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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.

Since ancient times, Capparis species have been widely used in traditional medicine to treat various diseases. Our recent investigations have suggested Capparis ovata-s potential anti-neuroinflammatory application for the treatment of multiple sclerosis (MS). The present study was designed to precisely determine the underlying mechanism of its anti-neuroinflammatory effect in a mouse model of MS. C. ovata water extract (COWE) was prepared using the plant-s fruit, buds, and flower parts (Turkish Patent Institute, PT 2012/04,093). We immunized female C57BL/6 J mice with MOG(35_55)/CFA. COWE was administered at a daily dose of 500 mg/Kg by oral gavage either from the day of immunization (T1) or at disease onset (12) for 21 days. Gene expression analysis was performed using a Mouse Multiple Sclerosis RT2 Profiler PCR Array, and further determinations and validations of the identified genes were performed using qPCR. Whole-genome transcriptome profiling was analyzed using Agilent SurePrint G3 Mouse GE 8X60K microarrays. Immunohistochemical staining was applied to brain sections of the control and treated mice to examine the degree of degeneration. COWE was further fractionated and analyzed phytochemically using the Zivak Tandem Gold Triple Quadrupole LC/MS-MS system. COWE remarkably suppressed the development of EAE in T1, and the disease activity was completely inhibited. In the T2 group, the maximal score was significantly reduced compared with that of the parallel EAE group. The COWE suppression of EAE was associated with a significantly decreased expression of genes that are important in inflammatory signaling, such as TNF alpha, IL6, NF-kappa B, CCL5, CXCL9, and CXCK10. On the other hand, the expression of genes involved in myelination/remyelination was significantly increased. Immunohistochemical analysis further supported these effects, showing that the number of infiltrating immune cells was decreased in the brains of COWE-treated animals. In addition, differential expression profiling of the transcriptome revealed that COWE treatment caused the down regulation of a group of genes involved in the immune response, inflammatory response, antigen processing and presentation, B-cell-mediated immunity and innate immune response. Collectively, these results suggest anti-neuroinflammatory mechanisms by which COWE treatment delayed and suppressed the development of EAE and ameliorated the disease in mice with persistent clinical signs. (C) 2016 Elsevier B.V. All rights reserved. Türkiye Bilimsel Ve Teknolojik Araştırma Kurumu ( Tübitak )

Objetivo Caracterizar la forma en que los agricultores se exponen a los plaguicidas y se presenta la intoxicación. Materiales y Métodos Estudio multi-métodos y multinivel (individuo y comunidad), que incluyó métodos etnográficos, encuesta y medición de plaguicidas en agua y muestras humanas. Resultados Se describió el proceso productivo y se conocieron los principales factores de riesgo. Los plaguicidas son considerados el Mayor peligro en el trabajo y en sus viviendas. Los trabajadores tienen precarias condiciones laborales y no están protegidos por el sistema de riesgos laborales. En las muestras de agua se encontraron azinfos-metil, endosulfán, b-BHC, bromofos-metil, bromofos-etil y 2,4-DDT. En la encuesta participaron 381 trabajadores de los cuales 12,9, 68 y 5,5 % tuvieron intoxicaciones leves, moderadas y severas, respectivamente. Los casos severos tenían menores niveles de escolaridad, menor nivel de afiliación al régimen contributivo del sistema de seguridad social y un Mayor número tenía enfermedad cardiovascular, diabetes, herpes u otras infecciones virales. Conclusión Existen precarias condiciones laborales que favorecen la exposición a plaguicidas caracterizadas por la exclusión del sistema de riesgos laborales, pobreza y baja educación. Es urgente la inclusión de estos trabajadores al sistema de riesgos laborales y la mejora de las condiciones de vida. De esa manera se podrán disminuir las prácticas inseguras en el manejo de plaguicidas. Objective Large quantities of pesticides are used in rice crops. The aim of this study is to characterize how farmers are exposed to pesticides and subsequent poisoning. Materials and Methods A multilevel (individual and community) multi-method study, which included ethnographic and survey methods, as well as measurement of pesticides in water and human samples, was performed. Results The production process is described and the main risk factors are presented. Pesticides are considered the greatest danger at work and at their homes. Workers have poor working conditions and are not protected by the system of occupational risks. Azinphos-methyl, endosulfan, β-BHC, bromophos-methyl, bromophos-ethyl and 2,4- DDT were found in water samples. The survey included 381 workers with mild (12.86 %), moderate (67.98 %) and severe (5.51 %) poisonings respectively. Severe cases presented lower levels of education, lower levels of health care access to the contributory regimen of the Colombian social security system and higher incidence of cardiovascular disease, diabetes, herpes or other viral infections. Conclusion There are precarious working conditions that favor exposure to pesticides correlated to the exclusion of farmers from the occupational risk system, to poverty and to poor education. It is urgent to include these workers to the system of occupational risk system and to improve their living conditions, thus reducing unsafe practices when handling pesticides.

Evidence supports a role of 17&-estradiol (E2) in carcinogenesis and the large majority of breast carcinomas are dependent on estrogen. The anti-estrogen tamoxifen (TAM) is widely used for both treatment and prevention of breast cancer; however, it is also carcinogenic in human uterus and rat liver, highlighting the profound complexity of its actions. The nature of E2- or TAM-induced chromosomal damage has been explored using relatively high concentrations of these agents, and only some numerical aberrations and chromosomal breaks have been analyzed. This study aimed to determine the effects of low doses of E2and TAM (10&8 mol L&1and 10&6 mol L&1respectively) on karyotypes of MCF7, T47D, BT474, and SKBR3 breast cancer cells by comparing the results of conventional karyotyping and multi-FISH painting with cell proliferation. Estrogen receptor (ER)-positive (+) cells showed an increase in cell proliferation after E2treatment (MCF7, T47D, and BT474) and a decrease after TAM treatment (MCF7 and T47D), whereas in ER& cells (SKBR3), no alterations in cell proliferation were observed, except for a small increase at 96 h. Karyotypes of both ER+ and ER& breast cancer cells increased in complexity after treatments with E2and TAM leading to specific chromosomal abnormalities, some of which were consistent throughout the treatment duration. This genotoxic effect was higher in HER2+ cells. The ER&/HER2+ SKBR3 cells were found to be sensitive to TAM, exhibiting an increase in chromosomal aberrations. Thesein vitroresults provide insights into the potential role of low doses of E2and TAM in inducing chromosomal rearrangements in breast cancer cells.

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.

The hypocretins, also known as orexins, are two neuropeptides now commonly described as critical components to maintain and regulate the stability of arousal. Several lines of evidence have raised the hypothesis that hypocretin-producing neurons are part of the circuitries that mediate the hypothalamic response to acute stress. Intracerebral administration of hypocretin leads to a dose related reinstatement of drug and food seeking behaviors. Furthermore, stress-induced reinstatement can be blocked with hypocretin receptor 1 antagonism. These results, together with recent data showing that hypocretin is critically involved in cocaine sensitization through the recruitment of NMDA receptors in the ventral tegmental area, strongly suggest that activation of hypocretin neurons play a critical role in the development of the addiction process. The activity of hypocretin neurons may affect addictive behavior by contributing to brain sensitization or by modulating the brain reward system. Hypocretinergic cells, in coordination with brain stress systems may lead to a vulnerable state that facilitates the resumption of drug seeking behavior. Hence, the hypocretinergic system is a new drug target that may be used to prevent relapse of drug seeking.

Background: There is little experience with the (neuro) psychological treatment of patients with solvent-induced chronic toxic encephalopathy (CSE). In this randomised controlled trial (RCT), a treatment programme was evaluated based on previous outcome studies of patients with chronic fatigue, whiplash and traumatic brain damage. Methods: The treatment consisted of 8 group sessions based on cognitive behavioural principles focusing on inadequate illness behaviours, and 8 sessions of cognitive strategy training to compensate memory problems. The research design was an RCT with follow-up, comparing the cumulative effect of the 2 interventions allocated in random order with a waiting-list control group. Outcome measures were treatment satisfaction, self-ratings of psychosocial and cognitive changes, psychosocial and memory questionnaires and neuropsychological tests. Multiple linear regression analyses were performed with baseline scores, treatment versus control condition, effort status, and litigation or financial compensation status as predictors. Results: Ninety-five patients started treatment, 84 patients had complete data. Treatment satisfaction was high. After the treatment, only the treatment group had improved on objective memory tests and on complaints related to CSE, but not on other questionnaires. Treatment effects diminished at follow-up. Insufficient effort and litigation were negatively associated with treatment outcome. Conclusions: The positive treatment effects on the cognitive tests were only temporary. It might be important to study the effect of booster sessions to update practiced cognitive strategies. Effort was an important predictor of success, more important than involvement in a litigation procedure. This finding should have implications for the selection of patients.

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.

The aim of the present study was to determine the impact of as nicotinic acetylcholine receptor (nAChR) subunit deletion in the mouse on the development and intensity of nociceptive behavior in various chronic pain models. The role of as-containing nAChRs was explored in mouse models of chronic pain, including peripheral neuropathy (chronic constriction nerve injury, CCI), tonic inflammatory pain (the formalin test) and short and long-term inflammatory pain (complete Freund's adjuvant, CFA and carrageenan tests) in alpha(5) knock-out (1(0) and wild-type (WT) mice. The results showed that paw-licking time was decreased in the formalin test, and the hyperalgesic and allodynic responses to carrageenan and CFA injections were also reduced. In addition, paw edema in formalin-, carrageenan- or CFA-treated mice were attenuated in alpha(5)-K-O mice significantly. Furthermore, tumor necrosis factor-alpha (TNF-alpha) levels of carrageenan-treated paws were lower in alpha(5)-K-O mice. The antinociceptive effects of nicotine and sazetidine-A but not varenicline were alpha(5)-dependent in the formalin test. Both hyperalgesia and allodynia observed in the CCI test were reduced in alpha(5)-K-O mice. Nicotine reversal of mechanical allodynia in the CCI test was mediated through alpha(5)-nAChRs at spinal and peripheral sites. In summary, our results highlight the involvement of the et, nAChR subunit in the development of hyperalgesia, allodynia and inflammation associated with chronic neuropathic and inflammatory pain models. They also suggest the importance of alpha(5)-nAChRs as a target for the treatment of chronic pain. United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) (DA-12610) United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) European Commission (R01DA032246) United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) European Commission (R01DA012610)

La acatisia aguda es un trastorno del movimiento bastante molesto, caracterizado por sensación subjetiva y signos objetivos de inquietud motora, que se presenta frecuentemente como efecto adverso de los neurolépticos; un tratamiento oportuno es necesario para garantizar una buena adherencia al manejo con antipsicóticos y prevenir recaídas. Se describe el estado actual de los tratamientos disponibles para la acatisia aguda inducida por neurolépticos, valorando efectividad y tolerabilidad. Se realizó una búsqueda electrónica en Pubmed, Science Alert, Springer link, SciELO, Ovid y Elsevier con criterios de selección específicos, obteniendo 87 estudios, de los cuales se escogieron 51 teniendo en cuenta relevancia clínica, nivel de evidencia y actualidad. En este artículo se describen los resultados de la búsqueda. Las benzodiacepinas, los betabloqueadores lipofílicos de acción central y los anticolinérgicos son los fármacos más estudiados para el tratamiento de este trastorno del movimiento; los dos primeros han mostrado superioridad, sin embargo, se necesita aún bastante investigación al respecto. Acute Akathisia is a movement disorder rather annoying; characterized by subjective feelings and objective signs of restlessness, which often presents as a side effect of neuroleptics, early treatment is necessary to ensure good adherence to treatment with antipsychotics and prevent relapses. To describe the state of the art of available treatments for neuroleptic-induced acute akathisia, taking into account effectiveness and tolerability. An electronic search in Pubmed, Science Alert, Springer link, SciELO, Ovid and Elsevier with specific eligibility criteria, obtaining 87 studies, of which were chosen 51 of them manually, according to their clinical relevance, topicality and level of evidence. In this paper, we describe the results of the search. The benzodiazepines, centrally acting lipophilic beta-blockers and anticholinergics, are the most studied drugs to treat this movement disorder, the first two have shown superiority; however, considerable research is still needed in this regard.

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.

Psychedelic agents have a long history of use by humans for their capacity to induce profound modifications in perception, emotion and cognitive processes. Despite increasing knowledge of the neural mechanisms involved in the acute effects of these drugs, the impact of sustained psychedelic use on the human brain remains largely unknown. Molecular pharmacology studies have shown that psychedelic 5-hydroxytryptamine (5HT)2A agonists stimulate neurotrophic and transcription factors associated with synaptic plasticity. These data suggest that psychedelics could potentially induce structural changes in brain tissue. Here we looked for differences in cortical thickness (CT) in regular users of psychedelics. We obtained magnetic resonance imaging (MRI) images of the brains of 22 regular users of ayahuasca (a preparation whose active principle is the psychedelic 5HT2A agonist N,N-dimethyltryptamine (DMT)) and 22 controls matched for age, sex, years of education, verbal IQ and fluid IQ. Ayahuasca users showed significant CT differences in midline structures of the brain, with thinning in the posterior cingulate cortex (PCC), a key node of the default mode network. CT values in the PCC were inversely correlated with the intensity and duration of prior use of ayahuasca and with scores on self-transcendence, a personality trait measuring religiousness, transpersonal feelings and spirituality. Although direct causation cannot be established, these data suggest that regular use of psychedelic drugs could potentially lead to structural changes in brain areas supporting attentional processes, self-referential thought, and internal mentation. These changes could underlie the previously reported personality changes in long-term users and highlight the involvement of the PCC in the effects of psychedelics. © 2015 Elsevier B.V. and ECNP.

Background: Bacterial translocation (BT) related to intestinal bacterial overgrowth (IBO) plays an important role in the pathogenesis of bacterial infections in cirrhosis. Inhibition of acid gastric secretion promotes IBO and might favor BT. We evaluated the effect of long-term inhibition of acid gastric secretion on BT in cirrhotic rats. Methods: Cirrhotic rats with and without ascites induced by oral CCl4 and controls were randomized to treatment with a daily subcutaneous injection of placebo, ranitidine (50 mg/kg), or pantoprazole (8 mg/kg) during 2 weeks. Continuous pH-metry was performed for 2 h before and at the end of treatment; thereafter, a laparotomy to obtain samples of blood, mesenteric lymph nodes, ascites, spleen, liver, and cecal stools was performed. Results: Ranitidine and pantoprazole increased gastric pH as compared with placebo (P < 0.001). However, antisecretory drugs increased the incidence of BT only in ascitic rats treated with ranitidine (P < 0.05) or pantoprazole (P = 0.07) when compared with placebo-treated ascitic rats or cirrhotic rats without ascites treated with the same drug. Cirrhotic ascitic rats treated with pantoprazole showed a trend toward an increased incidence of IBO (P = 0.08), a higher ileal malondialdehyde level (P < 0.01), and an increased production of tumor necrosis factor-a (P < 0.05). Conclusion: Although inhibition of acid gastric secretion increased gastric pH in all animals, the incidence of BT increased only in ascitic rats, and it was associated with a trend toward an increase in IBO incidence, a higher ileal malondialdehyde level, and an increased production of serum tumor necrosis factor-a. Therefore, antisecretory drugs should be carefully administered to cirrhotic ascitic patients. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Carbon capture and storage (CCS) technologies are considered vital and economic elements for achieving global CO2 reduction targets, and is currently introduced worldwide (for more information on CCS, consult for example the websites of the International Energy Agency (http://www.iea.org/topics/ccs/) and the Global CCS Institute (http://www.globalccsinstitute.com/)). One prominent CCS technology, the amine-based post-combustion process, may generate nitrosamines and their related nitramines as by-products, the former well known for their potential mutagenic and carcinogenic properties. In order to efficiently assess the carcinogenic potency of any of these by-products this paper reviews and discusses novel prediction approaches consuming less time, money and animals than the traditionally applied 2-year rodent assay. For this, available animal carcinogenicity studies with N-nitroso compounds and nitramines have been used to derive carcinogenic potency values, that were subsequently used to assess the predictive performance of alternative prediction approaches for these chemicals. Promising cancer prediction models are the QSARs developed by the Helguera group, in vitro transformation assays, and the in vivo initiation-promotion, and transgenic animal assays. All these models, however, have not been adequately explored for this purpose, as the number of N-nitroso compounds investigated is yet too limited, and therefore further testing with relevant N-nitroso compounds is needed.

Background: Evidence from systematic reviews of observational studies suggests that hormone therapy may have beneficial effects in reducing the incidence of cardiovascular disease events in post-menopausal women, however the results of randomised controlled trials (RCTs) have had mixed results. This is an updated version of a Cochrane review published in 2013. Objectives: To assess the effects of hormone therapy for the prevention of cardiovascular disease in post-menopausal women, and whether there are differential effects between use in primary or secondary prevention.Secondary aims were to undertake exploratory analyses to (i) assess the impact of time since menopause that treatment was commenced (= 10 years versus < 10 years), and where these data were not available, use age of trial participants at baseline as a proxy (= 60 years of age versus < 60 years of age); and (ii) assess the effects of length of time on treatment. Search methods: We searched the following databases on 25 February 2014: Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE and LILACS. We also searched research and trials registers, and conducted reference checking of relevant studies and related systematic reviews to identify additional studies. Selection criteria: RCTs of women comparing orally administered hormone therapy with placebo or a no treatment control, with a minimum of six months follow-up. Data collection and analysis: Two authors independently assessed study quality and extracted data. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for each outcome. We combined results using random effects meta-analyses, and undertook further analyses to assess the effects of treatment as primary or secondary prevention, and whether treatment was commenced more than or less than 10 years after menopause. Main results: We identified six new trials through this update. Therefore the review includes 19 trials with a total of 40,410 post-menopausal women. On the whole, study quality was good and generally at low risk of bias; the findings are dominated by the three largest trials. We found high quality evidence that hormone therapy in both primary and secondary prevention conferred no protective effects for all-cause mortality, cardiovascular death, non-fatal myocardial infarction, angina, or revascularisation. However, there was an increased risk of stroke in those in the hormone therapy arm for combined primary and secondary prevention (RR 1.24, 95% CI 1.10 to 1.41). Venous thromboembolic events were increased (RR 1.92, 95% CI 1.36 to 2.69), as were pulmonary emboli (RR 1.81, 95% CI 1.32 to 2.48) on hormone therapy relative to placebo. The absolute risk increase for stroke was 6 per 1000 women (number needed to treat for an additional harmful outcome (NNTH) = 165; mean length of follow-up: 4.21 years (range: 2.0 to 7.1)); for venous thromboembolism 8 per 1000 women (NNTH = 118; mean length of follow-up: 5.95 years (range: 1.0 to 7.1)); and for pulmonary embolism 4 per 1000 (NNTH = 242; mean length of follow-up: 3.13 years (range: 1.0 to 7.1)). We performed subgroup analyses according to when treatment was started in relation to the menopause. Those who started hormone therapy less than 10 years after the menopause had lower mortality (RR 0.70, 95% CI 0.52 to 0.95, moderate quality evidence) and coronary heart disease (composite of death from cardiovascular causes and non-fatal myocardial infarction) (RR 0.52, 95% CI 0.29 to 0.96; moderate quality evidence), though they were still at increased risk of venous thromboembolism (RR 1.74, 95% CI 1.11 to 2.73, high quality evidence) compared to placebo or no treatment. There was no strong evidence of effect on risk of stroke in this group. In those who started treatment more than 10 years after the menopause there was high quality evidence that it had little effect on death or coronary heart disease between groups but there was an increased risk of stroke (RR 1.21, 95% CI 1.06 to 1.38, high quality evidence) and venous thromboembolism (RR 1.96, 95% CI 1.37 to 2.80, high quality evidence). Authors' conclusions: Our review findings provide strong evidence that treatment with hormone therapy in post-menopausal women overall, for either primary or secondary prevention of cardiovascular disease events has little if any benefit and causes an increase in the risk of stroke and venous thromboembolic events. © 2015 The Cochrane Collaboration.

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.

Air pollution has gained considerable interest because of the multiple adverse effects reported on human health, although its impact on fertility remains unclear. A systematic search was performed to evaluate the impact of air pollutants on fertility. Controlled trials and observational studies assessing animal model and epidemiological model were included. Occupational exposure and semen quality studies were not considered. Outcomes of interest included live birth, miscarriage, clinical pregnancy, implantation, and embryo quality. Ten studies were included and divided into two groups: animal studies and human epidemiological studies including the general population as well as women undergoing in vitro fertilization and embryo transfer (IVF/ET). Results from this systematic review suggest a significant impact of air pollution on miscarriage and clinical pregnancy rates in the general population, whereas among subfertile patients certain air pollutants seem to exert a greater impact on fertility outcomes, including miscarriage and live birth rates. Besides, studies in mammals observed a clear detrimental effect on fertility outcomes associated to air pollutants at high concentration. The lack of prospective studies evaluating the effect of air pollution exposure in terms of live birth constitutes an important limitation in this review. Thus, further studies are needed to confirm these findings. © 2015 Informa UK Ltd.

Carbon capture and storage (CCS) technologies are considered vital and economic elements for achieving global CO2 reduction targets, and is currently introduced worldwide (for more information on CCS, consult for example the websites of the International Energy Agency (http://www.iea.org/topics/ccs/) and the Global CCS Institute (http://www.globalccsinstitute.com/)). One prominent CCS technology, the amine-based post-combustion process, may generate nitrosamines and their related nitramines as by-products, the former well known for their potential mutagenic and carcinogenic properties. In order to efficiently assess the carcinogenic potency of any of these by-products this paper reviews and discusses novel prediction approaches consuming less time, money and animals than the traditionally applied 2-year rodent assay. For this, available animal carcinogenicity studies with N-nitroso compounds and nitramines have been used to derive carcinogenic potency values, that were subsequently used to assess the predictive performance of alternative prediction approaches for these chemicals. Promising cancer prediction models are the QSARs developed by the Helguera group, in vitro transformation assays, and the in vivo initiation-promotion, and transgenic animal assays. All these models, however, have not been adequately explored for this purpose, as the number of N-nitroso compounds investigated is yet too limited, and therefore further testing with relevant N-nitroso compounds is needed.

Objective was to analyze the effect of various fluoride formulations in commercially available agents on working properties of various nickel- titanium orthodontic wires. Uncoated (NiTi), rhodium coated (RhNiTi) and nitrified (NNiTi) wires were immersed to dH2O, MiPaste, Elmex and Mirafluor for 1 h. Unloading slope characteristics (average force, bending action of the force and average plateau length) and the percentage of usable constant force during unloading were observed. Surface roughness (Ra) was measured. SEM and EDS were used for observation of the surface. NiTi had decreased loading and unloading elastic modulus (E) and yield strength (YS) after immersion to MIPaste and Mirafluor. The unloading YS decreased in the RhNiTi by the MIPaste. The loading and unloading YS of the NNiTi increased in Elmex and increased average plateau force. RhNiTi showed higher average plateau length and the percentage of useful constant force during unloading in Mirafluor and the average plateau force lowered after immersion to MIPaste. The unloading slope characteristics for NiTi were affected by all three prophylactic agents, mostly by Mirafluor, and produced significantly lower forces during both loading and unloading, similarly to the NNiTi wires. The RhNiTi had the lowest forces during both loading and unloading in MIPaste. All results were at significance ; p < 0.05. Difference in Ra was observed for RhNiTi after immersion to the MI Paste (p < 0.001 ; h2 = 0.761). The NiTi and NNiTi wires lose less working force when combined with Elmex. The RhNiTi improve their working properties with Mirafluor and deteriorate when combined with MiPaste.

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.

Objective.—To evaluate the effects of three schemes of oral hormone replacement therapy (HRT) on migraine course in postmenopausal women. Methods.—Thirty-eight patients presenting for clinical evaluation of menopausal status and suffering from migraine were enrolled. The observational period lasted 7 months, during which women filled in a daily diary with the clinical features of headache attacks and analgesic use. We evaluated climacteric symptoms, anxiety and depression. After a 1-month run-in period, women were assigned to one of three regimens of HRT: estradiol hemihydrate 1 mg/day plus norethisterone 0.5 mg/day for 28 days, in a continuous combined scheme; oral conjugated estrogens 0.625 mg/day for 28 days plus medroxyprogesterone acetate 10 mg/day in the last 14 days, in a sequential continuous scheme; and estradiol valerate 2 mg/day for 21 days plus cyproterone acetate 1 mg/day from day 12 to 21 in a sequential cyclical scheme. Follow-up evaluations were performed at 3 and 6 months. Results.—During the run-in period, the three subgroups of patients were similar as far as the features of migraine are concerned. Overall, a progressive increase in attack frequency (from 2.2 ± 1.0 to 3.8 ± 1.3, P

Cerebral microbleeds are microscopic hemorrhages with deposits of blood products in the brain, which can be visualized with MRI and are implicated in cerebrovascular diseases. Hematoxylin and eosin (H&E) and Perl’s Prussian blue are popular staining methods used to localize cerebral microbleeds in pathology. This paper compared these two staining techniques in a mouse model of cerebral microbleeds. We used lipopolysaccharide (LPS) to induce cerebral microhemorrhages. C57B6 mice were treated with LPS (5 mg/kg, i.p.) or vehicle at baseline and at 24 hr. The brains were extracted 48 hr after the first injection and adjacent coronal sections were stained with H&E and Prussian blue to compare the effectiveness of the two staining techniques. H&E-positive stains were increased with LPS treatment and were correlated with grossly visible microhemorrhages on the brain surface; Prussian blue-positive stains, by comparison, showed no significant increase with LPS treatment and did not correlate with either H&E-positive stains or surface microhemorrhages. H&E staining is thus a more reliable indicator of acute bleeding events induced by LPS in this model within a short time span.

Summary: Sixty patients diagnosed with generalized anxiety disorder and treated with either paroxetine, sertraline, or citalopram for at least 12 months were enrolled in this study, and the bone mineral density (BMD) of the patients was compared with that of 40 healthy volunteers. Selective serotonin reuptake inhibitor (SSRI) therapy in generalized anxiety disorder was found to be related with decreased BMD values., Introduction: The objectives of this study were to evaluate the effect of SSRI therapy on BMD in postmenopausal women diagnosed with generalized anxiety disorder (GAD) and to identify the effects of the duration of disease and treatment on risk factors for osteoporosis., Methods: Sixty patients diagnosed with GAD and treated with paroxetine, sertraline, or citalopram from the SSRI group for at least 12 months were enrolled. Social demographic features, the Hamilton Anxiety Scale (HAS) results, and the Hamilton Depression Scale (HDS) scores of all the patients were assessed. The BMD of the patients was measured by dual-energy X-ray absorptiometry (DXA) at the femoral and lumbar regions. The patients were divided into three groups which are the paroxetine, sertraline, and citalopram groups. The BMD of the patients was compared with that of 40 healthy volunteers., Results: The L2–L4, total lumbar vertebrae, femoral intertrochanteric, total femoral Z-scores, and femoral Ward’s region T-scores of the treatment group were lower than the median T- and Z-scores of the control group (p < 0.05). Of the treatment groups, the femoral neck, trochanteric and intertrochanteric T- and Z-scores, total femoral T- and Z-scores, and femoral Ward’s T- and Z-scores of the sertraline group were significantly lower than the BMD values measured at the identical regions in the paroxetine and citalopram groups (p < 0.05).There was a significant negative correlation between the duration of treatment and the BMD values., Conclusion: SSRI therapy in GAD was found to be related with decreased BMD values. Further randomized controlled studies are warranted to determine whether SSRI use is a risk factor for osteoporosis; such studies should investigate these factors by performing BMD assessments before treatment. © 2014, The Author(s).

We report on the performance of composite nerve grafts with an inner 3D multichannel porous chitosan core and an outer electrospun polycaprolactone shell. The inner chitosan core provided multiple guidance channels for regrowing axons. To analyze thein vivoproperties of the bare chitosan cores, we separately implanted them into an epineural sheath. The effects of both graft types on structural and functional regeneration across a 10 mm rat sciatic nerve gap were compared to autologous nerve transplantation (ANT). The mechanical biomaterial properties and the immunological impact of the grafts were assessed with histological techniques before and after transplantationin vivo. Furthermore during a 13-week examination period functional tests and electrophysiological recordings were performed and supplemented by nerve morphometry. The sheathing of the chitosan core with a polycaprolactone shell induced massive foreign body reaction and impairment of nerve regeneration. Although the isolated novel chitosan core did allow regeneration of axons in a similar size distribution as the ANT, the ANT was superior in terms of functional regeneration. We conclude that an outer polycaprolactone shell should not be used for the purpose of bioartificial nerve grafting, while 3D multichannel porous chitosan cores could be candidate scaffolds for structured nerve grafts.

The exact pathophysiology of contrast-induced nephropathy (CIN) is not fully clarified, yet the osmotic characteristics of contrast media (CM) have been a significant focus in many investigations of CIN. Osmotic effects of CM specific to the kidney include transient decreases in blood flow, filtration fraction, and glomerular filtration rate. Potentially significant secondary effects include an osmotically induced diuresis with a concomitant dehydrating effect. Clinical experiences that have compared the occurrence of CIN between the various classes of CM based on osmolality have suggested a much less than anticipated advantage, if any, with a lower osmolality. Recent animal experiments actually suggest that induction of a mild osmotic diuresis in association with iso-osmolar agents tends to offset potentially deleterious renal effects of high viscosity-mediated intratubular CM stagnation.

Kaya, Ertugrul/0000-0003-0081-682X WOS: 000334560800014 PubMed: 24831366 AIM: Epileptic seizures lead to neuronal loss in the hippocampus. Experimental epilepsy can be induced by direct application of various chemicals to cerebral cortex. Nifedipine is an L-type voltage-dependent calcium channel blocker. In spite of several studies that show the seizure-suppressing effects of nifedipine, it has been shown that nifedipine does not suppress but conversely increases epileptic seizures. Similarly, contradictory effects of nifedipine have been reported, such as neuroprotection, failed neuroprotection and neurotoxicity. We therefore aimed to investigate the effect of nifedipine on hippocampal neuronal loss in penicillin induced epileptic rats in this study. MATERIAL and METHODS: The effect of nifedipine on total hippocampal neuron number was estimated by using the optical fractionator method (an unbiased stereological method) in penicillin-G induced epileptic rats. RESULTS:The total number of hippocampal neurons in the control group was 183687 +/- 3184. In the penicillin-induced group, the total neuron number significantly decreased to 146318 +/- 3042 compared to the control group. In the nifedipine group, the neuron number significantly decreased to 128873 +/- 1157 compared to both control and penicillin-induced groups. CONCLUSION: Nifedipine increased neuronal loss and did not suppress epileptic seizures in penicillin-induced epileptic rats. Nifedipine could not protect against hippocampal neuronal loss in penicillin-induced epileptic rats.

Angiotensin II receptor blockers (ARBs) are drugs generally well tolerated. There are few reports about cutaneous side effects of ARBs. The present authors describe herein four cases of purpuric eruption mainly involving sites of friction in patients taking ARBs. These eruptions completely cleared after stopping the drug and implementing preservative measures to reduce friction.

Background: Blocking vascular endothelial growth factor (VEGF) mediated tumor angiogenesis by phytochemicals has emerged as an attractive strategy for cancer prevention and therapy.Methods: We investigated the anti-angiogenic effects of ellagic acid in a hamster model of oral oncogenesis by examining the transcript and protein expression of hypoxia-inducible factor-1alpha (HIF-1?), VEGF, VEGFR2, and the members of the PI3K/Akt and MAPK signaling cascades. Molecular docking studies and cell culture experiments with the endothelial cell line ECV304 were performed to delineate the mechanism by which ellagic acid regulates VEGF signaling.Results: We found that ellagic acid significantly inhibits HIF-1?-induced VEGF/VEGFR2 signalling in the hamster buccal pouch by abrogating PI3K/Akt and MAPK signaling via downregulation of PI3K, PDK-1, p-Aktser473, mTOR, p-ERK, and p-JNK. Ellagic acid was also found to reduce the expression of histone deacetylases that could inhibit neovascularization. Analysis of the mechanism revealed that ellagic acid inhibits hypoxia-induced angiogenesis via suppression of HDAC-6 in ECV304 cells. Furthermore, knockdown of endogenous HDAC6 via small interfering RNA abrogated hypoxia-induced expression of HIF-1? and VEGF and blocked Akt activation. Molecular docking studies confirmed interaction of ellagic acid with upstream kinases that regulate angiogenic signaling.Conclusions: Taken together, these findings demonstrate that the anti-angiogenic activity of ellagic acid may be mediated by abrogation of hypoxia driven PI3K/Akt/mTOR, MAPK and VEGF/VEGFR2 signaling pathways involving suppression of HDAC6 and HIF-1? responses. General Significance: Ellagic acid offers promise as a lead compound for anticancer therapeutics by virtue of its ability to inhibit key oncogenic signaling cascades and HDACs. � 2014 Bentham Science Publishers.

Objective: To determine whether demographic, clinical, and laboratory variables measurable at baseline predict the clinical efficacy or major toxic effects of methotrexate (MTX) therapy in children with chronic arthritis. Study design: Patient eligibility criteria: (1) monitored in our unit between 1986 and 1996 with a diagnosis of chronic arthritis and (2) treatment with MTX as the sole second-line agent and for at least 6 months. Outcomes investigated: (1) short-term (6-month) clinical response, (2) complete disease control, (3) disease relapse after MTX discontinuation after complete disease control, (4) aminotransferase elevation, (5) gastrointestinal toxicity. Independent variables that showed significant results with univariate tests or were clinically relevant for each outcome underwent multiple logistic or Poisson regression analyses. Results: Eighty patients were available for analysis. The disease onset subtype was systemic in 37 patients, polyarticular in 20 patients, and oligoarticular in 23 patients (all with polyarticular course: extended oligoarticular subtype). The extended oligoarticular subtype was the best predictor for both the short-term clinical response (odds ratio 6.80, P = .02) and, together with a better functional ability, the complete disease control (rate ratio 3.85, P = .03 and rate ratio 3.29, P = .006, respectively). Patients with this subtype of chronic arthritis tended to have earlier, and more frequently, a disease relapse after MTX discontinuation. Thrombocytosis was the only significant risk factor for liver biochemical abnormalities (rate ratio 2.94, P = .008), whereas no variable yielded significant results for gastrointestinal toxicity. Conclusion: Patients with extended oligoarticular chronic arthritis were more likely to benefit from MTX therapy and to have a relapse after treatment discontinuation, suggesting that MTX is distinctly more effective in this subset of chronic arthritis. (J Pediatr 1999;135:316-20)