bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chapter 4: Pre‐clinical efficacy and complication data required to justify a clinical trial
Authors: Cooper David K. C. , Casu Anna 
Published: September 2009

Abstract:  Pre‐clinical efficacy and complication data required to justify a porcine islet transplantation clinical trial have been considered. To be relevant to clinical islet transplantation, pre‐clinical data should be obtained in a pig‐to‐diabetic non‐human primate (NHP) model. In view of the difficulties of maintaining immunosuppressed NHPs for long periods of time, flexibility must be allowed with regard to the following recommendations. A pre‐clinical trial would be deemed a success if five of eight consecutive experiments in NHPs with proven diabetes meet the following guidelines.1. The fasting and non‐fasting blood glucose levels have been maintained in the NHP at approximately <150 mg/dl (>8.3 mmol/l) and <200 mg/dl (11.1 mmol/l), respectively, throughout a 6‐month follow‐up period (preferably with observations in one or two NHPs extending to 12 months).2. After the transplantation of adult or fetal/neonatal pig islets, no or greatly reduced exogenous insulin has been required after the development of a state of normoglycemia (that may take approximately the first 4 weeks for adult and 12 weeks for fetal/neonatal islets, respectively), except under exceptional, temporary circumstances.3. Sequential intravenous glucose tolerance tests [at 1, 3, 6 (and 12) months post‐transplantation] or arginine stimulation tests have indicated a significant response to glucose in the form of porcine C‐peptide in the absence of a significant response of NHP C‐peptide.4. Histologic study of the native pancreas (if present) after necropsy indicates no or minimal insulin‐positive β cells, and histologic examination of the liver or other site of islet transplantation indicates multiple viable insulin‐positive cells.5. Numerous or serious life‐threatening complications have not been associated with the transplantation procedure, immunosuppressive regimen, tolerance‐inducing regimen, or encapsulation of the islets.Pre‐clinical trials in which the recipient NHPs do not require continuing immunosuppressive therapy (e.g., when encapsulated islets have been transplanted) may possibly be considered acceptable as a basis for a clinical trial with slightly less stringent requirements with regard to points (1) and (2), but would be expected to provide evidence that points (3), (4), and (5) had been achieved.Table of Contents

Introduction
Induction of diabetes in the non‐human primate potential recipient
Porcine islet transplantation
Immunotherapeutic protocol
Determination of success of islet transplantation
Conclusions
Structural and Histochemical Studies on the Teleostean Bulbus Arteriosus
Authors: Leknes I. L. 
Published: September 2009

SummaryThe structure and histochemical properties of the bulbus arteriosus in two species from an evolutionary old teleost family, Characidae, and in three modern teleosts, family Cichlidae, are described. The bulbar wall was composed of an outer layer, a middle layer and a strongly folded inner layer covered by a thick, granule‐rich endothelial cell layer towards the lumen. One of the cichlid species (Thorichthys meeki) was injected intraperitoneally with horse ferritin; the endothelial cell layer of the heart atrium and ventricle displayed high ability to endocytose ferritin particles from the blood stream, but the corresponding layer in the bulbus arteriosus displayed no such uptake. This finding suggests that the bulbar endothelial cell layer plays no scavenger or immunological blood cleansing roles in this species. The bulbar endothelial cell granules were strongly coloured by periodic acid–Schiff (PAS) in the present cichlids, but weakly coloured by PAS in the present characids. These cell layers were uncoloured by alkaline carmine in ethanol in both cichlids and characids. The negative carmine test combined with a positive PAS test for the bulbar endothelial cell layer in the present cichlids indicates that these cells contain only small amounts of polysaccharides. The weak PAS‐colouring for the bulbar endothelial cell layer in characids indicates a very low content of sugars in these cells. These findings together with the fact that this cell layer in the present cichlids and characids was nearly uncoloured when treated with orcein, Heidenhain’s Azan or Schmorl’s solutions for elastic materials suggest that the bulbar endothelial granules do not play any role in the blood cleansing or in the rebuilding or maintenance of the ground substance or elastic material in the bulbar wall. Probably, the granules in the bulbar endothelial cell layer in the present species contain mainly proteins, connected to some PAS‐positive polysaccharides to enhance their solubility.
Initiation of Steroidogenesis Precedes Expression of Cholesterologenic Enzymes in the Fetal Mouse Testes
Authors: Büdefeld T. , Jezek D. , Rozman D. , Majdic G. 
Published: September 2009

SummarySexual differentiation is a carefully regulated process that ultimately results in a development of the male or female phenotype. Proper development of the male phenotype is dependent upon the action of testosterone and anti‐mullerian hormone. Leydig cells start to produce testosterone around day 12.5 in the fetal mouse testis, and continue to produce high levels of this hormone throughout gestation. In the present study, we examined whether expression of lanosterol 14α‐demethylase (cyp51) and cytochrome P450 NADPH reductase, both involved in the cholesterol production, occurs simultaneously with proteins required for the production of steroid hormones. Immunocytochemical staining with the antibodies against cyp51, cytochrome P450 NADPH reductase, steroidogenic acute regulatory protein (StAR) and 3beta‐hydroxysteroid dehydrogenase I (3β‐HSD I) was used to determine the ontogeny of expression of these four proteins. As expected, 3β‐HSD I and StAR proteins were detected on day 12.5 p.c., while expression of cyp51 and NADPH cytochrome P450 reductase appeared 1 day later, on day 13.5. Thereafter, the expression of all four proteins remained strong throughout gestation. Results of this study suggest that initial steps of steroid hormone production in murine Leydig cells are mostly dependent on exogenously derived cholesterol, while from day 13.5 onwards, mouse Leydig cells are able to synthesize cholesterol and are therefore not dependent on exogenous cholesterol resources.
Anatomicohistological Characteristics of the Female Genital Organs of the White‐lipped Peccary (Tayassu pecari) in the Peruvian Amazon
Authors: Mayor P. , Bodmer R. E. , Schettini L. , Mariño G. O. , López‐Béjar M. 
Published: September 2009

SummaryThis study examined the anatomical and histological characteristics of the genital organs of the female white‐lipped peccary in the wild in different reproductive stages, collected by rural hunters in the North‐eastern Peruvian Amazon. Mean ovulation rate was 2.12 ± 0.83 follicles and litter size was 1.78 ± 0.41 embryos or fetuses per pregnant female, resulting in a low rate of reproductive wastage, averaging 0.33 ± 0.66 (16.04%) oocytes or embryos per pregnancy. The ovulation rate and the anatomical performance of the uterus could limit the prolificacy of this species. Females in follicular phase showed follicular waves suggesting the synchronous growth of a cohort of follicles. Different uterine and vaginal epithelium features changed in accordance with the reproductive state of the female. Pregnant females and females in the luteal phase presented a significant proliferation of endometrial uterine glands, characterized by hyperplasia and branching of endometrial glands, and increase in the proportion of cervical epithelial cells with periodic acid‐schiff (PAS)‐positive granules compared with that in females in the follicular phase. Females in the follicular phase showed a more developed vaginal epithelium (in thickness and in layer composition) than females in the luteal phase and pregnant females.
7‐difluoromethyl‐5,4′‐dimethoxygenistein, a novel agent protecting against vascular endothelial injury caused by oxidative stress
Authors: Wang Li , Zheng Xing , Xiang Hong‐Lin , Fu Xiao‐Hua , Cao Jian‐Guo 
Published: September 2009

Summary1. Genistein is known to protect the vascular endothelium. However, genistein exhibits poor bioavailability, which limits its use in the treatment of cardiovascular diseases. 7‐Difluoromethyl‐5,4′‐dimethoxygenistein (dFMGEN), prepared by the difluoromethylation and alkylation of genistein, is a new active chemical entity. The protective effects of dFMGEN against vascular endothelial injury caused by oxidative stress were investigated in the present study.2. Human umbilical vein endothelial cells were treated with either genistein (10 μmol/L) or various concentrations of dFMGEN (0.1, 0.3, 1, 3 and 10 μmol/L) for 30 min before exposure to 1 mmol/L H2O2 for 24 h. The generation of reactive oxygen species (ROS) was assessed by fluorescence flow cytometry, the release of lactate dehydrogenase (LDH) was examined by biochemical assay, cell viability was measured by the 3‐(4,5‐dimethyl‐2 thiazoyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide assay, cell apoptosis was detected by flow cytometry and the expression of caspase 3 was examined by western blot analysis.3. Pretreatment with 0.1, 0.3, 1, 3 and 10 μmol/L dFMGEN decreased the generation of ROS and the release of LDH in H2O2‐exposed vascular endothelial cells, enhanced cell viability in a concentration‐dependent manner over the concentration range 0.1–10 μmol/L, suppressed H2O2‐induced apoptosis of vascular endothelial cells and downregulated the expression of caspase 3. The protective effect of 10 μmol/L dFMGEN against oxidative stress‐induced endothelial injury was stronger than that of 10 μmol/L genistein.4. The results of the present study suggest that dFMGEN can protect against vascular endothelial injury caused by oxidative stress.
Association of exon 9 but not intron 8 VDR polymorphisms with occult HBV infection in south‐eastern Iranian patients
Authors: Arababadi Mohammad Kazemi , Pourfathollah Ali Akbar , Jafarzadeh Abdollah , Hassanshahi Gholamhossein , Rezvani Mohammad Ebrahim 
Published: September 2009

AbstractBackground and Aim:  Occult hepatitis B infection (OBI) is characterized as a form of hepatitis in which, despite the absence of detectable hepatitis B surface antigen (HBsAg), hepatitis B virus DNA (HBV–DNA) is present in a patient's peripheral blood. Investigators believe that divergent genetics and immunological parameters vary between resistant individuals and patients with OBI. Vitamin D3 and its known receptor appear to be involved in antiviral immune responses. Therefore, because OBI is a form of viral infection, the aim of this study was to investigate the association between polymorphisms in intron 8 and exon 9 of the vitamin D receptor (VDR) with OBI.Methods:  In this experimental study, the plasma samples of 3700 blood donors were collected and tested for HBsAg and anti‐HBs using ELISA. The HBsAg–/anti‐HBc+ samples were selected and screened for HBV–DNA using polymerase chain reaction (PCR). HBV–DNA‐positive samples assigned as OBI cases and PCR–restricted fragment length polymorphism.Results:  The results of the current study demonstrated that 352 (9.5%) of 3700 blood samples were HbsAg‐/anti‐HBc+. HBV–DNA was detected in 57/352 (16.1%) of HBsAg–/anti‐HBc+ samples. Our results showed a significant difference in the T/T allele of exon 9 of VDR, but any differences were also observed in the other examined alleles.Conclusion:  The polymorphisms in the T/T allele of exon 9 of VDR is possibly associated with OBI, thus it can be concluded that VDR and its functional polymorphisms are likely to be related to sensitivity and resistance of the immune system to HBV in OBI patients.
Usefulness of non‐invasive markers for predicting liver cirrhosis in patients with chronic hepatitis B
Authors: Lee Kwang Gyun , Seo Yeon Seok , An Hyonggin , Um Soon Ho , Jung Eun Suk , Keum Bora , Yim Hyung Joon , Jeen Yoon Tae , Chun Hoon Jai , Kim Chang Duck , Ryu Ho Sang 
Published: September 2009

AbstractBackground and Aim:  Recently, various non‐invasive blood markers and indices have been studied to overcome the limitations of liver biopsy, such as its invasiveness and sampling errors. However, the majority of these studies have focused on patients with chronic hepatitis C. Accordingly, this study was performed to evaluate the significances of various non‐invasive serum markers in terms of predicting the presence of liver cirrhosis in chronic hepatitis B.Methods:  We included 125 chronic hepatitis B patients who had undergone liver biopsy. Fibrosis stage was assessed using the METAVIR scoring system (F0–F4), which defines liver cirrhosis as F4. In addition, we measured various blood markers at times of liver biopsy.Results:  Thirty four of the 125 patients (27.2%) were rated as F4 by liver biopsy. Age, platelet, white blood cells, aspartate aminotransferase (AST), alanine aminotransferase, haptoglobin, apolipoprotein‐A1 (Apo‐A1), collagen‐IV, hyaluronic acid, α2‐macroglobulin, matrix metalloproteinase‐2, and YKL‐40 were significantly different between patients with chronic hepatitis and those with liver cirrhosis. However, multivariate analysis showed that only platelet, AST, haptoglobin, and Apo‐A1 independently predicted the presence of liver cirrhosis. Having identified these four factors, we devised a system, which we refer to as platelet count, AST, haptoglobin, and Apo‐A1 (PAHA). The area under the receiver‐operating characteristics (AUROC) of PAHA indices for the presence of liver cirrhosis was 0.924 (95% confidence interval, 0.877–0.971), which was significantly greater than the AUROC of other indices of fibrosis.Conclusion:  The devised PAHA system was found to be useful for predicting the presence of liver cirrhosis in patients with chronic hepatitis B.
Chronic pancreatitis in Chinese children: Etiology, clinical presentation and imaging diagnosis
Authors: Wang Wei , Liao Zhuan , Li Zhao‐Shen , Shi Xin‐Gang , Wang Luo‐Wei , Liu Feng , Wu Ren‐Pei , Zheng Jian‐Ming 
Published: September 2009

AbstractBackground and Aims:  There is a paucity of literature regarding the clinical profile of chronic pancreatitis (CP) in children. The aims of this retrospective study were to determine the etiology and clinical presentation, and to present our experience in diagnosing CP in children in China.Methods:  Clinical data of children who were treated for CP at Changhai Hospital from January 1997 to August 2006 were reviewed.Results:  A total of 427 CP patients presented to our center. There were 42 (9.8%) children with CP, including 21 males and 21 females, with a mean age of 11.7 years at the first onset. The main etiological factor was idiopathic (73.8%). Of the patients, 78.5% had episodes of mild to moderate abdominal pain and 54.8% had multiple (≥ 4) episodes. The mean duration of symptoms prior to the diagnosis was 41.6 months and a definite diagnosis was not made until 2 years later in 57.1% of these patients. The positive rates of ultrasound (US), computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) (or magnetic resonance imaging [MRI]) for detecting ductal changes and intraductal stones or pancreatic calcification were 51.4% and 45.4%, 71.4% and 87.5%, 80.0% and 61.5%, respectively.Conclusion:  The main etiological factor of Chinese children with CP is idiopathic. The main symptom in these patients is multiple episodes of mild to moderate abdominal pain, which often lead to a delay in the definite diagnosis. CT and MRCP (or MRI) should be used as the first investigation in the evaluation of these cases.
MicroRNA‐224 is upregulated in HepG2 cells and involved in cellular migration and invasion
Authors: Li Qiong , Wang Ge , Shan Jin‐Lu , Yang Zhi‐Xiang , Wang Hong‐Zhong , Feng Jin , Zhen Ji‐Jun , Chen Chuan , Zhang Zhi‐Min , Xu Wen , Luo Xi‐Zhong , Wang Dong 
Published: September 2009

AbstractBackground and Aim:  MicroRNAs are a class of small non‐coding RNAs that negatively regulate the expression of their target genes. The aim of the present study was to explore the effects of microRNA on biological behaviors of HepG2 cells and further analyze its characteristics.Methods:  We detected different expression profiles of miRNAs in HepG2 and L02 cell lines by microRNA microarray. Northern blot, quantitative real‐time polymerase chain reaction, methylthiazolyl tetrazolium, fluorescence‐activated cell sorting, scratch wound, transwell migration and Matrigel invasion assays and western blot were carried out to determine whether or not microRNA‐224 (miR‐224) can influence the biological behaviors of HepG2 cells.Results:  MiR‐224 was significantly upregulated in HepG2 cells. Cell proliferation, migration and invasion, but not cell cycles, were altered after changing the expression of miR‐224. Taking invasion and migration as a breakthrough, a close relationship between the expression of miR‐224 and its proteins such as PAK4 and MMP9, which were involved in the invasion of tumor, was found.Conclusions:  Overexpression of miR‐224 was involved in the malignant phenotype of HepG2 cells, and it may be an important factor in regulating the migration and invasion of HepG2 cells.
Short‐term celecoxib to regress long‐term persistent gastric intestinal metaplasia after Helicobacter pylori eradication
Authors: Hung Kuei‐Hsiang , Yang Hsiao‐Bai , Cheng Hsiu‐Chi , Wu Jiunn‐Jong , Sheu Bor‐Shyang 
Published: September 2009

AbstractBackground and Aim:  The intestinal metaplasia (IM) has overexpressions of cyclooxygenase‐2 (COX‐2) and β‐catenin. This pilot study assessed whether celecoxib, a selective COX‐2 inhibitor, could regress IM that persisted long term after Helicobacter pylori eradication.Methods:  Thirty‐three patients with H. pylori eradication were enrolled in the present study due to the persistence of IM after a 3‐year follow up. These patients received celecoxib 200 mg/day for 8 weeks, and were serially checked for levels of blood urea nitrogen and creatinine once per 2 weeks. After 8‐week celecoxib treatment, IM regression was assessed by panendoscopy. The gastric specimens, taken before and after celecoxib, were immunochemically stained for COX‐2 and β‐catenin.Results:  The intention‐to‐treat and per‐protocol analyses to the rates of IM regression by 8‐week celecoxib treatment were 24.2% (8/33) and 28.6% (8/28), respectively. All enrolled patients had no renal impairment. Even in the patients without total IM regression, mean IM scores in the antrum decreased after 8‐week celecoxib treatment (P = 0.007). The patients with complete regression of IM after 8‐week celecoxib treatment had a significantly lower COX‐2 expression, but not β‐catenin expression, at enrollment than those patients without IM regression (P = 0.031).Conclusion:  Short‐term celecoxib treatment can be safe and promising to regress long‐term persistent IM after H. pylori eradication.
Interstitial cells of Cajal are present in human extrahepatic bile ducts
Authors: Ahmadi Omid , De L Nicholson Martha , Gould Maree L , Mitchell Allan , Stringer Mark D 
Published: September 2009

AbstractBackground and Aims:  Interstitial cells of Cajal (ICC) are distributed with smooth muscle throughout the gastrointestinal tract and are involved in regulating motility. ICC were recently discovered in the wall of the human gallbladder. This study sought to determine whether ICC are present in human bile ducts.Methods:  Biliary tract samples were obtained from several sources: surgical specimens (n = 16, 11 women, mean age 61 years); archival post‐mortem specimen (n = 1, 86 years, man); and cadavers (n = 2, 68 and 80 years, men). Paraffin‐embedded sections (3 µm) from the gallbladder (fundus, body and neck) and both extrahepatic and intrahepatic bile ducts were investigated. A double immunofluorescence protocol using polyclonal and monoclonal c‐kit antibodies and mast cell tryptase was used to distinguish c‐kit‐positive cells with typical ICC morphology from c‐kit‐positive mast cells. Small bowel samples were used as positive controls. ICC in the gallbladder were confirmed by ultrastructural study.Results:  c‐kit‐positive cells with characteristic ICC morphology were identified in the subepithelial and muscular layers of the gallbladder and extrahepatic bile ducts. They were most prominent within the muscle layer of the extrahepatic bile ducts where they were organized into loosely arranged laminae running parallel to circular smooth muscle fibers. ICC were not found in intrahepatic bile ducts.Conclusion:  This study demonstrates for the first time that ICC are present in human extrahepatic bile ducts where they are more densely aggregated than in the gallbladder. This cellular network is likely to be involved in biliary tract motility and its related disorders.
Compound Astragalus and Salvia miltiorrhiza extract inhibits cell invasion by modulating transforming growth factor‐β/Smad in HepG2 cell
Authors: Liu Xin , Yang Yan , Zhang Xiaoxiang , Xu Shengxin , He Shufang , Huang Weijuan , Roberts Michael S 
Published: September 2009

AbstractBackground and Aims:  Compound Astragalus and Salvia miltiorrhiza extract (CASE) is made up of astragalosides, astragalus polysaccharide and salvianolic acids extracted from Astragalus membranaceus Bunge (Leguminosae) and Salvia miltiorhiza Bunge (Lamiaceae) with a standard ratio. Previous reports showed that CASE inhibited hepatic fibrosis by mediating transforming growth factor (TGF)‐β/Smad signaling. This study further investigated the effect of CASE on hepatoma HepG2 cells stimulated by TGF‐β1 and its potential action mechanisms by TGF‐β/Smad signaling.Methods:  Cell proliferation was studied by MTT assay and cell invasion was evaluated by measuring cell migration through Matrigel. Protein expression in hepatoma HepG2 cells stimulated by TGF‐β1 was analyzed by western blotting and plasminogen activator inhibitor type 1 (PAI‐1) transcriptional activity in HepG2 cells was evaluated.Results:  CASE (40 µg/mL) markedly suppressed cell invasion triggered by TGF‐β1. Smad3 phosphorylation at the linker region (pSmad3L) and Samd2 phosphorylation at the C‐terminal region (pSmad2C) were significantly reduced by CASE. Mild elevated Smad3 phosphorylation at C‐terminal (pSmade3C) region was enhanced by CASE at 20 µg/mL. In addition, treatment of CASE decreased the level of Smad2/3/4 complex at 80 µg/mL, but upregulated the expression of Smad7 in a dose‐dependent manner. CASE also showed inhibitory effect on PAI‐1 transcriptional activity.Conclusion:  All these results suggest that CASE exerts anti‐HepG2 cell invasion effect by modulating TGF‐β/Smad signaling.
Oral health status in epileptic children
Authors: Gurbuz Taskin , Tan Huseyin 
Published: September 2009

AbstractBackground:  The aim of the present study was to evaluate the oral hygiene status and dental treatment requirements in children with epilepsy.Methods:  The treatment group consisted of 211 children with epilepsy (120 boys and 91 girls, 4–15 years old, mean age 7.85 ± 2.98 years). The control group consisted of healthy children, matched by age and gender. Clinical features of the patients were obtained from hospital records. Clinical examinations were conducted, under standard light, using a plane buccal mirror, a dental probe and air drying to evaluate caries experience and to record the periodontal health of each child. Statistical analysis was performed using χ2 test, Fisher exact test and anova.Results:  The number of decayed and missing teeth, the degree of abrasion and periodontal indexes were significantly worse in patients with epilepsy, compared to the control group (P < 0.001). Gingival enlargement was documented in 42% of patients on valproate monotherapy compared to only in 16% of patients on phenobarbital. Dental caries and halitosis were the most common oral disorders. Generalized tonic–clonic seizures often cause minor oral injuries and traumatized anterior teeth.Conclusions:  Epileptic children are at an increased risk of developing caries and gingivitis compared with healthy subjects.