxidase, and glutathione reductase. Whereas rats showed no significant changes in these measurements, hamsters showed significant derangement in GSH metabolism early after elastase instillation: 25% fall in total GSH (P < 0.05) with no increase in oxidized glutathione associated with reduced enzyme activities 24 h after elastase [60% for gamma-glutamylcysteine synthetase (P < 0.01), 30% for glutathione peroxidase (P < 0.01), and 75% for glutathione reductase (P < 0.001)]. GSH homeostasis was restored at the end of the first week, involving transient increased expression of these enzymes. We conclude that elastase induces significant alterations in GSH metabolism of hamster lungs and no overall change in rat lungs. Although differences in disease severity may account for our findings, the hamster becomes vulnerable to functional inhibition of alpha(1)-antitrypsin by oxidants and thus, even more susceptible to injury than it would be, considering only its low alpha(1)-antitrypsin level.

Prevalencia de la infección por Helicobacter pylori en niños: estimando la edad de adquisición / Frequency of Helicobacter pylori infection in 144 school age Chilean children

Background: A 73% prevalence of Helicobacter pylori infection was estimated in adults in the 2003 Chilean National Health Survey. However, this infection is usually acquired during childhood. Aim: To determine the frequency of H. pylori infection in healthy Chilean children from a school in Santiago. Material and Methods: A cross sectional study in a private/ subsidized school in Santiago. Children aged less than 18 years were invited to participate. The parents of those who accepted answered a demographic survey and a stool sample was obtained from participants to detect H. pylori antigen using a monoclonal antibody ELISA kit. Results: We studied 144 students aged 10.6 ± 3.1 years (54% females). Twenty six participants (18.1%, 95% CI: 12.4-24.9%) had a positive test. Children from higher socioeconomic levels had a non-significant lower frequency of infection. No differences in the frequency of infection were observed by age, gender, household type or number of people living in it or history of breastfeeding. Conclusions: In this sample of children, an 18.1% frequency of H. pylori infection was observed.

Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and prevents oxidative stress in uremic rats.

Chronic renal failure causes left ventricular hypertrophy, but the molecular mechanisms involved remain unknown. We, therefore, investigated whether the mineralocorticoid receptor is implicated in the cardiac hypertrophy observed in uremic rats and whether mineralocorticoid receptor blockade could be protective in chronic renal failure. Experimental groups were: control rats, uremic rats (NPX) with 5/6 nephrectomy (5 weeks), and NPX rats fed with spironolactone for 5 weeks. Systolic blood pressure was increased in both NPX rats and NPX rats fed with spironolactone for 5 weeks. Echocardiography revealed concentric left ventricular hypertrophy in uremia, which was attenuated by spironolactone. Enlarged cardiomyocyte size was observed in both left and right ventricles of NPX rats, an effect that was prevented by spironolactone. Mineralocorticoid receptor antagonism attenuated the increase of ventricular brain natriuretic peptide mRNA levels induced by nephrectomy. Left ventricular gene expressions of aldosterone synthase, mineralocorticoid receptor, and hydroxysteroid dehydrogenase type 2 were the same in the 3 groups, whereas gene expression of the glucocorticoid receptor was significantly diminished in chronic renal failure rats. No significant differences in cardiac aldosterone were observed between control rats and NPX rats, although NPX rats fed with spironolactone for 5 weeks showed increased plasma aldosterone levels. However, a significant increase in serum and glucocorticoid-inducible kinase-1 mRNA expression and protein was present in the NPX group; spironolactone treatment significantly reduced serum and glucocorticoid-inducible kinase-1 mRNA and protein in the left ventricle. Uremic rats exhibited a significant increase of superoxide production and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits expression (NOX-2, NOX-4, and p47(phox)) in the left ventricle, which was prevented by the mineralocorticoid receptor antagonist. Our findings provide evidence of the beneficial effects of spironolactone in cardiac hypertrophy and cardiac oxidative stress in chronic renal failure.