Tanju Ozkan

Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization

Arthrogryposis, renal dysfunction and cholestasis syndrome (ARC) is a multisystem disorder associated with abnormalities in polarized liver and kidney cells. Mutations in VPS33B account for most cases of ARC. We identified mutations in VIPAR (also called C14ORF133) in individuals with ARC without VPS33B defects. We show that VIPAR forms a functional complex with VPS33B that interacts with RAB11A. Knockdown of vipar in zebrafish resulted in biliary excretion and E-cadherin defects similar to those in individuals with ARC. Vipar- and Vps33b-deficient mouse inner medullary collecting duct (mIMDC-3) cells expressed membrane proteins abnormally and had structural and functional tight junction defects. Abnormal Ceacam5 expression was due to mis-sorting toward lysosomal degradation, but reduced E-cadherin levels were associated with transcriptional downregulation. The VPS33B-VIPAR complex thus has diverse functions in the pathways regulating apical-basolateral polarity in the liver and kidney.

Leptin concentration in breast milk and its relationship to duration of lactation and hormonal status

BackgroundLeptin, a hormone present in breast milk, is involved in energy regulation and metabolism. The objectives of this study were to assess leptin concentrations in breast milk during the first 180 days postpartum, and to determine the relationship between the concentrations of milk leptin and circulating hormone levels in lactating women.MethodsBetween April 2005 and January 2006, blood and breast milk samples were collected from 160 breastfeeding women enrolled either in the first three days (n = 37; colostrum), days 4–14 (n = 27; transitional milk), days 15–30 (n = 16; early mature milk), days 31–90 (n = 37; mature milk) or days 91–180 (n = 43; late mature milk) postpartum. Milk and serum leptin levels were measured by immunoradiometric assay. Cortisol was measured by radioimmunoassay method. Serum insulin, estradiol, prolactin and thyroxine were measured by chemiluminescent immunometric method.ResultsLeptin concentrations in breast milk were highest (3.28 ± 0.41 ng/ml) in colostrum, decreased during the first 180 days of lactation, showing a significant inverse relation (r = -0.694, p < 0.001) with the days of lactation. Colostrum leptin concentrations correlated with maternal serum leptin (r = 0.425, p < 0.01), cortisol (r = 0.549, p < 0.01) and thyroxine (r = -0.530, p < 0.01). Mature milk leptin concentrations correlated with maternal serum leptin (r = 0.547, p < 0.001), insulin (r = 0.331, p < 0.05) and thyroxine (r = -0.329, p < 0.01). Serum leptin concentrations correlated with serum insulin (r = 0.648, p < 0.001), estradiol (r = 0.639, p < 0.001), prolactin (r = 0.530, p < 0.001) and thyroxine (r = -0.327, p < 0.05) concentrations during days 1–3 postpartum. During 15–180 postpartum days, serum leptin concentrations correlated with serum insulin (r = 0.271, p < 0.01), and thyroxine (r = -0.345, p < 0.001).ConclusionLeptin concentrations in breast milk decrease with time during lactation and show significant relationships with other maternal hormones.

Current therapeutic approaches in childhood chronic hepatitis B infection: A multicenter study

Background and Aim:  The aim of the present study was to compare the therapeutic efficacy of three different regimens in childhood chronic hepatitis B (CHB) infection.

Therapeutic vaccination in the immunotolerant phase of children with chronic hepatitis B infection

Aim. Hepatitis B virus (HBV) infection is a major global health concern and is the most common cause of chronic liver disease worldwide. Our aim was to investigate the efficacy of specific HBV vaccination as active immunotherapy in treating chronic hepatitis B (CHB) infection during the immunotolerant phase of children with normal aminotransferase values and high viral load. Materials and methods. Seventy-four patients never vaccinated before were randomly and prospectively recruited into two groups. Group 1 included 43 patients vaccinated with three standard injections of the GenHevac B vaccine at 30-day intervals. Group 2 contained 31 patients who did not receive any medication or vaccination (control group). Postvaccination serologic and virologic evaluation was performed 6 months after the first injection and at the end of the 12th month. Response to therapy was defined as loss of HBV DNA in serum and hepatitis B e antigen (HBeAg) seroconversion (loss of HBeAg), development of hepatitis B e antibody (anti-HBe). Results. The mean baseline alanine aminotransferase (ALT) value in Group 1 was 33.0 ± 9.6 IU/l, 34.6 ± 13.9 IU/l at 6 months after first injection and 34.3 ± 17.1 IU/l at end of 12 months (P > 0.05). In Group 1 the HBV DNA load at the start of immunization was 3571 ± 1292 pg/ml; this value was 3220 ± 1217 pg/ml at the 6th month and 2931 ± 1292 pg/ml at the 12th month (P > 0.05). In Group 2 the mean ALT values at the beginning of therapy and at the 6th and 12th months were 32.6 ± 7.8, 32.3 ± 8.0 and 30.3 ± 7.3 IU/l, respectively (P > 0.05), and the mean viral load HBV DNA values were 3909 ± 1378, 3546 ± 869 and 3106 ± 718 pg/ml, respectively (P > 0.05). There was no statistically significant difference between Group 1 and Group 2 at the end of the 6th and 12th months in the mean ALT values and mean viral load of HBV DNA (P > 0.05). Except for one patient in each group, hepatitis B surface antigen and HBeAg clearance or hepatitis B surface antibody and anti-HBe seroconversion were not observed during follow-up (P > 0.05). Conclusion. In this multicentered study comparison of vaccinated and unvaccinated groups of immunotolerant children with CHB infection showed no difference in the clearance of HBV DNA or seroconversion from HBeAg to anti-HBe. Different immunization protocols should be considered for future investigations in the immunotolerant phase of children with CHB infection.

Effect of Saccharomyces boulardii in Children with Acute Gastroenteritis and Its Relationship to the Immune Response

We evaluated the effect of Saccharomyces boulardii administration in otherwise healthy children aged between 6 months and 10 years who were admitted for acute diarrhoea (15 males, 12 females). The patients were randomized into two groups: group 1 (n = 16) received 250 mg S. boulardii dissolved in 5 ml of water orally twice daily for 7 days and group 2 (n = 11) received placebo. Clinical and laboratory assessments were performed on admission and on day 7 of follow-up. Both groups experienced reduced daily stool frequency, the decrease being significantly greater in group 1 on days 3 and 4 compared with group 2. Group 1 demonstrated significant increases in serum immunoglobulin A and decreases in C-reactive protein levels on day 7. The percentage of CD8 lymphocytes on day 7 was significantly higher in group 1 than group 2. This study confirmed the efficacy of S. boulardii in paediatric acute gastroenteritis and the findings suggest that S. boulardii treatment enhances the immune response.

Antiviral therapy in neonatal cholestatic cytomegalovirus hepatitis

BackgroundNeonatal hepatitis refers to a heterogeneous group of disorders, caused by many factors including cytomegalovirus infection, revealing similar morphologic changes in the liver of an infant less than 3 months of age. Approximately 40% of cholestasis in infants is due to neonatal hepatitis. It may cause latent or acute cholestatic or chronic hepatitis, including cirrhosis in immunocompetant infant.MethodsTwelve infants diagnosed with neonatal cytomegalovirus hepatitis in the last one year were included in the study. Group 1 consisted of seven babies treated with ganciclovir for 21 days. Group 2 included five cases who did not receive antiviral treatment. Physical examination, biochemical, serologic and virologic tests were done for both groups at the time of diagnosis and in the third month.ResultsInitial levels of total bilirubin, aminotransferases, gamma glutamyl transpeptidase, and alkaline phosphatase revealed a significant decrease after the treatment in Group 1 (p < 0.05) when compared with Group 2. This study revealed that ganciclovir treatment is a safe and effective in cases with cholestatic hepatitis. Similarly, all the patients in the treatment group had evidence of improvement serologically and virologically, while the comparison group did not reveal any significant change(p < 0.01).ConclusionThe clinical spectrum of perinatal infection varies from an asymptomatic infection or a mild disease to a severe systemic involvement, including central nervous system. The treatment in the early period of infection improved serologic markers and cholestatic parameters significantly. Further studies will lead us to clarify the efficacy of ganciclovir treatment in the early period of cytomegalovirus hepatitis, and the preventive role of anti-viral therapy on progressive liver disease due to cholestasis and hepatitis in neonatal cytomegalovirus infection.

Helicobacter pylori Infection in Children: Nutritional Status and Associations with Serum Leptin, Ghrelin, and IGF-1 Levels

Helicobacter pylori is associated with gastrointestinal diseases such as gastritis, peptic ulcers, malignancy and lymphoma, and extra‐gastrointestinal conditions. H. pylori infection is negatively associated with childrens growth. Chronic inflammation of the stomach that results in the loss of appetite and, dysregulation of neuroendocrine hormones such as leptin, and ghrelin are the probable reasons of this negative association. The objective of this study is to determine the serum levels of leptin, ghrelin, and IGF‐1 in H. pylori‐infected children and their relations with growth.

Gliadin-specific IgA antibodies in breast milk

Breast-feeding helps to protect against coeliac disease because of the presence of antigliadin-IgA antibodies (AGA-IgA) in breast milk. The aim of this study was to assess the concentrations of AGA-IgA in breast milk during lactation, and whether these concentrations vary with the socioeconomic status of the women. Samples of serum for determination of IgA albumin and AGA-IgA, and samples of breast-milk for AGA-IgA were collected from 105 healthy mothers (aged 17–36 years). Women were divided into two groups: group 1 were of low and group 2 were of high socioeconomic status. No differences were observed between the study parameters in the two groups. Serum AGA-IgA in both groups was, however, significantly lower than that in colostrum. AGA-IgA concentrations in both groups gradually decreased during 45 days of lactation; the difference between colostrum and the samples taken at days 10 and 30–45 of lactation was significant. The encouragement of sufficient and long-term (e.g. 4–6 months) breast-feeding seems likely to be beneficial in preventing coeliac disease.

Do Liver IL-12 Levels Predict Sustained Response to IFN-α Therapy in Children with Chronic Hepatitis B?

The aim of this study is to investigate the immunoregulatory role of interleukin-12 and interferon-gamma in children with chronic hepatitis B who are treated with interferon-alpha therapy. The patients were divided into 2 groups: Group I included 16 children with naive chronic replicative hepatitis B infection, and Group II included 6 children who are inactive hepatitis B virus (HBV) carriers. Group I received interferon-alpha subcutaneously (10 mU/m(2)/dose), 3 times a week during 4 months. Initial serum alanine aminotransferase (ALT) levels, hepatitis B serologic markers, serum interleukin-12 and interferon-gamma levels were measured. In Group I, laboratory tests were re-evaluated in the second and fourth months. Liver biopsy was performed in all patients and samples were used for tissue interleukin-12 level evaluation and histopathological examination. Hepatic activity index (HAI) and serum interferon-gamma were significantly higher in Group I (P < 0.05). Initial tissue interleukin-12 levels in Group I were low but a significant increase was observed at the fourth month (P < 0.05). While responder patients in Group I had marked elevation of tissue interleukin-12 levels, nonresponders did not reveal considerable changes at the fourth month evaluation. A negative correlation was found between serum HBV-DNA copies and interferon-gamma levels prior to therapy (P < 0.01, r: -0.66). The analysis of cytokine levels with serum transaminases demonstrated a positive correlation between the tissue interleukin-12 levels at the fourth month and serum ALT levels at the beginning and second month of the therapy (r: 0.77, P < 0.05 and r: 0.92, P < 0.05, respectively). This is the first study emphasizing the relationship between tissue cytokine levels and therapy success. Understanding the course of chronic hepatits B in the pediatric population will help us to clarify some debates on the treatment.

Mannose-binding lectin gene polymorphism and chronic hepatitis B infection in children

Background/Aims: Mannose-binding lectin (MBL) is a member of innate immune system that activates complement system through lectin pathway. MBL deficiency is associated with susceptibility to infectious diseases. In this study, the relation between MBL gene polymorphism and chronic hepatitis B infection in children is evaluated. Patients and Methods: The study included 67 children with chronic hepatitis B and 99 healthy controls. The hepatitis B patients were divided into immuntolerant, chronic inactive, and treatment groups according to their laboratory findings. MBL gene codon 52, 54, and 57 polymorphisms were studied with polymerase chain reaction in all patients and controls. The associations of MBL gene polymorphism with clinical, laboratory, and histopathologic findings were evaluated. Results: Homozygous codon 54 polymorphism of MBL was found significantly higher in chronic hepatitis B patients than controls. Rate of the polymorphism was similar in all groups and, responsive and nonresponsive patients in the treatment group. Conclusions: The hepatitis B patients who are homozygous for codon 54 of MBL are prone to develop chronic infection. Longitudinal studies with larger groups are needed.