Fetal and early neonatal interleukin-6 response.

In 1998, a systemic fetal cytokine response, defined as a plasma interleukin-6 (IL-6) value above 11 pg/mL, was reported to be a major independent risk factor for the subsequent development of neonatal morbid events even after adjustments for gestational age and other confounders. Since then, the body of literature investigating the use of blood concentrations of IL-6 as a hallmark of the fetal inflammatory response syndrome (FIRS), a diagnostic marker of early-onset neonatal sepsis (EONS) and a risk predictor of white matter injury (WMI), has grown rapidly. In this article, we critically review: IL-6 biological functions; current evidence on the association between IL-6, preterm birth, FIRS and EONS; IL-6 reference intervals and dynamics in the early neonatal period; IL-6 response during the immediate postnatal period and perinatal confounders; accuracy and completeness of IL-6 diagnostic studies for EONS (according to the Standards for Reporting of Diagnostic Accuracy statement); and recent breakthroughs in the association between fetal blood IL-6, EONS, and WMI.

Helicobacter pylori therapy in children: a focus on proton pump inhibitors.

Over the last two decades, there have been many studies on children who have sought an effective and safe treatment to eradicate Helicobacter pylori infection, but as yet, no therapy regimen has been found which is always effective and safe. Differences in drug response among pediatric patients are common. Such individual variability in drug response is multifactorial, including environmental, genetic, development and disease determinants that affect the disposition of a given drug. In pediatric efficacy studies for the management of H. pylori eradication in children, the most commonly tested regimen has contained a combination of proton pump inhibitor (PPI), clarithromycin and amoxicillin, followed by triple therapies containing PPI, clarithromycin and nitroimidazoles. Thus, PPIs are an integral part of triple therapy for H. pylori eradication in children with gastroduodenal disease. In this article, we comprehensively review, from a pediatric point of view, the literature on the clinical, pharmacologic and microbiologic properties of PPIs. We also discuss genetic, developmental and other host-related factors that may affect the efficacy of these drugs. Finally, we provide some guidance regarding their potential role and limitations for H. pylori eradication in children.

Association between Vitamin D Levels and Nonalcoholic Fatty Liver Disease: Potential Confounding Variables.

Nonalcoholic fatty liver disease (NAFLD), historically considered to be the hepatic component of the metabolic syndrome, is a spectrum of fat-associated liver conditions, in the absence of secondary causes, that may progress to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Disease progression is closely associated with body weight or fatness, dyslipidemia, insulin resistance, oxidative stress, and inflammation. Recently, vitamin D deficiency has been linked to the pathogenesis and severity of NAFLD because of vitamin D "pleiotropic" functions, with roles in immune modulation, cell differentiation and proliferation, and regulation of inflammation. Indeed, several studies have reported an association between vitamin D and NAFLD/NASH. However, other studies have failed to find an association. Therefore, we sought to critically review the current evidence on the association between vitamin D deficiency and NAFLD/NASH, and to analyze and discuss some key variables that may interfere with this evaluation, such as host-, environment-, and heritability-related factors regulating vitamin D synthesis and metabolism; definitions of deficient or optimal vitamin D status with respect to skeletal and nonskeletal outcomes including NAFLD/NASH; methods of measuring 25(OH)D; and methods of diagnosing NAFLD as well as quantifying adiposity, the cardinal link between vitamin D deficiency and NAFLD.

Breath tests in pediatrics.

In order to reduce the need for invasive diagnostic tests in pediatrics, there has been a rapid development of tests based on the analysis of exhaled air for the investigation of a wide range of conditions. These tests are frequently extensions of procedures that have been developed and more intensively investigated for use in adults. Consequently, when these tests are used for children, the procedures are modified and diagnostic cut-off values are changed, and this results in lack of standardization and the possibility of differences of clinical interpretation.

Increased T-helper interferon-gamma-secreting cells in obese children.

OBJECTIVE: Leptin, an adipocyte-secreted hormone, has emerged as a potential candidate for the link between obesity and the proinflammatory state. Specifically, leptin modulates T-helper (Th) cells toward a Th1 phenotype, with the secretion of proinflammatory cytokines. The aim of this study was to evaluate the Th1/Th2 balance in obese children and its relation with hormonal and metabolic features. STUDY DESIGN: In 50 obese children and 20 control children, we measured the CD4-positive Th cells that secrete interferon (IFN)-gamma or interleukin (IL)-2 (taken as an index of Th1 cells), and IL-4 (taken as an index of Th2 cells) as well as serum glucose, insulin, insulin resistance (IR) index (as homeostasis model assessment model (HOMA)), lipid profile, aminotransferases, leptin and ghrelin. Obese children also underwent dual energy X-ray absorptiometry scan measurements, and liver ultrasound scanning. RESULTS: Geometric mean percentages of IL-2- and IL-4-CD4 secreting cells in obese children were not significantly different from those found in control children. However, the geometric mean percentage of CD4-positive T cells secreting IFN-gamma was significantly higher in the obese than in the control (P < 0.0001, t-test) group. Within the entire group of study children, the percentage of IFN-gamma-positive cells was positively associated with leptin (P = 0.002), insulin (P < 0.00 005), and HOMA-IR values (P < 0.00 005). However, when these associations were restricted to the group of obese subjects, insulin and HOMA-IR values, but not leptin, retained statistical significance. Yet, in the obese group, the percentage of IFN-gamma-positive cells was associated with nonalcoholic steatohepatitis (NASH) (P = 0.001), but not with body mass index-standard deviation score and total body fat mass. CONCLUSIONS: In obese children, a shift to Th1-cytokine profile dominated by the production of IFN-gamma is related to insulin resistance as well as to NASH independently of anthropometric features and other metabolic characteristics. The prevalent Th1 pattern of secreted cytokines may be regarded as a mechanism contributing to inflammation in obesity.

Excess in the spring and deficit in the autumn in birth rates of male schizophrenic patients in Italy: potential role of perinatal risk factors.

OBJECTIVE: The aim of this study was to evaluate whether there were different seasonal variations of births in an Italian population of patients with schizophrenia, with other psychotic disorders, and with personality disorders than in the general population. METHODS: Birth dates of 1270 patients admitted to one university psychiatric unit in Rome between 1990 and 2003, with a diagnosis of schizophrenia, other psychotic disorder (OPD) and personality disorder/cluster A (PD) were analyzed according to seasonal variation. RESULTS: A significant excess of births in spring (with a peak in May) and a deficit in autumn (with a trough in October) was found in the sample of male schizophrenics (n = 506). No statistically significant variations were found in either the sample of female schizophrenics (n = 88) or in the combined sample with OPD and PD (n = 676). CONCLUSIONS: The findings serve to strengthen the existing hypotheses that schizophrenia is related to environmental factors acting on the development of the central nervous system intrauterinely.

Early-Onset Neonatal Sepsis: Still Room for Improvement in Procalcitonin Diagnostic Accuracy Studies.

To perform a systematic review assessing accuracy and completeness of diagnostic studies of procalcitonin (PCT) for early-onset neonatal sepsis (EONS) using the Standards for Reporting of Diagnostic Accuracy (STARD) initiative.EONS, diagnosed during the first 3 days of life, remains a common and serious problem. Increased PCT is a potentially useful diagnostic marker of EONS, but reports in the literature are contradictory. There are several possible explanations for the divergent results including the quality of studies reporting the clinical usefulness of PCT in ruling in or ruling out EONS.We systematically reviewed PubMed, Scopus, and the Cochrane Library databases up to October 1, 2014. Studies were eligible for inclusion in our review if they provided measures of PCT accuracy for diagnosing EONS. A data extraction form based on the STARD checklist and adapted for neonates with EONS was used to appraise the quality of the reporting of included studies.We found 18 articles (1998-2014) fulfilling our eligibility criteria which were included in the final analysis. Overall, the results of our analysis showed that the quality of studies reporting diagnostic accuracy of PCT for EONS was suboptimal leaving ample room for improvement. Information on key elements of design, analysis, and interpretation of test accuracy were frequently missing.Authors should be aware of the STARD criteria before starting a study in this field. We welcome stricter adherence to this guideline. Well-reported studies with appropriate designs will provide more reliable information to guide decisions on the use and interpretations of PCT test results in the management of neonates with EONS.

Helicobacter pylori infection and extragastric disorders in children: a critical update.

Helicobacter pylori (H. pylori) is a highly prevalent, serious and chronic infection that has been associated causally with a diverse spectrum of extragastric disorders including iron deficiency anemia, chronic idiopathic thrombocytopenic purpura, growth retardation, and diabetes mellitus. The inverse relation of H. pylori prevalence and the increase in allergies, as reported from epidemiological studies, has stimulated research for elucidating potential underlying pathophysiological mechanisms. Although H. pylori is most frequently acquired during childhood in both developed and developing countries, clinicians are less familiar with the pediatric literature in the field. A better understanding of the H. pylori disease spectrum in childhood should lead to clearer recommendations about testing for and treating H. pylori infection in children who are more likely to develop clinical sequelae. A further clinical challenge is whether the progressive decrease of H. pylori in the last decades, abetted by modern clinical practices, may have other health consequences.

Procalcitonin in pediatrics.

Over the past two decades, the body of literature on the clinical usefulness of procalcitonin (PCT) in adults has grown rapidly. Although this approach has led to increased insight, it has also prompted debate regarding its potential use in diagnosis and management of severe infection. Clinicians, however, are less familiar with the use of PCT in pediatric populations. In this review, we examine PCT as a marker of severe clinical pediatric conditions including its role in systemic inflammation, infection, and sepsis.

How long will it take to reduce gastric cancer incidence by eradicating Helicobacter pylori infection?

Helicobacter pylori (H. pylori) is the most important risk factor for the development of gastric cancer. The objective of this article is to estimate how the number of clinically diagnosed cases caused by H. pylori would reduce in the years after the eradication of the infection from a population. It is assumed that the eradication of H. pylori will prevent the start of some new gastric tumors, but those that have passed the "point of no return" will continue to develop until diagnosed clinically. The observed reduction in the number of clinically diagnosed cases of gastric cancer will depend on the form and parameters of the distribution of the time t taken for tumor to develop into a clinical case after passing the "point of no return." This analysis assumes that the time t follows normal and log-normal distributions with means 5, 10, and 15 years. If the mean value of time t were 5 years, H. pylori caused cases should be almost eliminated after 10 years, whereas if the mean were 10 years, the number of cases should be halved. If the mean were 15 years, the reduction would only be about 15% after 10 years. The eradication of H. pylori from a population will reduce the incidence of gastric cancer, but the follow-up time needed to show and evaluate the reduction may be longer than that that has been used in studies published so far.

C reactive protein and procalcitonin: reference intervals for preterm and term newborns during the early neonatal period.

BACKGROUND: There is still no study evaluating the influence of gestational age (GA) per se on C reactive protein (CRP) and procalcitonin (PCT) reference intervals. We therefore investigated how length of gestation, age (hours), and prenatal and perinatal variables might influence the levels of CRP and PCT. We also determined 95% age-specific reference intervals for CRP and PCT in healthy preterm and term babies during the early neonatal period. METHODS: One blood sample (one observation per neonate) was taken for CRP and PCT from each newborn between birth and the first 4 (for term), or 5 days (for preterm newborns) of life by using a high-sensitive CRP and PCT assays. RESULTS: Independently of gender and sampling time, GA had a significantly positive effect on CRP, and a significantly negative effect on PCT. Compared with healthy term babies, healthy preterm babies had a lower and shorter CRP response, and, conversely, an earlier, higher, and longer PCT response. CRP reference intervals were affected by a number of pro-inflammatory risk factors. CONCLUSIONS: Age- and GA-specific reference ranges for both CRP and PCT should be taken into account to optimize their use in the diagnosis of early-onset neonatal sepsis.

Consequences of Helicobacter pylori infection in children.

Although evidence is emerging that the prevalence of Helicobacter pylori (H. pylori) is declining in all age groups, the understanding of its disease spectrum continues to evolve. If untreated, H. pylori infection is lifelong. Although H. pylori typically colonizes the human stomach for many decades without adverse consequences, children infected with H. pylori can manifest gastrointestinal diseases. Controversy persists regarding testing (and treating) for H. pylori infection in children with recurrent abdominal pain, chronic idiopathic thrombocytopenia, and poor growth. There is evidence of the role of H. pylori in childhood iron deficiency anemia, but the results are not conclusive. The possibility of an inverse relationship between H. pylori and gastroesophageal reflux disease, as well as childhood asthma, remains a controversial question. A better understanding of the H. pylori disease spectrum in childhood should lead to clearer recommendations about testing for and treating H. pylori infection in children who are more likely to develop clinical sequelae.

Relationships of acylated and des-acyl ghrelin levels to bone mineralization in obese children and adolescents.

AIMS: Bodyweight is a significant predictor of bone mass. Hormonal factors are thought to play a role in the mechanisms controlling the association of body weight and fat mass with bone mass. Very recently, the orexigenic hormone ghrelin has also been implicated in bone metabolism. In this study we examined the associations of circulating acylated and des-acyl ghrelin concentrations with measures of bone in a group of obese children and adolescents as well as in a group of healthy control children. We also determined whether the associations were independent of body composition, chronological age, gender, Tanner stage, and leptin, glucose, insulin and insulin-like growth factor (IGF)-1 levels. METHODS: We performed a prospective cross-sectional study of 100 obese children [age, 8.9 (8.3 to 9.4); BMI-Standard Deviation Score (SDS), 2.2 (2.0 to 2.3)], and 100 age-matched lean healthy subjects. Fasting insulin, leptin, IGF-1, acylated and total ghrelin were measured by radioimmunoassay. Des-acyl ghrelin values were calculated as total ghrelin minus acylated ghrelin. Whole body (WB) and lumbar spine (LS) BMD, and BMC as well as body composition were assessed by DXA (Hologic QDR-4500W). LS volumetric BMD (BMAD) was estimated using the formula of Katzman (BMC/area(1.5)), while WB BMC data were expressed as BMC/height. RESULTS: Backward linear regression analysis was performed for individual groups, with age, gender, Tanner stage, weight, height, body composition (lean and fat mass), acylated ghrelin, des-acyl ghrelin, leptin, glucose, insulin, and IGF-1, entered into the model. In healthy children, acylated ghrelin was a significant and independent negative predictor of WB BMD, and WB BMC/height, while lean mass was positively associated significantly with these bone measures. In contrast, in obese children, a positive significant association was observed between des-acyl ghrelin and WB BMD as well as WB BMC/height, along with lean mass, and to a lesser degree, with fat mass. Acylated as well as des-acyl ghrelin were not significant predictors of LS BMD and LS BMAD in obese as well as control children. CONCLUSIONS: The results of this investigation indicate that the influence of the two distinct isoforms of ghrelin on BMD is mediated by specific body composition parameters in obese and control healthy children.

Ghrelin, leptin, IGF-1, IGFBP-3, and insulin concentrations at birth: is there a relationship with fetal growth and neonatal anthropometry?

BACKGROUND: Insulin, growth hormone (GH), and growth factors (insulin-like growth factors [IGFs] and their binding proteins [IGFBPs]) are known to influence fetal growth and also the synthesis/secretion of the recently discovered hormones leptin and ghrelin. METHODS: In 153 delivering mothers and their offspring at birth, we prospectively investigated the association between mothers' and babies' serum concentrations of ghrelin, leptin, insulin, IGF-1, and IGFBP-3 and neonatal anthropometric characteristics and the growth of the fetus. We also tried to put babies' serum glucose and GH measurements in this context. RESULTS: Birth weight (BW), birth length, head circumference, and ponderal index (PI) were positively associated with cord IGF-1, IGFBP-3, and leptin and negatively associated with GH. BW was independently associated with maternal stature and prepartum weight, birth length with maternal stature, PI with maternal insulin and prepartum weight, and head circumference with maternal ghrelin. Compared with preterm infants whose development was appropriate for gestational age (AGA), preterm growth-restricted babies displayed alteration in GH-IGF axis (increased GH and low IGF-1 and IGFBP-3 concentrations), low leptin and glucose concentrations, and increased ghrelin concentrations. In large-for-gestational-age (LGA) babies, leptin, IGFBP-3, insulin, and glucose concentrations were significantly higher in asymmetric LGA newborns than in symmetric LGA and AGA newborns. CONCLUSIONS: We found relationships between metabolic factors, fetal growth, and anthropometry. Intrauterine growth restriction involved alteration in the fetal GH-IGF axis, with relatively low leptin and glucose concentrations and increased ghrelin concentrations. Leptin, insulin, and IGFBP-3 delineated subtypes of fetal overgrowth.

Long-term effects of Helicobacter pylori eradication on circulating ghrelin and leptin concentrations and body composition in prepubertal children.

BACKGROUND: Helicobacter pylori, and the chronic gastric inflammation that it causes, may compromise the function and survival of ghrelin-producing cells, resulting in a decrease of circulating ghrelin levels. This finding raises the possibility that the infection might affect growth in children by reducing the ghrelin production. AIMS: To determine baseline circulating levels of ghrelin and leptin in prepubertal children with and without H. pylori infection and to evaluate the long-term effects of H. pylori eradication on circulating levels of ghrelin and leptin as well as on body composition. PATIENTS: Thirty children with H. pylori-associated gastritis, 35 children with H. pylori-negative gastric mucosa, and 20 healthy controls were studied. RESULTS: At baseline, while leptin levels were significantly lower in H. pylori-positive patients, ghrelin concentrations did not differ among the three study groups. However, a significant inverse correlation between ghrelin concentrations and histological severity of gastritis was found. Eradication of the organism was associated with a progressive decrease in ghrelin concentrations over baseline at both 6- and 12-month follow-ups. SDS-body mass index (BMI), lean and fat mass, as well as leptin concentrations, significantly increased over baseline at both follow-ups. CONCLUSIONS: In prepubertal children, serum ghrelin concentrations are inversely related to the severity of H. pylori-associated gastritis. In these youngsters, long-term eradication of H. pylori infection is associated with a significant increase in BMI, lean and fat mass along with a significant decrease in circulating ghrelin levels and an increase in leptin levels.

Nonalcoholic fatty liver disease and carotid atherosclerosis in children.

Nonalcoholic fatty liver disease (NAFLD) is closely associated with several metabolic syndrome features, including obesity, dyslipidemia, insulin resistance, and increased cardiovascular risk. The present study was undertaken to assess whether NAFLD in children is associated with increased carotid artery intima-media thickness (IMT), a marker of early-generalized atherosclerosis. We analyzed carotid IMT along with serum triglycerides, total, low-density lipoprotein and high-density lipoprotein cholesterol, glucose, insulin, insulin resistance index (as homeostasis model assessment of insulin resistance), aminotransferases, leptin, and adiponectin in 29 obese children with NAFLD, 33 obese children without liver involvement, and 30 control children. The diagnosis and severity of NAFLD was based on ultrasound scan, after exclusion of infectious and metabolic disorders. Obese children with NAFLD had significantly increased carotid IMT [mean 0.58 (95% confidence intervals 0.54-0.62 mm)] than obese children without liver involvement [0.49 (0.46-0.52) mm; p = 0.001] and control children [0.40 (0.36-0.43) mm; p < 0.0005]. In a stepwise multiple regression model, after adjusting for age, gender, Tanner stage, and cardiovascular risk factors, the severity of fatty liver was significantly associated with maximum IMT (b = 0.08; p < 0.0005). Our results suggest that NAFLD is strongly associated with carotid atherosclerosis even in childhood.

Effect of proton pump inhibitors and antacid therapy on 13C urea breath tests and stool test for Helicobacter pylori infection.

OBJECTIVE: There is uncertainty about the best method of testing patients for Helicobacter pylori (H. pylori) infection while they are taking proton pump inhibitors. The aim of this study was to determine: (i) if the decreased sensitivity of the urea breath test during proton pump inhibitor is corrected by different techniques for breath testing and (ii) if the sensitivity of stool test is decreased with the administration of proton pump inhibitors. METHODS: Prospective randomized single-blind study was performed in a tertiary care university hospital. Out of 72 H. pylori infected patients endoscoped for upper abdominal symptoms 48 were randomized to proton pump inhibitors (omeprazole 20 mg each day or esomeprazole 40 mg each day) and 24 to antacid (aluminum hydroxide 800 mg each day) for 14 days. Several breath tests (standard 75 mg (13)C-UBT with citric acid, with orange juice, a tablet breath test with 100 and 50 mg of (13)C), and a stool test were carried out. Baseline samples were collected before and after treatment. RESULTS: The baseline sensitivity for all breath tests was 100% in both groups; for stool test it was 97.8% (95% CI: 88.7-96.6) and 90% (95% CI: 69.9-97.2) in the proton pump inhibitor and antacid group, respectively. After treatment, the sensitivity of tests was significantly low (UBTs range: 77.1%-85.4%; stool test: 83%; 95% CI: 63.9-91.1), while it was unchanged in the antacid group. CONCLUSIONS: False negative breath and stool tests are equally common in patients taking proton pump inhibitors. Antacids do not impair the sensitivity of the breath tests or the stool test.

C-reactive protein, interleukin-6, and procalcitonin in the immediate postnatal period: influence of illness severity, risk status, antenatal and perinatal complications, and infection.

BACKGROUND: Studies of the diagnostic accuracy of most laboratory tests for early-onset neonatal sepsis have yielded variable results. We investigated whether some of this variation might be attributable to differences in population baseline severity and risk status as well as to specific ante- and perinatal variables, independent of the presence of neonatal infection. METHODS: The Score for Neonatal Acute Physiology (SNAP) was used to define illness severity, with SNAP Perinatal Extension (SNAP-PE) used to define the combined physiologic and perinatal mortality risk. A total of 134 ill newborns (19 with early-onset infection and 115 with no infection) were available for simultaneous analysis of the association of SNAP, SNAP-PE, and maternal and perinatal variables with C-reactive protein (CRP), interleukin-6 (IL-6), and procalcitonin (PCT) concentrations at birth and at 24 and 48 h of life. RESULTS: Early-onset neonatal infection was associated with significant increases in CRP, IL-6, and PCT concentrations at all three time points, independent of illness severity. However, among babies without infection, higher SNAP and SNAP-PE scores were associated with higher IL-6 concentrations at birth. Certain maternal or perinatal variables altered IL-6 and PCT values in the infected as well as in the uninfected neonates. However, if different cutoff points were used at any of the three neonatal ages, PCT sensitivity and specificity were greater than those of CRP or IL-6. CONCLUSIONS: Illness severity and risk status are unlikely to interfere with the use of CRP and PCT for detection of early-onset neonatal sepsis. In contrast, the diagnostic value of IL-6 at birth may be altered by physiologic severity and risk indexes. The reliability of CRP, IL-6, and PCT for the diagnosis of early-onset neonatal infection requires specific cutoff values for each evaluation time point over the first 48 h of life.

Serological markers for gastric atrophy in asymptomatic patients infected with Helicobacter pylori.

OBJECTIVE: Atrophic gastritis is a precancerous condition that is commonly caused by chronic Helicobacter pylori (H. pylori) infection. This blinded, controlled study was designed to determine if serum gastrin and pepsinogens were reliable markers of atrophy in asymptomatic patients. METHODS: One hundred and forty-seven asymptomatic patients underwent endoscopy with multiple gastric biopsies obtained for histology, culture, and rapid urease test. Fasting serum gastrin (total and G-17) and serum pepsinogens (I-II) were determined by standard immunoassays. Gastric atrophy was histologically assessed in accordance with internationally accepted criteria; three main patterns of gastritis were distinguished: (a) nonatrophic gastritis, (b) atrophic antrum-restricted and antrum-predominant gastritis, and (c) corpus-restricted gastritis. Receiving operating characteristic (ROC) analysis was used to determine the best cut-off for each serum test in nonatrophic gastritis versus antrum-restricted/antrum-predominant atrophic gastritis. RESULTS: No significant differences in serum gastrin and pepsinogens I-II were detected in nonatrophic gastritis versus patients with antrum-restricted/antrum-predominant atrophic gastritis. The positive likelihood ratios for an abnormal serum test to detect antrum-restricted/antrum-predominant atrophy in the gastric body were total serum gastrin 2.13 (95% CI 0.99, 4.6), gastrin-17: 1.55 (95% CI 0.75, 36.17), pepsinogen I: 2.74 (1.4, 5.4), pepsinogen II: 1.74 (1.27, 2.39), and the ratio of pepsinogen I and II: 1.8 (1.2-2.8). Negative likelihood ratios ranged from 0.20 to 0.65. CONCLUSION: In an asymptomatic population, serum gastrin (total and G-17) and pepsinogens I-II (and their ratio) do not discriminate nonatrophic versus antrum-restricted/predominant atrophic gastritis.