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Systemic amyloidosis is a clinical manifestation of the accumulation of amyloid fibrils in tissues because of persistent acute phase elevation and chronic inflammation. Its most common causes are inflammatory diseases and malignancies. Here, we present a 12-year-old girl diagnosed with systemic amyloidosis and Hodgkin lymphoma (HL) who was also previously diagnosed with familial Mediterranean fever (FMF). Despite colchicine treatment for FMF, the patient had a persistent elevation of acute phase reactants and AA-type amyloid deposits were observed in a kidney biopsy. Anakinra, an interleukin-1 antagonist, was added to the treatment. Shortly after the diagnosis of amyloidosis, mediastinal lymphadenopathy was recognized, and she was also diagnosed with HL. A chemotherapy protocol of doxorubicin, bleomycin, vinblastine, and dacarbazine was initiated. After 6 cycles of the chemotherapy and 8 months of the anakinra treatment, no recurrence or residual malignancy was observed and proteinuria was decreased. To the authors' knowledge, this is the first reported case of systemic amyloidosis in the literature associated with both FMF and HL.

Bottom-up mass spectrometry-based proteomics utilizes proteolytic enzymes with well characterized specificities to generate peptides amenable for identification by high-throughput tandem mass spectrometry. Trypsin, which cuts specifically after the basic residues lysine and arginine, is the predominant enzyme used for proteome digestion, although proteases with alternative specificities are required to detect sequences that are not accessible after tryptic digest. Here, we show that the human cysteine protease legumain exhibits a strict substrate specificity for cleavage after asparagine and aspartic acid residues during in-solution digestions of proteomes extracted from Escherichia coli , mouse embryonic fibroblast cell cultures, and Arabidopsis thaliana leaves. Generating peptides highly complementary in sequence, yet similar in their biophysical properties, legumain (as compared to trypsin or GluC) enabled complementary proteome and protein sequence coverage. Importantly, legumain further enabled the identification and enrichment of protein N-termini not accessible in GluC- or trypsin-digested samples. Legumain cannot cleave after glycosylated Asn residues, which enabled the robust identification and orthogonal validation of N-glycosylation sites based on alternating sequential sample treatments with legumain and PNGaseF and vice versa. Taken together, we demonstrate that legumain is a practical, efficient protease for extending the proteome and sequence coverage achieved with trypsin, with unique possibilities for the characterization of post-translational modification sites.

Until now, the diagnosis of familial Mediterranean fever (FMF) was based on validated subsets of clinical criteria, but recently new Eurofever/PRINTO classification criteria concerning genetic analyses were proposed. The study aimed to compare the performances of three validated diagnostic criteria (Tel-Hashomer, Livneh, pediatric criteria) and new Eurofever/PRINTO classification criteria. The medical charts of study and control groups were reviewed retrospectively. Patients were evaluated for three diagnostic criteria and new Eurofever/PRINTO classification criteria. Control group consists of patients with other autoinflammatory diseases. A total of 1291 patients were classified into three groups according to their mutations: group 1: 447 patients with homozygous mutations; group 2: 429 patients with compound heterozygous mutations; and group 3: 415 patients with one heterozygous mutation. Similar diagnostic utility was found according to Livneh criteria between groups. But, proportion of patients fulfilling Tel-Hashomer and pediatric criteria was higher in groups 1 and 2. According to Eurofever/PRINTO criteria, 98.2% of patients with homozygous mutations, 94.2% of patients with compound heterozygous mutations and 80.2% of patients with heterozygous mutations were classified as FMF. In control group, 99.2% of them fulfilled the Livneh criteria, 66.9% met the pediatric criteria and 0.8% satisfied the Tel-Hashomer criteria, while none of control patients met the Eurofever/PRINTO classification criteria. Performances of three validated diagnostic criteria and new Eurofever/PRINTO classification criteria for FMF were similar and provide high utility in diagnosing/classifying patients with homozygous and compound heterozygous mutations. However, both Eurofever/PRINTO classification criteria and Tel-Hashomer criteria had significantly lower performance in heterozygous patients.

Heavy metal contamination is a serious environmental problem commonly monitored in various organisms. Small wild rodents are ideal biological monitors to show the extent of environmental pollution. The aim of this study was to evaluate the adverse effects of marble and stone quarries on the Levant vole, Microtus guentheri, inhabiting some polluted sites. In this context, Inductively Coupled Plasma Mass Spectrometry (ICP-MS) was used to analyze distribution of thirteen heavy metals (Fe, Al, Zn, Cu, Cr, Mn, Ni, B, Pb, As, Co, Cd, and Hg) in the organs (skins, bones, muscles, livers and kidneys) of the biological specimens, and the comet assay revealed DNA damage in blood lymphocytes for the first time. This study was conducted at close to the marble and stone quarries at Korkuteli, Antalya-Turkey during spring, summer, autumn (2017) and winter (2018) seasons. In spring and summer, genetic damage in blood lymphocytes from all polluted sites (sites 1-5) was significantly higher than that of controls, while in autumn it was higher in samples from three sites (sites 3-5). In terms of heavy metal distribution in organs, we found depositions of Fe, Al, Zn, Ni, Mn, Cr, Co, As and Pb primarily in the skin with its derivatives, Cu and Cd deposits in the kidney, Cu, Cd and B deposits in the liver, and As and Pb depositions in the bones. The study shows that certain organs (especially skin with its derivatives) and blood lymphocytes of Levant vole can be used as ideal indicators of heavy metal pollution. Our results suggest that the Korkuteli area could already be under the threat of heavy metal pollution., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: To analyze the correlation of clinicopathologic prognostic parameters with atypical meningiomas (AMs) and recurrence development as well as progression-free survival (PFS)., Material and Methods: The neuropathology archive and hospital records of 75 patients with AM who underwent surgery in our institution between 2010 and 2019 were retrospectively reviewed. The pathological revision was performed according to the 2016 World Health Organization (WHO) criteria. Other clinicopathological parameters, such as age, gender, tumor location, preoperative tumor size, degree of resection, Psammoma body, nuclear atypia, main histological pattern, Ki67 labeling index (LI), radiotherapy, and dura and bone invasion, were also analyzed. Statistically, univariate and multivariate analyses were assessed to determine their potential impact on recurrence-related prognostic factors., Results: Recurrence occurred in 20 patients. The mean PFS and follow-up time were 38.9 and 44.8 months, respectively. In univariate analysis, clinical and pathological features such as age of ?55 years, female sex, skull base tumor location, larger preoperative tumor size, increased mitotic count, small cells, hypercellularity, sheeting, necrosis, and dura and bone invasion were remarkable in patients with recurrence, but were not statistically significant. In multivariate analysis, increased mitotic activity and brain invasion either considered alone or combined were significantly associated with PFS. Nuclear atypia was also not associated with both tumor recurrence and PFS. However, clinical features did not significantly influence the PFS., Conclusion: This study found that recurrence could not be predicted by the presence of any of the clinicopathological features of AMs. We believe that molecular variables determined through routine neuropathological analysis will be needed in the future.

Treatment of lung diseases, which are the third most common cause of death in the world, is of great importance in the medical field. Many studies using lung sounds recorded with stethoscope have been conducted in the literature in order to diagnose the lung diseases with artificial intelligence-compatible devices and to assist the experts in their diagnosis. In this paper, ICBHI 2017 database which includes different sample frequencies, noise and background sounds was used for the classification of lung sounds. The lung sound signals were initially converted to spectrogram images by using time-frequency method. The short time Fourier transform (STFT) method was considered as time-frequency transformation. Two deep learning based approaches were used for lung sound classification. In the first approach, a pre-trained deep convolutional neural networks (CNN) model was used for feature extraction and a support vector machine (SVM) classifier was used in classification of the lung sounds. In the second approach, the pre-trained deep CNN model was fine-tuned (transfer learning) via spectrogram images for lung sound classification. The accuracies of the proposed methods were tested by using the ten-fold cross validation. The accuracies for the first and second proposed methods were 65.5% and 63.09%, respectively. The obtained accuracies were then compared with some of the existing results and it was seen that obtained scores were better than the other results., (© The Author(s) 2019.)

The aim of the study is to examine the reaction of calcined magnesite in the citric acid media, and after that it is determination of optimal conditions about the leaching performance of calcined magnesite by an experimental plan of Taguchi Statistical Method with L 16 (4 5 ). The parameters such as particle size, reaction temperature, acid concentration, solid-liquid ratio and reaction period are tested. In this work, the optimal combination of the parameters that achieves robustness against noise factors is found as: 50 °C, 45 min, -319 μm, 0.125 g/mL, and 2M, respectively. Extraction efficiency of the magnesium from calcined magnesite is 98.86 %., (© 2019 Published by Elsevier Ltd.)

Objectives: This study aims to evaluate the plasma expression of microribonucleic acids (miRNAs) that may be associated with the pathogenesis of familial Mediterranean fever (FMF)., Patients and Methods: Thirty patients with FMF (18 males, 12 females; mean age 9.1±4.7 years; range, 3 to 15.5 years) and 30 age- and sex-matched healthy children (18 males, 12 females; mean age 9.5±4.6 years; range, 4 to 16.5 years) were included in this study. The plasma levels of four candidate miRNAs (miRNA-16, miRNA-155, miRNA-204 and miRNA-451) were measured in all subjects. The plasma levels of miRNAs were analyzed with real- time polymerase chain reaction in attack and remission periods of patients and healthy controls (HCs)., Results: Plasma miRNA-204 levels of FMF patients were decreased 6.5 fold in remission period compared to HCs (p<0.001). This decrease was more prominent in M694V mutation carriers. Plasma miRNA-155 levels of FMF patients were lower in remission period (p=0.03)., Conclusion: Our findings showed significant alterations in the plasma expression of miRNA-155 and miRNA-204 in FMF patients compared to HCs. Our data suggest that miRNA-155 and miRNA-204 may be related to the pathogenesis of FMF. Further comprehensive and functional researches may help to clarify the role of miRNAs in FMF and elucidate the pathogenesis of the disease., Competing Interests: Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article., (Copyright © 2020, Turkish League Against Rheumatism.)

Objective: Normal reference values for the cardiac chambers are widely based on cohorts from European or American populations. In this study, we aimed to obtain normal echocardiographic measurements of healthy Turkish volunteers to reveal the age, gender, and geographical region dependent differences between Turkish populations and other populations., Methods: Among 31 collaborating institutions from all regions of Turkey, 1154 healthy volunteers were enrolled in this study. Predefined protocols were used for all participants during echocardiographic examination. Blood biochemical parameters were also obtained for all patients on admission. The American Society of Echocardiography and European Association of Cardiovascular Imaging recommendations were used to assess the echocardiographic cardiac chamber quantification., Results: The study included 1154 volunteers (men: 609; women: 545), with a mean age of 33.5±11 years. Compared to men, women had a smaller body surface area, lower blood pressure and heart rate, lower hemoglobin, total cholesterol, lower low-density lipoprotein (LDL) levels, and higher high density lipoprotein (HDL) levels. Cardiac chambers were also smaller in women and their size varied with age. When we compared the regions in Turkey, the lowest values of left cardiac chamber indices were seen in the Marmara region and the highest values were observed in the Mediterranean region. Regarding the right cardiac indices, the Mediterranean region reported the lowest values, while the Black Sea region and the Eastern Anatolia region reported the highest values., Conclusion: This is the first study that evaluates the normal echocardiographic reference values for a healthy Turkish population. These results may provide important reference values that could be useful in routine clinical practice as well as in further clinical trials. (.

Protein N termini unambiguously identify truncated, alternatively translated or modified proteoforms with distinct functions and reveal perturbations in disease. Selective enrichment of N-terminal peptides is necessary to achieve proteome-wide coverage for unbiased identification of site-specific regulatory proteolytic processing and protease substrates. However, many proteolytic processes are strictly confined in time and space and therefore can only be analyzed in minute samples that provide insufficient starting material for current enrichment protocols. Here we present High-efficiency Undecanal-based N Termini EnRichment (HUNTER), a robust, sensitive and scalable method for the analysis of previously inaccessible microscale samples. HUNTER achieved identification of >1000 N termini from as little as 2 μg raw HeLa cell lysate. Broad applicability is demonstrated by the first N-terminome analysis of sorted human primary immune cells and enriched mitochondrial fractions from pediatric cancer patients, as well as protease substrate identification from individual Arabidopsis thaliana wild type and Vacuolar Processing Enzyme-deficient mutant seedlings. We further implemented the workflow on a liquid handling system and demonstrate the feasibility of clinical degradomics by automated processing of liquid biopsies from pediatric cancer patients., (© 2019 Weng et al.)

Introduction and Objectives: Vitamin D deficiency is associated with increased susceptibility to infections and wheezing. We aimed to evaluate the relation between vitamin D levels, viral infections and severity of attacks in children with recurrent wheezing., Materials and Methods: A total of 52 patients who applied with wheezing, at the ages of 12-60 months with a history of three or more wheezing attacks in the last year and 54 healthy children were included. Sociodemographic data, risk factors for recurrent wheezing, and the severity of the wheezing attacks were recorded. 25(OH)D3, calcium, phosphor, alkaline phosphatase and parathormone levels of all children were measured. Nasopharyngeal samples of the patients for viruses were studied by multiplex polymerase chain reaction., Results: For the patient group, being breastfed for six months or less, history of cesarean section, cigarette exposure, humid home environment, and family history of allergic disease were significantly higher compared with the control group. Serum vitamin D levels in the patient group were significantly lower compared to the control group. There was no significant relationship between vitamin D levels and hospitalization, oxygen or steroid therapy. Virus was detected in 38 patients (73%). Rhinovirus (63.2%) was the most frequently detected virus. Coinfection was found in 14 (36.8%) patients. There was no statistically significant difference between detection of virus and vitamin D levels., Conclusions: Cigarette exposure, being breastfed six months or less, humid home environment, history of cesarean section, family history of allergic disease and vitamin D deficiency might be risk factors for recurrent wheezing., (Copyright © 2019 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: The aim of the current study are to determine the depression levels of adult oncology patients in the cancer treatment phase and identify both cancer-related stigma and the factors affecting their depression levels., Methods: In this correlational study, 303 adult patients who had been treated at a medical outpatient clinic were surveyed using the convenience sampling method. The "questionnaire for measuring attitudes toward cancer - patient version," a sociodemographic characteristics questionnaire, and the beck depression inventory were used. A multivariable linear regression model was used for the analysis., Results: The questionnaire and its subscale scores indicated a positive relationship between depression and attitudes toward cancer. The predictive variables for depression were "being younger than 40-year-old" and "feelings of social exclusion," which accounted for 4% of the total variance. Four factors indicating negative attitudes toward cancer were "being more than 60-year-old," "higher education," "low income," and "feelings of social exclusion," which accounted for 11% of the total variance., Conclusions: Cancer-related stigma, which underlies patients' emotional and behavioral outlooks, should be reduced in cancer patients. Members of health teams should be sensitive to cancer-related stigma., Competing Interests: There are no conflicts of interest., (Copyright: © 2019 Ann & Joshua Medical Publishing Co. Ltd.)

Leg ulcers may occur due to many autoimmune, hereditary, inflammatory, and infectious causes including venous, arterial, and neuropathic ulcers. Hyperhomocysteinemia is a metabolic disorder caused by various enzyme defects in methionine metabolism. The most common cause is methylenetetrahydrofolatreductase (MTHFR) enzyme gene mutations. Hyperhomocysteinemia is an independent risk factor for deep vein thrombosis and peripheral arterial disease. The effects of endothelial cell damage on smooth muscle hypertrophy, platelet aggregation, coagulation, and fibrinolysis cause atherogenesis and thrombosis, leading to venous and arterial lower extremity ulcers. In this article, we report the case of a 47-year-old male patient who was admitted to our clinic due to painful leg ulcers that started 1 year ago. He had a history of vena cava inferior thrombosis, deep vein thrombosis, and 40 pack-year smoking. Histopathological examination of punch biopsy taken from ulcerative lesion showed intense inflammatory infiltration in the middle dermis, erythrocyte extravasation, leukocytoclasia, and thrombus formation in a small diameter venule lumen. There were nonspecific findings in direct immunofluorescence examination. He was found as having MTHFR C677T homozygote and plasminogen activator inhibitor-1 4G/5G heterozygote gene mutation with high homocysteine level of 22.90 µmol/L, and he was diagnosed as hyperhomocysteinemia. He was recommended to quit smoking because it triggered thrombosis in hyperhomocysteinemia. Herein, we present a case of hyperhomocysteinemia due to MTHFR mutation, which is one of the rare hereditary thrombophilia causes.

Background and Objective: Heart sound contains various important quantities that help early detection of heart diseases. Many methods have been proposed so far where various signal-processing techniques have been used on heart sounds for heart disease detection., Methods: In this paper, a methodology is introduced for heart disease detection based on heart sounds. The proposed method employs three successive stages, such as spectrogram generation, deep feature extraction, and classification. In the spectrogram generation stage, the heart sounds are converted to spectrogram images by using time-frequency transformation., Results: The deep features are extracted from three different pre-trained convolutional neural network models such as AlexNet, VGG16, and VGG19. Support vector machine classifier is used in the third stage of the proposed method. The proposed method is evaluated on two datasets, which are taken from The Classifying Heart Sounds Challenge., Conclusions: The obtained results are compared with some of the existing methods. The comparisons show that the proposed method outperformed., Competing Interests: Conflict of interestThe authors of the paper declare that they have no conflict of interest.

Objectives: The aim of this study was to investigate the associations of asthma with the psychological profile (depression and anxiety) of children with asthma and their mothers as well as the attitudes of these mothers toward their children and their family relationships., Methods: Sixty-four children with asthma, 60 healthy children and their mothers were included in the study. The Children's Depression Inventory (CDI) and Childhood Anxiety Sensitivity Index (CASI) were applied to the children. All mothers completed the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Parental Attitude Research Instrument and the Family Assessment Device., Results: CASI scores were significantly higher in children with asthma (p < 0.001) than in healthy children. The increasing duration and severity of asthma were associated with increasing anxiety levels in children with asthma. Depression and anxiety scores were significantly higher in the mothers of children with asthma than in the comparison group. The mothers of children with asthma did not have supportive and friendly relationships with their children. In addition, these mothers had significantly higher Attitude of Hostility and Rejection, Attitude of Over-parenting and Authoritarian Attitude scores than those of the comparison group. Increasing duration and severity of asthma influenced family functions and the attitude of the mothers of children with asthma. There was a correlation between an increasing number of emergency department visits and increasing depression in the mothers of children with asthma., Conclusions: This cross-sectional study revealed that the disease may negatively affect the lives of children with asthma and their mothers and their family relationships.

Ustilago maydis is a biotrophic fungus causing corn smut disease in maize. The secreted effector protein Pit2 is an inhibitor of papain-like cysteine proteases (PLCPs) essential for virulence. Pit2 inhibitory function relies on a conserved 14 amino acids motif (PID14). Here we show that synthetic PID14 peptides act more efficiently as PLCP inhibitors than the full-length Pit2 effector. Mass spectrometry shows processing of Pit2 by maize PLCPs, which releases an inhibitory core motif from the PID14 sequence. Mutational analysis demonstrates that two conserved residues are essential for Pit2 function. We propose that the Pit2 effector functions as a substrate mimicking molecule: Pit2 is a suitable substrate for apoplastic PLCPs and its processing releases the embedded inhibitor peptide, which in turn blocks PLCPs to modulate host immunity. Remarkably, the PID14 core motif is present in several plant associated fungi and bacteria, indicating the existence of a conserved microbial inhibitor of proteases (cMIP).

Objectives: In this study, we aimed to investigate the predictive value of pre-ablative stimulated thyroglobulin (Tg) and Tg/thyroid-stimulating hormone (TSH) to identify lymph node metastasis (LNM) or distant metastases (DM) prior to radioactive iodine (RAI) treatment., Methods: Patients without metastasis were included in group 1 (n=100), those with LNM were included in group 2 (n=83), and those with DM constituted group 3 (n=23). Tg and TSH values were measured approximately 4 hours prior to RAI ablation therapy., Results: There was a significant difference between group 3 and other groups (group 1 and group 2) in terms of Tg (p<0.001) and Tg/ TSH (p<0.001). For Tg level and Tg/TSH ratio, the areas under ROC were 0.990 [95% confidence interval (CI): 0.979-1] and 0.991 (95% CI: 0.981-1), respectively. The cut-off points for Tg and Tg/TSH were 102 ng/mL and 1.06, respectively., Conclusion: Our results suggest that Tg and Tg/TSH values can be used to predict DM. On the other hand, our study indicates that patients should be carefully evaluated for LNM even when Tg levels are l ow.

Essentials Blood coagulation is driven by vitamin K (VK)-dependent proteases. We have identified and characterized 'sirtilin' as an additional VK-dependent protease. Sirtilins emerged early in the evolution of the coagulation system of vertebrates. Ubiquitous occurrence might indicate an important functional role of sirtilins. SUMMARY: Background Vitamin K (VK)-dependent proteases are major players in blood coagulation, including both the initiation and the regulation of the cascade. Five different members of this protease family have been described, comprising the following coagulation factors: factor VII, FIX, FX, protein C (PC), and prothrombin (FII). FVII, FIX, FX and PC share a typical domain architecture, with an N-terminal γ-carboxyglutamate (Gla) domain, two epidermal growth factor-like (EGF) domains, and a C-terminal trypsin-like serine protease (SP) domain. Objectives We have identified uncharacterized proteins in snake genomes showing the typical Gla-EGF1-EGF2-SP domain architecture but relatively low sequence conservation compared to known VK-dependent proteases. On the basis of sequence analysis, we hypothesized that these proteins are functional members of the VK-dependent protease family. Methods/results Using phylogenetic analyses, we confirmed the so-called 'sirtilins' as an additional VK-dependent protease class. These proteases were found in several vertebrates, including jawless fish, cartilaginous fish, bony fish, reptiles, birds, and marsupials, but not in other mammals. The recombinant zymogen form of Thamnophis sirtalis sirtilin was produced by in vitro renaturation, and was activated with human activated FXI. The activated form of sirtilin proteolytically cleaved peptide and protein substrates, including prothrombin. Mass spectrometry-based substrate profiling of sirtilin revealed a narrower sequence specificity than those of FIX and FX. Conclusions The ubiquitous occurrence of sirtilins in many vertebrate classes might indicate an important functional role. Understanding the detailed functions of sirtilins might contribute to a deeper understanding of the evolution and function of the vertebrate coagulation system., (© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Acute kidney injury (AKI) leads to significant morbidity and mortality; unfortunately, strategies to prevent or treat AKI are lacking. In recent years, several preconditioning protocols have been shown to be effective in inducing organ protection in rodent models. Here, we characterized two of these interventions-caloric restriction and hypoxic preconditioning-in a mouse model of cisplatin-induced AKI and investigated the underlying mechanisms by acquisition of multi-layered omic data (transcriptome, proteome, N-degradome) and functional parameters in the same animals. Both preconditioning protocols markedly ameliorated cisplatin-induced loss of kidney function, and caloric restriction also induced lipid synthesis. Bioinformatic analysis revealed mRNA-independent proteome alterations affecting the extracellular space, mitochondria, and transporters. Interestingly, our analyses revealed a strong dissociation of protein and RNA expression after cisplatin treatment that showed a strong correlation with the degree of damage. N-degradomic analysis revealed that most posttranscriptional changes were determined by arginine-specific proteolytic processing. This included a characteristic cisplatin-activated complement signature that was prevented by preconditioning. Amyloid and acute-phase proteins within the cortical parenchyma showed a similar response. Extensive analysis of disease-associated molecular patterns suggested that transcription-independent deposition of amyloid P-component serum protein may be a key component in the microenvironmental contribution to kidney damage. This proof-of-principle study provides new insights into the pathogenesis of cisplatin-induced AKI and the molecular mechanisms underlying organ protection by correlating phenotypic and multi-layered omics data., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Monatomic and molecular hydrogen and also oxygen, as well as water molecules and OH that are exposed to atomic copper in intimate contact, have been studied theoretically using computational methods. The authors optimized moderately large structures of Cu/H/Cu, Cu/HCuH/Cu, Cu/H 2 /Cu, Cu/H 2 O/Cu, Cu/OH/Cu, Cu/O/Cu, and Cu/O 2 /Cu and calculated appropriate values for conductance and inelastic tunneling spectroscopy (IETS) properties of the contact junctions, elucidating them as being a possible outcome resulting from the exposure of copper electrodes to the atomic/molecular contaminant species. Here we also demonstrate the IETS properties, by means of ab initio calculations, which can determine the form of the junction geometries. Furthermore, we identify the bonding geometries at the interfaces of the copper electrodes that directly give rise to the specific IETS signatures that have been observed in recent experiments. Based on low-bias conductance and IETS calculations, for the specific case of water exposure of copper electrodes, it was concluded that a single hydrogen or a single oxygen atom bridging the copper electrodes is not responsible for the high conductance peak measurements. Regarding Model 4, where an individual water molecule is considered to be the bridging constituent, our computational results suggest that it has a relatively low probability of being an appropriate candidate. Based upon current computational results, the two hydrogens in Model 3 appear to be in molecular form, although they still form a bond with the adjacent copper atoms. Comparing computational with experimental results indicates that Model 3 is in acceptable agreement with available data.

Bilici M, Fidancı-Dedeoğlu Z, Demir F, Akın A, Türe M, Balık H, Tan İ, Ertuğrul S. Prolonged QT dispersion is associated with pediatric syncope. Turk J Pediatr 2019; 61: 85-91. We aimed to find out whether QT dispersion can be used as a diagnostic marker in terms of syncope type, and recurrence risk. Fifty-two patients (28 male, 53.8%) admitted to the pediatric cardiology clinic with syncope were compared with 50 healthy controls (28 male, 56%; mean age: 13.8±2.3 years, range: 11-17 years) for QT dispersion (QTd) and other electrocardiographic findings. Gender, age, echocardiography, blood pressure while standing and sitting, electrolyte levels, liver and kidney function tests, and QTd and QTcd (calculated with corrected QT: QTc) in electrocardiography (ECG) of patients were all evaluated. Patients` ages varied between 7-17 years and the mean age at first syncope was 13.9±2.4 years. Mean follow-up duration of the patients was 10±5 months (range: 5-18 months). Mean number of syncope attacks was 2.8±2.2. QTd (72±46 ms vs. 34±14 ms) and QTcd (77±45 ms vs. 33±14 ms) values of the patients were significantly longer, compared to control group (p < 0.001). The age, gender, QTd, and QTcd values did not differ between the subtypes of syncope based on pathogenetic mechanism. Additionally, these parameters did not differ in terms of the number of syncope recurrence and tilt test. Patients` complaints reduced after cardiologic evaluation and advice regarding prevention of syncope. We think that in follow-up period, education and preventive precautions that can be taken in the daily life must be emphasized, and drug treatment can be started in unresponsive cases.

Objective: Risk factors of cranial migration were investigated in patients with lumbar disc herniation (LDH) that migrated in the cranial direction and the long-term outcomes are discussed in this study., Materials and Methods: Patients who underwent surgery for LDH at four different centers between 2012 and 2017 were studied. Extraligamentous discs were located in the lateral part of the posterior longitudinal ligament (PLL) within the spinal canal of the axial plane, and subligamentous discs were located under the PLL. The extent of cranial migration was calculated as a percentage of the height of the migrated corpus. Based on the extent of cranial migration, partial hemilaminectomy or hemilaminectomy was performed at different rates in each patient and the amount of laminectomy performed was recorded. During surgery, all free fragments were attempted to be removed. The appropriate technique was decided intraoperatively, and the surgery was performed on an individual patient basis., Results: Of 1289 patients who underwent surgery for LDH, 654 (50.73%) had caudal migration, 576 (44.68%) had migration at the level of the disc, and 59 (4.57%) had cranial migration. Analysis of 59 patients with cranial migration according to the localization of the disc fragment revealed that 31 had extraligamentous and 28 had subligamentous fragments ( P = 0.024)., Conclusions: Extraligamentous intervertebral disc fragments migrate more cranially than subligamentous intervertebral fragments. The anatomy of the PLL that varies along the corpus is the main reason for the weakness of the resistance of the disc material to the dorsolateral region, direction of discrete force vectors, and orientation of the disc fragment due to torsional vertebral movements., Competing Interests: There are no conflicts of interest.

Sabaz MN, Akın A, Bilici M, Demir F, Türe M, Balık H. Factors affecting mortality in children with dilated cardiomyopathy. Turk J Pediatr 2019; 61: 485-492. Dilated cardiomyopathy (DCMP) is a heart disease with high mortality rates that is often seen in children. Genetic and infectious reasons are primary in the etiology. The aim of this study was to investigate the etiology of DCMP and the parameters predicting mortality. A retrospective examination was made of 37 patients diagnosed with DCMP between January 2012 and October 2016. Data were recorded from the patient files of age, gender, complaints on presentation, findings of the physical examination, laboratory test results, echocardiography and electrocardiography findings at the time of diagnosis. These parameters were then compared between the surviving and nonsurviving patients. The patients comprised 21 males with a mean age of 27.50±50 months. Diagnosis was made at the age of < 12 months in 67.6% patients. Within mean 8 months of diagnosis, 16.2% of the patients were lost to mortality and 83.8% of the patients survived. In 83.3% of the non-surviving patients and in 29% of the surviving patients, sinus tachycardia was present at the time of diagnosis (p=0.023). Corrected QT (QTc) at the time of diagnosis was longer in the non-surviving patients (p=0.007). On ECG, the rate of ST-T wave change was higher in the non-surviving patients (80% vs. 17.8%, p=0.012). In conclusion, a significant proportion of the patients were diagnosed below the age of one year. In the non-surviving patients, as sinus tachycardia and ischaemic changes on ECG were seen more often and the QTc was longer, these findings could be considered to be predictors of mortality.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood, yet its etiology is unknown. It is known that microribonucleic acids (miRNAs) play a role in immunoregulation. We aimed to evaluate the plasma expression of some candidate miRNAs that are associated with the pathogenesis of autoimmunity. Thirty-one patients diagnosed with JIA and age-sex-matched 31 healthy children were enrolled for the study. The plasma levels of four candidate miRNAs (miRNA-16, miRNA-155, miRNA-204, and miRNA-451), which are known to be associated with autoimmunity, were examined in all the subjects. The plasma levels of miRNAs were measured with real-time PCR in the patients in active and inactive periods and in the healthy controls. The groups were compared with each other. The plasma miRNA-155 levels were found to increase in the JIA patients compared to the healthy controls, and it was statistically more significant in the inactive period. We found that the JIA patients had the higher levels of miRNA-16 and the lower levels of miRNA-204/miRNA-451 expressions compare with the control group, but there was no statistically significant difference. A statistically significant decrease in the plasma levels of miRNA-204 was found in the patients that were in inactive disease with only methotrexate therapy. The plasma miRNA expressions were compared in the JIA subtypes, and it was observed that miRNA-204 levels were higher in polyarticular JIA and miRNA-451 levels were higher in enthesitis-related arthritis without statistical significance. The significant alterations in the plasma expression of miRNA-155 and miRNA-204 suggest to us that these molecules may be related to the pathogenesis of JIA. More comprehensive and functional researches about the role of these molecules are needed in this regard.

Mass developments of toxin-producing cyanobacteria are frequently observed in freshwater ecosystems due to eutrophication and global warming. These mass developments can partly be attributed to cyanobacterial toxins, such as protease inhibitors (PIs), which inhibit digestive serine proteases of Daphnia, the major herbivore of phytoplankton and cyanobacteria. To date, mechanisms of this inhibition in the gut of the crustacean Daphnia magna are not known. Here, we characterize a single serine protease, chymotrypsin 448 (CT448), which is present in the gut of the crustacean D. magna. Sequence alignments with human serine proteases revealed that CT448 has a putative N-terminal pro-peptide which is extended compared to the mammalian homologs and within this pro-peptide two N-linked glycosylation motifs were found. CT448 was heterologously expressed in Sf21 insect cells using a baculovirus expression system for optimized protein production and secretion into the medium. The protein was purified via a one-step affinity chromatography, which resulted in a protein yield of 3.45 mg/l medium. The inactive precursor (zymogen) could be activated by tryptic digestion. This is the first example of a recombinant expression of an active crustacean serine protease, which functions in the gut of Daphnia. Proteomic identification of protease cleavage sites (PICS) and hydrolysation of various synthetic substrates showed that CT448 is a chymotrypsin-like elastase. In this study, we confirm that CT448 is a target of cyanobacterial protease inhibitors. Local evolutionary modifications of CT448 might render this proteolytic enzyme less susceptible against cyanobacterial secondary metabolites and might improve the fitness of Daphnia during cyanobacterial blooms., (Copyright © 2018 Elsevier B.V. All rights reserved.)

AMPA receptors are essential for fast excitatory transmission in the CNS. Autoantibodies to AMPA receptors have been identified in humans with autoimmune encephalitis and severe defects of hippocampal function. Here, combining electrophysiology and high-resolution imaging with neuronal culture preparations and passive-transfer models in wild-type and GluA1-knockout mice, we analyze how specific human autoantibodies against the AMPA receptor subunit GluA2 affect receptor function and composition, synaptic transmission, and plasticity. Anti-GluA2 antibodies induce receptor internalization and a reduction of synaptic GluA2-containing AMPARs followed by compensatory ryanodine receptor-dependent incorporation of synaptic non-GluA2 AMPARs. Furthermore, application of human pathogenic anti-GluA2 antibodies to mice impairs long-term synaptic plasticity in vitro and affects learning and memory in vivo. Our results identify a specific immune-neuronal rearrangement of AMPA receptor subunits, providing a framework to explain disease symptoms., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Familial Mediterranean fever (FMF) is an auto inflammatory disease characterized by periodic fever, synovitis and serositis. Patients may be admitted to gastroenterology units due to gastrointestinal symptoms. In this study; we aimed to analyze endoscopic findings and diagnostic utility of endoscopic procedure in children with FMF., Methods: Patient with FMF that was performed endoscopy for the gastrointestinal symptoms were included to the study (39 of 164 patients, 53 procedure). A control group was randomly designed as age and gender matched four endoscopic procedures per one endoscopic procedure of patients with FMF (n=212)., Results: No different was found between the patients and control group in esophagogastroscopy findings. However, the diagnosis of gastrointestinal pathology was made by esophagogastroscopy in 46.2% patients. Colonoscopic examination revealed that the frequency of inflammatory bowel disease (IBD) was higher in undiagnosed patients compared to both the control group (50.0% vs. 6.9%, p <0.05, odds ratio [OR]:13.4 and 95% confidence inteval [95% CI]: 2.1-84.3) and the patients under colchicine treatment (50.0% vs. 8.3%, p <0.05, OR: 11 and 95% CI: 0.8-147.8). Colonoscopic procedure that was made after the diagnosis was found to provide contribution by 16.7% in determining the etiology of the additional symptoms., Conclusion: Patients with FMF may be admitted to pediatric gastroenterology outpatient clinic prior to diagnosis or during the follow-up period. The frequency of IBD is high in undiagnosed patients with FMF. Endoscopic procedures may be helpful in these patients for the diagnosis accompanying mucosal lesions.

Background/objectives: The effect of pediatric psoriasis on quality of life has been demonstrated, but data regarding its influence on caregiver quality of life are scarce. The objective was to investigate how psoriasis affects quality of life of children and their caregivers., Methods: This multicenter study included 129 children with psoriasis and their caregivers, who were family members accompanying patients to the clinic. Patient quality of life was measured using the Child Dermatology Life Quality Index. Caregiver quality of life was assessed using Dermatological Family Impact Scale, a 15-item questionnaire validated for use in the Turkish language., Results: Mean Child Dermatology Life Quality Index score was 7.6, indicating a moderate effect on patient quality of life. Symptoms and feelings were the most severely impaired domains of patient quality of life, and emotions was the most severely impaired domain of caregiver quality of life. Dermatological Family Impact Scale score was significantly correlated with Child Dermatology Life Quality Index (correlation coefficient [r] = .554, P < .001) and Psoriasis Area and Severity Index (r = .350, P < .001). Caregivers of patients receiving systemic agents or phototherapy had relative impairment of multiple domains of quality of life compared to caregivers of patients receiving topical treatment only., Conclusion: Psychosocial effect of pediatric psoriasis was shown to extend beyond the individual, highlighting the importance of addressing patient and caregiver quality of life concerns in an integrated approach., (© 2018 Wiley Periodicals, Inc.)

Snoring is often associated with serious health risks such as obstructive sleep apnea and heart disease and may require targeted surgical interventions. In this regard, research into automatically and unobtrusively analysing the site of blockages that cause snore sounds is growing in popularity. Herein, we investigate the use of low level image texture features in classification of four specific types of snore sounds. Specifically, we explore histogram of local binary patterns (LBP) in dense grid of rectangular regions and histogram of oriented gradients (HOG) extracted from colour spectrograms for snore sound characterisation. Support vector machines with homogeneous mapping are used in the classification stage of the proposed method. Various experimental works are carried out with both LBP and HOG descriptors on the INTERSPEECH ComParE 2017 snoring sub-challenge dataset. Results presented indicate that LBP descriptors are better than the HOG descriptors in snore type detection and fusion of the LBP and HOG descriptors produces stronger results than either individual descriptor. Further, when compared to the challenge baseline and state-of-the-art deep spectrum features, our approach achieved relative percentage increases in unweighted average recall of 23.1% and 8.3% respectively.

Contents Summary 936 I. Introduction 936 II. The quest for plant protease substrates - proteomics to the rescue? 937 III. Quantitative proteome comparison reveals candidate substrates 938 IV. Dynamic metabolic stable isotope labeling to measure protein turnover in vivo 938 V. Terminomics - large-scale identification of protease cleavage sites 939 VI. Substrate or not substrate, that is the question 940 VII. Concluding remarks 941 Acknowledgements 941 References 941 SUMMARY: Proteolysis is a central regulatory mechanism of protein homeostasis and protein function that affects all aspects of plant life. Higher plants encode for hundreds of proteases, but their physiological substrates and hence their molecular functions remain mostly unknown. Current quantitative mass spectrometry-based proteomics enables unbiased large-scale interrogation of the proteome and its modifications. Here we provide an overview of proteomics techniques that allow profiling of changes in protein abundance, measurement of proteome turnover rates, identification of protease cleavage sites in vivo and in vitro and determination of protease sequence specificity. We discuss how these techniques can help to reveal protease substrates and determine plant protease function, illustrated by recent studies on selected plant proteases., (© 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.)

Neonatal inflammatory bowel disease (IBD) is a subclass of very early onset IBD that includes children younger than 1 month. It is characterized by more colonic involvement and monogenetic etiology, resistance to classical anti-inflammatory/immunomodulatory treatments and associated with colitis in first-degree family members. Herein we report a 3 month-old girl who was admitted with bloody diarrhea since 10 days of age. Her symptoms persist despite diet elimination. She was diagnosed with neonatal ulcerative colitis (UC) based on clinical, laboratory and histopathological examination. But, she was unresponsive to the immunosuppressive therapy. On the follow-up, she was hospitalized for the high fever two times. Genetic analysis revealed homozygote M694 V mutation. Bloody diarrhea and other clinical findings were improved after colchicine therapy. Neonatal UC associated with Familial Mediterranean fever is an extremely rare condition and to the best of our knowledge our case is the first case in literature. Early diagnosis autoinflammatory disease may prevent complications related to unnecessary immunosuppressive drug usage and the risk of development of amyloidosis associated with autoinflammatory disorders.

Akın A, Bilici M, Demir F, Yılmazer MM, İpek MŞ, Kara H. Percutaneous retrieval of umbilical vein catheter fragment in an infant two months after embolization. Turk J Pediatr 2018; 60: 191-193. Umbilical vein catheterization is frequently preferred and a safe route of venous access especially in newborns. However, some cases with breaking and embolization of those catheters have been rarely reported. Herein we present a two-and-a-half-month-old infant being catheterized within first postnatal week and diagnosed to have embolization of the catheter fragment to conjunction of hepatic vein and right atrium. Percutaneous withdrawal of broken catheter was achieved despite several months after the embolization took place. We suggest that transcatheter removal of catheter fragment embolizations may be safe even in late diagnosis cases.

The aim of this study was to evaluate the feasibility, efficacy and safety of transcatheter closure of patent ductus arteriosus (PDA) with the Occlutech duct occluder (ODO) in children. We reviewed the clinical records of 71 patients who underwent percutaneous closure of PDA with an ODO between September 2014 and August 2016. The Occlutech duct occluder was applied to 71 patients during the study period (September 2014-August 2016), and the results were analyzed in this study. Forty-two of the patients were female and 29 male. The median age was 20.5 months (range, 6-194 months) and median weight was 16 kg (range, 6-68 kg). The PDA was classified as type A in 54 patients (76.1%), type E in 14 (19.7%), type C in 2 (2.8%) and type B in 1 (1.4%) based on the Krichenko classification. A standard ODO device was used for the transcatheter closure procedure in 66 patients and the long-shank ODO device in 5. In the echocardiographic measurement of PDA, the median smallest diameter was 2.7 mm (range, 1.5-7.0 mm), and in the angiographic measurement, the median smallest diameter was 2.5 mm (range, 1.5-6.5 mm). All 71 patients underwent successful PDA closure with the ODO. Angiography following the procedure showed complete closure in 47 patients (66.2%), mild residual shunt in 13 patients (18.3%) and a trivial shunt in 11 patients (15.5%). Color flow Doppler echocardiogpaphy at 24 h post-implantation showed that complete closure was achieved in 65 patients (91.5%), and 6 patients (8.5%) had mild residual shunt. All patients (100%) had complete closure at 30 days of follow-up. The results of this study showed that the Occlutech PDA occluder device is safe and effective in the closure of PDA. As the pulmonary artery side of the device is wider than the aortic side, protrusion toward the aortic side and embolization are prevented, but there is residual shunt in the early period, although this residual shunt disappeared after a few months.

Objective: Autoimmune encephalitis is most frequently associated with anti-NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid (CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody-producing clones, and characterize their antibody signatures in recombinant form., Methods: Patients with recent onset typical anti-NMDAR encephalitis were subjected to flow cytometry analysis of the peripheral and intrathecal immune response before, during, and after immunotherapy. Recombinant human monoclonal antibodies (rhuMab) were cloned and expressed from matching immunoglobulin heavy- (IgH) and light-chain (IgL) amplicons of clonally expanded intrathecal plasma cells (cePc) and tested for their pathogenic relevance., Results: Intrathecal accumulation of B and plasma cells corresponded to the clinical course. The presence of cePc with hypermutated antigen receptors indicated an antigen-driven intrathecal immune response. Consistently, a single recombinant human GluN1-specific monoclonal antibody, rebuilt from intrathecal cePc, was sufficient to reproduce NMDAR epitope specificity in vitro. After intraventricular infusion in mice, it accumulated in the hippocampus, decreased synaptic NMDAR density, and caused severe reversible memory impairment, a key pathogenic feature of the human disease, in vivo., Interpretation: A CNS-specific humoral immune response is present in anti-NMDAR encephalitis specifically targeting the GluN1 subunit of the NMDAR. Using reverse genetics, we recovered the typical intrathecal antibody signature in recombinant form, and proved its pathogenic relevance by passive transfer of disease symptoms from man to mouse, providing the critical link between intrathecal immune response and the pathogenesis of anti-NMDAR encephalitis as a humorally mediated autoimmune disease.

Regulated intracellular proteostasis, controlled in part by proteolysis, is essential in maintaining the integrity of podocytes and the glomerular filtration barrier of the kidney. We applied a novel proteomics technology that enables proteome-wide identification, mapping, and quantification of protein N-termini to comprehensively characterize cleaved podocyte proteins in the glomerulus in vivo We found evidence that defined proteolytic cleavage results in various proteoforms of important podocyte proteins, including those of podocin, nephrin, neph1, α -actinin-4, and vimentin. Quantitative mapping of N-termini demonstrated perturbation of protease action during podocyte injury in vitro , including diminished proteolysis of α -actinin-4. Differentially regulated protease substrates comprised cytoskeletal proteins as well as intermediate filaments. Determination of preferential protease motifs during podocyte damage indicated activation of caspase proteases and inhibition of arginine-specific proteases. Several proteolytic processes were clearly site-specific, were conserved across species, and could be confirmed by differential migration behavior of protein fragments in gel electrophoresis. Some of the proteolytic changes discovered in vitro also occurred in two in vivo models of podocyte damage (WT1 heterozygous knockout mice and puromycin aminonucleoside-treated rats). Thus, we provide direct and systems-level evidence that the slit diaphragm and podocyte cytoskeleton are regulated targets of proteolytic modification, which is altered upon podocyte damage., (Copyright © 2017 by the American Society of Nephrology.)

The thermoelectric voltage developed across an atomic metal junction (i.e., a nanostructure in which one or a few atoms connect two metal electrodes) in response to a temperature difference between the electrodes, results from the quantum interference of electrons that pass through the junction multiple times after being scattered by the surrounding defects. Here we report successfully tuning this quantum interference and thus controlling the magnitude and sign of the thermoelectric voltage by applying a mechanical force that deforms the junction. The observed switching of the thermoelectric voltage is reversible and can be cycled many times. Our ab initio and semi-empirical calculations elucidate the detailed mechanism by which the quantum interference is tuned. We show that the applied strain alters the quantum phases of electrons passing through the narrowest part of the junction and hence modifies the electronic quantum interference in the device. Tuning the quantum interference causes the energies of electronic transport resonances to shift, which affects the thermoelectric voltage. These experimental and theoretical studies reveal that Au atomic junctions can be made to exhibit both positive and negative thermoelectric voltages on demand, and demonstrate the importance and tunability of the quantum interference effect in the atomic-scale metal nanostructures.

Objective: To assess the association between cigarette smoking and ventricular arrhythmias in adolescents. Novel electrocardiographic parameters -Tp-e interval, as well as Tpe/QT and Tpe/QTc ratios - were used to make this assessment., Methods: The study population consisted of 87 subjects aged between 16-19 years. Fifty-one adolescent smokers with no risk of arrhythmia comprised the Smoker Group, and 36 adolescents who had never smoked cigarettes comprised the Control Group. Smokers were defined as patients smoking more than three cigarettes per day, for at least 1 year. Body mass index, systolic, diastolic and mean blood pressures were measured, and electrocardiograms were performed on all subjects. Heart rate, PR and Tp-e intervals, and Tpe/QT, Tpe/QTc ratio were digitally measured., Results: Adolescents in Smoker Group had smoked cigarettes for 2.9±1.4 years (range 1 to 6 years). The mean age at starting smoking was 13.8±1.4 years. There were no differences between smokers and Control Group as to baseline clinical variables (p>0.05). The PR, QT and QTc intervals were similar in all groups. Tp-e interval (98.4±12.7ms and 78.3±6.9 ms; p<0.001), Tpe/QT (0.28±0.04 and 22±0.03; p<0.01), Tpe/QTc (0.24±0.03 and 0.19±0.01; p<0.001) ratios were significantly higher in Smoker Group. There were no correlations between years of smoking, number of cigarettes per day, Tpe interval, Tpe/QT or Tpe/QTc ratios., Conclusion: Cigarette smoking is associated with risk of ventricular arrhytmogenesis with prolonged Tp-e interval and increased Tpe/QT and Tpe/QTc ratios in adolescents.