bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Cathepsin S in Periodontal Inflammation and Infection
Authors: Memmert S. , Damanaki A. , Nogueira A. V. B. , Eick S. , Nokhbehsaim M. , Papadopoulou A. K. , Till A. , Rath B. , Jepsen S. , Götz W. , Piperi C. , Basdra E. K. , Cirelli J. A. , Jäger A. , Deschner J.
Published: December 2017

Cathepsin S is a cysteine protease and regulator of autophagy with possible involvement in periodontitis. The objective of this study was to investigate whether cathepsin S is involved in the pathogenesis of periodontal diseases. Human periodontal fibroblasts were cultured under inflammatory and infectious conditions elicited by interleukin-1βandFusobacterium nucleatum, respectively. An array-based approach was used to analyze differential expression of autophagy-associated genes. Cathepsin S was upregulated most strongly and thus further studiedin vitroat gene and protein levels.In vivo, gingival tissue biopsies from rats with ligature-induced periodontitis and from periodontitis patients were also analyzed at transcriptional and protein levels. Multiple gene expression changes due to interleukin-1βandF. nucleatumwere observedin vitro. Both stimulants caused a significant cathepsin S upregulation. A significantly elevated cathepsin S expression in gingival biopsies from rats with experimental periodontitis was foundin vivo, as compared to that from control. Gingival biopsies from periodontitis patients showed a significantly higher cathepsin S expression than those from healthy gingiva. Our findings provide original evidence that cathepsin S is increased in periodontal cells and tissues under inflammatory and infectious conditions, suggesting a critical role of this autophagy-associated molecule in the pathogenesis of periodontitis.
Could We Really Use Aloe vera Food Supplements to Treat Diabetes? Quality Control Issues
Authors: Habtemariam Solomon
Published: December 2017

Diabetes UK has recently listed a number of herbs and spices that have been clinically shown to improve blood glucose control in type‐2 diabetes patients and the diabetes high‐risk group. With Aloe vera being top in this list, its health benefit along with health and beauty/food retailers supplying it was illustrated in detail. Previous article from this laboratory scrutinised the merit of using A. vera as an alternative therapy to prescription antidiabetic drugs and the risk of using food supplements in the market which do not qualify as drug preparations. In continuation of this discussion, the present study assesses three Aloe Pura brands and one Holland and Barret brand of A. vera juice supplements in the UK market through chromatographic and spectroscopic analysis. While the polysaccharide active ingredient, acemannan, appears to be within the recommended limit, it was found that Aloe Pura (one of the best‐selling brands for A. vera supplement) products have benzoate additive that does not appear in the supplement levels. Moreover, two of the Aloe Pura brand juices contain methanol, suggesting that the International Aloe Science Council (IASC) certification does not guarantee the medicinal quality of these products. The therapeutic fitness of such supplements is discussed.
A Stability Analysis of Thermostatically Controlled Loads for Power System Frequency Control
Authors: Webborn Ellen , MacKay Robert S.
Published: December 2017

Thermostatically controlled loads (TCLs) are a flexible demand resource with the potential to play a significant role in supporting electricity grid operation. We model a large number of identical TCLs acting autonomously according to a deterministic control scheme to provide frequency response as a population of coupled oscillators. We perform stability analysis to explore the danger of the TCL temperature cycles synchronising: an emergent phenomenon often found in populations of coupled oscillators and predicted in this type of demand response scheme. We take identical TCLs as it can be assumed to be the worst case. We find that the uniform equilibrium is stable and the fully synchronised periodic cycle is unstable, suggesting that synchronisation might not be as serious a danger as feared. Then detailed simulations are performed to study the effects of a population of frequency-sensitive TCLs acting under real system conditions using historic system data. The potential reduction in frequency response services required from other providers is determined, for both homogeneous and heterogeneous populations. For homogeneous populations, we find significant synchronisation, but very minimal diversity removes the synchronisation effects. In summary, we combine dynamical systems stability analysis with large-scale simulations to offer new insights into TCL switching behaviour.
Maternal Dietary Patterns and Gestational Diabetes Risk: A Case-Control Study
Authors: Sedaghat Fatemeh , Akhoondan Mahdieh , Ehteshami Mehdi , Aghamohammadi Vahideh , Ghanei Nila , Mirmiran Parvin , Rashidkhani Bahram
Published: December 2017

Background. Maternal dietary patterns play an important role in the progress of gestational diabetes mellitus (GDM). The aim of the present study was to explore this association.Method. A total of 388 pregnant women (122 case and 266 control) were included. Dietary intake were collected using a food frequency questionnaire (FFQ). GDM was diagnosed using a 100-gram, 3-hour oral glucose tolerance test. Dietary pattern was identified by factor analysis. To investigate the relation between each of the independent variables with gestational diabetes, the odds ratio (OR) was calculated.Results. Western dietary pattern was high in sweets, jams, mayonnaise, soft drinks, salty snacks, solid fat, high-fat dairy products, potatoes, organ meat, eggs, red meat, processed foods, tea, and coffee. The prudent dietary pattern was characterized by higher intake of liquid oils, legumes, nuts and seeds, fruits and dried fruits, fish and poultry whole, and refined grains. Western dietary pattern was associated with increased risk of gestational diabetes mellitus before and after adjustment for confounders (OR = 1.97, 95% CI: 1.27–3.04, OR = 1.68, 95% CI: 1.04–2.27). However, no significant association was found for a prudent pattern.Conclusion. These findings suggest that the Western dietary pattern was associated with an increased risk of GDM.
Antinociceptive Activities of the Methanolic Extract of the Stem Bark of Boswellia dalzielii Hutch. (Burseraceae) in Rats Are NO/cGMP/ATP‐Sensitive‐K+ Channel Activation Dependent
Authors: Mbiantcha Marius , Ngouonpe Wembe Alain , Dawe Amadou , Yousseu Nana William , Ateufack Gilbert
Published: December 2017

Boswellia dalzielii (B. dalzielii) is traditionally used in the treatment of rheumatism, pain, and inflammation. The present investigation evaluates the property and possible mechanism of action of the methanolic extract of B. dalzielii (BDME) on inflammatory and neuropathic pain models. Effects of BDME (250 and 500 mg/kg), orally administered, were verified in mechanical hypernociception induced by LPS or PGE2. Mechanical hyperalgesia, cold allodynia, and heat hyperalgesia were used in vincristine‐induced neuropathic pain. NW‐nitro‐L‐arginine methyl ester (inhibitor of nitric oxide synthase), glibenclamide (ATP‐sensitive potassium channel blocker), methylene blue (cGMP blocker), or naloxone (opioid antagonist receptor) has been used to evaluate the therapeutic effects of BDME on PGE2‐induced hyperalgesia. Chemical profile of BDME was determined by using HPLC‐XESI‐PDA/MS. BDME showed significant antinociceptive effects in inflammatory pain caused by LPS and PGE2. The extract also significantly inhibited neuropathic pain induced by vincristine. The antinociceptive property of BDME in PGE2 model was significantly blocked by L‐NAME, glibenclamide, methylene blue, or naloxone. The present work reveals the antinociceptive activities of BDME both in inflammatory and in neuropathic models of pain. This plant extract may be acting firstly by binding to opioid receptors and secondly by activating the NO/cGMP/ATP‐sensitive‐K+ channel pathway.
Long-Term High Salt Intake Involves Reduced SK Currents and Increased Excitability of PVN Neurons with Projections to the Rostral Ventrolateral Medulla in Rats
Authors: Chapp Andrew D. , Wang Renjun , Cheng Zixi (Jack) , Shan Zhiying , Chen Qing-Hui
Published: December 2017

Evidence indicates that high salt (HS) intake activates presympathetic paraventricular nucleus (PVN) neurons, which contributes to sympathoexcitation of salt-sensitive hypertension. The present study determined whether 5 weeks of HS (2% NaCl) intake alters the small conductance Ca2+-activated potassium channel (SK) current in presympathetic PVN neurons and whether this change affects the neuronal excitability. In whole-cell voltage-clamp recordings, HS-treated rats had significantly decreased SK currents compared to rats with normal salt (NS, 0.4% NaCl) intake in PVN neurons. The sensitivity of PVN neuronal excitability in response to current injections was greater in HS group compared to NS controls. The SK channel blocker apamin augmented the neuronal excitability in both groups but had less effect on the sensitivity of the neuronal excitability in HS group compared to NS controls. In the HS group, the interspike interval (ISI) was significantly shorter than that in NS controls. Apamin significantly shortened the ISI in NS controls but had less effect in the HS group. This data suggests that HS intake reduces SK currents, which contributes to increased PVN neuronal excitability at least in part through a decrease in spike frequency adaptation and may be a precursor to the development of salt-sensitive hypertension.
Optimal Physics Parameterization Scheme Combination of the Weather Research and Forecasting Model for Seasonal Precipitation Simulation over Ghana
Authors: Agyeman Richard Yao Kuma , Annor Thompson , Lamptey Benjamin , Quansah Emmanuel , Agyekum Jacob , Tieku Sampson Adu
Published: December 2017

Seasonal predictions of precipitation, among others, are important to help mitigate the effects of drought and floods on agriculture, hydropower generation, disasters, and many more. This work seeks to obtain a suitable combination of physics schemes of the Weather Research and Forecasting (WRF) model for seasonal precipitation simulation over Ghana. Using the ERA-Interim reanalysis as forcing data, simulation experiments spanning eight months (from April to November) were performed for two different years: a dry year (2001) and a wet year (2008). A double nested approach was used with the outer domain at 50 km resolution covering West Africa and the inner domain covering Ghana at 10 km resolution. The results suggest that the WRF model generally overestimated the observed precipitation by a mean value between 3% and 64% for both years. Most of the scheme combinations overestimated (underestimated) precipitation over coastal (northern) zones of Ghana for both years but estimated precipitation reasonably well over forest and transitional zones. On the whole, the combination of WRF Single-Moment 6-Class Microphysics Scheme, Grell-Devenyi Ensemble Cumulus Scheme, and Asymmetric Convective Model Planetary Boundary Layer Scheme simulated the best temporal pattern and temporal variability with the least relative bias for both years and therefore is recommended for Ghana.
Prognostic Factors for Immune Thrombocytopenia Outcome in Greek Children: A Retrospective Single-Centered Analysis
Authors: Makis Alexandros , Gkoutsias Athanasios , Palianopoulos Theodoros , Pappa Eleni , Papapetrou Evangelia , Tsaousi Christina , Hatzimichael Eleftheria , Chaliasos Nikolaos
Published: December 2017

Immune thrombocytopenia (ITP) in children has a varied course and according to duration is distinguished as newly diagnosed (<3 months), persistent (3–12), and chronic (>12) types. Several studies have evaluated the prognostic factors for the progression of the disease, but similar works have yet to be performed in Greece. We aimed to identify prognostic markers for the three forms of the disease in 57 Greek children during a 13-year period. Information regarding age, gender, preceding infection, bleeding type, duration of symptoms and platelets at diagnosis, treatment, disease course, and immunological markers was recorded. 39 children had newly diagnosed, 4 persistent, and 14 chronic disease. Chronic ITP children were more likely to be of age > 10 years (p=0.015) and have gradual initiation of the disease (p=0.001), platelets > 10 × 109/L (p=0.01), and impaired immunological markers (p<0.003) compared to newly diagnosed/persistent groups. Recent history of infection was found mainly in the newly diagnosed/persistent group (p=0.013). None of the children exhibited severe spontaneous bleeding. Conclusion. Even though ITP in children usually has a self-limited course, with rare serious bleeding complications, the chronic form of the disease is characterized by different predictive parameters, which can be used in clinical practice.
Staphylococcus aureusandEscherichia coliin Curd Cheese Sold in the Northeastern Region of South America
Authors: Barreto de Deus Tamiles , Barros Ludmilla Santana Soares , Mendes da Silva Ricardo , Karine da Silva Lima Wanessa , Virgens Lima Danuza das , dos Santos Silva Adriana
Published: December 2017

The present study evaluated the microbiological and sanitary quality of curd cheese sold on the beaches of the Itaparica Island, Brazil, and verified whether a correlation exists between the commercialization conditions and the microbiological data. The research was performed between December 2015 and March 2017. Sixty samples of rennet-containing cheese were collected to estimate the populations of mesophylls, psychrotrophic microorganisms, mold and yeast,Staphylococcus aureus, total coliforms, andEscherichia coli. An observational analysis was performed during the collection, using a checklist to verify the sellers’ sanitary conditions and cheese marketing. A high nonconformity index was registered regarding aspects in the checklist. In the microbiological analyses, the number of mesophylls in raw and roasted samples ranged from 7,88 to 14,82 log CFU/mL, and those of psychrotrophs ranged from 2,80 to 3,84 log CFU/mL. Meanwhile, mold and yeast levels in the samples ranged from 8,06 to 5,54 log CFU/mL,S. aureuswas detected at levels from 3,24 to 4,94 log CFU/mL, and the total coliform counts ranged from 4,48 to 7,18 log CFU/mL. The number ofE. colispecimens ranged from 2,96 to 5,75 log CFU/mL. Microbial insecurity was noted for commercialized curd cheese, and the need for intervention was indicated.
Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2–ERα–GREB1 Transcriptional Axis
Authors: Wu Yanming , Zhang Zhao , Cenciarini Mauro E. , Proietti Cecilia J. , Amasino Matias , Hong Tao , Yang Mei , Liao Yiji , Chiang Huai-Chin , Kaklamani Virginia G. , Jeselsohn Rinath , Vadlamudi Ratna K. , Huang Tim Hui-Ming , Li Rong , De Angelis Carmine , Fu Xiaoyong , Elizalde Patricia V. , Schiff Rachel , Brown Myles , Xu Kexin
Published: December 2017

Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor, and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor α (ERα) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG-enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ERα cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or antiestrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ERα coregulators, converting the antiestrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program.

Significance: This study suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program defined within. Cancer Res; 78(3); 671–84. ©2017 AACR.
Perioperative Outcomes and Early Survival in Octogenarians Who Underwent Radical Cystectomy for Bladder Cancer
Authors: Zattoni Fabio , Palumbo Vito , Giannarini Gianluca , Crestani Alessandro , Kungulli Afrovita , Novara Giacomo , Zattoni Filiberto , Ficarra Vincenzo
Published: December 2017

Objective: To evaluate perioperative outcomes and early survival in a series of octogenarians who underwent radical cystectomy (RC) and urinary diversion for bladder cancer. Patients and Methods: We retrospectively evaluated the clinical records of 44 patients aged ≥80 years who underwent open RC and urinary diversion at 2 high-volume centers between July 2013 and December 2015. Estimated blood loss (EBL), transfusion rate, and length of hospital stay (LOS) were evaluated. Ninety-day postoperative complications were stratified according to the type of urinary diversion. Univariable analysis was performed to identify predictors of overall and major complications. Overall survival (OS) was estimated using the Kaplan-Meier method. Results: Median age was 83 years (interquartile range [IQR] 81-85). Age-adjusted Charlson score was ≥4 in 37 (84%) patients, and American Society of Anesthesiologists score was ≥3 in 34 (77%) patients. Ileal conduit (IC) was performed in 21/44 (48%) cases, cutaneous ureterostomy (CU) in 20/44 (45%), and no urinary diversion was required for 3 (7%) dialytic patients. Median EBL was 700 mL (IQR 500-1,000) and 23 (52%) patients required blood transfusion. Median LOS was 13 days (IQR 10-18). Overall complications were recorded in 29 (66%) patients, with major complications observed in 12 (27%), with death occurring in 1. No differences in complications were observed between IC and CU. The 2-year OS estimate was 62.5%. Conclusions: Open RC in octogenarians has an acceptable rate of major complications and mortality. IC should be considered a good urinary diversion in these patients.
The Mechanism and Representation of Korean Three-Way Phonation Contrast: External Photoglottography, Intra-Oral Air Pressure, Airflow, and Acoustic Data
Authors: Kim Hyunsoon , Maeda Shinji , Honda Kiyoshi , Crevier-Buchman Lise
Published: December 2017

This paper aims to refine our understanding of the speech mechanism and laryngeal features involved in the Korean lenis (/p t k/), aspirated (/ph th kh/), and fortis (/p' t' k'/) plosives. For this purpose we made measurements using a new noninvasive technique called external lighting and sensing photoglottography (ePGG) as well as intra-oral air pressure (Pio) above the glottis, airflow, and acoustic data. From simultaneous recordings of the experimental data, we were ableto quantify the laryngeal-oral coordination of glottal opening and a consonant release, and the covariance of airflow peak and duration of aspiration with glottal opening. The phasing of glottal opening and the 3-way phonation contrast occurs in the order, from early to late, fortis, lenis < aspirated plosives, and the glottal opening peak ranges from low to high in the same order. We also found that a Pio peak, the durations of a high Pio plateau and an oral closure, and F0 are independent of the glottal opening mechanism, varying in the order lenis < aspirated and fortis plosives. From these findings, we propose that the 2 independent patterns are accounted for by the articulator-based features [±spread glottis] and [±tense], respectively.
Electrochemotherapy in Breast Cancer - Discussion of the Method and Literature Review
Authors: Wichtowski Mateusz , Murawa Dawid , Kulcenty Katarzyna , Zaleska Karolina
Published: December 2017

Breast cancer is the most common cause of skin metastases in women. The probability of their occurrence ranges from about 5% in the entire population to as much as 30% in the late stages of the disease. Although rarely life-threatening, they have a major impact on the quality of life of patients with this diagnosis, being the cause of pain, effusion, ulceration, infection, and psychological discomfort. Available methods of treatment, both local and systemic, often fail to provide adequate control of the disease. A particular challenge seems to be the treatment of those patients with cutaneous metastases who, due to the extent of their metastases, are not eligible for resection, in whom the possibility of radiation therapy has already been used, and in whom systemic therapy is ineffective or contraindicated. A new method providing the opportunity for effective treatment is electrochemotherapy (ECT). ECT combines electropulsation of tumor cells (by local application of electric pulses) and administration of antineoplastic drugs such as cisplatin or bleomycin (either intravenous or intratumoral). Several clinical studies have demonstrated that ECT provides safe, efﬁcient, and non-invasive locoregional treatment for chest wall breast cancer recurrence.
The Meaning of Hope: Developmental Origins in Early Childhood
Authors: Montgomery Derek E.
Published: December 2017

This paper analyzes how the verb hope acquires meaning in early childhood. It begins by critiquing the assumption that mental verbs derive meaning from corresponding referents. Meaning is instead constructed as children learn the conventions and practices that guide use of the word within discourse. Describing these conventions and practices illustrates that hope expresses desires and preferences about future, uncertain, and possible events. The ways in which early cognitive development may contribute to children's understanding of hope are discussed. A case study of one child's early use of hope augments the theoretical analyses presented in the paper.
Adverse Events of Trastuzumab Emtansine (T-DM1) in the Treatment of HER2-Positive Breast Cancer Patients
Authors: Kowalczyk Lidia , Bartsch Rupert , Singer Christian F. , Farr Alex
Published: December 2017

The human epidermal growth factor receptor 2 (HER2) is commonly associated with poor prognosis and is overexpressed in approximately 15-20% of all breast cancers. The introduction of HER2-targeted therapies led to significant improvement in the prognosis of patients with HER2-positive breast cancer, for both early and advanced disease. These targeted therapies include the antibodies trastzumab and pertuzumab, the tyrosine kinase inhibitor lapatinib, and the antibody-drug conjugate trastuzumab emtansine (T-DM1). T-DM1 combines the anti-tumor activity of trastuzumab with that of DM1, a highly potent derivative of the anti-microtubule agent maytansine, resulting in increased anti-tumor activity. Notably, this agent has been demonstrated to be safe and is associated with low toxicity rates. However, maytansinoid, the cytotoxic component of T-DM1, does have the potential to induce various adverse events, particularly radiation necrosis, when used in combination with stereotactic radiosurgery. In this review, we aimed to summarize the current literature regarding T-DM1 safety and toxicity, with special emphasis on the existing landmark studies.
The Impact of Anti-TNF Therapy on CD4+ and CD8+ Cell Subsets in Ankylosing Spondylitis
Authors: Dulic Sonja , Vasarhelyi Zsofia , Bajnok Anna , Szalay Balazs , Toldi Gergely , Kovacs Laszlo , Balog Attila
Published: December 2017

Objectives: Ankylosing spondylitis (AS) is a chronic, progressive immune-mediated inflammatory disease, driven primarily by Th1 and Th17 cells. Anti-TNF therapies are successfully used in AS to achieve and maintain remission. However, their influence on the composition of T-cell subsets is not clear. We aimed to characterize the changes in the T-cell repertoire after a long-term anti-TNF treatment in AS patients. Methods: Twenty-two AS patients under long-term anti-TNF therapy were evaluated (15 anti-TNF responders and 7 nonresponders). A wide range of cell subtypes was analyzed with flow cytometry and compared with therapy-naïve and short-term data too. Results: Key findings include decreased proportions of naïve CD4 and CD8 cells, increased frequencies of Th1 and Th17 cells and higher Th1/Th2 ratios in the long-term anti-TNF-treated patients (responders, nonresponders and total), which was found to be significant not only when compared with healthy controls, but also with therapy-naïve and short-term anti-TNF-treated AS patients. We noted several alterations within the various activated T-cell subsets – increase in CD4HLADR cells in responders, in CD8HLADR cells in the whole AS group and in responders, and in CD4CD25 cells in responders, and decrease in CD4CD69 cell percentages in long-term treated patients – becoming evident only after long-term anti-TNF therapy. Conclusions: This study provides a comprehensive assessment of the impact of anti-TNF therapy on the T-cell repertoire in AS. Changes in T-cell phenotype seem to develop progressively during therapy, even in inactive disease, and reflect an ongoing effector T-cell differentiation and activation, along with the parallel compensatory increase in regulatory T cells.
Lenalidomide Maintenance after R-CHOP Therapy in Diffuse Large B-Cell Lymphoma: Can It Be a Standard of Care
Authors: Dada Reyad
Published: December 2017

Diffuse large B-cell lymphoma is an aggressive non-Hodgkin lymphoma subtype which requires immediate treatment. Standard treatment is usually a combined immune chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Since R-CHOP was approved, several attempts to combine it with novel agents and/or use them as maintenance therapy failed to improve the outcome. Recently, maintenance with lenalidomide after standard immune chemotherapy showed promising results. This review discusses the most pertinent published and running studies, analyzing study design, results, and practicality.
Resistance-Associated Mutations and Polymorphisms among Integrase Inhibitor-Naïve HIV-1 Patients in Kuwait
Authors: Chehadeh Wassim , Albaksami Osama , John Sonia Elezebeth , Al-Nakib Widad
Published: December 2017

Objectives: Resistance-associated mutations (RAMs) in the integrase of different HIV-1 subtypes were investigated in a cohort of patients never exposed to integrase strand transfer inhibitors (INSTIs). Methods: The viral RNA was extracted from plasma samples of 53 INSTI-naïve patients, and the integrase genetic region was sequenced and analyzed for subtype assignment and drug resistance. Results: The median viral load at sampling was 5.28 × 104 RNA copies/mL. Bayesian phylogenetic analysis showed 85% of the HIV-1 isolates were non-B subtypes, with a predominance of subtypes C (22.6%) and CRF01_AE (26.4%). A total of 52 and 110 mutations were found in the integrase region of HIV-1 B and non-B subtypes, respectively. Nonpolymorphic INSTI-RAMs were not detected in this study. However, the accessory mutation E157Q was found in 1 patient with CRF02_AG, and the polymorphic mutations L74M/I that may contribute to a reduced susceptibility to INSTIs in the presence of major mutations were observed in 6 (13.3%) patients with non-B subtypes and 1 (12.5%) patient with the B subtype. Polymorphic mutations at positions known to harbor primary and accessory RAMs were also detected in this study. Conclusion: Our results highlight the importance of monitoring the emergence of INSTI-RAMS before and after the initiation of INSTI-based therapy.
A Rare Cause of Abdominal Pain in a Patient with Acute Necrotizing Pancreatitis
Authors: Branco Joana C. , Cardoso Mariana F. , Lourenço Luís Carvalho , Santos Liliana , Horta David Valadas , Coimbra Élia , Reis Jorge A.
Published: December 2017

Introduction: Walled-off necrosis (WON) is a potentially lethal late complication of acute pancreatitis (AP) and occurs in less than 10% of AP cases. It can be located in or outside the pancreas. When infected, the mortality rate increases and can reach 100% if the collection is not drained. Its treatment is complex and includes, at the beginning, intravenous antibiotics, which permit sepsis control and a delay in the therapeutic intervention, like drainage. Nowadays, a minimally invasive approach is advised. Depending on the location of the collection, computed tomography (CT)-guided drainage or endoscopic necrosectomy are the primary options, then complemented by surgical necrosectomy if needed. Infected WON of the abdominal wall has been rarely described in the literature and there is no report of any infection with Citrobacter freundii. Case: We present the case of a 61-year-old man with necrotizing AP complicated by WON of the left abdominal wall, infected with Citrobacter freundii that was successfully treated with CT-guided percutaneous drainage and intravenous antibiotics. Conclusion: Infected WON accounts for considerable mortality and its location in the abdominal wall is rare; it can be treated with antibiotics and CT-guided drainage with no need for further intervention.
Disease Control on Lanreotide Autogel® 120 mg in a Patient with Metastatic Gastrinoma: A Case Report
Authors: Aerts Maridi , Reynaert Hendrik
Published: December 2017

Gastrinomas are functionally active pancreatic neuroendocrine tumors (NETs) secreting gastrin and are associated with local or regional metastases in 60% of the cases. Somatostatin analogs (SSAs) are currently recommended as a first-line treatment for the symptomatic treatment of NETs. Although antiproliferative activity of SSAs has been demonstrated in various cancer types in several in vivo and in vitro studies, clinical benefits with SSAs have been only achieved in a small proportion of patients. We report a disease control on a long-acting SSA lanreotide in a patient with metastatic gastrinoma. A 60-year-old man, who had previously undergone a surgical resection of metastatic pancreatic gastrinoma, presented with abdominal bloating, edema in the lower limbs, fatigue, and weight loss. The gastrinoma relapse with additional metastases in the pancreas, duodenum, and liver was confirmed by positron emission tomography-computed tomography (PET-CT) scan; the patient’s blood gastrin level was >5,000 ng/L. Treatment with the SSA octreotide long-acting release was initiated to treat the gastrinoma relapse. On the CT scan done in September 2011, the liver metastases were still identifiable. In December 2011, the treatment was switched to lanreotide Autogel® (120 mg every 2 weeks). Following the treatment, the gastrin levels were reduced to <1,200 ng/L in September 2013, and 812 ng/L in July 2016. Since November 2012, the gastrinoma lesions were no longer visible in abdominal CT. At the time of this report, the patient’s gastrinoma was under control with lanreotide Autogel®. This case report supports the use of lanreotide Autogel® as effective treatment for metastatic gastrinoma.
Long-Term Outcomes after Surgery for Appendiceal Mucinous Tumours
Authors: Dulskas Audrius , Poskus Tomas , Poskus Eligijus , Strupas Kestutis
Published: December 2017

Background: Appendiceal mucinous tumour (AMT) is a very uncommon disease. We aimed to evaluate preoperative and postoperative characteristics as well as long-term outcomes of patients with appendiceal mucinous adenomas and peritoneal pseudomyxoma (PMP). Methods: A consecutive cohort of patients diagnosed with AMT were included in the study. Tumour recurrence and the development of PMP was diagnosed based on the patients' complaints, physical examination, imaging studies, and biopsy results. The calculation of survival rates was performed using the Kaplan-Meier method. Results: Between January 2003 and February 2013, 25 patients had AMT. 15 patients underwent appendectomy only (60%), 5 patients (20%) right hemicolectomy, 4 patients (16%) cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC), and 1 patient (4%) appendectomy with caecal resection. Another 2 patients underwent CRS and HIPEC 4 days and 3 years, respectively, following initial appendectomy. In the histopathologic examination, adenoma was diagnosed in 12 patients (48%); among these, low-grade PMP was found in 1 patient (4%). Low-grade appendiceal mucinous adenocarcinoma (AMCa) was diagnosed in 11 patients (44%); among these, low-grade PMP was found in seven cases (28%) and high-grade AMCa was diagnosed in 2 patients (8%). 2 of 8 PMP patients did not undergo CRS ± HIPEC because of comorbidities. The 5-year overall survival was 100% for the adenomas and 62% for PMP patients. Conclusion: AMT is a very rare entity with a considerably good outcome even in disseminated disease. CRS and HIPEC is a gold standard treatment for PMP with excellent prognosis. However, our results could still be improved in the future.
Age-Induced Changes in White, Brite, and Brown Adipose Depots: A Mini-Review
Authors: Schosserer Markus , Grillari Johannes , Wolfrum Christian , Scheideler Marcel
Published: December 2017

Aging is a time-related process of functional decline at organelle, cellular, tissue, and organismal level that ultimately limits life. Cellular senescence is a state of permanent growth arrest in response to stress and one of the major drivers of aging and age-related disorders. Senescent cells accumulate with age, and removal of these cells delays age-related disorders in different tissues and prolongs healthy lifespan. One of the most studied aging mechanisms is the accumulation of reactive oxygen species damage in cells, organs, and organisms over time. Elevated oxidative stress is also found in metabolic diseases such as obesity, metabolic syndrome and associated disorders. Moreover, dysregulation of the energy homeostasis is also associated with aging, and many age-related genes also control energy metabolism, with the adipose organ, comprising white, brite, and brown adipocytes, as an important metabolic player in the regulation of whole-body energy homeostasis. This review summarizes transformations in the adipose organ upon aging and cellular senescence and sheds light on the reallocation of fat mass between adipose depots, on the metabolism of white and brown adipose tissue, on the regenerative potential and adipogenic differentiation capacity of preadipocytes, and on alterations in mitochondria and bioenergetics. In conclusion, the aging process is a lifelong, creeping process with gradual decline in (pre-)adipocyte function over time. Thus, slowing down the accumulation of (pre-)adipocyte damage and dysfunction, removal of senescent preadipocytes as well as blocking deleterious compounds of the senescent secretome are protective measures to maintain a lasting state of health at old age.
Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma
Authors: Eckert Marita , Klumpp Lukas , Huber Stephan
Published: December 2017

Background/Aims: Valproic acid (VPA), an anticonvulsant and mood-stabilizing drug is used to treat epileptic seizure of glioblastoma patients. Besides its antiepileptic activity, VPA has been attributed further functions that improve the clinical outcome of glioblastoma patients. Those comprise the inhibition of some histone deacetylase (HDAC) isoforms which reportedly may result in radiosensitization. Retrospective analysis of patient data, however, could not unequivocally confirm a prolonged survival of glioblastoma patients receiving VPA. The present study aimed to identify potential VPA targets at the cellular level. Methods: To this end, the effect of VPA on metabolism, Ca2+-, biochemical and electro-signaling, cell-cycling, clonogenic survival and transfilter migration was analyzed in three human glioblastoma lines (T98G, U-87MG, U251) by MTT assay, Ca2+ imaging, immunoblotting, patch-clamp recording, flow cytometry, delayed plating colony formation and modified Boyden chamber assays, respectively. In addition, the effect of VPA on clonogenic survival of primary glioblastoma spheroid cultures treated with temozolomide and fractionated radiation was assessed by limited dilution assay. Results: In 2 of 3 glioblastoma lines, clinical relevant concentrations of VPA slightly slowed down cell cycle progression and decreased clonogenic survival. Furthermore, VPA induced Ca2+ signaling which was accompanied by pronounced K+ channel activity and transfilter cell migration. VPA did not affect metabolic NAD(P)H formation or radioresistance of the glioblastoma lines. Finally, VPA did not impair clonogenic survival or radioresistance of temozolomide-treated primary spheroid cultures. Conclusions: Combined, our in vitro data do not propose a general use of VPA as a radiosensitizer in anti-glioblastoma therapy.
Activation of Secretagogue Independent Gastric Acid Secretion via Endothelial Nitric Oxide Synthase Stimulation in Rats
Authors: Kitay Alice Miriam , Link Alexander , Geibel John P.
Published: December 2017

Background/Aims: L-arginine is an important mediator of cell division, wound healing, and immune function. It can be transformed by the nitric oxide synthase (NOS) to nitric oxide (NO), an important cell signaling molecule. Recent studies from our laboratory demonstrate specific effects of L-arginine (10mM) exposure on gastric acid secretion in rat parietal cells. Methods: Studies were performed with isolated gastric glands and the pH sensitive dye BCECF-AM +/- L-arginine to examine its effects on acid secretion. The direct NO-donor diethylamine NONOate sodium salt hydrate, was also used while monitoring intracellular pH. The specific inhibitor of the intracellular NO signal cascade ODQ was also used. Results: We found that gastric proton extrusion was activated with application of L-arginine (10mM), in a separate series when L-arginine (10mM) + L-NAME (30µM) were added there was no acid secretion. Addition of the NO-donor diethylamine NONOate sodium salt hydrate (10µM) also induced acid secretion. When the selective sGC-inhibitor ODQ was added with NONOate we did not observe acid secretion. Conclusion: We conclude that L-arginine is a novel secretagogue, which can mediate gastric acid secretion. Furthermore, the intake of L-arginine causes direct activation of the H+, K+ ATPase and increased proton extrusion from parietal cells resulting in the increased risk for acid-related diseases. The NO/sGC/cGMP pathway has never been described as a possible intracellular mechanism for H+, K+ ATPase activation before and presents a completely new scientific finding. Moreover, our studies demonstrate a novel role for L-NAME to effectively eliminate NOS induced acid secretion and thereby reducing the risk for L-arginine inducible ulcer disease.
Genetic Variants Contributing to Circulating Matrix Metalloproteinase 8 Levels and Their Association With Cardiovascular Diseases
Authors: Salminen Aino , Vlachopoulou Efthymia , Havulinna Aki S. , Tervahartiala Taina , Sattler Wolfgang , Lokki Marja-Liisa , Nieminen Markku S. , Perola Markus , Salomaa Veikko , Sinisalo Juha , Meri Seppo , Sorsa Timo , Pussinen Pirkko J.
Published: December 2017

Background—

Matrix metalloproteinase 8 (MMP-8) is a proinflammatory enzyme expressed mainly by neutrophils. Elevated serum and plasma concentrations of MMP-8 are associated with the risk for and outcome of cardiovascular diseases (CVDs). The origin of circulating MMP-8 is not completely clear.

Methods and Results—

We performed a genome-wide association study of serum MMP-8 levels in 2 populations comprising altogether 6049 individuals. Moreover, we studied whether MMP-8–associated variants are linked to increased risk of CVDs and overall mortality in >20 000 subjects. The strongest association with serum MMP-8 was found in locus 1q31.3, containing the gene for complement factor H (lead single nucleotide polymorphism: rs800292;
P
=2.4×10
–35
). In functional experiments, activation of the alternative pathway of complement in the carriers of rs800292 minor allele (Ile62 in factor H) led to decreased release of MMP-8 from neutrophils compared with the major allele (Val62 in factor H). Another association was detected in 1q21.3, containing genes
S100A8
,
S100A9
, and
S100A12
(strongest association: rs1560833;
P
=5.3×10
–15
). The minor allele of rs1560833 was inversely associated with CVD (odds ratio [95% confidence interval]: 0.90 [0.82–0.99];
P
=0.032) and the time to incident CVD event (hazard ratio [95% confidence interval]: 0.91 [0.84–0.99];
P
=0.032) in men but not in women.

Conclusions—

According to our results, the activation of the alternative pathway of the complement system strongly contributes to serum MMP-8 concentration. Genetic polymorphism in
S100A9–S100A12–S100A8
locus affects serum and plasma MMP-8 and shows a suggestive association with the risk of CVDs. Our results show that genetic variation determines a significant portion of circulating MMP-8 concentrations.
Novel Mutation in
FLNC
(Filamin C) Causes Familial Restrictive Cardiomyopathy
Authors: Tucker Nathan R. , McLellan Micheal A. , Hu Dongjian , Ye Jiangchuan , Parsons Victoria A. , Mills Robert W. , Clauss Sebastian , Dolmatova Elena , Shea Marisa A. , Milan David J. , Scott Nandita S. , Lindsay Mark , Lubitz Steven A. , Domian Ibrahim J. , Stone James R. , Lin Honghuang , Ellinor Patrick T.
Published: December 2017

Background—

Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy characterized by impaired diastolic ventricular function resulting in a poor clinical prognosis. Rarely, heritable forms of RCM have been reported, and mutations underlying RCM have been identified in genes that govern the contractile function of the cardiomyocytes.

Methods and Results—

We evaluated 8 family members across 4 generations by history, physical examination, electrocardiography, and echocardiography. Affected individuals presented with a pleitropic syndrome of progressive RCM, atrioventricular septal defects, and a high prevalence of atrial fibrillation. Exome sequencing of 5 affected members identified a single novel missense variant in a highly conserved residue of FLNC (filamin C; p.V2297M).
FLNC
encodes filamin C—a protein that acts as both a scaffold for the assembly and organization of the central contractile unit of striated muscle and also as a mechanosensitive signaling molecule during cell migration and shear stress. Immunohistochemical analysis of FLNC localization in cardiac tissue from an affected family member revealed a diminished localization at the z disk, whereas traditional localization at the intercalated disk was preserved. Stem cell-derived cardiomyocytes mutated to carry the effect allele had diminished contractile activity when compared with controls.

Conclusion—

We have identified a novel variant in
FLNC
as pathogenic variant for familial RCM—a finding that further expands on the genetic basis of this rare and morbid cardiomyopathy.
Genome-Wide Gene–Potassium Interaction Analyses on Blood Pressure
Authors: Li Changwei , He Jiang , Chen Jing , Zhao Jinying , Gu Dongfeng , Hixson James E. , Rao Dabeeru C. , Jaquish Cashell E. , Rice Treva K. , Sung Yun Ju , Kelly Tanika N.
Published: December 2017

Background—

Gene–environmental interaction analysis can identify novel genetic factors for blood pressure (BP). We performed genome-wide analyses to identify genomic loci that interact with potassium to influence BP using single-marker (1 and 2
df
joint tests) and gene-based tests among Chinese participants of the GenSalt study (Genetic Epidemiology Network of Salt Sensitivity).

Methods and Results—

Among 1876 GenSalt participants, the average of 3 urine samples was used to estimate potassium excretion. Nine BP measurements were taken using a random-zero sphygmomanometer. A total of 2.2 million single nucleotide polymorphisms were imputed using Affymetrix 6.0 genotype data and the Chinese Han of Beijing and Japanese of Tokyo HapMap reference panel. Promising findings (
P
<1.00×10
−
4
) from GenSalt were evaluated for replication among 775 Chinese participants of the MESA (Multi-ethnic Study of Atherosclerosis). Single nucleotide polymorphism and gene-based results were meta-analyzed across the GenSalt and MESA studies to determine genome-wide significance. The 1
df
tests identified interactions for
ARL15
rs16882447 on systolic BP (
P
=2.83×10
−9
) and
RANBP3L
rs958929 on pulse pressure (
P
=1.58×10
−8
). The 2
df
tests confirmed the
ARL15
rs16882447 signal for systolic BP (
P
=1.15×10
−9
). Genome-wide gene-based analysis identified
CC2D2A
(
P
=2.59×10
−7
) at 4p15.32 and
BNC2
(
P
=4.49×10
−
10
) at 9p22.2 for systolic BP,
GGNBP1
(
P
=1.18×10
−
8
), and
LINC00336
(
P
=1.36×10
−
8
) at 6p21 for diastolic BP,
DAB1
(
P
=1.05×10
−
13
) at 1p32.2, and
MIR4466
(
P
=5.34×10
−
8
) at 6q25.3 for pulse pressure. The
BNC2
(
P
=3.57×10
−
8
) gene was also significant for mean arterial pressure.

Conclusions—

We identified 2 novel BP loci and 6 genes through the examination of single nucleotide polymorphism- and gene-based interactions with potassium.
Selective NLRP3 (Pyrin Domain–Containing Protein 3) Inflammasome Inhibitor Reduces Brain Injury After Intracerebral Hemorrhage
Authors: Ren Honglei , Kong Ying , Liu Zhijia , Zang Dongyun , Yang Xiaoxia , Wood Kristofer , Li Minshu , Liu Qiang
Published: December 2017

Background and Purpose—

Intracerebral hemorrhage (ICH) is a devastating disease without effective treatment. As a key component of the innate immune system, the NOD-like receptor (NLR) family, NLRP3 (pyrin domain–containing protein 3) inflammasome, when activated after ICH, promotes neuroinflammation and brain edema. MCC950 is a potent, selective, small-molecule NLRP3 inhibitor that blocks NLRP3 activation at nanomolar concentrations. Here, we examined the effect of MCC950 on brain injury and inflammation in 2 models of ICH in mice.

Methods—

In mice with ICH induced by injection of autologous blood or bacterial collagenase, we determined the therapeutic potential of MCC950 and its mechanisms of neuroprotection.

Results—

MCC950 reduced IL-1β (interleukin-1β) production and attenuated neurodeficits and perihematomal brain edema after ICH induction by injection of either autologous blood or collagenase. In mice with autologous blood-induced ICH, the protection of MCC950 was associated with reduced leukocyte infiltration into the brain and microglial production of IL-6. MCC950 improved blood–brain barrier integrity and diminished cell death. Notably, the protective effect of MCC950 was abolished in mice depleted of either microglia or Gr-1
+
myeloid cells.

Conclusions—

These results indicate that the NLRP3 inflammasome inhibitor, MCC950, attenuates brain injury and inflammation after ICH. Hence, NLRP3 inflammasome inhibition is a potential therapy for ICH that warrants further investigation.