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One family of designs that can noticeably improve efficiency in later stages of drug development are multi-arm multi-stage (MAMS) designs. They allow several arms to be studied concurrently and gain efficiency by dropping poorly performing treatment arms during the trial as well as by allowing to stop early for benefit. Conventional MAMS designs were developed for the setting, in which treatment arms are independent and hence can be inefficient when an order in the effects of the arms can be assumed (eg, when considering different treatment durations or different doses). In this work, we extend the MAMS framework to incorporate the order of treatment effects when no parametric dose-response or duration-response model is assumed. The design can identify all promising treatments with high probability. We show that the design provides strong control of the family-wise error rate and illustrate the design in a study of symptomatic asthma. Via simulations we show that the inclusion of the ordering information leads to better decision-making compared to a fixed sample and a MAMS design. Specifically, in the considered settings, reductions in sample size of around 15% were achieved in comparison to a conventional MAMS design.

The identification and quantification of predictive biomarkers characterize personalized medicine approaches and patient-centric clinical development. In practice, the sponsor needs evaluating whether biomarker-informed clinical development strategies are more likely to benefit current and future patients. To this end, a simple metric is proposed and assessed here quantifying the expected clinical benefit (ECB) of clinical development programmes. Using simulation scenarios and endpoints relevant to oncology, the ECB of a simple biomarker-informed strategy is shown to be specific and sensitive. Also, the ECB difference is shown to increase in the biomarker-driven incremental efficacy and with the population prevalence of biomarker-positive study participants.

The non-tasting form of the bitter taste receptor, TAS2R38, has been shown as a genetic risk factor associated with the development of Parkinson's disease (PD). Specific taste receptors that are expressed in the lower gastrointestinal tract may respond to alteration in gut microbiota composition, detecting bacterial molecules, and regulate immune responses. Given the importance of brain-gut-microbiota axis and gene-environment interactions in PD, we investigate the associations between the genetic variants of TAS2R38 and gut microbiota composition in 39 PD patients. The results confirm that the majority of PD patients have reduced sensitivity to 6-n-propylthiouracil (PROP) and are carriers of at least one non-functional TAS2R38 AVI haplotype. Moreover, we found this correlation to be associated with a reduction in bacteria alpha-diversity with a predominant reduction of Clostridium genus. We hypothesised that the high frequency of the non-taster form of TAS2R38 associated with a diminuition of Clostridium bacteria in PD might determine a reduction in the activation of protective signalling-molecules useful in preserving gut homeostasis. This pilot study, by identifying a decrease in specific bacteria associated with a reduced sensitivity to PROP, adds essential information that opens new avenues of research into the association of PD microbiota composition and sensory modification.

Purpose: The standard bibliometric indexes (“ m-quotient “ H-,” “ H2-,” “ g-,” “ a-,” “ m-,” and “ r-” index) do not considered the research’ position in the author list of the paper. We proposed a new methodology, System of Authorship Best Assessment (SABA), to characterize the scientific output based on authors’ position. Material and Methods: Four classes S1A, S1B, S2A, and S2B include only papers where the researcher is in first, first/last, first/second/last, and first/second/second-last/last position respectively were used for the calculation of H-index and number of citations The system was tested with Noble prize winners controlled with researchers matched for H-index. The different in percentage between standard bibliometric index and S2B was calculated and compared. Results: The percentage differences in Noble prize winners between S2B- H-index versus Global H-index and number of citations is very lower comparing with control group (median 4.15% [adjusted 95% CI, 2.54–5.30] vs 9.00 [adjusted 95% CI, 7.16–11.84], p < 0.001; average difference 8.7% vs 20.3%). All different in percentage between standard bibliometric index and S2B except two ( H2- and m-index) were significantly lower among Noble prize compared with control group. Conclusion: The SABA methodology better weight the research impact by showing that for excellent profiles the S2B is similar to global values whereas for other researchers there is a significant difference.

The antagonistic effect of glutathione (GSH) against the cytotoxicity of cisplatin was observed in both wild type and cisplatin-resistant human leukaemia and ovarian carcinoma cell lines. The simultaneous presence of the cytotoxic copper complex [Cu(phen)2(OH2)](ClO4)2 (C0) restored the sensitivity of the cells to cisplatin, and, at selected concentrations, led to strong synergistic effects. The C0–cisplatin–glutathione system showed a synergistic toxic effect even in the presence of 1000 μM GSH. The three-drug cocktail exerted a higher potency against leukemic cells than against freshly isolated lymphocytes from healthy donors. Compared to actively proliferating normal lymphocytes, leukaemia cells were much more susceptible to the cytocide effect of the three-drug combination and underwent the dying process(es) much faster. When the ovarian carcinoma cells were treated with cisplatin, alone or in combination with C0, late apoptotic effects were mainly observed, suggesting that DNA interactions with the C0–cisplatin complex trigger a process of programmed cell death. In contrast, the ternary combination induced apoptotic effects similar to that shown by C0 in single treatment, that is, early apoptosis. One possible explanation is that C0 and cisplatin compete for GSH-binding in the culture medium. GSH in combination with C0 and cisplatin caused a significant induction of the apoptotic process(es), through a pathway which does not compromise the integrity of the plasma membrane of cells.

Background: Patients at risk of breast cancer are submitted to mammography, resulting in a classification of the lesions following the Breast Imaging Reporting and Data System (BI-RADS®). Due to BI-RADS 3 classification problems and the great uncertainty of the possible evolution of this kind of tumours, the integration of mammographic imaging with other techniques and markers of pathology, as metabolic information, may be advisable. Design and Methods: Our study aims to evaluate the possibility to quantify by gas chromatography-mass spectrometry (GCMS) specific metabolites in the plasma of patients with mammograms classified from BI-RADS 3 to BI-RADS 5, to find similarities or differences in their metabolome. Samples from BI-RADS 3 to 5 patients were compared with samples from a healthy control group. This pilot project aimed at establishing the sensitivity of the metabolomic classification of blood samples of patients undergoing breast radiological analysis and to support a better classification of mammographic cases. Results: Metabolomic analysis revealed a panel of metabolites more abundant in healthy controls, as 3-aminoisobutyric acid, cholesterol, cysteine, stearic, linoleic and palmitic fatty acids. The comparison between samples from BI-RADS 3 and BI-RADS 5 patients, revealed the importance of 4-hydroxyproline, found in higher amount in BI-RADS 3 subjects. Conclusion: Although the low sample number did not allow the attainment of high validated statistical models, some interesting data were obtained, revealing the potential of metabolomics for an improvement in the classification of different mammographic lesions. Significance for public health The breast cancer risk is evaluated after mammographic exam by the BI-RADS classification of lesion. The BI-RADS 3 classified cases comprise a wide class of lesions and their treatment must be subjected to multidisciplinary discussion and consideration. Metabolomic analysis of plasma from subjects undergoing mammography may give new information on metabolite content and allow a better classification for BI-RADS 3 cases.

Parkinson&rsquo, s disease (PD) is a clinically heterogenic disorder characterized by distinct clinical entities. Most studies on motor deficits dichotomize PD into tremor dominant (TD) or non-tremor dominant (non-TD) with akinetic-rigid features (AR). Different pathophysiological mechanisms may affect the onset of motor manifestations. Recent studies have suggested that gut microbes may be involved in PD pathogenesis. The aim of this study was to investigate the gut microbiota and metabolome composition in PD patients in relation to TD and non-TD phenotypes. In order to address this issue, gut microbiota and the metabolome structure of PD patients were determined from faecal samples using 16S next generation sequencing and gas chromatography&ndash, mass spectrometry approaches. The results showed a reduction in the relative abundance of Lachnospiraceae, Blautia, Coprococcus, Lachnospira, and an increase in Enterobacteriaceae, Escherichia and Serratia linked to non-TD subtypes. Moreover, the levels of important molecules (i.e., nicotinic acid, cadaverine, glucuronic acid) were altered in relation to the severity of phenotype. We hypothesize that the microbiota/metabolome enterotypes associated to non-TD subtypes may favor the development of gut inflammatory environment and gastrointestinal dysfunctions and therefore a more severe &alpha, synucleinopathy. This study adds important information to PD pathogenesis and emphasizes the potential pathophysiological link between gut microbiota/metabolites and PD motor subtypes.

In the past years the significance of white matter hyperintensities (WMH) has gained raising attention because it is considered a marker of severity of different pathologies. Another condition that in the last years has been assessed in the neuroradiology field is cerebral microbleeds (CMB). The purpose of this work was to evaluate the association between the volume of WMH and the presence and characteristics of CMB.Sixty-five consecutive (males 45; median age 70) subjects were retrospectively analyzed with a 1.5 Tesla scanner. WMH volume was quantified with a semi-automated procedure considering the FLAIR MR sequences whereas the CMB were studied with the SWI technique and CMBs were classified as absent (grade 1), mild (grade 2; total number of CMBs: 1-2), moderate (grade 3; total number of CMBs: 3-10), and severe (grade 4; total number of CMBs:10). Moreover, overall number of CMBs and the maximum diameter were registered.Prevalence of CMBs was 30.76% whereas WMH 81.5%. Mann-Whitney test showed a statistically significant difference in WMH volume between subjects with and without CMBs (p 0.001). Pearson analysis showed significant correlation between CMB grade, number and maximum diameter and WMH. The better ROC area under the curve (Az) was obtained by the hemisphere volume with a 0.828 (95% CI from 0.752 to 0,888; SD = 0.0427; p value = 0.001). The only parameters that showed a statistically significant association in the logistic regression analysis were Hemisphere volume of WMH (p = 0.001) and Cholesterol LDL (p = 0.0292).In conclusion, the results of this study suggest the presence of a significant correlation between CMBs and volume of WMH. No differences were found between the different vascular territories.

Background and purpose Recent data suggest that imbalances in the composition of the gut microbiota (GM) could exacerbate the progression of Parkinson disease (PD). The effects of levodopa (LD) have been poorly assessed, and those of LD-carbidopa intestinal gel (LCIG) have not been evaluated so far. The aim of this study was to identify the effect of LD and LCIG, in particular, on the GM and metabolome. Methods Fecal DNA samples from 107 patients with a clinical diagnosis of PD were analyzed by next-generation sequencing of the V3 and V4 regions of the 16S rRNA gene. PD patients were classified in different groups: patients on LCIG (LCIG group, n = 38) and on LD (LD group, n = 46). We also included a group of patients (n = 23) without antiparkinsonian medicaments (Naive group). Fecal metabolic extracts were evaluated by gas chromatography mass spectrometry. Results The multivariate analysis showed a significantly higher abundance in the LCIG group of Enterobacteriaceae, Escherichia, and Serratia compared to the LD group. Compared to the Naive group, the univariate analysis showed a reduction of Blautia and Lachnospirae in the LD group. Moreover, an increase of Proteobacteria, Enterobacteriaceae, and a reduction of Firmicutes, Lachnospiraceae, and Blautia was found in the LCIG group. No significant difference was found in the multivariate analysis of these comparisons. The LD group and LCIG group were associated with a metabolic profile linked to gut inflammation. Conclusions Our results suggest that LD, and mostly LCIG, might significantly influence the microbiota composition and host/bacteria metabolism, acting as stressors in precipitating a specific inflammatory intestinal microenvironment, potentially related to the PD state and progression.

Resumo O Salmo 1211 é uma canção dos peregrinos para ir a Jerusalém, pertencente a um conjunto de quinze salmos (120-134) nos quais aparece o título: "Cântico das subidas" ou "Cântico dos degraus". Deste conjunto, e em relação aos "degraus", os salmos utilizam frequentemente o ritmo gradual: as mesmas palavras ou expressões são retomadas em eco de um verso para o outro. Esta característica marcante na poesia hebraica, presente no livro dos Salmos e muito bem marcada no Salmo 121, possibilita o prazer de estudá-lo conforme os pressupostos e a metodologia da Análise Retórica Semítica Bíblica, percebendo semelhanças e contrastes em seus versos, paralelismos e antíteses, além de quiasmos internos - até mesmo em um único verso - e outros elementos encontrados na beleza do ritmo do salmo. Ligando poesia à atividade cotidiana, a imagem de uma costura que enlaça menores e maiores pontos em um mesmo tecido, ou o une a outro, vem à mente e aponta que YHWH tece, socorre e guarda a vida daquele que busca nele forças para continuar sua caminhada na íngreme subida dos degraus da vida. Resumen El Salmo 121 es una canción de los peregrinos para ir a Jerusalén, perteneciente a un conjunto de quince salmos (120-134) en los que aparece el título: "Cántico de las subidas" o "Cántico de los escalones". De este conjunto, y en relación con los "escalones", los salmos utilizan frecuentemente el ritmo gradual: las mismas palabras o expresiones son retomadas en eco de un verso al otro. Esta característica marcante en la poesía hebrea, presente en el libro de los Salmos y muy bien marcada en el Salmo 121, posibilita el placer de estudiarlo según los presupuestos y la metodología del Análisis Retórico Bíblico Semítico, percibiendo similitudes y contrastes en sus versos, paralelismos y antítesis, además de quiasmos internos - incluso en un solo verso - y otros elementos encontrados en la belleza del ritmo del salmo. Ligando poesía a la actividad cotidiana, la imagen de una costura que enmarca menores y mayores puntos en un mismo tejido, o lo une a otro, viene a la mente y apunta que YHWH teje, socorre y guarda la vida de aquel que busca en él fuerzas para continuar su caminata en la vida cotidiana el empalado ascenso de los escalones de la vida. Abstract Psalm 121 is a song of the pilgrims to Jerusalem, belonging to a set of fifteen psalms (120-134) in which the same title appears: "Song of the Ascents" or "Song of the steps". From this set, and in relation to the "steps", the psalms often use the gradual rhythm: the same words or expressions are echoed from one verse to another. This remarkable characteristic in the Hebrew poetry present in the book of Psalms and very well marked in Psalm 121 makes it possible to study it according to the presuppositions and methodology of Semitic Biblical Rhetoric Analysis, perceiving similarities and contrasts in its verses, parallels and antitheses, besides of inner chiasms - even in a single verse - and other elements found in the beauty of the rhythm of the psalm. Linking poetry to daily activity, the image of a seam that ties smaller and larger points in the same fabric or unites it to another comes to mind and points out that YHWH weaves, helps and saves the life of the one who seeks in him the strength to continue his journey in the steep climb of the steps of life.

This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6 ± 7.3 years, 229 males) and 243 control subjects (67.2 ± 10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P

Thiourea derivatives have been reported to possess many biological activities, among them antiviral and antitumoral properties. As part of our continuing effort to develop new active compounds, we report the synthesis and the evaluation of new fifteen thiourea derivatives with 1,3-benzothiazole-2-yl moiety, among them a group of biologically active (1-7) also underwent cyclization to 1,3-thiazolidin-4-ones. Molecular structure of four compounds (4, 13, 15 and 3a) was determined by an X-ray crystallography. We here report the evaluation of their cytotoxicity against human leukaemia/lymphoma- and solid tumour-derived cell lines and of their antiviral activity against HIV-1 and representatives of ssRNA and dsDNA viruses. Derivative 5 showed an interesting activity against HIV-1 wild type and against variants carrying clinically relevant mutations. A colorimetric enzyme immunoassay clarified its mode of action as a non-nucleoside inhibitor of the reverse transcriptase.

Study ObjectivesThe neurophysiological hallmark of REM sleep behavior disorder (RBD) is loss of atonia during REM sleep. Indeed, signs and symptoms of neurodegeneration can occur after years, even decades, from its beginning. This study aimed to measure neurophysiological alterations of the brainstem that potentially correlate with the severity of atonia loss, and determining whether a prodromal neurodegenerative disorder underlines this condition when it occurs as an isolated condition (iRBD).MethodsSubjects with iRBD and matched healthy controls were recruited. The study included the recording of one-night polysomnography, vestibular-evoked myogenic potentials (VEMPs), and a [123I]-FP-CIT dopamine transporter (DAT) scan. The quantification of REM sleep without atonia (RSWA) was made according to two previously published manual methods and one automated method.ResultsThe rate of alteration of VEMPs and VEMP score were significantly higher in iRBD patients than controls. Moreover, VEMP score was negatively correlated with the automated REM atonia index; a marginal statistical significance was also reached for the positive correlation with the visual tonic electromyographic parameter, while the other correlations, including that with DAT-scan score were not statistically significant.ConclusionsBrainstem neurophysiology in iRBD can be assessed by VEMPs and their alterations may possibly indicate an early expression of the neurodegenerative process underlying this disorder at the brainstem level, which awaits future longitudinal confirmation. The correlation between RSWA and VEMP alteration might also represent a prodromal aspect anticipating the possible evolution from iRBD to neurodegeneration, whereas DAT-scan abnormalities might represent a later step in this evolution.

Cynomorium coccineum is a non-photosynthetic plant that grows in Mediterranean countries and that is amply used in the traditional medicine. The aim of this study was to extend previous studies on the chemical and biological properties of C. coccineum, evaluating the potential antiviral and antiproliferative activity of the methanolic extract. The MTT assay was used for the in vitro cytotoxic studies against human cancer-derived cell lines, while both MTT and plaque reduction (PRT) methods were used to evaluate the potential inhibitory effect of the extract against a panel of mammal viruses. The results obtained showed no selective activity against any DNA and RNA virus but revealed an interesting antiproliferative activity against human leukaemia-derived cell lines.

Nerium oleander (NO), a member of the Apocynaceae family, is an ornamental plant. In this study, we evaluated the antiviral activity of hot and cold extract of NO against six different viruses such as herpes simplex virus type 1 (HSV-1), polio virus type 1 (Sb-1), vesicular stomatitis virus (VSV), reovirus type-1 (Reo-1), human immunodeficiency virus type-1 (HIV-1), and yellow fever virus (YFV). Interestingly the results of plaque reduction assay demonstrated that both, hot extract and cold extract (breastin) of NO inhibited Sb-1 viral infection. In order to identify the mechanism by which NO exerts its antiviral activity, the virucidal effect, the time of addition and the adsorption assay were carried out. Results demonstrated that NO exerts its effect after infection period, particularly during the first two hours post infection.

Este sucinto trabalho pretende trazer uma conversa acerca de uma mulher que Homero nos apresenta entre os cantos VI-XI da Odisseia: a forte e nobre Arete. A rainha dos Feaces e esposa do rei Alcínoo é alguém de quem não se ouve falar muito. No entanto, quando nos aproximamos dessa mulher através da poesia épica, deparamo-nos, na verdade, com a própria virtude em pessoa, a areté como bem o nome lhe representa.Por isso, fica no ar um questionamento: quem é a mulher cheia de virtude na Antiguidade grega? Eis a provocacão -- positiva -- em que este escrito quer envolver o leitor.

Rute é uma mulher pobre, viúva e estrangeira moabita. Não obstante isso, é uma mulher de força/valor, em atitudes e palavras; é uma mulher decidida que se comporta em termos de paridade com Booz, o homem que ao seu lado divide a cena central em Rt 3: a cena da eira. A presente tese, intitulada Uma heroína chamada Rute: análise narrativa e intertextual de Rt 3, buscou mostrar, por meio da exegese narrativa, as possibilidades que assinalam essa paridade entre os protagonistas, Rute e Booz, através da análise de seus atos e falas, quer pelo tratamento que o autor, através da voz do narrador dá a cada um, quer pelo discurso destes personagens, valorizando, ainda, a importância e o papel de Noemi nas cenas anterior e posterior à cena da eira. A seguir, a partir da análise intertextual bíblica e extrabíblica, foi possível identificar outras mulheres que em muito se assemelham à pessoa, às características e ao comportamento de paridade entre Rute e Booz em Rt 3: as mulheres bíblicas Débora, Jael, Abigail e a mulher de Pr 31,10-31, bem como as mulheres extrabíbicas Arete e Alceste, todas com seus pares masculinos em cena. Esta aproximação permitiu aplicar a Rute o conceito de heroína, conforme o modelo literário dos textos da Antiguidade. Nestes, mulheres fortes, corajosas e pares dos homens caracterizam as heroínas, seja nos textos que retratavam a sociedade em Israel, no Antigo Oriente Próximo, ou entre os povos da Grécia continental e insular, os quais circulavam na bacia do Mediterrâneo. Ruth is a poor, widowed and moabite foreigner woman. Nevertheless, she is a woman of strength/value, in attitudes and words; a decided woman that behaves at parity with Booz, the man with whom she shares side by side the central scene in Rt 3: at the threshing floor. This thesis, entitled A heroine called Ruth: narrative and intertextual analysis of Rt 3, sought to show, through the narrative exegesis, the possibilities that point out that parity between the protagonists, Ruth and Booz, either by the treatment the author, through the Narrator s voice, gives to each one or by the speeches of these characters, giving value, still, to Naomi s importance and role before and after the threshing floor scene.Then, from the bible and extrabible intertextual analysis, it was possible to identify other women who very much resemble the person, characteristics and behavior of parity between Ruth and Booz in Rt 3: the bible women Deborah, Jael, Abigail and woman of Pr 31,10 31, as well as the extrabible women Arete and Alcestis, all with their male counterparts at the scene. This approach made it possible to apply to Ruth the concept of heroin, as the literary model of the texts of Antiquity. In these strong, courageous women and men s counterparts characterize the heroines in texts that depict the society in Israel, in the ancient Near East, or between the people of continental and insular Greece, which circulated in the Mediterranean basin.

O presente trabalho pretende abordar a importância da representação social do corpo e suas implicações ao longo do tempo. Tomamos por base inicial a construção narrativa da imagem do herói grego, na figura do guerreiro homérico, pertencente aos áristoi, isto é, aos melhores e, ao mesmo tempo, apontamos as representações do corpo, perpassando o período arcaico e exemplificando permanências na atualidade. Deste modo, apresentamos uma abordagem comparativa que interrelaciona História e Literatura e, ainda, trazemos a discussão para os dias atuais, para que percebamos a “ditadura” dos modelos de beleza do corpo que atravessam as sociedades e chegam a nós, movimentando a inclusão e a exclusão nos modelos hodiernos.

Enteroviruses are among the most common and important human pathogens for which there are no specific antiviral agents approved by the US Food and Drug Administration so far. Particularly, coxsackievirus infections have a worldwide distribution and can cause many important diseases. We here report the synthesis of new 14 quinoxaline derivatives and the evaluation of their cytotoxicity and antiviral activity against representatives of ssRNA, dsRNA and dsDNA viruses. Promisingly, three compounds showed a very potent and selective antiviral activity against coxsackievirus B5, with EC50 in the sub-micromolar range (0.3 - 0.06 μM). A combination of experimental techniques (i.e. virucidal activity, time of drug addition and adsorption assays) and in silico modeling studies were further performed, aiming to understand the mode of action of the most active, selective and not cytotoxic compound, the ethyl 4-[(2,3-dimethoxyquinoxalin-6-yl)methylthio]benzoate (6).

It has been shown that different genes could be associated with distinctive clinical and radiological phenotypes of FTD. TARDBP gene has been described worldwide in few cases of FTD so its phenotype is still unclear. The objective is to study the clinical and radiological characteristics of TARDBP-related FTD. In the present study, we report clinical, neuropsychological and radiological features of five new Sardinian non-related cases of FTD carriers of the p.A382T TARDBP mutation. Furthermore, we reviewed non-related FTD cases with TARDBP mutations previously described in literature. The p.A382T missense mutation of TARDBP was present in the 21.7 % of familial cases of our FTD cohort (5/23) and in no one of the sporadic patients. 3 of 5 patients showed a temporal variant FTD and 4/5 a predominant temporal involvement at MRI. The review of the literature of FTD cases with TARDBP mutations showed that in 5 of 16 cases, the clinical phenotype was consistent with temporal variant of FTD or semantic dementia (31 %) and in 7 of 16 cases neuroimaging showed predominant temporal lobe involvement (43.7 %). Our study further supports the pathogenetic role of TARDBP mutations in pure FTD and in the full spectrum of FTD/ALS. The presence of a predominant temporal lobe involvement in a high percentage of FTD mutated patients with a peculiar clinical pattern could be useful in the differential diagnosis with other forms of dementia/FTD both sporadic and familial.

Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects.FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762.Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839-1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26-6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38-2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months.Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function.UK Stroke Association and NIHR Health Technology Assessment Programme.

DesignTo evaluate the efficacy of the main tools in the diagnostic localization of hyperfunctioning parathyroids (HP) in primary hyperparathyroidism (pHPT) with concomitant thyroid diseases.MethodsForty-three patients with pHPT associated with nodular goiter (NG, n=32) and/or autoimmune thyroid diseases (AITDs, n=11) for a total of 63 neck lesions were considered. Sixteen patients displaying HP (16 lesions), unequivocally localized by sestaMIBI scintigraphy (MIBI) and neck ultrasound (US) (group I), were compared with 27 patients (47 neck lesions) displaying equivocal parathyroid localization (group II). In all cases, neck US, MIBI scan, cytology, and parathyroid hormone assay in fine-needle aspiration washout fluid (FNA–PTH) were performed. All patients finally underwent surgery.ResultsAccording to histological examination, high FNA–PTH values (>103 pg/ml) correctly identified all HP in both groups of patients (100% of sensitivity and specificity). Both MIBI and US correctly identified all HP only in group I patients; in contrast, four patterns of mismatch between these techniques were observed in group II patients, leading to low diagnostic performances of neck US (71.4% sensitivity and 78.9% specificity) and of MIBI scan (35.7% sensitivity and 42.1% specificity). The latter was due to both false-negative (mainly in AITD) and false-positive (mainly in NG) scan images.ConclusionsCoexistent thyroid diseases are responsible for mismatch between MIBI and US images resulting in equivocal HP localization. In these cases, FNA–PTH resulted in the most accurate tool to identify HP. However, although safe, it should be advised only to patients with uncertain HP localization.

O artigo a seguir apresenta uma análise sucinta das obras Uma aprendizagem ou O livro dos prazeres e A paixão segundo G.H., de Clarice Lispector e O homem da mão seca, de Adélia Prado, sob um elemento peculiar às três leituras: o encontro entre a questão antropológica – que demarca o conhecimento, o cuidado e a aceitação de si e do outro – e o pensamento teológico – que se manifesta no conhecimento de Deus (em Adélia, e do Deus, como Clarice costuma nomear), a partir da ‘humanidade do mais humano’ presente em ambas as obras. De fato, o texto bíblico do profeta Isaías ilustra o que se quer (d)escrever nas linhas abaixo, isto é, conseguir ver a Deus está intrínseca e corolariamente imbricado a ver-se a si mesmo: “ai de mim, que estou perdido! Pois sou homem de lábios impuros e habito no meio de um povo de impuros lábios, e os meus olhos viram ao Rei, o Senhor os Exércitos” (Is. 6,5). Eis o ‘encontro feliz’ de Adélia e Clarice

Problem statement: Healthcare Associated Infections (HAI) are frequent and important complications, most commonly affecting hospitalized patients in intensive care units. Hospital average length of stay is usually 5-10 days higher in these patients. In HIV positive/Aids patients HAI vary from 8,7 and 15% in prevalence. The aims of this study was to compare HAI data from HIV positive (HIV+) and HIV negative (HIV-) patients admitted to the adult Intensive Care Unit (ICU) of an Infectious Disease reference hospital located in the state of Ceara, Northeast Brazil. Approach: This was a retrospective study of all patients admitted to the Hospital Sao Jose ICU, from January 2006 to December 2007, which were diagnosed with a HAI. Results: During the study period, 144 cases of HAI were diagnosed in 106 patients. Sixty were HIV- and 46 HIV+. Eighty nine (62%) HAI occurred in the HIV-group. The use of invasive devices, such as mechanical ventilation, central-line catheter and vesicle catheter, was identified in 114 HAI. Pneumonia was the most prevalent HAI (83/144- 80%), almost all of them related to mechanical ventilation (81/83-96%). Density of incidence of ventilator-associated pneumonia was higher in HIV+ (HIV- : 19.9 Vs. HIV+: 24.0-p = 0.38), while the density of incidence of catheter associated urinary tract infection was higher in HIV- (HIV-: 4.5 vs. HIV+: 1.6-p = 0.09), although without statistical significance. Conclusion/Recommendation: HAI were similar in both groups. Therefore our data suggest that, HAI prevention precautions should be intensively used in all patients, especially in ICU ones, in order to minimize HAI risks and serious consequences.

The aims of your case report is to show the predictivity ofTc99m-sestamibi (MIBI) scintigraphy and doppler ultrasound imaging on secondary hyperparathyroidism (SHPT) in a patient responsive to calcimimetic treatment. Moreover, it has been reported that calcimimetic has great potential in reducing the volume of the parathyroid gland. On the other hand, the MIBI scintigraphy is considered a crucial diagnostic procedure to monitor the response to therapy in terms of turnover and cellular metabolism; whereas, ultrasound to monitor the volume variation in response to treatment. It is described the case of a 73-year-old man on hemodialysis from 1995 for ESRD. Within 2 years the patient gradually developed SHPT with progressively increased iPTH up to 1,000 ρg/ml. The ultrasound, highlighted the presence of two parathyroid hyperplasia, confirmed by scintigraphy, showing focal increase uptake of sestamibi in the same anatomical areas. As a result of the patient's refusal to perform a parathyroidectomy, cinacalcet, was administered (65 mg overage daily dose). After a year of treatment, there was a striking decrease of iPTH (from 1300 to 57 ρg/ml, −95%); but, on the contrary to expectations, this positive metabolic outcome, was not followed by parathyroid changes in ultrasound and scintigraphic findings.

Mood disorders and circulating thyroid antibodies are very prevalent in the population and their concomitant occurrence may be due to chance. However, thyroid antibodies have been repeatedly hypothesized to play a role in specific forms of mood disorders. Potentially related forms include treatment-refractory cases, severe or atypical depression, and depression at specific phases of a woman’s life (early gestation, postpartum depression, perimenopausal). With regard to bipolar disorder, studies of specific subgroups (rapid cycling, mixed, or depressive bipolar) have reported associations with thyroid antibodies. Offspring of bipolar subjects were found more vulnerable to develop thyroid antibodies independently from the vulnerability to develop psychiatric disorders. A twin study suggested thyroid antibodies among possible endophenotypes for bipolar disorder. Severe encephalopathies have been reported in association with Hashimoto’s thyroiditis. Cases with pure psychiatric presentation are being reported, the antithyroid antibodies being probably markers of some other autoimmune disorders affecting the brain. Vasculitis resulting in abnormalities in cortical perfusion is one of the possible mechanisms.

Brain perfusion abnormalities have recently been demonstrated by single-photon emission computed tomography (SPECT) in rare cases of severe Hashimoto’s thyroiditis (HT) encephalopathy; moreover, some degree of subtle central nervous system (CNS) involvement has been hypothesised in HT, but no direct evidence has been provided so far. The aim of this study was to assess cortical brain perfusion in patients with euthyroid HT without any clinical evidence of CNS involvement by means of 99mTc-ECD brain SPECT. Sixteen adult patients with HT entered this study following informed consent. The diagnosis was based on the coexistence of high titres of anti-thyroid auto-antibodies and diffuse hypoechogenicity of the thyroid on ultrasound in association with normal circulating thyroid hormone and TSH concentrations. Nine consecutive adult patients with non-toxic nodular goitre (NTNG) and ten healthy subjects matched for age and sex were included as control groups. All patients underwent 99mTc-ECD brain SPECT. Image assessment was both qualitative and semiquantitative. Semiquantitative analysis was performed by generation of four regions of interest (ROI) for each cerebral hemisphere—frontal, temporal, parietal and occipital—and one for each cerebellar hemisphere in order to evaluate cortical perfusion asymmetry. The Asymmetry Index (AI) was calculated to provide a measurement of both magnitude and direction of perfusion asymmetry. As assessed by visual examination, 99mTc-ECD cerebral distribution was irregular and patchy in HT patients, hypoperfusion being more frequently found in frontal lobes. AI revealed abnormalities in 12/16 HT patients, in three of the nine NTNG patients and in none of the normal controls. A significant difference in the mean AI was found between patients with HT and both patients with NTNG (p

OBJECTIVE: To assess the relevance of (99m)Tc-SestaMIBI (MIBI) scan in the diagnostic evaluation of thyroid nodules with oncocytic cytology. SUBJECTS AND METHODS: Twenty-four patients with a single (or prevalent) 'cold' solid nodule with Hurthle cells (HC) at fine needle aspiration cytology (FNAC) were studied. Cytological diagnosis of oncocytic metaplasia (OM) or HC tumor (HCT) was made when HC on the smear were comprised 10-75%, or >75%. Nodules concentrating MIBI at early and late (2 h after washout) stages were considered MIBI-positive. In all cases histological findings were obtained after total thyroidectomy. RESULTS: FNAC was malignant or suspect for malignancy in 16 cases (six HCT and 10 OM) and not suspect in eight (two HCT and six OM). Histological examination revealed 14 malignant tumors (11 HCT and three OM), and 10 benign thyroid lesions (three HCT and seven OM). Sensitivity of FNAC for malignancy was 92.8% and specificity was 70.0%; HCT were identified by FNAC in only 35.7% and OM in 70.0% of cases. No significant difference in MIBI positivity was found between malignant and benign thyroid nodules. The highest percentage of MIBI positivity was found in HCT (78.5%), but MIBI-positive nodules were also observed in thyroid lesions with HC metaplasia (40.0%). CONCLUSIONS: MIBI scintiscan has no value in differentiating malignant from benign HC thyroid neoplasias. Most HCT are MIBI-positive, but this scan is not sufficiently specific to differentiate true HC neoplasias from other thyroid lesions showing HC at FNAC, although an MIBI-negative scan strongly supports the absence of true HCT.

Objectives – The purpose of this study is to evaluate the efficiency of a few methodologies in detecting anatomo-functional brain abnormalities in patients with Wilson's disease. Materials and methods – Twenty-three patients with Wilson's disease underwent almost simultaneously brain magnetic resonance imaging (MRI), computerized electroencephalography (EEG), multimodal evoked potentials (EPs) and ECD single photon computerized tomography (SPECT) evaluation. The clinical picture was of the neurologic type in 8 patients and of the hepatic type in 15. Results – MRI was abnormal in 7 patients with neurological manifestations. The EPs proved pathologic in 7 neurologically symptomatic patients and in 4 cases with hepatic form. These results agree with those reported in other case studies. The EEG records were abnormal only in 3 cases. Nevertheless, the most interesting finding of this study is the particular frequency (86%) of diffuse or focal decrease of ECD uptake shown by brain SPECT. Conclusion – We highlight the use of this interesting procedure in the therapeutic monitoring of this disease.