A key problem and challenge for hepatology: Obesity-related metabolic liver diseases

With the arrival of the new millennium,gastroenterologists have been faced with the problem of metabolic liver diseases associated with obesity.The active role of the liver in metabolism and inflammation make it a key organ in the war against the rapidly-spreading worldwide epidemic of obesity.Many lives and much money could be saved if the work of hepatologists led to the development of effective diagnostic and therapeutic strategies against this growing leader of cirrhosis.     

Surgical management of post-SCIWORA spinal deformities in children

Background  

Patients with spinal cord injury without radiographic abnormality (SCIWORA) are prone to develop spinal deformities. The purpose of this study is to report on the clinical and radiological features of post-SCIWORA spinal deformities.     

Cyclosporine level at the second hour in pediatric hematopoietic stem cell transplant patients

In this retrospective study, cyclosporine levels at the second hour (C2 levels) were measured during oral cyclosporine intake in 28 pediatric hematopoietic stem cell transplant patients, and the relations between cyclosporine dosage and C0, C2 levels, C2/C0 ratio, and cyclosporine-related adverse effects were investigated. Cyclosporine levels at the second hour levels were found to be significantly lower in children younger than 7 years old, suggesting age-related differences in absorption and metabolism of the drug. There were statistically significant correlations of both C0 and C2 levels with blood creatinine values. In addition, a statistically significant negative relation was found between C0 and C2 levels and serum potassium levels; this unexpected finding was attributed to multiple drug effects in the early posttransplant period. The common adverse effects of cyclosporine (gingival overgrowth, gynecomastia, and hypertrichosis) were also evaluated in this study, and no correlation was found between those adverse effects and C0, C2 levels, C2/C0 ratio, and cyclosporine dosage. In the present study, despite the highly significant correlation of C2 levels with renal and metabolic effects, in pediatric hematopoietic stem cell transplant patients, measurement of C2 levels as a standard practice did not provide an advantage over C0 monitoring. However, the preliminary results suggest that C2 level monitoring could be useful in selected patients with increased risk of renal toxicity or in states where a better estimation of gastrointestinal absorption is needed.     

Increasing Low Birth Weight Rates: Deliveries in a Tertiary Hospital in Istanbul

Objective

Prevalence of low birth weight deliveries may vary across different environments. The necessity of determination of regional data prompted this study.

Methods

Information of all deliveries from January 2004 to December 2008 was obtained from delivery registry records retrospectively. Initial data including birth weight, vital status, sex, maternal age and mode of delivery were recorded using medical files. The frequency of low birth weight, very low birth weight, extremely low birth weight and stillbirth deliveries were determined.

Findings

Among 19,533 total births, there were 450 (23.04 per 1000) stillbirths. Low birth weight rate was 10.61%. A significant increase in yearly distribution of low birth weight deliveries was observed (P<0.001). Very low birth weight and extremely low birth weight delivery rates were 3.14% and 1.58% respectively. Among 2073 low birth weight infants, 333 (16.06%) were stillbirths. The stillbirth delivery rate and the birth of a female infant among low birth weight deliveries were significantly higher than infants with birth weight ≥2500g (P<0.001, OR=28.37), (P<0.001) retrospectively. There was no statistical difference between low birth weight and maternal age. The rate of cesarean section among low birth weight infants was 49.4%.

Conclusion

High low birth weight and stillbirth rates, as well as the increase in low birth weight deliveries over the past five years in this study are striking. For reduction of increased low birth weight rates, appropriate intervention methods should be initiated.     

NOD2/CARD15, NOD1/CARD4, and ICAM-1 gene polymorphisms in Turkish patients with inflammatory bowel disease

Purpose The genetic susceptibility of people with certain NOD2/CARD15, NOD1/CARD4, and ICAM-1 gene variants to inflammatory bowel disease is still under investigation. The aim of this study was to investigate polymorphisms in the NOD2/CARD15 (R702W, G908R, and 3020insC), NOD1/CARD4 (E266K, D372N), and ICAM-1 (G241R, K469E) genes, which are known to be associated with inflammation, in Turkish patients with inflammatory bowel disease and healthy control groups. Methods The genotypes of 70 patients with endoscopically and histopathologically diagnosed Crohn's disease (38 men, 32 women; mean age, 38.8 ± 1.3), 120 patients with ulcerative colitis (67 men, 53 women; mean age, 41.7 ± 1.3) and 106 healthy control subjects (37 men, 69 women; mean age, 35.7 ± 1.4), who stated that they had never had any prior bowel disease history, were compared. A polymerase chain reaction-restriction fragment length polymorphism analysis was performed for two variants of the ICAM-1 gene, the three main variants of the NOD2/CARD15 gene, and the E266K variant of the NOD1/CARD4 gene, and DNA sequencing was used for the D372N polymorphism of the NOD1/CARD4 gene. Results In this study, the three previously described Crohn's disease-predisposing variants of the NOD2/CARD15 gene and the polymorphisms examined in the NOD1/CARD4 and ICAM-1 genes were not found to be associated with ulcerative colitis or Crohn's disease. Conclusions These findings suggest that the polymorphisms observed in the NOD2/CARD15, NOD1/CARD4, and ICAM-1 genes are not genetic susceptibility factors for Crohn's disease or ulcerative colitis in Turkey.     

Evaluation of ectodermal dysplasia

This case series report outlines possible cranio-maxillofacial deformation consequences associated with ectodermal dysplasia (ED) and embryonic malformations, including dental agenesis. Also described are the oral aspects and rehabilitation. A total of 14 ED patients (7 males and 7 females, aged 5-45 years) underwent clinical examination before assessment and treatment. Lateral cephalometric radiography, Steiner's analysis, and respiratory capacity tests were performed. Most of the patients had sparse or absent hair, a short face with an unusual facial concavity, a maxillary retrusion, and a relative mandible protrusion. Depending on age and orthopedic abnormalities, patients were treated with prosthodontic and orthodontic approaches or implant treatment. Therapists should take a comprehensive and multidisciplinary approach with these patients to improve their dental, masticatory, growth, and orthognathic conditions, as well as esthetic appearance.     

The prognostic significance of angiogenesis and the effect of vascular endothelial growth factor on angiogenic process in Wilms' tumour

AIMS: There is a subgroup of patients with Wilms' tumour (WT) having favourable clinicopathological features but adverse outcome. We aimed to investigate the prognostic significance of angiogenesis and whether it can be used for predicting which patients will fall into this category, and the possible role of vascular endothelial growth factor (VEGF) on angiogenesis in WT. METHODS: Tumours in nephrectomy specimens from 63 WT patients were investigated for neovascularisation and VEGF expression by immunohistochemistry. The endothelial cells were highlighted by anti-CD34 and anti-CD31, and the microvessels in the hot-spots were counted. Correlations between the microvessel density (MVD), VEGF expression, clinicopathological features and prognosis were studied. RESULTS: Among 21 patients with follow-up data, favourable histology was detected in 17, seven of which died of disease. Patients with highly vascular tumours showed significantly poorer prognosis than those with low vascular tumours. There was no significant relationship between angiogenesis and VEGF expression. VEGF immunostaining revealed various patterns in different components of WT. CONCLUSIONS: We suggest that high MVD can be used as an indicator of poor prognosis with WT patients displaying favourable histology and there might be some additional growth factors other than VEGF which may also be responsible for angiogenesis in WTs.     

Concomitant inhibition of epidermal growth factor and vascular endothelial growth factor receptor tyrosine kinases reduces growth and metastasis of human salivary adenoid cystic carcinoma in an orthotopic nude mouse model

We hypothesized that epidermal growth factor (EGF) receptor (EGFR) activation and vascular endothelial growth factor (VEGF)-induced angiogenic signals are important for the progression and metastasis of human salivary adenoid cystic carcinoma (ACC). To test this hypothesis, we evaluated the therapeutic effect of AEE788, a dual inhibitor of EGF and VEGF receptor (VEGFR) tyrosine kinases, on human salivary ACC. In clinical specimens of salivary ACC, EGF and VEGF signaling proteins were expressed at markedly higher levels than in adjacent normal glandular tissues. We examined the effects of AEE788 on salivary ACC cell growth and apoptosis and on the phosphorylation of EGFR and VEGFR-2 in salivary ACC cells. Treatment of salivary ACC cells with AEE788, alone or in combination with chemotherapy, led to growth inhibition, induction of apoptosis, and dose-dependent inhibition of EGFR and VEGFR-2 phosphorylation. To determine the in vivo antitumor effects of AEE788, nude mice with orthotopic parotid tumors were randomized to receive oral AEE788 alone, paclitaxel alone, cisplatin alone, a combination of AEE788 plus paclitaxel, a combination of AEE788 plus cisplatin, or a placebo. AEE788 inhibited tumor growth and prevented lung metastasis in nude mice. To study the mechanism of interaction between AEE788 and chemotherapy, AEE788 was found to potentiate growth inhibition and apoptosis of ACC tumor cells mediated by chemotherapy. Tumors of mice treated with AEE788 and AEE788 plus chemotherapy exhibited down-regulation of activated EGFR and VEGFR-2, increased tumor and endothelial cell apoptosis, and decreased microvessel density, which correlated with a decrease in the level of matrix metalloproteinase-9 and matrix metalloproteinase-2 expression and a decrease in the incidence of vascular metastasis. These data show that EGFR and VEGFR can be molecular targets for therapy of salivary ACC.     

Erythrocyte deformability, plasma viscosity and oxidative status in patients with severe obstructive sleep apnea syndrome

BACKGROUND AND PURPOSE: In patients with severe obstructive sleep apnea syndrome (OSAS), diurnal changes of plasma viscosity and erythrocyte deformability were measured to elucidate the possible mechanism of cardiovascular diseases in OSAS patients. PATIENTS AND METHODS: Plasma viscosity and erythrocyte deformability was determined in 11 OSAS patients and 11 healthy subjects matched by sex and age. Plasma viscosity was measured by a cone-plate viscometer, and erythrocyte deformability was determined by filtration technique. Whole blood counts were performed and oxidative status of the patients' plasma and erythrocytes were evaluated. RESULTS: OSAS patients had higher plasma viscosity than controls, both in the morning (1.74+/-0.3 vs. 1.36+/-0.2 mPas, P<0.002) and evening (1.55+/-0.2 vs. 1.27+/-0.1 mPas, P<0.002), and morning plasma viscosity was significantly higher than the evening level (P<0.05). Morning plasma viscosity of patients was inversely correlated with their mean nocturnal SaO(2). Morning plasma malonyldialdehyde level was significantly higher in the patients than in the controls (69.7+/-30.5 vs. 45.5+/-11.0 nmol/l, P<0.005). Erythrocyte deformability of the patients was slightly lower. CONCLUSIONS: We have observed that plasma viscosity is high both in the morning and in the evening in severe OSAS patients. This elevation may predispose OSAS patients to myocardial infarction and stroke by increasing blood viscosity. Low nocturnal mean SaO(2) may be responsible for the high plasma viscosity in these patients.     

Hypoxia and cytokines regulate carbonic anhydrase 9 expression in hepatocellular carcinoma cells in vitro

AIM: To study the expression of carbonic anhydrase (CA) 9 in human hepatocellular carcinoma (HCC) cells.METHODS: We studied CA9 protein, CA9 mRNA and hypoxia-inducible factor-1 alpha (HIF-1α) protein levels in Hep3B cells exposed in different parallel approaches. In one of these approaches, HCC cells were exposed to extreme in vitro hypoxia (24 h 0.1% O₂) without or with interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) stimulation for the same hypoxic exposure time or exposed to normoxic oxygenation conditions without or with cytokine stimulation.RESULTS: The tumour cell line analysed showed a strong hypoxic CA9 mRNA expression pattern in response to prolonged severe hypoxia with cell-line specific patterns and a marked induction of CA9 protein in response to severe hypoxia. These results were paralleled by the results for HIF-1α protein under identical oxygenation conditions with a similar expression tendency to that displayed during the CA9 protein expression experimental series. Continuous stimulation with the cytokines, IL-1, IL-6, TNF-α and TGF-β, under normoxic conditions significantly increased the carbonic anhydrase 9 expression level at both the protein and mRNA level, almost doubling the CA9 mRNA and CA9 and HIF-1α protein expression levels found under hypoxia. The findings from these experiments indicated that hypoxia is a positive regulator of CA9 expression in HCC, and the four signal transduction pathways, IL-1, IL-6, TNF-α and TGF-β, positively influence CA9 expression under both normoxic and hypoxic conditions.CONCLUSION: These findings may potentially be considered in the design of anti- cancer therapeutic approaches involving hypoxia-induced or cytokine stimulatory effects on expression. In addition, they provide evidence of the stimulatory role of the examined cytokine families resulting in an increase in CA9 expression under different oxygenation conditions in human cancer, especially HCC, and on the role of the CA9 gene as a positive disease regulator in human cancer.