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Background: The distinction between definitive nonalcoholic steatohepatitis (NASH) and other histological patterns of nonalcoholic fatty liver disease (NAFLD) continues to rely on liver biopsy, which has risks and limitations., Objectives: We explored the usefulness of a Bayesian approach to establish the likelihood ratios (LRs) of different noninvasive diagnostic modalities (circulating cytokeratin-18 fragment levels, hydrogen breath test, transient elastography) for distinguishing definitive NASH from other forms of NAFLD., Patients and Methods: From a series of 235 consecutive patients with biopsy-proven NAFLD enrolled at a tertiary referral hepatology clinic, we identified 135 patients with definitive NASH and 100 with other forms of NAFLD. Bayesian probabilities in the form of LRs were estimated for predicting definitive NASH., Results: In conditional logistic regression models, the probability of having definitive NASH was associated with diabetes mellitus [odds ratio (OR) 2.89; 95% confidence interval (CI) 1.71-4.85], positive transient elastography results (OR 2.11; 95% CI 1.08-4.09), and apoptosis marker M30 (OR 2.57; 95% CI 1.78-3.93). We then estimated the LRs for variables independently related to definitive NASH, which were as follows: diabetes(+) LR=2.42; M30(+) LR=2.12; and transient elastography(+) LR=1.77. On the basis of the LR form of Bayes' theorem, the prediction model that took into account diabetes, M30 measurements, and the results of transient elastography at a tertiary hospital determined an 81% probability of distinguishing definitive NASH from other forms of NAFLD., Conclusion: A Bayesian approach combining clinical, laboratory, and imaging data may be useful for identifying patients with the highest probability of having definitive NASH.

Congenital adrenal hyperplasia (CAH) is a group of genetic endocrine disorders, caused by enzyme deficiencies in the conversion of cholesterol to cortisol. More than 90% of the cases have 21-hydroxylase deficiency (21-OHD). The clinical phenotype of the disease is classified as classic, the severe form, and nonclassic, the mild form. In this study, it was planned to characterize the mutations that cause 21-OHD in Turkish CAH patients by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis and to investigate the type of CAH (classic or nonclassic type) that these mutations cause. A total of 124 CAH patients with 21-OHD and 100 healthy volunteers were recruited to the study. Most of the mutations were detected by direct sequencing. Large gene deletions/duplications/conversions were investigated with MLPA analysis. Results were evaluated statistically. At the end of our study, 66 different variations were detected including SNPs and deletions/duplications/conversions. Of these variations, 18 are novel, of which three cause amino acid substitutions. In addition, 15 SNPs which cause amino acid changes were identified among these variations. If similar results are obtained in different populations, these mutations, in particular the novel mutation 711 G>A, may be used as markers for prenatal diagnosis., (© 2014 John Wiley & Sons Ltd/University College London.)

Background: Noninvasive markers that purport to distinguish patients with non-alcoholic fatty liver disease (NAFLD) with fibrosis from those without must be evaluated rigorously for their classification accuracy. Herein, we seek to compare the diagnostic performances of three different noninvasive methods (FibroMeter™ NAFLD score, NAFLD Fibrosis score (NFSA), and Transient Elastrography [TE]) for the detection of liver fibrosis in NAFLD patients., Methods: A total of 88 patients with biopsy-proven NAFLD were included. The Kleiner system was used for grading fibrosis in liver biopsies. The FibroMeter™ NAFLD score was determined using a proprietary algorithm (regression score). The NFSA score was calculated based on age, hyperglycemia, body mass index, platelets, albumin and serum aminotransferase levels. TE was performed using the Fibroscan apparatus., Results: The sensitivities/specificities for the FibroMeter™ NAFLD score, NFSA, and TE for the diagnosis of significant fibrosis (F2 + F3 + F4 fibrosis) were 38.6%/86.4%, 52.3%/88.6%, and 75.0%/93.2%, respectively. The areas under the receiver operating characteristic curves of TE were significantly higher than those of both the FibroMeter™ NAFLD score and NFSA. No significant differences were found between the FibroMeter™ NAFLD score and NFSA for the detection of significant and severe fibrosis, although the diagnostic performance of the FibroMeter™ NAFLD score was higher than that of the NFSA score for cirrhosis., Conclusions: In summary, TE showed the best diagnostic performance for the noninvasive assessment of liver fibrosis in NAFLD patients. The diagnostic performances of the FibroMeter™ NAFLD score and NFSA did not differ significantly for the detection of both significant and severe fibrosis.

Unlabelled: Nasal deformities affecting the bone and lower two-thirds of the nose due to the loss of septal height and tip support are defined as "saddle-nose" deformity. Reconstruction of a saddle-nose deformity essentially necessitates structural grafting. This article presents an alternative approach for correction of saddle-nose deformity using a microplate and costal cartilage. The results are compared with those of the previously applied costal cartilage repair methods. Between 2004 and 2013, 16 patients were treated with costal cartilage autografts. Of these 16 patients, 7 were treated with a microplate and costal cartilage autograft combination, 4 were treated with a costal cartilage autograft and Kirschner (K)-wire, and 5 were treated with onlay costal cartilage grafts. The mean follow-up periods were 16 months for group treated with microplate-adapted autologous costal cartilage, 12 months for the group treated with K-wire and autologous costal cartilage, and 16 months for the group treated with onlay costal cartilage. The patients treated with K-wire inserted cartilages and the patients treated onlay dorsal costal cartilages encountered complications such as extrusion of the wire and warping, respectively. The seven patients treated with microplate and dorsal onlay costal cartilage graft did not experience any infection, warping, or extrusion complication. The warping tendency of the costal cartilage autograft can be efficiently prevented without a prominent complication risk by using microplate-adapted costal cartilage grafts., Level of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

This paper presents an unusual case of frostbite injury to the breast area caused by faulty cryotherapy application. Cryotherapy, commonly used by patients and health professionals, relieves pain and edema after trauma and sports injuries. However, applying cold therapy is not common for surgical procedures involving soft tissue. The frostbite injury to the breast presented here occurred due to persistent use of a self-prepared ice pack following a needle aspiration biopsy. Cold exposure to soft tissue may cause frostbite. It is crucial to inform patients about proper application of cryotherapy and possible complications, particularly for the procedures in which cold therapy is not widely used.

Angiogenesis has been known to increase tumor growth and for its metastatic potential in human tumors. Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis and is a promising therapeutic target for breast cancer. VEGF is an essential target for RNAi-based gene therapy of breast cancer. Interleukin-4 (IL-4) may act as an anti-angiogenic molecule that inhibits tumor growth and migration in rats. The purpose of the present study was to improve therapeutic efficacy in breast cancer with the codelivery of siRNA-expressing plasmid targeting VEGF and IL-4-expressing plasmid encapsulating into chitosan nanoparticles (NPs). The codelivery of psiVEGF and pIL-4 plasmids greatly enhanced in vitro and in vivo gene-silencing efficiency. For the in vitro study, when psiVEGF and pIL-4 into chitosan NPs were combined (81%), the gene-silencing effect was higher than psiVEGF and pIL-4 NPs alone. The in vivo study breast tumor model demonstrated that the administration of coencapsulation of psiVEGF and pIL-4 into chitosan NPs caused an additive effect on breast tumor growth inhibition (97%), compared with containing NPs psiVEGF or pIL-4 alone. These results indicate that chitosan NPs can be effectively used for the codelivery of pIL-4 and siVEGF-expressing plasmid in a combination therapy against breast cancer., (© 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Introduction: Trichilemmal cysts (TCs) are common skin lesions that occur in hairy areas. A TC involving a fingertip has not been previously described in the literature. We herein report a case of a TC occupying a fingertip region., Case Presentation: A 43-year-old woman presented with a 1.5 × 1.5 cm nodular lesion on the third fingertip. The lesion was completely excised, and histopathological examination revealed a TC., Conclusion: TCs may involve atypical locations, such as fingertips, where there are no hair follicles. After surgical excision, a careful histopathological examination should be performed to differentiate TCs from proliferating pilar tumors.

Cardiovascular risk factors and atherosclerosis precursors were examined in 365 Turkish children and adolescents. Study participants were recruited at five different state schools. We tested single and multi-locus effects of six polymorphisms from five candidate genes, chosen based on prior known association with lipid levels in adults, for association with low (≤10th percentile) high density lipoprotein cholesterol (HDL-C) and high (≥90th percentile) triglycerides (TG), and the related continuous outcomes. We observed an association between CETP variant rs708272 and low HDL-C (allelic p=0.020, genotypic p=0.046), which was supported by an independent analysis, PRAT (PRAT control p=0.027). Sex-stratified logistic regression analysis showed that the B2 allele of rs708272 decreased odds of being in the lower tenth percentile of HDL-C measurements (OR=0.36, p=0.02) in girls; this direction of effect was also seen in boys but was not significant (OR=0.64, p=0.21). Logistic regression analysis also revealed that the T allele of rs6257 (SHBG) decreased odds of being in the top tenth percentile of TG measurements in boys (OR=0.43, p=0.03). Analysis of lipid levels as a continuous trait revealed a significant association between rs708272 (CETP) and LDL-C levels in males (p=0.02) with the B2B2 genotype group having the lowest mean LDL-C; the same direction of effect was also seen in females (p=0.05). An effect was also seen between rs708272 and HDL-C levels in girls (p=0.01), with the B2B2 genotype having the highest mean HDL-C levels. Multi-locus analysis, using quantitative multifactor dimensionality reduction (qMDR) identified the previously mentioned CETP variant as the best single locus model, and overall model, for predicting HDL-C levels in children. This study provides evidence for association between CETP and low HDL-C phenotype in children, but the results appear to be weaker in children than previous results in adults and may also be subject to gender effects.

Background: Staging systems have considerable impact on hepatocellular carcinoma (HCC) treatment approaches and outcomes. There is an unmet need to improve their stratification ability. We have evaluated four commonly used staging systems and assessed whether angiogenic biomarker vascular endothelial growth factor (VEGF) could improve their prognostic stratification., Material and Methods: Four staging systems; Okuda, Cancer of the Liver Italian Program (CLIP), Barcelona Clinic Liver Cancer (BCLC), and Child-Pugh were evaluated in 78 HCC patients; their stratification abilities were detected by Kaplan-Meier curves and log-rank test; their accuracies of predicting survival were compared with the concordance index. Serum VEGF levels were measured using ELISA method. Recursive partitioning was used to determine the optimal VEGF cutoff. The prognostic significance of VEGF cutoff and other parameters were analyzed using univariate and multivariate models., Results: None of the staging systems demonstrated better discriminatory ability in predicting survival. The four staging systems did not reveal significant differences in probability of survival across their intermediate-advanced stages. Optimal cutoff identified for VEGF was 445 pg/mL. In advanced HCC, VEGF level (p = 0.004) and in early HCC, bilirubin level (p = 0.009) were identified as the independent prognostic factors. Survival comparison with high and low VEGF levels was significant for advanced HCC, while insignificant for early disease., Conclusion: Staging systems with conventional parameters did not provide good prognostic stratification for survival in advanced HCC population. Serum VEGF level was an independent predictor of survival in advanced HCC, and provided more survival homogeneity within the advanced stages of conventional staging systems.

Soft-tissue defects of the pretibial region constitute a major reconstructive challenge because of the insufficiency of the local tissues. In such cases, a long cross-leg flap may be an alternative option. This study presents a case with an atonic wound in the pretibial region caused by a previous traffic accident, which had received cross-leg flap repair following the excision.

Postburn cervical contractures involving the anterior neck represent a serious social, public, and medical problem. The expanded supraclavicular artery flap is a good reconstructive option for these defects to improve functional and aesthetic appearance. Its main vascular supply is the supraclavicular artery, and it may be harvested as either a skin pedicled flap or an island flap. In our clinic, 10 patients with severe cervical burn contractures were reconstructed with preexpanded supraclavicular artery flaps between 2005 and 2012. All the flaps primarily healed with good functional and cosmetic results, and the donor sites primarily closed without any tension. A complete range of motion at the cervical region was obtained in all patients by the end of the reconstruction period. The preexpanded supraclavicular artery flap is a suitable alternative for coverage of the cervical defects after the release of the burn contractures. It is a thin tissue of both good color and texture, and is easy to harvest.

Introduction: Standard treatment for caries removal and cavity preparation for restorations using mechanical means is often accompanied by fear and pain for the patient. Although the pain may be reduced by local anaesthesia, fear of the needle, noise, and the vibration of mechanical preparation remain a cause of discomfort. Erbium, chromium:yttriumscandium- gallium-garnet (Er,Cr:YSGG) laser irradiation indicates that pain perception may be reduced relative to that caused by mechanical preparation., Aim: The aim of this pilot clinical study was to perform a preliminary evaluation of pain perception during cavity preparation comparing the mechanical removal and Er,Cr:YSGG laser removal of caries from enamel and dentine., Methods: The study sample was ten children aged 7 to 12 years. Half of the preparations were completed by the laser alone and the other half were mechanically prepared. All cavities were restored with light-cured composite resin following the application of acid etch and a bonding agent. The time spent on cavity preparation and the behaviour of the patients during cavity preparation were recorded. Children were instructed to rate their pain on a visual analogue scale. In addition, the patients were asked to decide which was the more uncomfortable form of treatment and the preferred treatment for future caries therapy., Results: Children showed considerably more body and head movement with the conventional mechanical preparation. The subjects rated the perception of pain lower when the laser technique was used., Conclusion: In the small number of children studied, the application of the Er,Cr:YSGG laser system was a more comfortable alternative or adjunctive method to conventional mechanical cavity preparation. A far larger study is necessary to confirm this finding.

Endobronchial lipomas are rare benign tumours of the lung. The reported case was a 56-year-old man who visited the public hospital with complaints of chest pain and persistent cough. On bronchoscopy, a smooth-surfaced polypoid tumour obstructing the main bronchus in the left lobe was detected. The case was evaluated and surgical resection was performed. Histopathological investigation revealed that the tumour was an endobronchial lipoma; the tumour composed of mature fat tissue and was covered with bronchial epithelium.

Introduction: Although vascular injury during lumbar disc surgery is quite rare, it may be life threatening if not recognized and treated immediately., Case: We report the case of a woman who had a left common iliac artery laceration during spinal surgery and was treated by endovascular therapy. In the past, open surgery was the only way to repair a vascular injury, but thanks to the advance of new endovascular techniques and devices, endovascular therapy has become a strong alternative., Conclusion: This case differs from those published in the literature as we used a single balloon inflation and subtotal occlusion without the need for a covered stent.

Traumatic arteriovenous fistulas (AVF) are almost exclusively the result of penetrating trauma and there is usually a history of hemorrhage. Typically, the patient demonstrates a thrill and bruit over the site of injury. We report a woman who presented with longstanding pain and swelling of the right hand due to radial AVF that possibly occurred following an injury to the right hand that happened 10 years prior to the date of admission. Since surgery was considered high risk due to multiple fistulas and previous surgery, percutaneous coil embolization was performed via the ipsilateral antegrade radial approach.

Background: Insulin resistance is associated with obesity, glucose intolerance or diabetes, hypertension, dyslipidemia, and cardiovascular disease. Constellation of these risk factors iscalled metabolic syndrome (MetS). MetS is common among postmenopausal women. Low sex hormone binding globulin (SHBG) levels associate with an increased risk of MetS in postmenopausal women. Variations in SHBG gene associate with low levels of circulating SHBG levels. We aim to study the association between SHBG gene polymorphisms - rs1799941 (A/G) and rs6257 (T/C) - with MetS among postmenopausal women., Methods: The study population consisted of 182 postmenopausal women with MetS and 119 control subjects. We analyzed the allele frequencies of SHBG gene polymorphisms in relation to the risk components of MetS., Results: MetS patients displayed significantly lower SHBG levels compared to the lean control subjects (p = 0.036). rs1799941 A allele was associated with high SHBG levels (p = 0.031), low blood pressure, body mass index and waist circumference. The number of 'high risk' alleles (G allele of the rs1799941 and T allele of rs6257) correlated positively with waist circumference (r = 0.203, p = 0.006) and negatively with SHBG levels (r = -0.291, p = 0.024)., Conclusions: SHBG gene polymorphisms associate with SHBG levels and MetS risk components among postmenopausal women. Hence, A allele (rs1799941) may have a protective effect for MetS through its association with high SHBG levels among postmenopausal women.

Background: Osteopontin is a secreted phosphorylated glycoprotein that is expressed by a variety of cell types and that mediates numerous and diverse biological functions. Osteopontin knockout mice are protected from obesity-induced hepatic steatosis. In the present study, we sought to investigate whether serum osteopontin concentrations are associated with liver histology in patients with nonalcoholic fatty liver disease., Methods: Serum levels of osteopontin were measured by enzyme-linked immunosorbent assay in 179 well-characterized patients with nonalcoholic fatty liver referred for liver histology and 123 control subjects., Results: Serum osteopontin levels were markedly higher in patients with nonalcoholic fatty liver disease than in controls (p<0.001). Multivariable analysis showed that osteopontin levels were strongly and independently associated with both portal inflammation (β=0.294, p<0.01) and serum aminotransferase levels (aspartate aminotransferase: β=0.295, p<0.01; alanine aminotransferase; β=0.285, p<0.01)., Conclusion: In summary, these data demonstrate that serum levels of osteopontin are elevated in nonalcoholic fatty liver disease and are a significant independent predictor of portal inflammation in this clinical entity., (Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Aims and Background: Nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) are two major causes of liver disease worldwide. Epidemiological and clinical data have clearly demonstrated that NAFLD and its associated metabolic abnormalities are a risk factor for HCC. Traditionally, the mechanisms whereby NAFLD acts as a risk for HCC are believed to include replicative senescence of steatotic hepatocytes and compensatory hyperplasia of progenitor cells as a reaction to chronic hepatic injury. Recent years have witnessed significant advances in our understanding of the mechanisms underlying the link between NAFLD and HCC., Methods: In the present review, we provide an update on the pathophysiological pathways linking NAFLD and its associated metabolic derangements to malignant hepatic transformation, with a special focus on insulin resistance, adipokines, inflammation, and angiogenesis. We will also discuss the potential therapeutic implications that such molecular links carry., Results: Although treating NAFLD could reduce the risk of malignant hepatic transformation, no long-term studies focusing on this issue have been conducted thus far. Insulin resistance, inflammation as well as derangements in adipokines and angiogenic factors associated with NAFLD are closely intertwined with the risk of developing HCC., Conclusions: Traditional therapeutic approaches in NAFLD including metformin and statins may theoretically reduce the risk of HCC by acting on common pathophysiological pathways shared by NAFLD and HCC.

Background: Although liver biopsy remains the best diagnostic standard for nonalcoholic steatohepatitis (NASH), non-invasive tests are eagerly awaited. In this study, we sought to develop a support vector machine (SVM) algorithm to discriminate with high accuracy between subjects with NASH and controls using a blood-based biomarker panel., Methods: A total of 17 biomarkers were measured by commercially available enzyme-linked immunosorbent assays in 136 serum samples from patients with biopsy-proven NASH (n = 60) and subjects with normal ALT and no evidence of fatty liver on ultrasound (n = 76). The database was randomly divided (1:1 fashion) into a discovery set for classification training and in a validation set of the chosen biomarkers in blinded samples. Multivariate analysis was performed by means of SVM., Results: After the identification of a group of three most discriminative biomarkers (osteoprotegerin, fibroblast growth factor 21, and M30) in the discovery set, the application of SVM to the validation test resulted in a 92.5% sensitivity and 84.1% specificity for distinguishing subjects with NASH from controls., Conclusions: A targeted biomarker profiling combined with a SVM-based pattern identification approach may allow the identification of patients with NASH with clinically relevant accuracy and validity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background and Aims: Syndecan-1 (CD138) is a transmembrane heparan sulfate proteoglycan expressed in the liver which may exert metabolic effects by mediating the hepatic clearance of triglyceride-rich lipoproteins. In the present study, we assayed serum levels and the hepatic expression of syndecan-1 and examined their association with clinical, biochemical, and histologic phenotypes in patients with histology-proven nonalcoholic fatty liver disease (NAFLD)., Methods: A total of 59 patients with biopsy-proven NAFLD and 54 matched controls were enrolled. The analysis of syndecan-1 expression in liver biopsies was performed by immunohistochemistry on formalin-fixed, paraffin-embedded samples. Serum syndecan-1 levels were measured by ELISA., Results: NAFLD patients had significantly higher serum syndecan-1 levels [median: 61 ng/mL (interquartile range: 36-97 ng/mL)] than controls [median: 37 ng/mL (interquartile range: 25-59 ng/mL, Mann-Whitney U test, p < 0.001]. However, we did not find any significant association between serum syndecan-1 and the mean syndecan-1 immunohistochemical score (n = 59, r = 0.064, p = 0.63). Interestingly, the syndecan-1 immunohistochemical score was an independent predictor of HDL cholesterol in NAFLD patients (β = 0.27; t = 1.99, p < 0.05)., Conclusions: Our data suggest that serum syndecan-1 levels are raised in patients with NAFLD. Moreover, the syndecan-1 immunohistochemical score in the liver is independently associated with HDL cholesterol in this group of patients. These pilot results support further investigation of this molecule in metabolic liver diseases.

Unlabelled: Sudden death in persons with intracranial neoplasms is a rare mechanism of death detected in the forensic autopsies. 10 years-old girl was brought to a local clinic death shortly after analgesic therapy for headache. Autopsy findings showed a large, solid cerebellar mass. Histological diagnosis was pilomyxoid astrocytoma, low-grade tumor with features alike to pilocytic astrocytomas. In this case report we present and discuss rare autopsy case of pilomyxoid astrocytoma from medicolegal point of view., Keywords: sudden death - brain - pilomyxoid astrocytoma - autopsy.

Ameloblastoma is a benign tumor of the mandible, which is not commonly diagnosed in the early stages. The extensive mandible resection may be needed for treatment. In this report, we present 6-year follow-up results of a patient who had undergone hemimandibulectomy and mandible reconstruction with free vascularized fibular flap, costochondral rib graft to restoration of the temporomandibular joint, and iliac bone graft to enhance the vertical height of the mandible. The long-term results are very satisfactory.

Objectives: We sought to determine whether serum concentrations of fibroblast growth factor 19 (FGF19) - an ileum-derived enterokine which plays a role in the control of glucose and lipid homeostasis - are altered in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD)., Design and Methods: Serum levels of FGF19 were measured using enzyme-linked immunosorbent assay in 91 patients with biopsy-proven NAFLD and 74 controls., Results: FGF19 levels were significantly lower in patients with biopsy-proven NAFLD (median: 130pg/mL) than in controls (median: 210pg/mL, P<0.001). Serum FGF19 levels were significantly but modestly associated with hepatocyte ballooning scores in univariate analysis (r=-0.25, P<0.05) but not after adjustment for potential confounders (β=-0.18; t=1.78, P=0.08)., Conclusions: This pilot study suggests that serum FGF19 levels are decreased in patients with NAFLD but are not independently associated with liver histology findings., (Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Gastrointestinal stromal tumors represent the most common mesenchymal tumor of the digestive tract. Although the stomach is the most common location for gastrointestinal stromal tumor with the co-primary tumors, the synchronous appearance of a neuroendocrine tumor and gastrointestinal stromal tumor in the stomach is rare. We present here the case of a 48-year-old male with gastric well-differentiated neuroendocrine tumor and gastrointestinal stromal tumor discovered incidentally during surgical treatment of the neuroendocrine tumor. We discuss the current guidelines for the management of small gastrointestinal stromal tumors (&lt;2 cm in diameter) and the gastric carcinoids. We also review the literature for the co-occurrence of gastrointestinal stromal tumor and neuroendocrine tumor in a gastric location.

Endometrial intraepithelial neoplasia (EIN) applies specific diagnostic criteria to designate a monoclonal endometrial preinvasive glandular proliferation known from previous studies to confer a 45-fold increased risk for endometrial cancer. In this international study we estimate accuracy and precision of EIN diagnosis among 20 reviewing pathologists in different practice environments, and with differing levels of experience and training. Sixty-two endometrial biopsies diagnosed as benign, EIN, or adenocarcinoma by consensus of two expert subspecialty pathologists were used as a reference comparison to assess diagnostic accuracy of 20 reviewing pathologists. Interobserver reproducibility among the 20 reviewers provided a measure of diagnostic precision. Before evaluating cases, observers were self-trained by reviewing published textbook and/or online EIN diagnostic guidelines. Demographics of the reviewing pathologists, and their impressions regarding implementation of EIN terminology were recorded. Seventy-nine percent of the 20 reviewing pathologists' diagnoses were exactly concordant with the expert consensus (accuracy). The interobserver weighted κ values of 3-class EIN scheme (benign, EIN, carcinoma) diagnoses between expert consensus and each of reviewing pathologists averaged 0.72 (reproducibility, or precision). Reviewing pathologists demonstrated one of three diagnostic styles, which varied in the repertoire of diagnoses commonly used, and their nonrandom response to potentially confounding diagnostic features such as endometrial polyp, altered differentiation, background hormonal effects, and technically poor preparations. EIN diagnostic strategies can be learned and implemented from standard teaching materials with a high degree of reproducibility, but is impacted by the personal diagnostic style of each pathologist in responding to potential diagnostic confounders.

The ductal intraepithelial neoplasia (DIN) classification which proposes new approaches to the diagnosis, terminology and differential diagnosis of intraductal proliferative lesions of the breast was applied to a series of female patients comprising C-erbB2 oncogene expression which may serve as an adjunct to the morphology by immunohistochemistry. The study was performed using the data of 94 patients. There was no difficulty encountered in the diagnosis of intraductal hyperplasia (IDH). In patients with Atypical Ductal Hyperplasia (AIDH), the diagnosis could be made by using the 2-mm rule of the DIN classification in patients who exhibited cytologic and structural characteristics of Ductal Carcinoma in Situ (DCIS) alone or in conjunction with classical IDH patterns. However, in lesions that mimicked classical IDH patterns despite displaying cytological features of in situ carcinomas, the experience and view point of the pathologist played a more prominent role. When the DIN classification criteria were applied to grade DCIS lesions, although the system was found to be practical, it did not provide adequate differentiation in intermediate grade (grade II-DIN 2) patients and further improvement was considered desirable. Fourty-five cases (47.8%) IDH, 19 (20.2%) AIDH, and 30 (31.9%) were DCIS. There were statistically significant differences in the levels of c-erbB2 oncogene expression between IDH, AIDH and DCIS lesions (p<0.001). In DCISs, grade, cell size, pleomorphic nuclear atypia showed statistically significant associations with c-erbB2 oncogene expression. These results suggest that c-erbB2 oncogene expression is a valuable marker in the differential diagnosis and prognostic evaluation of patients with intraductal proliferative lesions.

Vascular endothelial growth factor (VEGF) is the important angiogenic factor associated with tumor growth and metastasis in a wide variety of solid tumors. The aim of this study is to investigate the tumor suppressive effect of chitosan/small interfering RNA (siRNA)-VEGF nanoplexes in the rat breast cancer model. Chitosan/siRNA nanoplexes (siVEGF-A, siVEGFR-1, siVEGFR-2) and NRP-1 were prepared in a 15 to1 ratio and injected (intratumorally) into the breast-tumor-bearing Sprague-Dawley rats. Tumor volumes were measured during 21 days. To investigate the effect of chitosan/siRNA nanoplexes on VEGF expression in tumors, VEGF was analyzed with immunohistochemistry and western blotting. The mRNA levels of VEGF in tumor samples were determined with real-time PCR (RT-PCR). After siRNA treatment, a marked reduction in tumor volumes was measured in complex-injected rats (97%). Free siRNA injection showed lower tumor inhibition. Reduction of VEGF protein was also shown with western blotting and immunohistochemistry. Similar results were obtained with RT-PCR also. These results indicate that the chitosan/siRNA targeting to VEGF nanoplexes have a remarkably suppressive effect on VEGF expression and tumor volume in breast cancer model of rats.

Background: Increased serum concentrations of pigment epithelium-derived factor (PEDF) have been linked to the metabolic syndrome in the general population. However, the relationship between serum PEDF and nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, remains unknown., Methods: We assayed serum PEDF levels in 156 patients with biopsy-proven NAFLD and 103 nonsteatotic control subjects who were matched for age and sex. The association between levels of PEDF and clinical, biochemical, and histological phenotypes was examined., Results: NAFLD patients had significantly higher serum PEDF levels (1.97±0.50 μg/mL) than control subjects (1.51±0.49 μg/mL, Student's t test, P<0.001). Multivariable-adjusted stepwise regression analysis showed that PEDF ([beta]=0.32, t=3.13, P=0.002) and triglycerides ([beta]=0.22, t=2.23, P=0.02) were, in the order they entered into the model, the main independent predictors of steatosis scores in our patients with NAFLD., Conclusions: Serum PEDF levels are significantly increased in patients with biopsy-proven NAFLD and are associated with liver steatosis independently of traditional risk factors., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: Galectin-3 might serve as a biomarker of human metabolic alterations. We measured serum levels of galectin-3 in patients with nonalcoholic fatty liver disease (NAFLD) and examined their association with clinical and histological phenotypes., Design and Methods: Serum levels of galectin-3 were assayed in 71 patients with biopsy-proven NAFLD and 39 controls., Results: Serum galectin-3 levels did not differ in patients with NAFLD (median 4.1 ng/mL; interquartile range: 1.5-5.5 ng/mL) compared with healthy controls (median 3.1 ng/mL; interquartile range: 0.8-7.5 ng/mL, P=0.93). Among patients with NAFLD, however, serum galectin-3 levels correlated significantly with BMI (r=0.267, P<0.05). This association persisted after adjustment for potential confounders (β=0.30; t=2.11, P<0.05)., Conclusions: Although galectin-3 was modestly associated with BMI, our results do not support the hypothesis that levels of this molecule are altered in patients with NAFLD., (Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Livedoid vasculopathy (LV) is a chronic, recurrent, painful cutaneous disease with distinctive clinical features and an uncertain etiology. The skin lesions are recognizable by focal purpura, depigmentation and shallow ulcers. Thrombophilic conditions occur frequently in patients with LV. While no definitive treatment exists for LV, smoking cessation, antiplatelet therapy, immunosuppressive treatment, and anabolic steroids are often included in the therapeutic ladder. Recently, a possible link between LV and impaired fibrinolysis was established as cutaneous LV lesions responded to tissue plasminogen activator (t-PA) infusion suggesting that inhibition of the fibrinolysis through plasminogen activator inhibitor-1 (PAI-1) activity may determine the disease course in patients with LV. In this study, we investigated PAI-1 antigen (Ag) and activity levels in 20 patients with biopsy proven LV (mean age 26 ± 11, M/F = 7/13, median disease duration 3.5 years). All patients received antiplatelet treatment with aspirin and/or dipyrimadole and 14 patients received anabolic steroids or immunosuppressive treatment. Fasting PAI-1 Ag and activity levels were measured at 9 AM in all patients. Both Ag (34 (26) ng/ml) (median (interquartile range)) and specific activity (17 (23) IU/fmole) levels of PAI-1 were moderately elevated in LV patients compared to the controls, however, PAI-1 kinetic studies demonstrated markedly enhanced stability of PAI-1 activity in plasma from patients with LV. Specific activity at 16 h was significantly higher than expected specific activity levels (7 (11) vs. 0.07 (0.09) IU/fmole, P < 0.01). While the exact mechanism of increased stability of PAI-1 activity is not known, it may be due to post-translational modifications or increased binding affinity for a stabilizing cofactor. In conclusion, enhanced stability of PAI-1 may contribute to the pathophysiology of LV, and systemic or local treatment with PAI-1 inhibitors may offer a potential treatment alternative in patients with LV.

Hyperlipidemia is a major risk factor for coronary artery disease (CAD). Lipoprotein lipase (LPL) is an important enzyme in lipoprotein metabolism. S447X polymorphism of the LPL gene has been implicated in the pathogenesis of CAD. Carriers of X447 allele were reported to have lower triglyceride and higher high-density lipoprotein cholesterol levels as well as a reduced risk of CAD. We hypothesized that S447X gene polymorphism might have a protective effect for CAD. A total of 178 subjects (mean age 42.97 ± 6.5 years) who underwent coronary angiography for clinical indications were included in the study. The patients had been referred for evaluation of chest pain and/or abnormal stress tests, and were selected consecutively. Gensini scores were used to assess the severity of CAD; 97 patients were diagnosed with angiographically proven CAD, and 81 subjects did not display significant CAD (≥ 70%) angiographically. Genotyping of LPL S447X polymorphism was performed by real-time polymerase chain reaction amplification and fluorescent probe melting point analysis on the light cycler. The minor allele frequencies of LPL 447X allele were 11.1% and 6.2% among subjects without CAD compared with CAD subjects (P = 0.081) and 447X allele had favorable effects on lipid levels among CAD patients; 447X homozygotes and heterozygotes displayed lower total cholesterol (171 ± 37 vs 208 ± 48 mg/dl, P = 0.02), lower triglycerides (121 ± 72 vs 184 ± 86 mg/dl, P = 0.02), lower low-density lipoprotein cholesterol (102 ± 27 vs 129 ± 39 mg/dl, P = 0.03). Gensini scores were significantly lower among the heterozygotes and homozygotes of LPL 447X allele than in the LPL S447 homozygotes (15 ± 23 vs 25 ± 30, P = 0.048). S447X polymorphism of LPL gene may have a protective role for the severity of CAD. The beneficial effects of S447X polymorphism of the LPL gene may be through its favorable effects on lipid levels.

Background: Patients with nonalcoholic fatty liver disease (NAFLD) have a reduced coronary flow reserve (CFR) and an increased risk of cardiovascular disease. The fat cells that surround coronary arteries may play a central and underrecognized role in development of cardiovascular disease through the systemic secretion of adipokines. We therefore evaluated the relation of epicardial fat thickness, serum levels of epicardial fat-related adipokines (chemerin and vaspin), and CFR in patients with NAFLD., Methods: We investigated 54 patients with biopsy-proven NAFLD and 56 age- and sex-matched controls. CFR and epicardial fat thickness (EFT) were measured by transthoracic echocardiography. Serum levels of chemerin and vaspin were measured by ELISA., Results: EFT was significantly higher (0.64 ± 0.13 vs. 0.54 ± 0.10 cm, P<0.001) and CFR significantly lower (2.11 ± 0.45 vs. 2.52 ± 0.62, P < 0.001) in patients with NAFLD than in controls. Serum levels of vaspin and chemerin were both significantly increased in patients with NAFLD compared with controls. Stepwise regression analysis showed that EFT (β=-0.53, t=-3.7, P<0.001), serum vaspin levels (β=-0.30, t=-2.5, P=0.014), and liver fibrosis (β=-0.31, t=-2.11, P=0.041), in the order they entered into the model, were independent predictors of CFR in NAFLD patients., Conclusion: Our data suggest the presence of a complex interplay between EFT, serum vaspin, and liver histology in promoting an impaired hyperemic stimulation of coronary blood flow in patients with NAFLD., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Lecithin:cholesterol acyltransferase (LCAT) is one of the key enzymes controlling cholesterol homeostasis and plays a primary role in high-density lipoprotein cholesterol (HDL-C) maturation., Objective: The aim of our study was to evaluate the effects of LCAT gene polymorphisms 511C/T (exon4), 4886C/T (rs5923), and 608C/T (rs5922) on LCAT enzyme level, activity, and HDL-C levels., Methods: The study population was selected from consecutive subjects with low (<35 mg/dL) and high HDL-C levels (>65 mg/dL) seen in our lipid clinic. LCAT polymorphisms were analyzed with a restriction fragment length polymorphism assay. LCAT activity and levels were measured by colorimetric enzymatic and enzyme-linked immunoassay methods, respectively., Results: The 4886C/T polymorphism was the most commonly observed variant of LCAT gene. T-allele frequencies in subjects with low (n = 50) and high (n = 50) HDL-C were 0.54 and 0.37, respectively (P = .019). TT genotype was more common among low HDL-C group (30% vs 14%, P = .05). The effects of LCAT enzyme appeared to depend on the HDL-C level. In subjects with low HDL-C, LCAT enzyme levels correlated positively with body mass index (P < .001, r = 0.544), HDL-C (P = .006, r = 0.404), triglycerides (P = .001, r = 0.487), total cholesterol (P < .001, r = 0.541), and low-density lipoprotein-cholesterol (P = .001, r = 0.477) levels. LCAT activity correlated positively with fasting glucose levels (P = .008, r = 0.390)., Conclusion: LCAT genotype, enzyme level, and activity modulate HDL-C metabolism, particularly among subjects with low HDL-C levels., (Copyright © 2011 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

The novel adipokines vaspin, obestatin, and apelin-36 are associated with insulin resistance and the components of the metabolic syndrome. We assayed circulating levels of these molecules and examined their association with clinical, biochemical, and histologic phenotypes in patients with nonalcoholic fatty liver disease (NAFLD). Serum levels of vaspin, obestatin, and apelin-36 were assayed by enzyme-linked immunosorbent assay in 91 patients with biopsy-proven NAFLD and 81 controls. We analyzed associations between adipokines and the characteristics of patients with NAFLD using multivariable linear regression models. Univariable analysis showed that concentrations of vaspin and apelin-36 were significantly higher in patients with NAFLD than in controls, whereas no differences in obestatin levels were found. Serum vaspin levels showed a statistically significant association with C-reactive protein (r = 0.378, P < .001) and liver fibrosis scores (r = 0.401, P < .001), whereas apelin-36 levels showed a modest association with homeostasis model assessment of insulin resistance (r = 0.204, P < .01). After stepwise linear regression analysis, serum vaspin levels were the only independent predictor of liver fibrosis scores in patients with NAFLD (β = 0.37, t = 3.99, P < .01). Serum vaspin levels are raised in patients with NAFLD regardless of potential confounders and represent an independent predictor of liver fibrosis scores. These findings support further investigation of this novel adipokine in metabolic liver diseases., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aim: The purpose of this in vitro study was to evaluate the potential effect of laser therapy on the prevention of erosive demineralisation either alone or combined with acidulated phosphate fluoride gel on human enamel. It was hypothesized that such a treatment would decrease enamel solubility., Study Design: Efficacy of 2940 nm Er:YAG laser with preset parameters--alone or combined with APF (Acidulated Phosphate Fluoride) gel--was tested on freshly extracted human permanent molars., Materials and Methods: Ten sound human third molars were sectioned into 5 surfaces (2 x 3 mm) with hard tissue microtome and were randomly allocated into different treatment groups as follows. The Vicker's hardness of each surface was obtained at the baseline. Group 1, negative control group: no treatment. Group 2, positive control group: only 1.23% APF gel (Denti-Care gel, Medicom) 1 minute application. Group 3: irradiated with surface modification mode (2940 nm, 1.2j/cm², 10 Hz, 300 μm) Er:YAG laser. Group 4: Er:YAG laser application following 1.23% APF gel. Group 5: 1.23% APF gel following Er:YAG laser application. The demineralisation process was obtained by immersion of specimens in a soft drink for 10 minutes and then the Vickers hardness was reevaluated., Statistics: For statistical analyses within groups the Kruskal Wallis test was used, while for comparing groups the paired sample t test (significance p<0.05) was used., Results: The difference in microhardness values of each group obtained following the treatments was not statistically significant (p>0.05). Beside, no statistical difference was found in Vickers value related to the application of fluoride prior or after laser therapy. Conclusion Er:YAG laser irradiation alone or combined with APF decreased the enamel solubility but combined treatment did not show any significant additional effect.

Background: Increasing evidence suggests that innate immune system may have a key role in the pathogenesis of the inflammatory bowel disease (IBD). Bactericidal/permeability increasing protein (BPI) has an important role in the recognition and neutralization of gram-negative bacteria by host innate immune system. The polymorphism on BPI gene called Lys216Glu is on the suspected list of IBD pathogenesis., Methods: We studied the Lys216Glu polymorphism on BPI gene, in a Turkish IBD patient population. A total of 238 IBD patients; 116 Crohn's disease (CD) and 122 ulcerative colitis (UC), besides 197 healthy controls were included in this study., Results: The Glu/Glu genotype and allele frequencies were found to be statistically higher compared to healthy control group not only in CD patients [P: 0.03, OR: 1.87 (CI 95% 1.02-3.42) and P: 0.00001 (OR: 2.07 CI 95% 1.47-2.91) respectively] but also in UC patients [P: 0.0002, OR: 2.71 (CI 95% 1.53-4.80) and P: 0.00002 (OR: 2.71 CI 95% 1.53-4.80) respectively]., Conclusions: BPI polymorphism (Lys216Glu) is associated both to CD and UC. Our findings differ from the two Western European studies; one without any association and the other indicating an association only with CD. Our study is the first one reporting a novel association between BPI gene mutation (Lys216Glu) and UC., (Copyright © 2010 European Crohn's and Colitis Organisation. All rights reserved.)

We describe a lateral intercostal artery perforator-based pedicled reverse thoraco-abdominal flap for coverage of the antecubital fossa after burn scar release. In this study we describe raising and insetting the flap and reported our clinical results and observations. Antecubital contracture release was carried out in six patients, and the lateral intercostal artery perforator-based pedicled reverse thoraco-abdominal flap was raised based on the anterolateral cutaneous perforator of the appropriate intercostal artery. The defects were repaired with this flap. All the flaps survived and antecubital contractures were repaired successfully. No recurrent contracture occurred in any of the patients at a mean of 15.3 months. The lateral intercostal artery perforator-based pedicled reverse thoraco-abdominal flap can be used effectively for repair of antecubital tissue defects as an alternative to other reconstructive methods., (Copyright © 2010 Elsevier Ltd and ISBI. All rights reserved.)

Background: Elevated progranulin levels are associated with visceral obesity, elevated plasma glucose, and dyslipidemia. Progranulin has not been previously investigated as a biomarker of nonalcoholic fatty liver disease (NAFLD). We sought to determine whether serum progranulin levels are altered in patients with biopsy-proven NAFLD and if they are associated with their clinical, biochemical, and histological characteristics., Subjects and Methods: We measured serum progranulin levels in 95 patients with biopsy-proven NAFLD and 80 age- and sex-matched controls. The potential associations between progranulin and the characteristics of NAFLD patients were examined by multiple linear regression analysis., Results: Serum progranulin levels were significantly higher in NAFLD patients (34 ± 13 ng/mL) than in controls (28 ± 7 ng/mL, P < 0.001). In NAFLD patients, serum progranulin levels were associated with lipid levels and the degree of hepatic fibrosis. After adjustment for potential confounders, serum progranulin remained an independent predictor of the degree of hepatic fibrosis in NAFLD patients (β = 0.392; t = 2.226, P < 0.01)., Conclusions: Compared with controls, NAFLD patients have higher serum progranulin concentrations, which are closely associated with lipid values and the extent of hepatic fibrosis.

Adenoid cystic carcinoma (ACC) of the Bartholin's gland is a rare malignancy of the female genital tract. Seventy-nine cases have been reported in the literature. A 40-year-old women presented to our clinic with twice locally recurrent ACC of Bartholin's gland of the left vulva despite hemivulvectomy. Adjuvant radiotherapy was delivered after the third resection. There was no local recurrence after three years follow-up, although she developed lung metastases that remain under control with oral cyclophosphamide. Our case confirms the literature review, which indicates a slow growing tumor with frequent local recurrences (30%) and distant metastases (31%). Adjuvant radiotherapy and/or chemotherapy should be considered in the management of ACC of Bartholin's gland.

Background: Evidence suggests that zinc-α(2)-glycoprotein (ZAG) might serve as a biomarker for human metabolic alterations. We measured serum ZAG in patients with non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, and examined its association with clinical, biochemical, and histological phenotypes., Methods: Serum ZAG was determined using ELISA in 90 patients with biopsy-proven NAFLD and 81 controls., Results: Serum ZAG concentrations did not differ in patients with NAFLD (median 61 μg/mL; interquartile range: 56-73 μg/mL) compared with healthy controls (median 66 μg/mL; interquartile range: 56-78 μg/mL, Mann-Whitney U-test, p=NS). However, among patients with NAFLD serum ZAG concentrations were significantly higher in males and in those with the metabolic syndrome. After stepwise linear regression analysis, serum ZAG concentrations were the only independent predictor of the number of metabolic syndrome components in patients with NAFLD (β=0.22; t=2.001, p<0.05)., Conclusions: In summary, the hypothesis of an association between NAFLD and serum ZAG concentrations is not supported by the present results. However, ZAG remains an interesting molecule for further research in the field of human metabolic disorders.