Impact on grafted kidney function of rocuronium-sugammadex vs cisatracurium-neostigmine strategy for neuromuscular block management. An Italian single-center, 2014-2017 retrospective cohort case-control study.

BACKGROUND: The impact of sugammadex in patients with end-stage renal disease undergoing kidney transplantation is still far from being defined. The aim of the study is to compare sugammadex to neostigmine for reversal of rocuronium- and cisatracurium-induced neuromuscular block (NMB), respectively, in patients undergoing kidney transplantation. METHODS: A single-center, 2014-2017 retrospective cohort case-control study was performed. A total of 350 patients undergoing kidney transplantation, equally divided between a sugammadex group (175 patients) and a neostigmine group (175 patients), were considered. Postoperative kidney function, evaluated by monitoring of serum creatinine and urea and estimated glomerular filtration rate (eGFR), was the endpoint. Other endpoints were anesthetic and surgical times, post-anesthesia care unit length of stay, postoperative intensive care unit admission, and recurrent NMB or complications. RESULTS: No significant differences in patient or, with the exception of drugs involved in NMB management, anesthetic, and surgical characteristics, were observed between the two groups. Serum creatinine (median [interquartile range]: 596.0 [478.0-749.0] vs 639.0 [527.7-870.0] µmol/L, p = 0.0128) and serum urea (14.9 [10.8-21.6] vs 17.1 [13.1-22.0] mmol/L, p = 0.0486) were lower, while eGFR (8.0 [6.0-11.0] vs 8.0 [6.0-10.0], p = 0.0473) was higher in the sugammadex group than in the neostigmine group after surgery. The sugammadex group showed significantly lower incidence of postoperative severe hypoxemia (0.6% vs 6.3%, p = 0.006), shorter PACU stay (70 [60-90] min vs 90 [60-105] min, p < 0.001), and reduced ICU admissions (0.6% vs 8.0%, p = 0.001). CONCLUSIONS: Compared to cisatracurium-neostigmine, the rocuronium-sugammadex strategy for reversal of NMB showed a better recovery profile in patients undergoing kidney transplantation.

Psychometric properties of the Brazilian version of the Difficulties in Emotion Regulation Scale (DERS) / Propriedades psicométricas da versão Brasileira da Difficulties in Emotion Regulation Scale (DERS)

Abstract Introduction: Emotion regulation can be defined as the process by which individuals manage their emotional experience. It has been demonstrated that deficits in this ability are associated with various psychiatric disorders. In this direction, the Difficulties in Emotion Regulation Scale (DERS) was developed to measure difficulties in emotion regulation. Objective: To examine the psychometric properties of the Brazilian Portuguese version of the DERS. Method: A total of 377 individuals from the general population, selected by convenience, completed a sociodemographic form, the adapted Brazilian Portuguese DERS and the Depression Anxiety Stress Scale (DASS-21). Factor structure, reliability, and concurrent validity of the adapted version of the instrument were investigated. Results: The confirmatory factor analysis replicated the six-factor structure originally proposed for the instrument and confirmed the acceptability of a hierarchical model where all DERS subscales loaded on a general emotion dysregulation factor. Internal consistency indicators had adequate values for the general factor and subscales. The positive association between DERS and DASS-21 scores supports the instrument's concurrent validity. Conclusion: These results suggest that the Brazilian version of the DERS is reliable both as a general measure of difficulties in emotion regulation and as a measure of the constituents of this construct. Future research should investigate the psychometric properties of the scale in clinical and nonclinical populations, with equal gender proportions and diverse backgrounds, and preferably employing longitudinal designs.

Resumo Introdução: Regulação emocional pode ser definida como o processo pelo qual os indivíduos regulam sua experiência emocional. Tem sido demonstrado que déficits na regulação emocional podem estar associados a vários transtornos psiquiátricos. Nesta linha, a Difficulties in Emotion Regulation Scale (DERS) é um instrumento que foi desenvolvido para acessar dificuldades na regulação emocional. Objetivo: Examinar as propriedades psicométricas de uma versão da DERS adaptada ao português brasileiro. Método: Um total de 377 indivíduos da população geral foram selecionados por conveniência para completar um questionário sociodemográfico, a versão adaptada ao português brasileiro da DERS e a Depression Anxiety Stress Scale (DASS-21). Foram investigadas a estrutura fatorial, confiabilidade e validade concorrente da versão adaptada da DERS. Resultados: A análise fatorial confirmatória replicou a estrutura de seis fatores originalmente proposta para o instrumento e confirmou a aceitabilidade de um modelo hierárquico em que todas as subescalas são carregadas em um fator de desregulação emocional geral. Os indicadores de consistência interna apresentaram valores adequados para o fator geral e subescalas. A associação positiva entre os escores obtidos na DERS e na DASS-21 dá suporte à validade concorrente do instrumento. Conclusão: Esses resultados sugerem que a versão brasileira da DERS é confiável como medida geral de dificuldades na regulação emocional e como medida dos constituintes desta construção. Pesquisas futuras devem investigar as propriedades psicométricas da escala em populações clínicas e não clínicas, com igual proporção de gênero e diversas origens e, de preferência, empregando desenhos longitudinais.

Psychometric properties of the Brazilian version of the Difficulties in Emotion Regulation Scale (DERS).

INTRODUCTION: Emotion regulation can be defined as the process by which individuals manage their emotional experience. It has been demonstrated that deficits in this ability are associated with various psychiatric disorders. In this direction, the Difficulties in Emotion Regulation Scale (DERS) was developed to measure difficulties in emotion regulation. OBJECTIVE: To examine the psychometric properties of the Brazilian Portuguese version of the DERS. METHOD: A total of 377 individuals from the general population, selected by convenience, completed a sociodemographic form, the adapted Brazilian Portuguese DERS and the Depression Anxiety Stress Scale (DASS-21). Factor structure, reliability, and concurrent validity of the adapted version of the instrument were investigated. RESULTS: The confirmatory factor analysis replicated the six-factor structure originally proposed for the instrument and confirmed the acceptability of a hierarchical model where all DERS subscales loaded on a general emotion dysregulation factor. Internal consistency indicators had adequate values for the general factor and subscales. The positive association between DERS and DASS-21 scores supports the instrument's concurrent validity. CONCLUSION: These results suggest that the Brazilian version of the DERS is reliable both as a general measure of difficulties in emotion regulation and as a measure of the constituents of this construct. Future research should investigate the psychometric properties of the scale in clinical and nonclinical populations, with equal gender proportions and diverse backgrounds, and preferably employing longitudinal designs.

Modeling tumor growth inhibition and toxicity outcome after administration of anticancer agents in xenograft mice: A Dynamic Energy Budget (DEB) approach.

Host features, such as cell proliferation rates, caloric intake, metabolism and energetic conditions, significantly influence tumor growth; at the same time, tumor growth may have a dramatic impact on the host conditions. For example, in clinics, at certain stages of the tumor growth, cachexia (body weight reduction) may become so relevant to be considered as responsible for around 20% of cancer deaths. Unfortunately, anticancer therapies may also contribute to the development of cachexia due to reduced food intake (anorexia), commonly observed during the treatment periods. For this reason, cachexia is considered one of the major toxicity findings to be evaluated also in preclinical studies. However, although various pharmacokinetic-pharmacodynamic (PK-PD) tumor growth inhibition (TGI) models are currently available, the mathematical modeling of cachexia onset and TGI after an anticancer administration in preclinical experiments is still an open issue. To cope with this, a new PK-PD model, based on a set of tumor-host interaction rules taken from Dynamic Energy Budget (DEB) theory and a set of drug tumor inhibition equations taken from the well-known Simeoni TGI model, was developed. The model is able to describe the body weight reduction, splitting the cachexia directly induced by tumor and that caused by the drug treatment under study. It was tested in typical preclinical studies, essentially designed for efficacy evaluation and routinely performed as a part of the industrial drug development plans. For the first time, both the dynamics of tumor and host growth could be predicted in xenograft mice untreated or treated with different anticancer agents and following different schedules. The model code is freely available for downloading at http://repository.ddmore.eu (model number DDMODEL00000274).

Vírus zika - Epidemiologia e diagnóstico laboratorial / Zika virus - Epidemiology and laboratory diagnosis

O vírus Zika (ZIKV) pode ser considerado um patógeno emergente disseminado para a Oceania e a América causando surtos sazonais. No Brasil a infecção começou a ser registrada em 2015 no Nordeste do país, embora a doença seja autolimitada e manifeste sintomas brandos, ocorreram relatos de complicações neurológicas associadas ao ZIKV em recém-nascidos e em adultos. Essa revisão descreve as características epidemiológicas da infecção pelo ZIKV no Brasil e no Rio Grande do Sul, e efetua análise dos métodos utilizados no diagnóstico laboratorial da infecção. As fontes de pesquisa foram artigos científicos em português e em inglês que referiam casos de infecção por ZIKV, no período de 2007 a 2017, citados nos repositórios digitais PubMed, PubMed Central (PMC) e SciELO, foram utilizados os descritores: Zika, diagnóstico, sorologia e epidemiologia. Apesar do decréscimo nos casos notificados no ano de 2017, o ZIKV continua em circulação. O diagnóstico laboratorial utiliza técnicas em métodos moleculares e sorológicas. A reação da transcriptase reversa (RT-PCR) é a metodologia com maior especificidade comparada à de enzimaimunoensaio e à de neutralização por redução de placas. (AU)

Zika virus can be considered a widespread emerging pathogen for Oceania and America causing seasonal outbreaks. Zika's disease began registered in 2015 in Brazil northeast, although the disease is self limited and manifest mild symptoms, there have been reports of neurological complications associated with ZIKV in neonates and adults. This review describes the epidemiological characteristics of ZIKV infection in Brazil and Rio Grande do Sul, and reports the methods used in laboratory diagnosis. The sources of research were scientific articles in Portuguese and English that reported cases of ZIKV infection and with a focus on laboratory diagnosis cited in the digital repositories PubMed, PubMed Central (PMC) and SciELO, from 2007 to 2017, the descriptors : Zika, diagnosis, serology and epidemiology. Despite the decrease in cases described in 2017, ZIKV keeps circulating. The definitive diagnosis is based on molecular and serological methods. Molecular diagnosis by reverse transcription polymerase chain reaction (RT-PCR) is the more specific method than the serological methods by enzyme immunoassay and platelet neutralization test. (AU)

Long-term wireless pH monitoring of the distal esophagus: prolonging the test beyond 48 hours is unnecessary and may be misleading.

Wireless pH monitoring of the esophagus has been widely used to detect GERD for more than a decade. It is generally well tolerated and accepted by patients, but it is still unclear whether prolonging a recording beyond the usual 48 hours can improve the test's diagnostic value. The aim of this study is to examine the diagnostic yield of 96-hour pH monitoring vis-à-vis 24- and 48-hour tests, and to ascertain whether any gain in diagnostic terms was of genuine clinical utility. Patients with suspected GERD underwent 4-day PPI-off wireless pH monitoring of the distal esophagus. The capsule was inserted under endoscopic control, 6 cm above the squamocolumnar junction. Average acid exposure time was calculated after 24, 48, and 96 hours of recording. Ninety-nine patients completed the 96 hour test, and formed the study sample. The wireless test method was used in 42 patients (42.4%) unable to tolerate the traditional pH-monitoring catheter, and in 57 (57.6%) with a previous negative pH study despite symptoms suggestive of GERD. On complete analysis, 47 patients (47.5%) had a pathological test result: 19 patients within the first 24 hours (19.2%, 24 hour group); another 16 after 48 hours (+16.2%, 48 hour group), and a further 12 (+12.1%, 96 hour group) only after 96 hours of monitoring. All 47 patients with an abnormal acid exposure were offered and accepted surgery (10 patients) or medical therapy (37 patients). Clinical follow-up was obtained in all patients with a positive Bravo test result after a median 67 months (IQR: 38-98) using a validated symptom questionnaire. A good outcome after fundoplication or medical therapy was achieved in 73.7% of patients in the 24 hour group, in 62.5% of those in the 48 hour group, and in only 25% of those in the 96 hour group, P = 0.02. Long-term wireless pH monitoring enables an increase in the diagnostic yield over traditional 24- and 48-hour pH studies, but prolonging the test may constitute an unwanted bias and prompt the recruitment of more complex patients, in whom the outcome of surgical or medical therapy may prove less than satisfactory. These findings should be taken into account when establishing the guidelines for assessing GERD with such long-term pH monitoring methods.

Anti-tumour efficacy on glioma models of PHA-848125, a multi-kinase inhibitor able to cross the blood-brain barrier.

BACKGROUND AND PURPOSE: Malignant gliomas, the most common primary brain tumours, are highly invasive and neurologically destructive neoplasms with a very bad prognosis due to the difficulty in removing the mass completely by surgery and the limited activity of current therapeutic agents. PHA-848125 is a multi-kinase inhibitor with broad anti-tumour activity in pre-clinical studies and good tolerability in phase 1 studies, which could affect two main pathways involved in glioma pathogenesis, the G1-S phase progression control pathway through the inhibition of cyclin-dependent kinases and the signalling pathways mediated by tyrosine kinase growth factor receptors, such as tropomyosin receptors. For this reason, we tested PHA-848125 in glioma models. EXPERIMENTAL APPROACH: PHA-848125 was tested on a panel of glioma cell lines in vitro to evaluate inhibition of proliferation and mechanism of action. In vivo efficacy was evaluated on two glioma models both as single agent and in combination with standard therapy. KEY RESULTS: When tested on a subset of representative glioma cell lines, PHA-848125 blocked cell proliferation, DNA synthesis and inhibited both cell cycle and signal transduction markers. Relevantly, PHA-848125 was also able to induce cell death through autophagy in all cell lines. Good anti-tumour efficacy was observed by oral route in different glioma models both with s.c. and intracranial implantation. Indeed, we demonstrate that the drug is able to cross the blood-brain barrier. Moreover, the combination of PHA-848125 with temozolomide resulted in a synergistic effect, and a clear therapeutic gain was also observed with a triple treatment adding PHA-848125 to radiotherapy and temozolomide. CONCLUSIONS AND IMPLICATIONS: All the pre-clinical data obtained so far suggest that PHA-848125 may become a useful agent in chemotherapy regimens for glioma patients and support its evaluation in phase 2 trials for this indication.

Cisplatin plus paclitaxel and maintenance of bevacizumab on tumour progression, dissemination, and survival of ovarian carcinoma xenograft models.

BACKGROUND: Bevacizumab is being incorporated as first-line therapy with standard-of-care chemotherapy on epithelial ovarian carcinoma (EOC). We investigated bevacizumab combined with chemotherapy on tumour progression and mouse survival in EOC xenograft models. METHODS: Bevacizumab was administered concomitantly with cisplatin plus paclitaxel (DDP+PTX), continued after induction (maintenance) or started after chemotherapy. The effect on tumour progression was monitored by bioluminescence imaging (BLI) (1A9-luc xenograft). Tumour dissemination into the peritoneal organs and ascites formation (HOC22 xenograft) was evaluated by histological analysis at the end of treatment (interim) and at euthanasia (survival). The effects on overall survival (OS) were investigated in both EOC models. RESULTS: Bevacizumab with PTX+DDP delayed tumour progression in mice bearing EOC xenografts. OS was significantly extended, with complete responses, by bevacizumab continued after stopping chemotherapy in the HOC22 xenograft. Bevacizumab alone inhibited ascites formation, with only limited effect on tumour burden, but combined with PTX+DDP reduced ascites and metastases. Bevacizumab started after induction with PTX+DDP and maintained was equally effective on tumour progression and survival on 1A9-luc xenograft. CONCLUSION: Bevacizumab combined with chemotherapy not only affected tumour progression, but when administered as maintenance regimen significantly prolonged survival, reducing ascites, and tumour dissemination. We believe our findings are consistent with the clinical results and shed light on the potential effects of this kind of treatment on tumour progression.

Testing additivity of anticancer agents in pre-clinical studies: a PK/PD modelling approach.

In clinical oncology, combination regimens may result in a synergistic, additive or antagonistic interaction (i.e. the effect of the combination is greater, similar or smaller than the sum of the effects of the individual compounds). For this reason, during the drug development process, in vivo pre-clinical studies are performed to assess the interaction of anticancer agents given in combination. Starting from a widely used single compound PK/PD model, a new additivity model able to predict the tumour growth inhibition in xenografted mice after the administration of compounds in combination was developed, under the assumption of a pharmacodynamic null interaction. By comparing the predicted curves with actual tumour weight data, possible departures from additivity can be immediately ascertained by visual inspection; a statistical procedure based on a chi(2) test has also been developed for this aim. The advantages of the proposed approach in comparison to other modelling methodologies are discussed and its application to four combination studies is presented.

Immunohistopathological and neuroimaging characterization of murine orthotopic xenograft models of glioblastoma multiforme recapitulating the most salient features of human disease.

Tumorigenesis in human glioblastoma multiforme (GBM) is driven by several genetic abnormalities with disruption of important molecular pathways, such as p53/MDM2/p14ARF and EGFR/PTEN/Akt/mTOR. The malignant progression of human GBM is also primarily associated with a peculiar multistep pathophysiological process characterized by intratumoral ischemic necrosis (i.e. pseudopalisading necrosis) and activation of the hypoxia-inducible factor (HIF)-1alpha pathway with consequent peritumoral microvascular proliferation and infiltrative behaviour. Predictable preclinical animal models of GBM should recapitulate the main pathobiological hallmarks of the human disease. In this study we describe two murine orthotopic xenograft models using U87MG and U251 human cell lines. Ten Balb/c nude male mice were orthotopically implanted with either U87MG (5 mice) or U251 (5 mice) cell lines. Intracranial tumor growth was monitored through Magnetic Resonance Imaging (MRI). Immunohistopathological examination of the whole cranium was performed 30 days after implantation. U251 orthotopic xenografts recapitulated the salient pathobiological features described for human GBM, including invasive behaviour, wide areas of pseudopalisading necrosis, florid peripheral angiogenesis, GFAP and vimentin expression, nonfunctional p53 expression, striking active-caspase-3 and HIF-1alpha expression along pseudopalisades. U87MG orthotopic xenografts proved to be very dissimilar from human GBM, showing expansile growth, occasional necrotic foci without pseudopalisades, intratumoral lacunar pattern of angiogenesis, lack of GFAP expression, functional p53 expression and inconsistent HIF-1alpha expression. Expression of pAkt was upregulated in both models. The results obtained suggest that the U251 orthotopic model may be proposed as a predictive and reliable tool in preclinical studies since it recapitulates the most salient pathobiological features reported for human GBM.