In vitro synergisms obtained by amphotericin B and voriconazole associated with non-antifungal agents against Fusarium spp

AbstractFusarium spp is an opportunistic fungal pathogen responsible for causing invasive hyalohyphomycosis in immunocompromised patients. Due to its susceptibility pattern with a remarkable resistance to antifungal agents the treatment failures and mortality rates are high. To overcome this situation, combination therapy may be considered which must be subjected to in vitro tests.In vitro activities of amphotericin B, itraconazole, and voriconazole associated with azithromycin, ciprofloxacin, fluvastatin, ibuprofen, metronidazole, and also the combination of amphotericin B plus rifampin against 23 strains of Fusarium spp. through the checkerboard technique based on M38-A2 [Clinical and Laboratory Standards Institute (2008). Reference method for broth dilution antifungal susceptibility testing of filamentous fungi; approved standard, 2nd ed. (CLSI document M38-A2) (ISBN 1-56238-668-9). Wayne, PA: CLSI] were evaluated.The best synergistic interactions with amphotericin B were with ibuprofen (43.5%) (FICI [fractional inhibitory concentration index] range = 0.25–2). Combinations with voriconazole showed synergism, mainly with ciprofloxacin (30.4%) (FICI range = 0.25–3) and metronidazole (30.4%) (FICI range = 0.1–4); however, all the combinations with itraconazole were indifferent. In general, antagonistic interactions were not registered.Our results showed that in vitro synergisms obtained by some combinations studied deserve attention since they were better than those showed by the antimycotic

Nandrolone and resistance training induce heart remodeling: Role of fetal genes and implications for cardiac pathophysiology

Aims: This study was conducted to assess the isolated and combined effects of nandrolone and resistance training on cardiac morphology, function, and mRNA expression of pathological cardiac hypertrophy markers.Main methods: Wistar rats were randomly divided into four groups and submitted to 6 weeks of treatment with nandrolone and/or resistance training. Cardiac parameters were determined by echocardiography. Heart was analyzed for collagen infiltration. Real-time RT-PCR was used to assess the pathological cardiac hypertrophy markers.Key findings: Both resistance training and nandrolone induced cardiac hypertrophy. Nandrolone increased the cardiac collagen content, and reduced the cardiac index in non-trained and trained groups, when compared with the respective vehicle-treated groups. Nandrolone reduced the ratio of maximum early to late transmitral flow velocity in non-trained and trained groups, when compared with the respective vehicle-treated groups. Nandrolone reduced the alpha-myosin heavy chain gene expression in both non-trained and trained groups, when compared with the respective vehicle-treated groups. Training reduced the beta-myosin heavy chain gene expression in the groups treated with vehicle and nandrolone. Only the association between training and nandrolone increased the expression of the skeletal alpha-actin gene and atrial natriuretic peptide in the left ventricle.Significance: This study indicated that nandrolone, whether associated with resistance training or not, induces cardiac hypertrophy, which is associated with enhanced collagen content, re-expression of fetal genes the in left ventricle, and impaired diastolic and systolic function. (C) 2011 Elsevier Inc. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAEPEX/UNICAMPConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Estadual Campinas, Piracicaba Dent Sch, Dept Physiol Sci, Piracicaba, SP, BrazilUniv São Paulo, Sch Med, Heart Inst InCor, Hypertens Unit, São Paulo, SP, BrazilUniversidade Federal de São Paulo, Inst Sci & Technol, São Paulo, SP, BrazilUniv São Paulo, Sch Phys Educ & Sports, Biochem Lab, São Paulo, SP, BrazilUniv Estadual Campinas, Piracicaba Dent Sch, Dept Morphol, Piracicaba, SP, BrazilPontifical Catholic Univ Campinas, Life Sci Ctr, Campinas, SP, BrazilUniversidade Federal de São Paulo, Inst Sci & Technol, São Paulo, SP, BrazilFAPESP: 05/60284-6Web of Scienc

Magnetization on rough ferromagnetic surfaces

Journal ArticleUsing Ising-model Monte Carlo simulations, we show a strong dependence of surface magnetization on surface roughness. On ferromagnetic surfaces with spin-exchange coupling larger than that of the bulk, the surface magnetic ordering temperature decreases toward the bulk Curie temperature with increasing roughness. For surfaces with spin-exchange coupling smaller than that of the bulk, a crossover behavior occurs: at low temperature, the surface magnetization decreases with increasing roughness; at high temperature, the reverse is true

DETERMINAÇÃO DE VALORES NORMAIS DA PRESSÃO INTRA-ABDOMINAL DE CÃES PELA CATETERIZAÇÃO VESICAL COM SONDA URETRAL DE P.V.C

A pressão intra-abdominal define-se como um estado de pressão na cavidade abdominal, o qual é determinado pelo índice de massa corporal, pela postura, atividade muscular da parede abdominal e pela respiração. O método padrão ouro para mensuração da pressão intra-abdominal recomendado pela Sociedade Mundial de Síndrome do Compartimento Abdominal é o método indireto por meio da sondagem vesical com sonda de Foley e infusão de 25 mL de solução fisiológica na bexiga. O desenvolvimento de uma técnica de aferição da PIA por meio de sonda uretral de policloreto de vinila (P.V.C.), torna essa técnica mais prática e fácil de ser realizada em Medicina Veterinária. Objetivou-se neste estudo, realizar a mensuração da PIA em 29 cães anestesiados saudáveis, com uma técnica que utiliza a sonda uretral de P.V.C. e a infusão de 1mL/Kg de solução fisiológica, correlacionando os valores encontrados com o peso dos animais. A média da PIA de cadelas anestesiadas com propofol e isoflurano pelo método proposto foi de 1,78 cmH20 (± 1,39) e a mediana de 1,9 cmH20. Os valores da PIA tem relação direta com o peso dos animais

Regulatory T cells from patients with end-stage organ disease can be isolated, expanded and cryopreserved according good manufacturing practice improving their function

Background Here, we isolated, expanded and functionally characterized regulatory T cells (Tregs) from patients with end stage kidney and liver disease, waiting for kidney/liver transplantation (KT/LT), with the aim to establish a suitable method to obtain large numbers of immunomodulatory cells for adoptive immunotherapy post-transplantation. Methods We first established a preclinical protocol for expansion/isolation of Tregs from peripheral blood of LT/KT patients. We then scaled up and optimized such protocol according to good manufacturing practice (GMP) to obtain high numbers of purified Tregs which were phenotypically and functionally characterized in vitro and in vivo in a xenogeneic acute graft-versus-host disease (aGVHD) mouse model. Specifically, immunodepressed mice (NOD-SCID-gamma KO mice) received human effector T cells with or without GMP-produced Tregs to prevent the onset of xenogeneic GVHD. Results Our small scale Treg isolation/expansion protocol generated functional Tregs. Interestingly, cryopreservation/thawing did not impair phenotype/function and DNA methylation pattern of FOXP3 gene of the expanded Tregs. Fully functional Tregs were also isolated/expanded from KT and LT patients according to GMP. In the mouse model, GMP Tregs from LT or KT patient proved to be safe and show a trend toward reduced lethality of acute GVHD. Conclusions These data demonstrate that expanded/thawed GMP-Tregs from patients with end-stage organ disease are fully functional in vitro. Moreover, their infusion is safe and results in a trend toward reduced lethality of acute GVHD in vivo, further supporting Tregs-based adoptive immunotherapy in solid organ transplantation

EAN Guideline on Palliative Care of People with Severe, Progressive Multiple Sclerosis

Background and Purpose: Patients with severe, progressive multiple sclerosis (MS) have complex physical and psychosocial needs, typically over several years. Few treatment options are available to prevent or delay further clinical worsening in this population. The objective was to develop an evidence-based clinical practice guideline for the palliative care of patients with severe, progressive MS. Methods: This guideline was developed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Formulation of the clinical questions was performed in the Patients–Intervention– Comparator–Outcome format, involving patients, carers and healthcare professionals (HPs). No uniform definition of severe MS exists: in this guideline, constant bilateral support required to walk 20m without resting (Expanded Disability Status Scale score >6.0) or higher disability is referred to. When evidence was lacking for this population, recommendations were formulated using indirect evidence or good practice statements were devised. Results: Ten clinical questions were formulated. They encompassed general and specialist palliative care, advance care planning, discussing with HPs the patient’s wish to hasten death, symptom management, multidisciplinary rehabilitation, interventions for caregivers and interventions for HPs. A total of 34 recommendations (33 weak, 1 strong) and seven good practice statements were devised. Conclusions: The provision of home-based palliative care (either general or specialist) is recommended with weak strength for patients with severe, progressive MS. Further research on the integration of palliative care and MS care is needed. Areas that currently lack evidence of efficacy in this population include advance care planning, the management of symptoms such as fatigue and mood problems, and interventions for caregivers and HPs

Adeno-associated virus type 5 infection via PDGFRα is associated with Interstitial lung disease in systemic sclerosis and generates composite peptides and epitopes recognized by the agonistic immunoglobulins present in patients with systemic sclerosis

Objectives: The etiopathogenesis of systemic sclerosis (SSc) is unknown. Platelet-derived growth factor receptors (PDGFRs) are overexpressed in SSc patients. Since PDGFRα is targeted of the adeno-associated virus type 5 (AAV5), we investigated whether AAV5 forms a complex with PDGFRα exposing epitopes that may induce the immune responses to the virus-PDGFRα complex. Methods: The binding of monomeric human PDGFRα to the AAV5 capsid was analyzed by in silico molecular docking, surface plasmon resonance (SPR), and genome editing of the PDGFRα locus. AAV5 was detected in SSc lungs by in situ hybridization, immunohistochemistry, confocal microscopy, and molecular analysis of bronchoalveolar lavage (BAL). Immune responses to AAV5 and PDGFRα were evaluated by SPR using SSc monoclonal anti-PDGFRα antibodies and Immunoaffinity-purified anti-PDGFRα antibodies from sera of SSc patients. Results: AAV5 was detected in the BAL of 41 out of 66 (62.1%) SSc patients with interstitial lung disease and in 17 of 66 controls (25.75 %; p<0.001). In SSc lungs, AAV5 localized in type II pneumocytes and in interstitial cells. A molecular complex formed of spatially contiguous epitopes of the AAV5 capsid and PDGFRα was identified and characterized. In silico molecular docking analysis and binding to the agonistic anti-PDGFRα antibodies identified spatially contiguous epitopes derived from PDGFRα and AAV5 that interacted with SSc agonistic antibodies to PDGFRα. These peptides were also able to bind total IgG isolated from SSc patients, not from healthy controls. Conclusions: These data link AVV5 with the immune reactivity to endogenous antigens in SSc, and provide a novel element in the pathogenesis of SSc

Survey radiography and computerized tomography imaging of the thorax in female dogs with mammary tumors

<p>Abstract</p> <p>Background</p> <p>Accurate early diagnosis of lung metastases is important for establishing therapeutic measures. Therefore, the present study aimed to compare survey thoracic radiographs and computerized tomography (CT) scans to specifically identify lung metastases in female dogs with mammary tumors.</p> <p>Methods</p> <p>Twenty-one female dogs, weighing 3 to 34 kg and aged from 5 years to 14 years and 10 months, with mammary tumors were studied. In all dogs before the imaging examinations, fine-needle aspiration cytology of the mammary tumors was performed to confirm the diagnosis. Three-view thoracic radiographs were accomplished: right lateral, left lateral and ventrodorsal views. Sequential transverse images of the thorax were acquired on a spiral Scanner, before and after intravenous bolus injection of nonionic iodine contrast. Soft-tissue and lung windows were applied. All the mammary tumors were surgically removed and examined histologically.</p> <p>Results</p> <p>The correlation between the cytological and histological results regarding presence of malignancy was observed in only 17 cases. In radiographic examinations, no dog displayed signs of lung metastases or thorax chest lesions. CT detected lung metastasis in two cases, while small areas of lung atelectasis located peripherally were found in 28.57% of the dogs.</p> <p>Conclusion</p> <p>In this study population, spiral CT showed higher sensitivity than chest radiographies to detect lung metastasis; this indicates that CT should be performed on all female dogs with malignant mammary tumors.</p

Systemic inflammatory status predict the outcome of k-RAS WT metastatic colorectal cancer patients receiving the thymidylate synthase poly-epitope-peptide anticancer vaccine

TSPP is an anticancer poly-epitope peptide vaccine to thymidylate synthase, recently investigated in the multi-arm phase Ib TSPP/VAC1 trial. TSPP vaccination induced immune-biological effects and showed antitumor activity in metastatic colorectal cancer (mCRC) patients and other malignancies. Progression-free and overall survival of 41 mCRC patients enrolled in the study correlated with baseline levels of CEA, immune-inflammatory markers (neutrophil/lymphocyte ratio, CRP, ESR, LDH, ENA), IL-4 and with post-treatment change in p-ANCA and CD56dimCD16brightNKs (p < 0.04). A subset of 19 patients with activating k-ras mutations showed a different immune-inflammatory response to TSPP as compared to patients with k-ras/wt and a worse outcome in term of PFS (p = 0.048). In patients with k-ras/mut, inflammatory markers lost their predictive value and their survival directly correlated with the baseline levels of IL17/A over the median value (p = 0.01). These results provide strong hints for the design of further clinical trials aimed to test TSPP vaccination in mCRC patients

Patient and caregiver involvement in the formulation of guideline questions: findings from the European Academy of Neurology guideline on palliative care of people with severe multiple sclerosis

Background and purpose: Patient and public involvement in clinical practice guideline development is recommended to increase guideline trustworthiness and relevance. The aim was to engage multiple sclerosis (MS) patients and caregivers in the definition of the key questions to be answered in the European Academy of Neurology guideline on palliative care of people with severe MS. Methods: A mixed methods approach was used: an international online survey launched by the national MS societies of eight countries, after pilot testing/debriefing on 20 MS patients and 18 caregivers, focus group meetings of Italian and German MS patients and caregivers. Results: Of 1199 participants, 951 (79%) completed the whole online survey and 934 from seven countries were analysed: 751 (80%) were MS patients (74% women, mean age 46.1) and 183 (20%) were caregivers (36% spouses/partners, 72% women, mean age 47.4). Participants agreed/strongly agreed on inclusion of the nine pre-specified topics (from 89% for ‘advance care planning’ to 98% for ‘multidisciplinary rehabilitation’), and <5% replied ‘I prefer not to answer’ to any topic. There were 569 free comments: 182 (32%) on the pre-specified topics, 227 (40%) on additional topics (16 guideline-pertinent) and 160 (28%) on outcomes. Five focus group meetings (three of MS patients, two of caregivers, and overall 35 participants) corroborated the survey findings. In addition, they allowed an explanation of the guideline production process and the exploration of patient-important outcomes and of taxing issues. Conclusions: Multiple sclerosis patient and caregiver involvement was resource and time intensive, but rewarding. It was the key for the formulation of the 10 guideline questions and for the identification of patient-important outcomes