Epidermal growth factor (EGF) plays a key role in survival of neural and glial precursor cells. The +61A/G polymorphism of the EGF gene is located in the 5'-untranslated region of EGF mRNA and may affect DNA folding or gene transcription, leading to the increase in EGF protein expression. The association between the +61G allele and glioma risk has been widely reported; however, in general the data from published studies with individually low statistical power were controversial and underpowered. We conducted a search in the PubMed database without a language limitation, covering all papers published by the end of October 2010. Overall, 6 case-control studies with 1453 glioma cases and 1947 controls were retrieved based on the search criteria for glioma susceptibility related to the +61A/G polymorphism. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. We found that EGF +61G allele is associated with the low glioma risk in Chinese population [G-allele vs. A-allele, OR = 0.93, 95%CI (0.89-0.97), Pheterogeneity = 0.318, I2 = 0.0], but with the high glioma risk in European population [G-allele vs. A-allele, OR = 1.14, 95%CI (1.04-1.24), Pheterogeneity = 0.310, I2 = 14.6]. In the stratified analysis by source of control, significant association was observed between hospital-based control and glioma risk [homozygote comparison, OR = 1.14, 95%CI (1.02-1.27), Pheterogeneity = 0.179, I2 = 71.8]. In conclusion, EGF +61G allele represents a risk factor for glioma in European population and conversely a protective factor in Chinese population.
Bronchiectasis is one of the common chronic respiratory diseases and associated with respiratory morbidity and mortality. However, neither its prevalence nor its etiology is well-defined. We aimed to estimate the prevalence and risk factors of bronchiectasis in adults. In a retrospective study, we analyzed radiologic findings on chest computed tomography (CT) images performed as part of a health-screening program. From January to December 2008, 1,409 (24.6%) of 5,727 participants in the screening program of a health promotion center at a university hospital underwent chest CT scans based on the subject's decision. Bronchiectasis was diagnosed, if there was abnormal bronchial dilatation in any area of both lungs on chest CT. Respiratory symptoms, smoking status, and past medical history were also analyzed to define clinical characteristics and risk factors of bronchiectasis. Of 1,409 patients (aged 23-86 years), who were screened for respiratory diseases using chest CT for one year in a health promotion center, 129 patients (9.1%) were diagnosed with bronchiectasis. The prevalence of bronchiectasis was higher in females than in males (11.5% vs. 7.9%, p = 0.022) and increased with age. Respiratory symptoms were reported in 53.7% of subjects. Previous history of tuberculosis (TB) (OR 4.61, 95% CI 2.39-8.88, p = 0.001) and age (OR 2.49, 95% CI 1.56-3.98, p = 0.001) were significantly associated with bronchiectasis. This retrospective analysis of chest CT findings in health screening examinees revealed a very high prevalence of bronchiectasis in adults. Previous TB infection is one of the major causes of bronchiectasis.
The activation of K-ras gene and expression of annexin A1 play an important role in colorectal tumorigenesis. We initiated this study to analyze the possible relationship between the annexin A1 expression and the K-ras mutation status in colorectal cancer. K-ras mutations are present in one fourth to one half of colorectal cancers. Annexin A1, a 37-kDa calcium- and phospholipid-binding protein, is over-expressed in colorectal cancers and may be involved in invasive tumor growth and metastasis. Here, we examined twenty paired specimens of colorectal cancer and adjacent normal tissues for K-ras mutations and annexin A1 expression. Sequencing analysis of codons 12 and 13 of K-ras revealed the presence of K-ras mutations in six colorectal cancer tissue specimens (30%). RT-PCR and immunoblotting studies further found that the expression levels of annexin A1 mRNA and protein were increased (2.9-fold and 1.7-fold, respectively) in colorectal cancers harboring K-ras codon 12 or codon 13 mutation compared with adjacent normal tissues (P < 0.05). In colorectal cancer tissues with wild-type K-ras, 12 (85.7%) specimens showed reduced expression of annexin A1 (0.48-fold and 0.81-fold, respectively). No significant association was found between K-ras mutations or annexin A1 over-expression and demographic or other clinicopathological parameters such as gender, differentiation or metastasis. However, a significant and positive correlation was identified between K-ras mutations and annexin A1 over-expression. Our findings indicate that annexin A1 could be implicated in colorectal cancer development and progression and could be of potential use as a predictive marker for guiding targeted therapy for colorectal cancer.
Proinflammatory cytokines, including tumor necrosis factor (TNF)-α, augment the progression of heart failure (HF) that is characterized by sympathoexcitation. In this study, we explored the role of TNF-α in hypothalamic paraventricular nucleus (PVN) in the exaggerated sympathetic activity observed in HF. Heart failure rats were made by ligating the left anterior descending coronary artery. The expression levels of angiotensin type 1 receptor (AT1-R) and neurotransmitters were analyzed in the PVN of HF rats that received direct PVN infusion of a TNF-α blocker (pentoxifylline or etanercept) or vehicle. Sham-operated control (SHAM) or HF rats were treated for 4 weeks through PVN infusion with each TNF-α blocker or vehicle. Rats with HF had higher levels of glutamate, norepinephrine, AT1-R and tyrosine hydroxylase (TH), and lower levels of gamma-aminobutyric acid (GABA), neuronal nitric oxide synthase (nNOS) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN when compared to SHAM rats. Plasma levels of cytokines, norepinephrine and angiotensin II and renal sympathetic nerve activity (RSNA) were increased in HF rats. PVN infusion of pentoxifylline or etanercept attenuated the decreases in PVN GABA, nNOS and GAD67, and the increases in RSNA and PVN glutamate, norepinephrine, TH and AT1-R observed in HF rats. We have developed a novel method for chronic and continuous infusion of drugs directly into the PVN and provided evidence that TNF-α in the PVN modulates neurotransmitters and the expression of AT1 receptor, which could account for exaggerated sympathetic activity in HF.
Oxidative stress is an important pathogenic factor in diabetes. Bilirubin may serve a cytoprotective function as an anti-oxidant. The Gunn rat lacks the enzyme uridine-diphosphate glucuronosyltransferase that is responsible for conjugation of bilirubin, exhibiting elevation of plasma bilirubin. We examined the effect of hyperbilirubinemia on the pancreatic damage caused by streptozotocin (STZ) in the Gunn rat. Male Wistar rats and male Gunn rats were treated with STZ (WS and GS groups, respectively) or vehicle (WC and GC groups, respectively). All 5 rats in the WS group developed diabetes, defined as fasting blood glucose 300 mg/dL or more, at 3 days, whereas only 2 of the 5 GS rats became diabetic at 7 days after STZ injection. Without insulin supplement at 7 days after STZ injection, the WS group displayed higher levels of fasting blood glucose (510.3 ± 50.3 vs. 236.4 ± 42.5 mg/dL, p = 0.003) and HbA1c (5.0 ± 0.1 vs. 3.9 ± 0.1, p = 0.001), compared to those of GS group. In Wistar rats, STZ induced apoptosis of the pancreatic islet cells, accompanied with activation of NADPH oxidase and increased production of reactive oxygen species and nitric oxide, but not in Gunn rats. Moreover, in a rat insulinoma cell line (RIN-m5F), pre-treatment with bilirubin (0.1 mg/dL) decreased cell death and apoptosis caused by STZ, and also reduced H2O2 production. Considering the protective effect of hyperbilirubinemia against STZ-induced injury, we postulate that bilirubin could be a potential therapeutic modality for oxidative stress of pancreas islets.
The combination therapy with hepatitis B immunoglobulin (HBIG) and nucleoside analogue is well tolerated for the hepatitis B recipients after liver transplantation, but its cost is an important problem in these days. Here we report the efficacy of nucleoside analogue therapy following one-year course of HBIG plus nucleoside analogue after living donor liver transplantation (LDLT). Out of 103 LDLTs, we selected 14 recipients who received the post-transplant therapy against reactivation of hepatitis B virus for more than 30 months. Those were eight patients with chronic hepatitis B, three with fulminant hepatitis, and three whose donors were positive for antibody to HB core antigen (HBc). During two days after the operation, HBIG (40,000 units) was administered, and the serum level of antibody to HB surface antigen (HBs) was maintained at around 150 IU/L for one year by monthly administration of HBIG. After one year, HBIG was withdrawn. A nucleoside analogue was administered daily from just after LDLT, and it was continued up to the present. Among the 14 patients, two recipients had recurrence of hepatitis B. Three patients, including one patient with recurrence of hepatitis B, died due to hepatocellular carcinoma or its associated cirrhosis; namely, their deaths are unrelated to hepatitis B-related diseases. The remaining 11 patients are leading normal lives. In conclusion, nucleoside analogue therapy after one-year course of HBIG plus nucleoside analogue is feasible and cost-effective in preventing HBV reactivation. But the patients are still at risk of breakthrough and some patients may need continued prophylaxis with HBIG.
The poor survival and differentiation of the donor cells in the infarcted myocardium has hampered the therapeutic efficacy of cell transplantation. A self-assembling polypeptide RAD16-II (Ac-RARADADARARADADA-CONH2) spontaneously assembles into stable nanofiber scaffolds, which mimic natural extracellular matrix at 0.1-1% peptide concentrations in the myocardium. We isolated mesenchymal stem cells from the bone marrow of adult male rats that express both c-kit and Nkx2.5, a cardiac transcription factor, yielding selected mesenchymal stem cells (SMSCs). We initially confirmed that the self-assembling polypeptide scaffolds are conducive to growth, survival and differentiation of SMSCs in vitro. Subsequently, SMSCs mixed with the self-assembling polypeptide were injected into the infarcted area at 30 min after the establishment of myocardial infarction in female rats. The donor cells were tracked with Y chromosome in the myocardium. The changes of cardiac function, myocardial structure and capillary density were detected at 4 weeks after cell transplantation. The hearts transplanted with SMSCs incorporated into the nanofiber scaffolds showed smaller infarction size (19.55 ± 2.1%) than the hearts injected with SMSCs (27.37 ± 4.8%). Importantly, the systolic function indices, left ventricle ejection fraction and left ventricle fractional shortening, were significantly improved in the animals transplanted with SMSCs mixed with the nanofiber scaffolds (59.31 ± 4.9% and 31.91 ± 8.1%), compared to those with SMSCs alone (48.31 ± 9.2% and 23.58 ± 8.5%). In conclusion, transplantation of SMSCs mixed with the self-assembling polypeptide RAD16-II is more effective to promote myocardial regeneration and attenuate cardiac injury in a rat model of myocardial infarction.
Plasminogen activator inhibitor-1 (PAI-1) is the most effective protease inhibitor in the fibrinolysis system, and plays an important role in the remodeling of the extracellular matrix. We therefore explored whether PAI-1 is involved in the change of lung structure with increasing age. PAI-1 gene knockout mice and wild-type mice were sacrificed at age 3 weeks, 3 months, 6 months and 15 months for histopathology analysis, and assessed the relationship between PAI-1 and the change in lung structure with age. Six-month-old mice were chosen for further studies. Elastin in the lung was detected using Weigert staining. We measured the expression of matrix metalloproteinase-12 (MMP-12) that is a major protease in elastin degradation by real time PCR and immunostaining. Transforming growth factor-β1 (TGF-β1) expression was measured by western blot analysis. PAI-1 gene knockout mice showed significant increases in alveolar size with increasing age and damaged alveolar structure at the age of 15 months, compared with wild-type mice. At the age of 6 months, elastin protein was decreased in the lungs of PAI-1 gene knockout mice. PAI-1 null mice had higher MMP-12 mRNA expression, and lower expression level of active TGF-β1 in the lung. Taken together, these results indicate that the emphysema-like change attributed to PAI-1 deficiency might be facilitated with increased MMP-12 expression that accelerates elastin degradation in mice lungs, and TGF-β1 might be involved in the modulation of this process.
Radiology has attracted the world of art with the esthetic value of its images, and as a new medium for the artistic expression. In order to investigate the links between neuroradiology and art, we examined 12,763 artworks presented in corresponding publications and in Google images on the Internet. The selected artworks were created by 1,964 authors. To give our own contribution to this field, we produced several artful radiological images using the X-ray of 4 cerebral hemispheres, one dissected brain, serial sections of one head and brain, the vascular casts of 2 brains, the magnetic resonance imaging (MRI) scans of one volunteer, and various options in Photoshop. Among the examined artworks, neuroradiological images were used in 129 artworks (1.01%) that were created by 31 artists (1.58%). The artists applied different radiological techniques: X-ray, angiography, computed tomography (CT), multislice CT, MRI, functional MRI, positron emission tomography (PET) or single-photon emission computed tomography (SPECT), either alone or in various combinations. They used the original images, i.e. radiographs or scans, or their electronic modifications in Photoshop or three-dimensional (3D) software. Some artworks presented the skull, yet others the brain, and still others both, either with or without a head image. The neuroradiological artworks were created as paintings, photographs, digital works and sculptures. Their authors were professional artists, designers, amateurs and radiologists. In conclusion, thanks to the esthetics of some radiological images and the valuable creations of certain artists, neuroradiology has become an important field of contemporary art.
Subclinical hypothyroidism (SCH) is defined as an asymptomatic state characterized by normal serum levels of free thyroxine and elevated serum concentrations of thyrotropin (> 4.0 μU/ml). The association between SCH and type 2 diabetes has been well established. Proliferative diabetic retinopathy (PDR) that is characterized by neovascularization is a leading cause of visual loss in adults worldwide. However, whether SCH is related to PDR has not been studied. This study thus aimed to evaluate the relationship between SCH and PDR in type 2 diabetes. A total of 371 type 2 diabetic subjects were enrolled: 187 subjects with PDR and 184 subjects without diabetic retinopathy (with HbA1c above 6.5% and at least 10 years of diabetes duration). Subjects with PDR had higher blood pressure, higher serum levels of total cholesterol, low-density lipoprotein cholesterol and thyrotropin, and higher urinary albumin excretion rate. Of the 371 diabetics, 83 subjects (22.4%) were diagnosed as SCH (male 12.1% and female 29.9%). The prevalence of SCH in the PDR group (51/187, 27.3%) was higher than that in the subjects without diabetic retinopathy (32/184, 17.4%). Logistic regression analysis showed that after adjusting for compounding variables, SCH was independently related with PDR (p = 0.032, adjusted OR = 2.485). These results indicate that type 2 diabetic patients with PDR are at an increased risk of SCH. A routine screening for thyroid function may thus be considered advisable in PDR subjects. This may be helpful in investigating new strategies preventing or treating PDR in clinical practice.
Oculo-auriculo-vertebral spectrum (OAVS) is a common developmental disorder involving first and second pharyngeal arches. Although some family cases and such patients showing chromosomal aberrations suggest that OAVS have a genetic basis, no consistent genetic defects have been recorded at present time. Thus, we conducted genetic studies of a three-generation family with five OAVS patients to identify a causative variant for OAVS. Cytogenetic studies revealed those family members had a normal karyotype and no causative mutations were founded in SALL1 and TCOF1, which known to be responsible for two other syndromes that have clinical overlapping with OAVS. Genotyping with commercially available BeadChips was performed on 13 individuals in the same family, showing no significant difference between the affected and normal members in terms of copy number variations (CNVs) in either number or size and no definitive causative CNV. A total of 8,224 informative autosomal SNPs that are evenly distributed throughout the genome were selected for both parametric and non-parametric linkage analysis. Significant negative LOD scores were obtained for the reported OAVS locus, providing further evidence for genetic heterogeneity of this complex disorder. The highest LOD score of 1.60 was noted on chromosome 15q26.2-q26.3 showing a potential linkage to this locus. The variable phenotypes of the affected members and the failure to identify a causative variant indicate that a complex etiology may be present even in a consanguineous family, which makes it more challenging to ascertain the cause of OAVS in further analysis.
Hepatic fibrosis is characterized by excessive accumulation of extracellular matrix. Matrix metalloproteinases (MMPs) play an important role in the remodeling of the extracellular matrix during hepatic fibrosis. Lipocalin-2 (LCN2) forms complexes with MMP-9 and can be detected in the urine of patients with several types of cancers. The objective of this study was to examine the relationship between urinary LCN2 levels and MMP-9 activity with respect to the stage of liver fibrosis in patients with chronic hepatitis C (CHC), and to assess the utility of urine LCN2 as a non-invasive marker of hepatic fibrosis. Fresh spot urine samples were prospectively collected from forty-two interferon-naive CHC patients who underwent liver biopsy. The stage of hepatic fibrosis was assessed according to the METAVIR fibrosis score; 18 patients had no or mild fibrosis (stages F0 and F1) and 24 patients showed significant fibrosis (stages F2-F4). Immunoblot analyses demonstrated co-migration of urine LCN2 and MMP-9. Gelatin zymography showed that urinary MMP-9/MMP-2 activity ratios were higher in patients with significant fibrosis (F2-F4) than in patients no or mild fibrosis (F0-F1). Urine LCN2 levels which were normalized to urine creatinine concentration (urine LCN2-to-creatinine ratio; ULCR) were higher in F2-F4 patients compared to F0-F1 patients. There was a positive correlation between ULCR and urine MMP-9/MMP-2 activity ratios (r = 0.735). ULCR and AST-to-platelet ratio index were independent predictors of significant fibrosis by multivariate analysis. The present study suggests that urinary LCN2 is a novel marker of hepatic fibrosis by reflecting urine MMP-9 activity in CHC.