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International audience; In February–March, 2021, a Working Group of 11 scientists from eight countries met remotely at the invitation of the International Agency for Research on Cancer (IARC) to finalise their evaluation of the carcinogenicity of five agents used as dyes and reagents, and for their antibacterial and antifungal properties.

Aim: The aim of this study was to investigate the beneficial effects of 18ß-glycyrrhetinic acid (GA) on the experimental allergic encephalomyelitis (EAE) in C57BL/6 mice. GA is a natural substance found in the root of licorice and is used in traditional Chinese medicine. It has many pharmacological activities such as antioxidant, anti-inflammatory, and anti-cancer effects. Materials and methods: A total of 40 C57BL/6 mice were divided equally into four groups: (1) Control, (2) EAE, (3) GA and (4) GA + EAE. 14 days after induction of EAE with MOG35-55 and pertussis toxin, mice were treated with GA at doses of 100 mg/kg/day for 7 days intraperitoneally. Results: To our results, oxidative stress and lipid peroxidations (elevated TBARS levels, decreased GPx, SOD, CAT, and GSH levels) were significantly (p

cited By 2; International audience; Purpose: To analyze the incidence, risk factors, and time course of intraocular pressure elevation after intravitreal dexamethasone implant (Ozurdex). Methods: The medical charts of 421 consecutive eyes (361 patients) receiving one or more Ozurdex implant between October 2010 and February 2015 were reviewed retrospectively. Ocular hypertension was defined as intraocular pressure of at least 25 mmHg or an increase of at least 10 mmHg from baseline. The main indications for treatment were retinal vein occlusion (34%), diabetic macular edema (30%), postsurgical macular edema (17%), uveitis (14%), and other etiologies (5%). Results: Among 1,000 intravitreal injections, ocular hypertension was recorded for 28.5% of injected eyes over a mean follow-up period of 16.8 months (3-55). Intraocular pressure-lowering medication was required for 31% of eyes. Only three eyes with preexisting glaucoma required filtering surgery to manage postinjection intraocular pressure elevation. Early retreatment between the third and fourth month does not increase the risk of intraocular pressure elevation. Younger age, male sex, Type 1 diabetes, preexisting glaucoma treated with dual or triple therapy, and a history of retinal vein occlusion or uveitis were significant risk factors for ocular hypertension after dexamethasone implant injection (P < 0.05 for all the above). Conclusion: Episodes of ocular hypertension after Ozurdex implant were generally transient and successfully managed with topical treatment. An analysis of the risk factors may help to determine the risk-benefit ratio for individual patients treated with dexamethasone implants.

Paclitaxel, one of the most commonly used cancer chemotherapeutic drugs, effectively extends the progression-free survival of breast, lung, and ovarian cancer patients. However, paclitaxel and other chemotherapy drugs elicit peripheral nerve fiber dysfunction or degeneration that leads to peripheral neuropathy in a large proportion of cancer patients. Patients receiving chemotherapy also often experience changes in mood, including anxiety and depression. These somatic and affective disorders represent major dose-limiting side effects of chemotherapy. Consequently, the present study was designed to develop a preclinical model of paclitaxel-induced negative affective symptoms in order to identify treatment strategies and their underlying mechanisms of action. Intraperitoneal injections of paclitaxel (8 mg/kg) resulted in the development and maintenance of mechanical and cold allodynia. Carboplatin, another cancer chemotherapeutic drug that is often used in combination with paclitaxel, sensitized mice to the nociceptive effects of paclitaxel. Paclitaxel also induced anxiety-like behavior, as assessed in the novelty suppressed feeding and light/dark box tests. In addition, paclitaxel-treated mice displayed depression-like behavior during the forced swim test and an anhedonia-like state in the sucrose preference test. In summary, paclitaxel produced altered behaviors in assays modeling affective states in C57BL/6J male mice, while increases in nociceptive responses were longer in duration. The characterization of this preclinical model of chemotherapy-induced allodynia and affective symptoms, possibly related to neuropathic pain, provides the basis for determining the mechanism(s) underlying severe side effects elicited by paclitaxel, as well as for predicting the efficacy of potential therapeutic interventions. United States Department of Health & Human Services National Institutes of Health (NIH) - USA - R01-CA206028 VCU Massey Cancer Center NIH-NCI Cancer Center Support Grant - P30 CA016059 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) - R01CA206028 - P30CA016059

SUMMARY OBJECTIVE: The effects of Certolizumab, a pegylated monoclonal antibody to tumor necrosis factor α, on experimentally induced acute pancreatitis (AP) were examined. METHODS: Thirty-six Wistar Albino male rats were randomly divided into four groups. Group I was the control group and no medication administered to this group. Group II was the Certolizumab group, and 100 ml/kg serum physiologic administered into the biliopancreatic duct and a single dose of 10 μg Certolizumab was simultaneously administered intraperitoneally. Acute pancreatitis was induced with a retrograde injection of 3% Na taurocholate into the common biliopancreatic duct in the study (Group III) and treatment (Groups IV) groups. Rats were sacrificed 72 hours later. Serum amylase, lipase, lactate dehydrogenase activities, along with pancreatic histopathology, were examined. RESULTS: Certolizumab treatment significantly decreased serum amylase, lipase, and LDH levels; histopathologically edema, hemorrhage, parenchymal necrosis, fat necrosis, and infiltration scores; immunohistochemically MDA, MPO, TNF-α and Caspase-3 activity. CONCLUSION: The results support the idea that certolizumab might be beneficial for the severity of AP. RESUMO OBJETIVO: Os efeitos de Certolizumab, um anticorpo monoclonal pegilado para o fator de necrose tumoral α, na pancreatite aguda induzida experimentalmente (PA) foram examinados. MÉTODO: Trinta e seis ratos Wistar Albino foram divididos aleatoriamente em quatro grupos. O Grupo I foi considerado o grupo controle e não recebeu medicação; o Grupo II foi o grupo Certolizumab e recebeu 100 ml/kg de soro fisiológico administrado no ducto biliopancreático e dose única de 10 mg Certolizumab administrada por via intraperitoneal simultaneamente. A pancreatite aguda foi induzida com uma injeção retrógrada de uma solução de 3% taurocolato de sódio aplicada no ducto biliopancreático comum nos grupos de estudo (Grupo III) e tratamento (Grupos IV). Os ratos foram sacrificados 72 horas depois. As atividades séricas de amilase, lipase, lactato desidrogenase, juntamente com a histopatologia pancreática, foram examinadas. RESULTADOS: O tratamento com Certolizumab diminuiu significativamente os níveis séricos de amilase, lipase e LDH; edema histopatológico, hemorragia, necrose paranquimatosa, necrose gordurosa e escores de infiltração; atividade imuno-histoquímica de MDA, MPO, TNF-α e Caspase-3. CONCLUSÃO: Estes resultados suportam a ideia de que o Certolizumab pode ser benéfico para a gravidade da PA.

Background Diabetes mellitus become an epidemic problem throughout the world. Relation of the diabetes with diet is known. Some evidence is reported about mother died and risk of diabetes in babies during the life related with gestational diabetes. This study was conducted to examine the effects of the exposure of high-dose sucrose to rats and pups during pregnancy and lactation. Methods The mother rats were categorized into four groups, during pregnancy and until the offspring were 1-month-old, as follows: Group 1, provided with normal drinking water; Group 2, provided with water containing 10%; Group 3, 20%; and Group 4, 30% table sugar. During the study, the weights and daily fluid consumption of the animals were recorded. At the end of the study, the changes in blood, urine, and pancreatic tissues of the rats were examined. Results The pups in the groups supplemented with sugar had more weight gain than those of the control group. Although serum glucose levels of mothers and young rats in the groups fed with sugar-containing water did not reach the diabetic limits, it was observed that these animals had statistically significantly higher blood glucose levels than those in the control group. Insulin levels were also similarly increased by an increase in the amount of sugar. Immunohistochemical studies on the mother rats showed that insulin secreted cell numbers and insulin receptors significantly decreased in some pancreatic islets in the groups supplemented with sugar. Glucagon immunoreactivity examination showed that the number of glucagon-expressing cells decreased in the rat groups supplemented with sugar. Similar and more severe findings were observed in the offspring. Conclusion This study has experimentally demonstrated that high daily intake of sugar in healthy pregnancies causes adverse effects on the mother and offspring.

Background Immune cells are involved in all stages of acute ischaemic stroke (AIS) and possess both neuroprotective and neurodamaging properties. It has been suggested that immune system activation after stroke may be associated with the development of haemorrhagic transformation (HT), which is the main complication limiting the clinical use of intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) for AIS. The purpose of our study was to analyse the association between absolute eosinophil count (AEC) at admission and the occurrence of HT after intravenous rtPA therapy for AIS. Methods In this retrospective study we enrolled AIS patients who were treated with rtPA within 4.5 h of symptom onset. Baseline stroke severity was evaluated using the National Institutes of Health Stroke Scale (NIHSS). Patients underwent head computed tomography scans at admission which were repeated 24 h after treatment with rtPA or promptly in case of clinical deterioration. HT was defined as blood at any site in the brain on follow-up head computed tomography scans. Spearman’s rank correlation test was used to analyse the correlation between AEC and NIHSS scores. The optimal AEC cut-off value for predicting HT was calculated using the area under the receiver operating characteristic curve. Multiple logistic regression was used to determine the association between AEC included as a binary variable and the incidence of HT. Results The data of 201 patients was analysed (59.7% females; median age 77 years); 23 (11.4%) of them developed HT. The median of AEC was 62.5% greater in the non-HT group compared to the HT group (0.13 × 109/l and 0.08 × 109/l, respectively, p = 0.026). No correlation was found between AEC and baseline NIHSS scores (r = 0.061, p = 0.393). AEC ≥ 0.11 × 109/l predicted the occurrence of HT with 69.6% sensitivity and 60.7% specificity. AEC ≥ 0.11 × 109/l was independently associated with a 78% reduction in the odds of developing HT (adjusted odds ratio = 0.223, 95% confidence interval = 0.069–0.723, p = 0.012). Conclusion Higher values of AEC were associated with lower odds of developing HT, thus, AEC at admission could be considered an independent predictive marker of HT after treatment with rtPA for AIS.

Osteoarthritis (OA) is one of the most common chronic conditions in the world today. It results in breakdown of cartilage in joints and causes the patient to experience intense pain and even disability. The pathophysiology of OA is not fully understood; therefore, there is currently no cure for OA. Many researchers are investigating the pathophysiology of the disease and attempting to develop methods to alleviate the symptoms or cure the OA entirely using animal models. Most studies on OA use animal models; this is necessary as the disease develops very slowly in humans and presents differently in each patient. This makes it difficult to effectively study the progression of osteoarthritis. Animal models can be spontaneous, in which OA naturally occurs in the animal. Genetic modifications can be used to make the mice more susceptible to developing OA. Osteoarthritis can also be induced via surgery, chemical injections, or non-invasive trauma. This review aims to describe animal models of inducing osteoarthritis with a focus on the models used on mice and their advantages and disadvantages that each model presents.

The slow force response (SFR) of a cardiac muscle to a sudden stretch is thought to be important in the regulatory adaptation of myocardial contraction. Autocrine-paracrine regulation pathways which involve angiotensin II are participating in this mechanism. On the other hand, renin-angiotensin-aldosterone system (RAS) is altered in hypertrophic or failing myocardium. We compared the effects of sudden stretch to SFR as well as to twitch and Ca2+ transient characteristics in rat myocardium with monocrotaline-induced heart failure with those in normal rat myocardium without and with inhibition of angiotensin II type-1 (AT1) receptors. Our findings indicate that the myocardium of rats with monocrotaline-induced right ventricular failure is deficient with activation of local RAS and therefore expresses blunted SFR, very similar to the depression of SFR observed in normal myocardium under inhibition of AT1 receptors. The "failing" myocardium does not further respond to the "putative" inhibition of AT1 receptors by losartan. In conclusion, SFR is related to autocrine-paracrine regulation of myocardial contraction in normal rat myocardium and that the involvement of RAS into stretch-induced modulation of contractility may be significantly altered in failing heart. © 2018 Slovak Academy of Sciences. All rights reserved. Российский Фонд Фундаментальных Исследований (РФФИ): 16-04-00545 Ural Branch, Russian Academy of Sciences: 15-5-4-6 Division of Industrial Innovation and Partnerships Russian Academy of Sciences: A18-118020590031-8 Acknowledgements. Authors thank Daniil Kuznetsov for his help in the implementation of the monocrotaline-based experimental model of pulmonary hypertension in rats. The work was conducted in IIP UB RAS accordingly to the officially registered plan of scientific investigations (#AAAA-A18-118020590031-8) and was supported by Russian Foundation for Basic Research (grant #16-04-00545) and the Program for Basic Research of Ural Branch of the Russian Academy of Sciences for 2015–2017 (project #15-5-4-6).

Purpose: To evaluate the impact of systemic cyclophosphamide treatment on the rat uterus and investigate the potential therapeutic effects of natural antioxidant preparations curcumin and capsaicin against cyclophosphamide side effects. Methods: A 40 healthy adult female Wistar albino rats were used in this study. Rats were randomly divided into four groups to determine the effects of curcumin and capsaicin against Cyclophosphamide side effects on the uterus (n=10 in each group); Group 1 was the control group (sham-operated), Group 2 was the cyclophosphamide group, Group 3 was the cyclophosphamide + curcumin (100mg/kg) group, and Group 4 was the cyclophosphamide + capsaicin (0.5 mg/kg) group. Results: Increased tissue oxidative stress and histological damage in the rat uterus were demonstrated due to the treatment of systemic cyclophosphamide chemotherapy alone. The level of tissue oxidant and antioxidant markers and histopathological changes were improved by the treatment of curcumin and capsaicin. Conclusion: Cytotoxic effects of natural alkylating chemotherapeutic agents like cyclophosphamide on the uterus can be prevented by curcumin and capsaicin. © 2018, Sociedade Brasileira para o Desenvolvimento de Pesquisa em Cirurgia. All rights reserved.

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WOS: 000369120000006, PubMed ID: 25914025, Objective: Immune thrombocytopenia (ITP) is an immune-mediated disease characterized by transient or persistent decrease of the platelet count to less than 100x109/L. Although it is included in a benign disease group, bleeding complications may be mortal. With a better understanding of the pathophysiology of the disease, thrombopoietin receptor agonists, which came into use in recent years, seem to be an effective option in the treatment of resistant cases. This study aimed to retrospectively assess the efficacy, long-term safety, and tolerability of eltrombopag in Turkish patients with chronic ITP in the Aegean region of Turkey. Materials and Methods: Retrospective data of 40 patients with refractory ITP who were treated with eltrombopag in the Aegean region were examined and evaluated. Results: The total rate of response was 87%, and the median duration of response defined as the number of the platelets being over 50x10(9)/L was 19.5 (interquartile range: 5-60) days. In one patient, venous sinus thrombosis was observed with no other additional risk factors due to or related to thrombosis. Another patient with complete response and irregular follow-up for 12 months was lost due to sudden death as the result of probable acute myocardial infarction. Conclusion: Although the responses to eltrombopag were satisfactory, patients need to be monitored closely for overshooting platelet counts as well as thromboembolic events.

Malignant mesothelioma (MM) is an important health problem due to ongoing asbestos exposure. Environmental asbestos exposure leads to a high risk of MM in Turkey. The Turkish Mesothelioma Working Group and the Turkish Public Health Institute designed and performed the Turkey National Mesothelioma Surveillance and Environmental Asbestos Exposure Control Program (TUNMES-EAECP). The aim of this study was to analyze the results of the TUNMES-EAECP. Patients diagnosed with MM (code C45.0-C45.9) between 2008 and 2012 were identified. The -from case to the field- method was used to determine the villages with current or previous asbestos exposure. Special public health teams took soil samples from these villages, which were then examined using an X-ray diffractometer. Direct Standardized Average Annual Mesothelioma Incidence Rate (AMIR) and relative risk (RR) of MM were calculated. Finally, a projection on the incidence of MM between 2013 and 2033 was made. The number of confirmed MM cases was 5617 with a male to female ratio of 1.36. Mean age was 61.7 +/- 13.4 (20-96) years. The median survival was eight (95% CI 7.6-8.4) months. Asbestos exposure continues in 379 villages, with 158,068 people still living in high risk areas. The standardized AMIR was 2.33/100,000 per year. The risk of MM was higher in males, in both sexes over the age of 40, in asbestos-containing provinces, and in those where the TUNMES was organized. Among the population with continuing asbestos exposure in rural areas, the number of MM cases between 2013 and 2033 was estimated as 2511. As such, the incidence of MM in Turkey is as high as in industrialized countries. Asbestos exposure in rural areas continues to be a serious problem in Turkey, which obviates the necessity for effective preventive measures.

Chronic hyperglycaemia and glucose variability are associated with the development of chronic diabetes-related complications. We conducted a pooled analysis of patient-level data from three 24-week, randomized, phase III clinical trials to evaluate the impact of lixisenatide (LIXI) on glycaemic variability (GV) vs placebo as add-on to basal insulin. The main outcome GV measures were standard deviation (s.d.), mean amplitude of glycaemic excursions (MAGE), mean absolute glucose (MAG) level, area under the curve for fasting glucose (AUC-F), and high (HBGI) and low blood glucose index (LBGI). The change in GV metrics over 24 weeks and relationships among baseline GV, patient characteristics and outcomes were assessed. Data were pooled from 1198 patients (665 LIXI, 533 placebo). Values for s.d., MAG level, MAGE, HBGI, and AUC-F significantly decreased with LIXI vs placebo, while LBGI values were unchanged. Higher baseline GV measures correlated with older age, longer type 2 diabetes duration, lower body mass index, higher baseline glycated/haemogobin, greater reduction in postprandial glucose (PPG) level, and higher rates of symptomatic hypoglycaemia. These data show that LIXI added to basal insulin significantly reduced GV and PPG excursions vs placebo, without increasing the risk of hypoglycaemia (LBGI). © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley and Sons Ltd.

Shortly after the International Agency for Research on Cancer (IARC) determined that formaldehyde causes leukemia, the United States Environmental Protection Agency (EPA) released its Draft IRIS Toxicological Review of Formaldehyde (“Draft IRIS Assessment”), also concluding that formaldehyde causes leukemia. Peer review of the Draft IRIS Assessment by a National Academy of Science committee noted that “causal determinations are not supported by the narrative provided in the draft” (NRC 2011). They offered recommendations for improving the Draft IRIS assessment and identified several important research gaps. Over the six years since the NRC peer review, significant new science has been published. We identify and summarize key recommendations made by NRC and map them to this new science, including extended analysis of epidemiological studies, updates of earlier occupational cohort studies, toxicological experiments using a sensitive mouse strain, mechanistic studies examining the role of exogenous versus endogenous formaldehyde in bone marrow, and several critical reviews. With few exceptions, new findings are consistently negative, and integration of all available evidence challenges the earlier conclusions that formaldehyde causes leukemia. Given formaldehyde's commercial importance, environmental ubiquity and endogenous production, accurate hazard classification and risk evaluation of whether exposure to formaldehyde from occupational, residential and consumer products causes leukemia are critical. © 2017 The Authors

Background: Scientific data provide the evidence that secondary K-RAS mutations do not occur during anti-epidermal growth factor receptor therapy in colorectal cancer patients. This multicenter phase II prospective study aims to investigate the activity of a retreatment with a cetuximab-based therapy. Patients and methods: We enrolled 39 irinotecan-refractory patients who had a clinical benefit after a line of cetuximab- plus irinotecan-based therapy and then a progression of disease for which underwent a new line chemotherapy and finally, after a clear new progression of disease, were retreated with the same cetuximab- plus irinotecan-based therapy. Results: Median number of therapeutic lines before accrual was 4. Median interval time between last cycle of first cetuximab-based therapy and first cycle of the retreatment was 6 months. Overall response rate was 53.8% with 19 partial responses (48.7%) and 2 complete responses (5.1%). Disease stabilization was obtained in 35.9% of patients and progression in four patients (10.2%). Median progression-free survival was 6.6 months. The correlation between skin toxicity during first cetuximab therapy and during cetuximab rechallenge was significant (P = 0.01). Conclusion: Rechallenge with the same cetuximab-based therapy may achieve a new important clinical benefit further delaying the progression of disease and improving the therapeutic options. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Introduction: α7 nicotinic acetylcholine receptors (nAChRs) play an important role in vagus nerve-based cholinergic anti-inflammatory effects. This study was designed to assess the role of α7 nAChRs in dextran sodium sulfate (DSS)-induced colitis in male and female mouse. We first compared disease activity and pathogenesis of colitis in α7 knockout and wild-type mice. We then evaluated the effect of several α7 direct and indirect agonists on the severity of disease in the DSS-induced colitis. Methods: Male and female adult mice were administered 2.5% DSS solution freely in the drinking water for 7 consecutive days and the colitis severity (disease activity index) was evaluated as well as colon length, colon histology, and levels of tumor necrosis factor-alpha colonic levels. Results: Male, but not female, α7 knockout mice displayed a significantly increased colitis severity and higher tumor necrosis factor-alpha levels as compared with their littermate wild-type mice. Moreover, pretreatment with selective α7 ligands PHA-543613, choline, and PNU-120596 decreased colitis severity in male but not female mice. The anti-colitis effects of these α7 compounds dissipated when administered at higher doses. Conclusions: Our results suggest the presence of a α7-dependent anti-colitis endogenous tone in male mice. Finally, our results show for the first time that female mice are less sensitive to the anti-colitis activity of α7 agonists. Ovarian hormones may play a key role in the sex difference effect of α7 nAChRs modulation of colitis in the mouse. Implications: Our collective results suggest that targeting α7 nAChRs could represent a viable therapeutic approach for intestinal inflammation diseases such as ulcerative colitis with the consideration of sex differences.

Introduction: Use of non-cigarette tobacco products such as cigars and pipe has been increasing, even though these products entail exposure to similar carcinogens to those in cigarettes. More research is needed to explore the risk of these products to guide cancer prevention efforts. Methods: To measure the association between cigars and/or pipe smoking, and cancer incidence in men, we performed meta-analyses of data from five prospective cohorts. Cox regression was used to evaluate the association between different aspects of cigars and pipe smoking and risk of each smoking-related cancer (head and neck, esophagus, lung, stomach, liver, pancreas, kidney, and bladder) for each study. Adjusted HRs were combined using random-effects models. Results: Cigars and/or pipe smokers were at increased risk for head and neck [HR, 1.51; 95% confidence interval (CI), 1.22–1.87], lung (HR, 2.04; 95% CI, 1.68–2.47), and liver cancers (HR, 1.56; 95% CI, 1.08–2.26). Ever-smokers of cigars and/or pipe had an increased risk of developing a smoking-related cancer when compared with never smokers of any tobacco product (overall HR, 1.07; 95% CI, 1.03–1.12). The risk for smoking-related cancers was also increased in mixed smokers who smoked cigars or pipe as well as cigarettes, even when they were smoking predominantly pipe or cigars. Discussion: This pooled analysis highlights the increased risk for smoking-related cancers, particularly for lung and head and neck cancers in exclusive and predominant smokers (former and current) of cigars and pipe. Tobacco prevention efforts should include these products in addition to cigarettes. Cancer Prev Res; 10(12); 704–9. ©2017 AACR.

Anticancer drugs are presently guarantying more survivors as a result of more powerful drugs or combinations of drugs used in therapy. Thus, it has become more crucial to study and overcome the side effects of these therapies. Cardiotoxicity is one of the most relevant side effects on the long-term cancer survivors, because of its high social and economic impact. Drug metabolism can result in active metabolites or toxic metabolites that can lead to important side effects. The metabolites of anticancer drugs are possible culprits of cardiotoxicity; however, the cardiotoxicity of many of the metabolites in several drug classes was not yet suitably studied so far. On the other hand, the use of prodrugs that are bioactivated through metabolism can be a good alternative to obtain more cardio safe drugs. In this review, the methods to obtain and study metabolites are summarized and their application to the study of a group of anticancer drugs with acknowledged cardiotoxicity is highlighted. In this group of drugs, doxorubicin (DOX, 1), mitoxantrone (MTX, 2), cyclophosphamide (CTX, 3) and 5-fluorouracil (5-FU, 4) are included, as well as the tyrosine kinase inhibitors, such as imatinib (5), sunitinib (6) and sorafenib (7). Only with the synthesis and purification of considerable amounts of the metabolites can reliable studies be performed, either in vitro or in vivo that allow accurate conclusions regarding the cardiotoxicity of anticancer drug metabolites and then pharmacological prevention or treatment of the cardiac side effects can be done. © 2017 Informa UK Limited, trading as Taylor & Francis Group. This work was supported by FEDER funds through the Operational Programme for Competitiveness Factors?COMPETE and by national funds by the Funda??o para a Ci?ncia e Tecnologia (FCT) FCT/MCTES?Foundation for Science and Technology from the Minister of Science, Technology and Higher Education (PIDDAC) and European Regional Development Fund (ERDF) through the COMPETE?Programa Operacional Factores de Competitividade (POFC) programme, within the projects ?PTDC/DTP-FTO/1489/2014?POCI-01-0145-FEDER-016537?, in the framework of the programme PT2020 and by the project INNOVMAR - Innovation and Sustainability in the Management and Exploitation of Marine Resources (reference NORTE-01-0145-FEDER-000035, within Research Line NOVELMAR), supported by North Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). V.M.C. (SFRH/BPD/110001/2015) acknowledges ?Funda??o para a Ci?ncia e Tecnologia (FCT)? for her Post Doc grant.

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Background and aims: ADSCs transplantation had been shown in some experimental models of kidney damage that it improves kidney function and reduces fibrosis. In this study we evaluated the effect of human adipose tissue-derived stem cell (hADSC) therapy in a chronic kidney damage experimental model. Methods A chronic kidney injury was induced by daily orogastric administration of adenine (100mg/ kg) to male Wistar rats for 28 days. hADSCs were isolated, expanded and characterized before transplantation. hADSC administration was performed in a tail vein at a dose of 2 x106 cells/animal. Animals were sacrificed at 7 days post-treatment. The percentage of fibrotic tissue, serum and urine levels of urea, creatinine, total protein and renal mRNA of COL1A1, TGFB1, CTGF, ACTA2, IL6, IL10, TNF were analyzed. Results hADSCs treatment significantly reduces kidney fibrosis, improves urea and creatinine serum and urine levels, and diminishes COL1A1, TGFB1, CTGF, ACTA2 mRNA kidney levels. Conclusions These results showed that cell therapy using hADSCs improves renal function and reduces fibrosis. © 2017 Rivera-Valdes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Setting exposure standards for environmental pollutants may consider the aged as a susceptible population but the few published studies assessing susceptibility of the aged to air pollutants are inconsistent. Episodic ozone (O-3) is more reflective of potential exposures occurring in human populations and could be more harmful to the aged. This study used radiotelemetry to monitor heart rate (HR), core temperature (T-c) and motor activity (MA) in adult (9-12 months) and senescent (20-24 months) male, Brown Norway rats exposed to episodic O-3 (6 h/day of 1 ppm O-3 for 2 consecutive days/week for 13 weeks). Acute O-3 initially led to marked drops in HR and T-c. As exposures progressed each week, there was diminution in the hypothermic and bradycardic effects of O-3. Senescent rats were less affected than adults. Acute responses were exacerbated on the second day of O-3 exposure with adults exhibiting greater sensitivity. During recovery following 2 d of O-3, adult and senescent rats exhibited an elevated Tc and HR during the day but not at night, an effect that persisted for at least 48 h after O-3 exposure. MA was elevated in adults but not senescent rats during recovery from O-3. Overall, acute effects of O-3, including reductions in HR and T-c, were attenuated in senescent rats. Autonomic responses during recovery, included an elevation in T-c with a pattern akin to that of a fever and rise in HR that were independent of age. An attenuated inflammatory response to O-3 in senescent rats may explain the relatively heightened physiological response to O-3 in younger rats.

IMPORTANCE: Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative.OBJECTIVE: To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock.DESIGN, SETTING, AND PARTICIPANTS: A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock.INTERVENTIONS: Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103).MAIN OUTCOMES AND MEASURES: The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes.RESULTS: A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]).CONCLUSIONS AND RELEVANCE: Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further.TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN 20769191.

The aim of the study was to evaluate the efficiencies of selected anti-emetic drugs (metoclopramide, ondansetron and maropitant) in preventing vomiting in the treatment of canine parvoviral enteritis. We designed a randomized, prospective clinical study. PVE quick ELISA test-positive dogs between 4 and 12 months of age were included in the study. Each of metoclopramide, ondansetron, maropitant and control group had 8 dogs. Metoclopramide and ondansetron were administered as 0.5 mg/kg doses three times a day via intravenous route, and maropitant was administered as 1 mg/kg doses once a day subcutaneously. The number and severity of daily vomitings were recorded. All dogs were treated and monitored for five days; treatments were continued until all animals healed. Metoclopramide, ondansetron and maropitant decreased the severity of vomiting from the first day and the vomiting numbers from the third day in PVE treatment. Obtained results showed that maropitant can be used successfully such as metoclopramide and ondansetron, which are frequently used for PVE treatment. At the same time, it was discovered that metoclopramide, ondansetron and maropitant were equally effective in reducing the frequency and severity of vomiting.

Çalışmada 24 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır. In this multicenter, retrospective study, we evaluated the efficacy and safety of biologic therapies, including anti-TNFs, in secondary (AA) amyloidosis patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA). In addition, the frequency of secondary amyloidosis in RA and AS patients in a single center was estimated. Fifty-one AS (39M, 12F, mean age: 46.7) and 30 RA patients (11M, 19F, mean age: 51.7) with AA amyloidosis from 16 different centers in Turkey were included. Clinical and demographical features of patients were obtained from medical charts. A composite response index (CRI) to biologic therapy-based on creatinine level, proteinuria and disease activity-was used to evaluate the efficacy of treatment. The mean annual incidence of AA amyloidosis in RA and AS patients was 0.23 and 0.42/1000 patients/year, respectively. The point prevalence in RA and AS groups was 4.59 and 7.58/1000, respectively. In RA group with AA amyloidosis, effective response was obtained in 52.2 % of patients according to CRI. RA patients with RF positivity and more initial disease activity tended to have higher response rates to therapy (p values, 0.069 and 0.056). After biologic therapy (median 17 months), two RA patients died and two developed tuberculosis. In AS group, 45.7 % of patients fulfilled the criteria of good response according to CRI. AS patients with higher CRP levels at the time of AA diagnosis and at the beginning of anti-TNF therapy had higher response rates (p values, 0.011 and 0.017). During follow-up after anti-TNF therapy (median 38 months), one patient died and tuberculosis developed in two patients. Biologic therapy seems to be effective in at least half of RA and AS patients with AA amyloidosis. Tuberculosis was the most important safety concern.

Introduction: Pharmacological prophylaxis for venous thromboembolism is recommended for the vast majority of patients undergoing major orthopedic surgery. Increased risk of bleeding after the use of these agents has been widely documented in general population. Conversely, the frequency of this complication has not been studied in the subpopulation of elderly patients. The purpose of this study is to determine whether the risk of major bleeding after major orthopedic surgery is higher in elderly patients, compared to those operated at a younger age. Methods: We performed a retrospective cohort study including patients who underwent total hip and total knee arthroplasty during five consecutive years. Patients with other causes of bleeding were excluded. Medical records were reviewed in order to determine the occurrence and manifestation of major bleeding. A nested case-control analysis was used to determine which age group had the greatest odds ratio (OR) for major bleeding. Then, we compared two cohorts grouped by age. Relative risks (RR) and confidence intervals (CI) were calculated and a multivariate analysis was performed. Results: A total of 1048 patients were included in the analysis. Of these, 56% corresponded to hip joint replacements and 44% to knee joint replacements. The case control analysis reported that patients who were 70 years or older at the time of surgery had the highest OR (2.61) for major bleeding, therefore a limit of 70 years old was established to create two cohorts. At the time of surgery 553 (53%) patients were 70 years or older while 495 (47%) were younger. Patients who were ≥70 years old showed an increased risk of major bleeding: RR 2,42 (95% CI: 1.54-3.81). After total hip arthroplasty the RR was 2,61 (95%CI: 1.50-4.53) and after total knee arthroplasty was 2.25 (95% CI: 1.03-4.94). After the multivariate analysis, age continued to be independently associated with a higher risk of major bleeding. Conclusion: This study allows to conclude that patients who are 70 years or older are at a higher risk of major bleeding after major orthopedic surgery than younger patients. Therefore, the use of appropriate strategies to mitigate the risk in this group of patients is encouraged

Background: Contrast induced nephropathy (CIN) has been proven to be a clinical condition related to adverse cardiovascular outcomes. In recent studies, the monocyte to high density lipoprotein ratio (MHR) has been postulated as a novel parameter associated with adverse renal and cardiovascular outcomes. In this study we investigated the association of MHR with CIN in ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PCI). Methods: Consecutive STEMI patients treated with primary PCI were prospectively recruited. Subjects were categorized into two groups; as patients who developed CIN (CIN+) and patients who did not develop CIN (CIN–) during hospitalization. CIN was defined as either a 25% increase in serum creatinine from baseline or 44.20 µmol/L increase in absolute value, within 72 h of intravenous contrast administration. Results: A total number of 209 patients were included in the study. Thirty-two patients developed CIN (15.3%). In the CIN (+) patients, monocytes were higher [1.02 (0.83–1.39) vs. 0.69 (0.53–0.90) 109/L, p9/mmol, p Conclusions: Higher MHR levels may predict CIN development after primary PCI in STEMI patients.

WOS: 000376610900006, PubMed: 27219687, Introduction: Neuropathy is a common complication of diabetes mellitus and is closely related to quality of life. There are many studies in which biological ingredients, such as alpha lipoic acid (ALA), that may inhibit or reduce the generation of diabetic neuropathy were investigated. Another biological agent that may reduce the generation of diabetic neuropathy is melatonin and there are a few studies that investigate the effects of melatonin on diabetic neuropathy. In this study we aimed to examine the effect of melatonin on experimentally induced diabetic neuropathy by comparing it with both ALA and control groups. Methods: We included 24 male Wistar rats. Tibial motor nerve conduction and cortical tibial nerve somatosensory evoked potentials (SEP) studies were performed before and after diabetes mellitus (DM) for all rats. Rats were divided into 3 (ALA, melatonin and control) groups. After 2 weeks of treatment period, tibial motor nerve conduction and cortical tibial SEP studies were repeated. Results: Our data showed that ALA significantly increased nerve conduction velocity and ampli-tude in rats with diabetic neuropathy (p = 0,001; p = 0,002). Also, melatonin significantly increased nerve conduction velocity and amplitude in rats with diabetic neuropathy (p = 0.002; p = 0.002). There was no significant difference between the electrophysiological effects of ALA and melatonin. Besides, neither ALA nor melatonin did significantly affect P1 and N1 latency values on cortical tibial nerve SEP studies. Conclusion: Our study is the study in which both tibial nerve conduction and cortical tibial SEP studies were performed to compare effects of ALA and melatonin on experimental diabetic neuropathy. Lack of significant difference on cortical tibial SEP study would be attributed to the involvement of other central nervous system pathways which do not include ALA or melatonin in the pathogenesis. Results of ALA group are important by means of giving objective evidences for results of biochemical studies about the role of ALA in the pathogenesis of diabetic neuropathy. However, there is not enough information about the effect of melatonin in the pathogenesis of diabetic neuropathy. Consequently, results of our study may anticipate further biochemical and clinic studies which investigate the about the role of melatonin in diabetic neuropathy., faculty of medicine, Pamukkale University, Denizli, Turkey, This study was under financial support of faculty of medicine, Pamukkale University, Denizli, Turkey. All authors declare no conflict of interest.

Safety issues have been raised about dabigatran. We aimed to investigate the occurrence of safety outcomes in patients who had atrial fibrillation and a risk of stroke. We analyzed 439 patients prescribed dabigatran (n = 220) or warfarin (n = 219). Ischemic stroke occurred in 15 (6.8%) patients in the warfarin group versus 5 (5.2%) patients in the 110-mg group versus 1 (0.8%) patient in the 150-mg dabigatran group ( P = .015). Intracranial hemorrhage occurred in 6 (2.7%) patients in the warfarin group versus 3 (2.4%) patients in the 150-mg dabigatran group ( P = .104). Death from any cause occurred in 10 (4.6%) patients in the warfarin group versus 1 (1.0%) patient in the 110-mg dabigatran group ( P = .005). Dabigatran was associated with less ischemic stroke and death from any cause than warfarin. Dabigatran may be a better option for stroke prophylaxis, where recommended monitoring with warfarin is suboptimal.

Bevacizumab (Avastin; Roche, Basel, Switzerland) is a humanized monoclonal antibody binding vascular endothelial growth factor (VEGF) that was originally developed to treat metastatic carcinoma of the colon and rectum. Michels et al1 used intravenous bevacizumab infusions as an off-label treatment for neovascular age-related macular degeneration (n-AMD). Its efficacy in this context led to off-label intravitreal bevacizumab (IVB) administration and eventually widespread use as a treatment for ocular diseases associated with retinal neovascularization and edema, including macular edema secondary to retinal vein occlusion (RVO), n-AMD myopic choroidal neovascularization (m-CNV), CNV secondary to angioid streaks, diabetic macular edema (DME), and neovascular glaucoma.2 IVB can cause procedure-related complications (traumatic cataract, retinal detachment, hemovitreous, and infectious endophthalmitis) and drug-related systemic and local side effects, including noninfectious endopththalmitis,3 which must be distinguished from infectious endopththalmitis,4–16 because management and prognosis of these two entities differs greatly. We report a cluster of noninfectious endophthalmitis ranging in severity from mild inflammation to severe vitritis with or without retinal involvement after IVB. In our patients, we employed single-use syringes of bevacizumab from the same batch, prepared by a single compounding pharmacy.

OBJETIVO: Avaliar o efeito do dinitrato de isossorbida (DNI) sobre a hiperalgesia corneana e a infiltração de neutrófilos em um modelo experimental de ceratite superficial induzida pelo lipopolissacarídeo (LPS). MÉTODOS: A hiperalgesia foi estudada através da indução de uma ceratite inflamatória em ratos (n = 60), pela exposição da córnea ao LPS (LPS +). Após a exposição, os olhos foram tratados durante quatro dias, com as soluções tópicas: DNI (200 mg, 65 mg e 20 mg), prednisolona 1% (PRED) ou Veículo. Olhos controles foram expostos apenas à solução salina (LPS -). Para avaliar a dor ocular, contouse o número de piscadas em 40 segundos, após instilação de uma gota de capsaicina 0,01 mM. A análise histopatológica foi realizada para avaliação da infiltração neutrofílica. RESULTADOS: Foram observadas áreas esbranquiçadas no estroma corneano dos olhos com a ceratite induzida pelo LPS, entre os dias 3 e 15 dias. Esses olhos (LPS +) apresentaram um número significativamente maior de piscadas que os LPS - (P = 0,019) à estimulação química. O tratamento tópico com o DNI reduziu o número de piscadas observadas (P = 0,010). Da mesma forma, olhos expostos ao LPS e tratados com DNI demonstraram redução significativa na infiltração neutrofílica (P = 0,0031). CONCLUSÃO: Baixas doses de DNI reduziram a hiperalgesia corneana e a infiltração neutrofílica nesse modelo de ceratite. Dessa forma, doadores de óxido nítrico, como o DNI, poderão ser úteis no futuro ao tratamento clínico de diversas condições dolorosas da superfície ocular. PURPOSE: To analyze effects of isosorbide dinitrate (DNI) on corneal hyperalgesia and neutrophil infiltration in an experimental model of superficial keratitis induced by lipopolysaccharide (LPS). METHODS: Hyperalgesia was studied through the induction of inflammatory keratitis in rats (n=60), by corneal exposure to LPS. Following exposure, the inflamed eye was treated for four days, with one of the following solutions: topical DNI (200 μg, 65 μg and 20 μg), prednisolone 1% (PRED), and vehicle. Saline-exposed eyes (LPS -) underwent the same protocol. To evaluate ocular pain, the number of blinks in 40 seconds was counted, after one drop of 0.01 μM capsaicin. Histopathological analysis was performed with evaluation of neutrophil infiltration. RESULTS: White clouding areas were observed in the corneal stroma of eyes with LPS-induced keratitis, between day 3 and day 15. Eyes exposed to LPS had a significantly higher number of blinks than LPS - (P=0.019). Topical treatment of LPS-induced keratitis eyes with DNI reduced capsaicin-induced blinks (P=0.010). Similarly, eyes exposed to LPS and treated with DNI also displayed reduced neutrophil infiltration (P=0.0031). CONCLUSION: Low doses of topical NO donors, like DNI, reduce corneal hyperalgesia and neutrophil infiltration in this keratitis model. NO donors may be useful in the clinical treatment of painful conditions associated with surgical procedures of the ocular surface.

Pyogenic granuloma (PG) is a benign non-neoplastic mucocutaneous lesion. It is a reactional response to constant minor trauma and might be related to hormonal changes. In the mouth, PG is manifested as a sessile or pedunculated, resilient, erythematous, exophytic and painful papule or nodule with a smooth or lobulated surface that bleeds easily. PG preferentially affects the gingiva, but may also occur on the lips, tongue, oral mucosa and palate. The most common treatment is surgical excision. This paper describes a mucocutaneous PG on the upper lip, analyzing the clinical characteristics and discussing the features that distinguish this lesion from other similar oral mucosa lesions. The diagnosis of oral lesions is complex and leads the dentist to consider distinct lesions with different diagnostic methods. This case report with a 4 year-follow-up calls the attention to the uncommon mucocutaneous labial location of PG and to the fact that surgical excision is the safest method for diagnosis and treatment of PG of the lip, even when involving the mucosa and skin.

Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-course oral tablet therapy in patients with relapsing–remitting multiple sclerosis. We randomly assigned 1326 patients in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo, given in two or four short courses for the first 48 weeks, then in two short courses starting at week 48 and week 52 (for a total of 8 to 20 days per year). The primary end point was the rate of relapse at 96 weeks. Among patients who received cladribine tablets (either 3.5 mg or 5.25 mg per kilogram), there was a significantly lower annualized rate of relapse than in the placebo group (0.14 and 0.15, respectively, vs. 0.33 ; P

Leukocytoclastic vasculitis is a rare complication of the use of granulocyte colony-stimulating factor (G-CSF). We present two cases of severe congenital neutropenia (SCN) associated with GCSF use. It is reported that skin rashes and biopsy findings of leukocytoclastic vasculitis following the use of G-CSF.

Introduction: Among the adverse effects of different calcineurin inhibitors (CIs), nephrotoxicity is the most common (incidence: 18.1 % at 13 y from liver transplantation) and depends on a variable degree of tubular-interstitial injury accompanied by focal glomerular sclerosis. A new immunosuppressive drug was introduced in solid organ transplant management, Sirolimus (SRL). It is a non-nephrotoxic immunosuppressor. Methods: Twenty-six patients who developed nephrotoxicity owing to CIs, showing an increment of serum creatinine levels ( > 1.8 mg/dL) were switched to SRL monotherapy, initially at a dosage between 3 and 5 mg/d, and subsequently adapted to achieve trough level between 8 to 10ng/mL. Results: Patients were followed-up for a mean period of 40.3 months (range, 8.4 to 76.7) from liver transplantation. Mean follow-up after switch was 27.5 months (range, 2 to 71.2). Immunosuppression therapy was converted after a mean period of 12.8 months (range, 0.2 to 43.4). Serum creatinine, urea, and estimated glomerular filtration rate were significantly improved. Discussion: Patients developing renal dysfunction after liver transplantation may be successfully treated by conversion from CI to SRL. Hypertriglyceridemia and hypercholesterolemia represent the principal side effects from SRL, but are treatable. Furthermore, SRL can significantly improve glucose tolerance.

Objective.Acne vulgaris is a chronic inflammatory disease involving the pilosebaceous unit of the skin. Isotretinoin is a systemic retinoid that is often used as an effective treatment option for severe and treatment-resistant acne. Isotretinoin may also cause rheumatologic symptoms. The aim of this prospective observational study was to present followup results regarding the rheumatologic symptoms of patients who received systemic therapy for the treatment of acne (isotretinoin and tetracycline).Methods.For inclusion in the study, all consecutive patients with acne who were aged > 18 years were evaluated by the same dermatologist. The first 42 consecutive patients were included in the isotretinoin group, and after matching for age and sex, 32 consecutive patients were included in the tetracycline group. Isotretinoin treatment was planned as an average dose of 30 mg daily and a total dose of 120–150 mg/kg for 4–6 months. The patients were administered a dose of 1 g/day of tetracycline as 2 equal doses for 3 months.Results.Forty-two patients diagnosed with acne vulgaris were treated with isotretinoin 20.6 ± 4.4 (male/female: 17/22), and 32 patients were treated with tetracycline 20.6 ± 2.7 (male/female: 8/24). There was no significant difference between the 2 groups with respect to age and sex. Unilateral Achilles enthesopathy developed in 3 patients, whereas both Achilles enthesopathy and unilateral sacroiliitis developed in 1 patient. Inflammatory back pain developed in 6 patients in the isotretinoin group.Conclusion.To our knowledge, this was the first prospective observational study that assessed the rheumatologic symptoms of isotretinoin treatment. The spondyloarthropathy findings were identified in 23.1% of the patients who used isotretinoin.

Objective: The aim of this study was to investigate the protective effects of aspirin (AS) and vitamin C (VC) against cardiac damage induced by chronic corn syrup (CS) consumption via a mechanism involving sirtuin-1 (ST-1), hypoxia-inducible factor-1? (HIF-1?), and the caspase-3 pathway in rats. Methods: Forty male Sprague-Dawley rats (14-16 weeks) that weighed 250-300 g were randomly distributed into 5 groups, each containing 8 rats: control group, CS+AS group, CS+VC group, CS+AS+VC group, and CS group. AS (10 mg/kg/day) and VC (200 mg/kg/day) were orally given to the rats. F30 (30% fructose syrup solution) was given to the rats in drinking water for 6 weeks. The rats were sacrificed by exsanguination 24 h after the last administration. Blood samples and tissue were collected for biochemical, histopathological, and immunohistochemical examinations. Non-parametric Kruskal-Wallis test and Mann-Whitney U test used for the parameters without normal distribution and ANOVA and post-hoc LSD tests were used for parameters with a normal distribution to compare groups. Results: Uric acid, creatine kinase (CKMB), and lactate dehydrogenase (LDH) levels were increased in the CS group compared with the control group (1.45±0.39 and p=0.011; 3225.64±598.25 and p=0.004; 3906.83±1064.22 and p=0.002, respectively) and decreased in all the treatment groups. In addition, increased levels of MDA and decreased activity of CAT in the CS group (0.172±0.03 and p=0.000; 0.070±0.005 and p=0.007, respectively) were reversed with AS and VC therapy. A decrease in ST-1 activity and increases in caspase-3 and HIF-1 activities corrected by VC and AS therapy were observed. Conclusion: AS and VC, which display antioxidant and antiapoptotic activities, ameliorated cardiac damage induced by chronic fructose consumption by increasing the levels of ST-1 and decreasing the levels of HIF-1? and caspase-3. © 2016 by Turkish Society of Cardiology.

Epidermal growth factor receptor inhibitors are recent antineoplastic treatments used for the treatment of some non-cutaneous tumours, which aberrantly express EGFR. Because of their specificity, these drugs have low systemic toxicity, but frequent undesired cutaneous effects, the most common of which is an acneiform eruption, occurring after 1-3 weeks of treatment. Management of this rash is not well standardized.We evaluated efficacy, tolerability and impact on quality of life of a clindamycin phosphate 1.2%-benzoyl peroxide 5% gel in 12 male adults who developed acneiform eruption during treatment with cetuximab for metastatic colorectal cancer.Patients applied the clindamycin phosphate-benzoyl peroxide gel once daily, at evening, for 8 weeks. The Skin-Score was used to evaluate reduction of erythema, papules, pustules and pruritus, the Dermatology Life Quality Index questionnaire to evaluate the improvements of health-related quality of life.Significant clinical improvements occurred after 2 weeks of treatment and were even more evident after 8 weeks (mean Skin-Score 20.54 ± 7.83, p = 1.37 × 10(-6) vs. second week visit, p = 1.26 × 10(-7) vs. before treatment). Accordingly, DLQI values decreased from 13.64 ± 2.01 before treatment to 6.45 ± 1.37 after 8 weeks (p = 1.12 × 10(-5)).A clindamycin phosphate-benzoyl peroxide gel may be an effective and safe option in the treatment of cetuximab-associated acneiform eruptions.

Background Tumor necrosis factor-alpha (TNF-α) antagonist treatment is associated with 1.6 to 27 times higher risk of tuberculosis (TB). Objective To find TB incidence of psoriasis patients treated with TNF- α antagonists and define risk factors related with this condition in a country with moderately high risk of TB. Methods Three hundred seventy psoriasis patients treated by anti-TNF agents in four referral centers were included. The data on the characteristics of the patients, TB history, tuberculosis skin test results, anti-TNF agent type and exposure time, localization of TB, and isoniazide prophylaxis state were analyzed. Results Four patients (1.08%) developed TB, three pulmonary and one gastrointestinal, 2–23 months after initiating anti-TNF agents. Other than the patient with gastrointestinal TB, who was using methotrexate and corticosteroid concomitantly, none had contributing risk factors for TB. Two patients developed pulmonary TB in spite of chemoprophylaxis. Three patients with pulmonary TB completely recovered following antiTB treatment whereas patients with gastroinrestinal TB developed renal failure. Limitations The major limitation of the study is the lack of a diseased control group, which enables us to compare the risk of psoriatics with that of patients having other inflammatory diseases. Conclusion Tuberculosis is a rare but a severe complication of anti-TNF treatment and may develop in spite of chemoprophylaxis. The risk of TB in psoriasis patients in the present study is comparable to literature mostly based on rheumatology patients.

Objective.To assess bladder toxicity of cyclophosphamide (CYC) and uroprotective effect of mesna in rheumatic diseases.Methods.Data of 1018 patients (725 women/293 men) treated with CYC were evaluated in this retrospective study. All of the following information was obtained: the cumulative CYC dose, route of CYC administration, duration of therapy, concomitant mesna usage, and hemorrhagic cystitis. Cox proportional hazard model was used for statistics.Results.We identified 17 patients (1.67%) with hemorrhagic cystitis and 2 patients (0.19%) with bladder cancer in 4224 patient-years. The median time for diagnosis to hemorrhagic cystitis was 10 months (4–48) and bladder cancer was 8 years (6–10.9). There were 583 patients (57.2%) who received mesna with intravenous CYC therapy. We observed similar incidence rate for hemorrhagic cystitis in both patient groups concomitantly treated with or without mesna [9/583 (1.5%) vs 8/425 (1.8%) respectively, p = 0.08]. Cumulative CYC dose (HR for 10-g increments 1.24, p < 0.001) was associated with hemorrhagic cystitis.Conclusion.Cumulative dose was the only risk factor for hemorrhagic cystitis in patients treated with CYC. No proof was obtained for the uroprotective effect of mesna in our cohort.

Background Many targeted therapies used in the treatment of cancer can lead to the development of xerosis, but the incidence and relative risk of xerosis have not been ascertained. Objective We conducted a systematic review and metaanalysis of clinical trials, to ascertain the incidence and risk of developing xerosis after taking anticancer drugs. Methods The PubMed (1966-October 2013), Web of Science (January 1998-October 2013), and American Society of Clinical Oncology abstracts (2004-2013) databases were searched for clinical trials of 58 targeted agents. Results were calculated using random or fixed effects models. Results The incidences of all- and high-grade xerosis were 17.9% (95% confidence interval [CI]: 15.6-20.4%) and 1.0% (95% CI: 0.9-1.5%), respectively. The risk of developing all-grade xerosis was 2.99 (95% CI: 2.0-4.3), and it varied across different drugs (P less than .001). Limitations The reporting of xerosis may vary among clinicians and institutions, and the incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions. Conclusion Patients receiving targeted therapies have a significant risk of developing xerosis. Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality of life impairment.

The reporting of infection/sepsis in chemo/radiation-treated head and neck cancer patients is sparse and the problem is underestimated. A multidisciplinary group of head and neck cancer specialists from Italy met with the aim of reaching a consensus on a clinical definition and management of infections and sepsis. The Delphi appropriateness method was used for this consensus. External expert reviewers then evaluated the conclusions carefully according to their area of expertise. The paper contains seven clusters of statements about the clinical definition and management of infections and sepsis in head and neck cancer patients, which had a consensus. Furthermore, it offers a review of recent literature in these topics. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

PubMed ID: 25697921, Objective: To evaluate tolerability/safety and the efficacy of the combination of vildagliptin plus metformin in a real-life population of patients with type 2 diabetes mellitus (T2DM). Research design and methods: This multicenter, single-arm, 6 month, observational, prospective cohort study was conducted at 39 centers across Turkey. T2DM patients on vildagliptin and metformin for ?4 weeks were enrolled regardless of their previous antidiabetic therapy. Main outcome measures: Efficacy was evaluated by measuring hemoglobin A1c (HbA1c) levels. Tolerability/safety parameters evaluated included hypoglycemic events, gastrointestinal events, peripheral edema and weight gain. Results: This study enrolled 665 patients with a mean±standard deviation (SD) age of 55.1±10.2 years and female predominance (n=394, 59.2%). Safety was assessed in all enrolled patients. Hypoglycemia was reported in 10 (1.5%) patients (95% confidence interval = 0.8-2.7%). Efficacy was assessed in 289 (43.5%) patients treated for 6±1 months; these patients showed a mean decrease in HbA1c of 0.8% from baseline value of 7.8% (p65 years) and body mass index (, Novartis Pharmaceuticals Canada, The study was funded by Novartis Pharmaceuticals Turkey., The authors thank Cagla Ayhan MD and Prof. Sule Oktay MD PhD from Kappa Consultancy Training Research Ltd, Istanbul, who provided editorial support, and Mehmet Berktas MD MICR from Kappa Consultancy Training Research Ltd, Istanbul, who performed statistical analysis funded by Novartis Pharmaceuticals Turkey.

El síndrome antifosfolípido es un desorden autoinmune caracterizado por hipercoagulabilidad que requiere terapia anticoagulante como pilar fundamental, siendo la warfarina el tratamiento de elección en los casos que requieren manejo por largos periodos. Sin embargo, los pacientes con anticoagulante lúpico positivo representan un reto porque tienen mayor riesgo de presentar eventos trombóticos, sumado a que el seguimiento con el International Normalized Ratio (INR) no es confiable, ya que estos anticuerpos generan interferencia con las pruebas de laboratorio basadas en fosfolípidos, como es el caso del tiempo de protrombina (PT) con INR basal prolongado, incluso antes del inicio de la terapia anticoagulante. Por tal razón, se ilustra el caso de una paciente con síndrome antifosfolípido primario y anticoagulante lúpico positivo quien ha presentado múltiples episodios trombóticos, a pesar de recibir terapia anticoagulante. Además se hace una revisión de la literatura disponible y se postulan nuevas metas de INR en estos pacientes diferentes de las que se plantean actualmente. Antiphospholipid syndrome (APS) is an autoimmune disorder characterised by hypercoagulability requiring anticoagulant therapy as the basis, with warfarin as the treatment of choice in cases requiring long-term management. However, patients with positive lupus anticoagulant (LA) present a challenge because they have an increased risk of thrombotic events, in addition to the fact that the monitoring of the international normalised ratio (INR) is unreliable because these antibodies generate interference with the laboratory tests based on phospholipids, as is the case for prothrombin time (PT) with prolonged baseline INR, even before the start of anticoagulant therapy. For this reason, we present the case of a patient with primary APS and positive LA who had multiple thrombotic events despite receiving anticoagulant therapy.

In July 2013 a 43-year-old Caucasian man presented to our outpatient Dermatology clinic with multiple extensive ulcerative lesions on the posterior aspects of both legs, which reportedly appeared some weeks before and had since rapidly extended. The lesions, which were very painful, had first developed as multiple erythemato-violaceous plaques which later became deeply ulcerated, showing irregular margins and a seropurulent bed. The patient suffered from severe psoriasis, for which he had been under [...]

AIM: To demonstrate the effect of glatiramer acetate (GA) in chick embryos on neural tube (NT) development, and to explore its effects of FOXP1, apoptosis, and N-cadherin. MATERIAL and METHODS: One hundred fertile, specific pathogen free eggs were divided into 5 groups for this study. The eggshell was windowed specifically at 24 hours of incubation. The embryos in Group 1 (n=20) were treated with 10 mu l physiological saline; in Group 2 the embryos (n=20) were given 10 mu l GA (equal to daily human therapeutic dose); 20 mu l GA (equal to twice daily human therapeutic dose) was injected to embryos in Group 3 (n=20); in Group 4 and 5, 30 mu l and 40 mu l GA were administered to the embryos (n=20) (equal to x3 and x4 daily human therapeutic dose, respectively). Each egg was re-incubated for 24 hours more. Then, histological and immunohistochemical evaluation of the subjects were done. RESULTS: The embryos with NT defect showed FOXP1 expression without N-cadherin or staining with N-cadherin in another location in our study. We interpreted this result as GA leading to an NT closure defect by increasing FOXP expression. Moreover, we also showed the reverse relation between FOXP1 and N-cadherin at the immunohistochemical level for the first time. CONCLUSION: GA affects the spinal cord development through FOXP in the chick embryo model at high doses.

PurposeCytotoxic T-lymphocyte–associated antigen 4 (CTLA4) is an inhibitory receptor on T cells. Knocking out CTLA4 in mice causes lethal lymphoproliferation, and polymorphisms in human CTLA4 are associated with autoimmune disease. Trials of the anti-CTLA4 antibody ipilimumab (MDX-010) have resulted in durable cancer regression and immune-mediated toxicities. A report on the diagnosis, pathology, treatment, clinical outcome, and significance of the immune-mediated enterocolitis seen with ipilimumab is presented.Patients and MethodsWe treated 198 patients with metastatic melanoma (MM) or renal cell carcinoma (RCC) with ipilimumab.ResultsThe overall objective tumor response rate was 14%. We observed several immune mediated toxicities including dermatitis, enterocolitis, hypophysitis, uveitis, hepatitis, and nephritis. Enterocolitis, defined by grade 3/4 clinical presentation and/or biopsy documentation, was the most common major toxicity (21% of patients). It presented with diarrhea, and biopsies showed both neutrophilic and lymphocytic inflammation. Most patients who developed enterocolitis responded to high-dose systemic corticosteroids. There was no evidence that steroid administration affected tumor responses. Five patients developed perforation or required colectomy. Four other patients with steroid-refractory enterocolitis appeared to respond promptly to tumor necrosis factor alpha blockade with infliximab. Objective tumor response rates in patients with enterocolitis were 36% for MM and 35% for RCC, compared with 11% and 2% in patients without enterocolitis, respectively (P = .0065 for MM and P = .0016 for RCC).ConclusionCTLA4 seems to be a significant component of tolerance to tumor and in protection against immune mediated enterocolitis and these phenomena are significantly associated in cancer patients.

The evaluation of a link between two heroin seizures using a descriptive method is presented. It is based on the measure of the angles between two chromatograms assimilated to vectors, and interpreted using a continuous approach based on the likelihood ratio of Bayes' theorem. A complete evaluation model thus avoids the drawbacks of decision thresholds used until now to establish a link. Validation is obtained through tests and simulation methods.