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Limb-girdle muscular dystrophy D2 (LGMDD2) is an ultrarare autosomal dominant myopathy caused by mutation of the normal stop codon of the TNPO3 nuclear importin. The mutant protein carries a 15 amino acid C-terminal extension associated with pathogenicity. Here we report the first animal model of the disease by expressing the human mutant TNPO3 gene in Drosophila musculature or motor neurons and concomitantly silencing the endogenous expression of the fly protein ortholog. A similar genotype expressing wildtype TNPO3 served as a control. Phenotypes characterization revealed that mutant TNPO3 expression targeted at muscles or motor neurons caused LGMDD2-like phenotypes such as muscle degeneration and atrophy, and reduced locomotor ability. Notably, LGMDD2 mutation increase TNPO3 at the transcript and protein level in the Drosophila model Upregulated muscle autophagy observed in LGMDD2 patients was also confirmed in the fly model, in which the anti-autophagic drug chloroquine was able to rescue histologic and functional phenotypes. Overall, we provide a proof of concept of autophagy as a target to treat disease phenotypes and propose a neurogenic component to explain mutant TNPO3 pathogenicity in diseased muscles.

Lean Construction has become a popular concept to improve performance and reduce costs in construction projects. Assessment tools and implementation strategies that focus on lean practices such as the Last Planner System, the use of Kanbans, the routine of Kaizens and, recently, the integration with information technology are also common. However, barriers to the wide adoption of lean principles remain and implementation challenges continue to intrigue scholars. Previous studies suggest that barriers to the successful implementation can be either political, economical, social and/or technical, with the focus on lack of knowledge about lean concepts, resistance to the required organisational culture change, and lack of support from top management. Few studies present the lean implementation process from the practitioners’ perspective. Using the narrative enquiry methodology, the authors aim to describe how a construction company from Brazil matured from the implementation of lean operational tools to achieve excellence in the lean culture and mindset. Key themes that emerge from this study for a successful lean construction journey are; effort to stabilise the environment, knowledge creation and management, transparency in the process to enable simplicity and shared understanding, and building trust for further growth. ®

INTRODUCTION: Bowel preparation for colonoscopy and/or colorectal surgery can cause electrolyte imbalances. The risk of electrolyte imbalances seems to be related to the type of bowel cleansing solution, age of patients and comorbidities. CASE REPORT: We report two cases of symptomatic hyponatremia (focal neurological signs and coma) after bowel preparation with sodium picosulfate/magnesium citrate for colonoscopy. In both cases, symptoms related to hyponatremia rapidly disappeared after sodium level correction with intravenous administration of hypertonic saline (3% NaCl). DISCUSSION: Electrolyte imbalances are more common with sodium phosphate-based solutions (NaP) and sodium picosulfate/magnesium citrate, in patients older than 65, in patients treated with thiazide diuretics, angiotensin-converting-enzyme inhibitor, betablockers or antidepressants and in gastrectomized patients. These patients should use macrogol-based solutions (polyethylene glycol). CONCLUSION: In patients at risk (patient > 65 years old, patients taking thiazide diuretics, angiotensin-converting-enzyme inhibitors, beta-blockers and antidepressants and with previous gastrectomy) we recommend macrogol-based solutions info:eu-repo/semantics/publishedVersion

Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene. Mutant DMPK transcripts are toxic and alter gene expression at several levels. Chiefly, the secondary structure formed by CUGs has a strong propensity to capture and retain proteins, like those of the muscleblind-like (MBNL) family. Sequestered MBNL proteins cannot then fulfill their normal functions. Many therapeutic approaches have been explored to reverse these pathological consequences. Here, we review the myriad of small molecules that have been proposed for DM1, including examples obtained from computational rational design, HTS, drug repurposing and therapeutic gene modulation.

Drosophila muscleblind (mbl), the ortholog of human Muscleblind-like 1 (MBNL1) gene involved in Myotonic Dystrophy (DM), gives raise to protein isoforms MblA to G. The specific functions and subcellular distribution of isoforms are still largely unknown. To overcome the lack of isoform-specific antibodies we generated transgenic flies that express a GFP:MblC fusion protein under the control of the Gal4/UAS system. The reporter fusion protein was able to functionally complement mbl loss of function mutations, demonstrating activity, and accumulated predominantly in adult muscle nuclei. The fluorescent nature of the reporter makes it appropriate for live imaging detection of MblC protein isoform.

Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apoptosis and autophagy. Inhibition of apoptosis or autophagy mediated by the overexpression of DIAP1, mTOR (also known as Tor) or muscleblind, or by RNA interference (RNAi)-mediated silencing of autophagy regulatory genes, achieved a rescue of the muscle-loss phenotype. In fact, mTOR overexpression rescued muscle size to a size comparable to that in control flies. These results were validated in skeletal muscle biopsies from DM1 patients in which we found downregulated autophagy and apoptosis repressor genes, and also in DM1 myoblasts where we found increased autophagy. These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis.

ResumoO Cryptosporidium descrito, pela primeira vez em 1976, como causador de doença no Homem assume, actualmente, particular importância como uma zoonose emergente, responsável por epidemias de diarreia secundárias à ingestão de água contaminada e como causador de diarreia aguda auto-limitada em crianças imunocompetentes.

Submitted by Helena Donato (bibliotecacuf@jmellosaude.pt) on 2014-10-26T23:38:38Z No. of bitstreams: 1 Acta med Port.pdf: 412427 bytes, checksum: eee4a8bf0a46bf7606a0689296c09141 (MD5) Made available in DSpace on 2014-10-26T23:38:38Z (GMT). No. of bitstreams: 1 Acta med Port.pdf: 412427 bytes, checksum: eee4a8bf0a46bf7606a0689296c09141 (MD5) Previous issue date: 2014

A case of paracoccidioidomycosis presenting as a solitary pulmonary nodular lesion in a patient with acquired immunodeficiency syndrome (AIDS) is presented. This case illustrates that restricted lung lesions can also be found and diagnosed in immunodeficient patients.

Myotonic dystrophy type 1 (DM1) is caused by the expansion of CTG repeats in the 3' untranslated region of the DMPK gene. Several missplicing events and transcriptional alterations have been described in DM1 patients. A large number of these defects have been reproduced in animal models expressing CTG repeats alone. Recent studies have also reported miRNA dysregulation in DM1 patients. In this work, a Drosophila model was used to investigate miRNA transcriptome alterations in the muscle, specifically triggered by CTG expansions. Twenty miRNAs were differentially expressed in CTG-expressing flies. Of these, 19 were down-regulated, whereas 1 was up-regulated. This trend was confirmed for those miRNAs conserved between Drosophila and humans (miR-1, miR-7 and miR-10) in muscle biopsies from DM1 patients. Consistently, at least seven target transcripts of these miRNAs were up-regulated in DM1 skeletal muscles. The mechanisms involved in dysregulation of miR-7 included a reduction of its primary precursor both in CTG-expressing flies and in DM1 patients. Additionally, a regulatory role for Muscleblind (Mbl) was also suggested for miR-1 and miR-7, as these miRNAs were down-regulated in flies where Mbl had been silenced. Finally, the physiological relevance of miRNA dysregulation was demonstrated for miR-10, since over-expression of this miRNA in Drosophila extended the lifespan of CTG-expressing flies. Taken together, our results contribute to our understanding of the origin and the role of miRNA alterations in DM1.

The antigenic components of a semipurified fraction of Leishmania donovani infantum were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis using 14 serum samples from dogs with symptomatic visceral leishmaniasis and 11 serum samples from apparently healthy dogs collected in an area endemic for canine visceral leishmaniasis (CVL). It was found that these antigens were composed of many polypeptides, among which seven components recognized by symptomatic CVL sera, had molecular weights of approximately 18, 28, 30, 33, 63, 70, and 72 kilodaltons (kD) ; two components of 63 and 70 kD were recognized by three of 11 healthly dog sera. These findings suggest that specific antigens induce humoral immune response in dogs with asymptomatic or active visceral leishmaniasis. Infected dogs are not readily identifiable by their symptoms. The potential interest of the immunoblot test for CVL diagnostic purposes is discussed.

Introdução: A hipovitaminose D (hipoD) é uma carência vitamínica cada vez mais frequente nos países desenvolvidos, devido não só a erros alimentares, mas também à pouca exposição solar e ao sedentarismo. Objectivo: Determinar a prevalência de hipoD em doentes internados num Serviço de Medicina Interna e identificar possíveis variáveis associadas. Método: Estudo transversal e observacional onde foram incluídos 123 doentes internados, no período de Abril e Maio. Foram determinados os níveis séricos de vitamina D [25-hidroxivitamina D, 25(OH)D] e subdividida a amostra em três grupos com base nos níveis da 25(OH)D: hipoD grave (10 ng/mL e 20 ng/mL). Foram registadas variáveis demográficas e factores potencialmente relacionados com a deficiência de vitamina D. Resultados: Nesta amostra de doentes (52,0% mulheres) a média das idades foi 71±17 anos; 67,5% dos indivíduos apresentavam hipoD grave; 25,2% hipoD moderada e 7,3% níveis normais de vitamina D. Os doentes do grupo com hipoD grave eram mais idosos (p=0,027). O mesmo grupo apresentava um maior número de doentes acamados (p=0,022), índices funcionais mais elevados (p=0,009) e maior percentagem de indivíduos com IRC (p=0,011). A análise multivariada com aplicação de modelo de regressão logística revelou que as variáveis associadas a uma probabilidade aumentada de desenvolver hipoD grave foram: consumo de diuréticos (furosemida) [OR=3,673 (1,232-10,956) p=0,020] e a albumina ≤3,25 [OR=5,617 (2,257-13,981) p

Introduction: Paraquat is a contact herbicide commercially available since 1962. Paraquat intoxication (PI) is usually voluntary and highly lethal, since there is no effective antidote. Toxicity occurs through cyclic redox reactions, damaging mainly the kidneys and lungs. Aim, material and methods: featuring the clinical presentation, management and outcome of patients with PI over an 18 years period (from the 01st January 1993 to the 31st December 2010) through the retrospective analysis of clinical files and comparing the survivors and the deceased. Results: Thirty-one cases of Paraquat intoxication were included, with a male: female ratio 1:1. Age range from 13 to 80 years, mean age 42.4years (±18.7).All intoxications were voluntary and by oral route. There was statistical difference in the amount ingested (22.1 mL vs. 72.7 mL, p

Many publications show an incidence increase of Clostridium difficile (CD) associated disease (CDAD), affecting both in- and outpatients being these recent infections more severe and difficult to treat. The aim of this retrospective study is to evaluate the incidence and clinical impact of CDAD in patients hospitalized from the 1st January 2004 to the 31st December 2009. Suggestive clinical manifestations and at least one of the following were the inclusion criteria: CDAD compatible colonoscopy or CD positive toxin. We identified 83 cases of CDAD (32M, 51W), in a total of 9581 patients (5198M, 4383W). Age ranging from 47 to 94 years (average 79). Five patients had CDAD acquired in the community and 78 in hospital environment. The incidence of CDAD increased almost six fold between 2004 and 2009 (4.35/1000 vs. 21.63/1000), and 77.11% developed the disease during hospitalization. The disease was more frequent in women (11.64/1000 vs. 6.16/1000). All patients had undergone prior antibiotherapy. The comorbidities, number of antibiotics used, advanced age, duration of the antibiotherapy and the length of hospitalization did not seem to justify the increase in incidence and severity. In 96% the diagnosis was confirmed by the presence of Clostridium toxin and in 4% by colonoscopy. Seventy three patients (88%) were treated with metronidazole and 30% died (the department overall mortality was 13%). Probably, it was the advanced age related with the worst severity scenario which caused the high mortality in our cases.

Churg-Strauss syndrome (CSS) is a systemic necrotizing vasculitis of the small and medium vessels, associated with extravascular eosinophilic granulomas, peripheral eosinophilia and asthma. This is a rare syndrome of unknown etiology, affecting both genders and all age groups. CSS patients usually respond well to steroid treatment, although relapses are common after it ends. Timely diagnosis and treatment generally lead to a good prognosis with a 90% survival rate at one year. A brief review of CSS is presented, with particular attention to diagnosis, therapy and recent developments in this area. The authors then report and discuss the clinical, laboratory and imaging characteristics of four patients admitted to an Internal Medicine Department with this diagnosis. The treatment, response and follow-up of the cases are also described.

Chronic periaortitis (CP) refers to a spectrum of diseases whose common denominator is a fibro-inflammatory tissue developing in the periaortic space and frequently encasing surrounding structures like the kidney and ureters. There is no unified concept regarding the primary aetiology of CP, but recent studies have demonstrated that CP may present features of auto-immune diseases. CP involves three main entities, namely idiopathic retroperitoneal fibrosis (IRF), inflammatory aneurysms of the abdominal aorta (IAAAs) and perianeurysmal retroperitoneal fibrosis (PRF). These entities are usually diagnosed using computed tomography or magnetic resonance imaging, which typically show a retroperitoneal mass surrounding the aorta and that extends laterally without displacing it. Positron emission tomography is useful for the full assessment of the extent of the disease and its metabolic activity. The inflammatory and chronic relapsing nature of these diseases compels the use of medical therapy, which is based on high-dose steroids with a tapering scheme combined with immunosuppressive agents in refractory or relapsing disease. The authors report the clinical and radiological characteristics of a nonaneurysmatic form of chronic periaortitis in a woman presented with pericarditis, pericardial effusion and a pancreatitis. They also describe the investigation and management of this unusual condition

The vast majority of focal liver lesions are hyperintense on T2-weighted magnetic resonance (MR) images. Rarely, however, hepatic nodules may appear totally or partially hypointense on those images. Causes for this uncommon appearance include deposition of iron, calcium, or copper and are related to the presence of blood degradation products, macromolecules, coagulative necrosis, and other conditions. Although rare, low signal intensity relative to surrounding liver on T2-weighted images may be seen in a wide spectrum of lesions. Examples include cases of focal nodular hyperplasia, hepatocellular adenoma, hepatocellular carcinoma, metastases, leiomyoma, siderotic or dysplastic nodules, nodules in Wilson disease, granuloma, and hydatid cyst. On fat-suppressed T2-weighted images, nodules with a lipomatous component, such as lipoma, angiomyolipoma, hepatocellular adenoma, and hepatocellular carcinoma may also appear partially or totally hypointense. The conjunction of other MR imaging findings and their integration in the clinical setting may allow a correct diagnosis in a considerable proportion of cases. The cause for T2-weighted hypointensity may not be, however, always recognized, and only pathologic correlation may provide the answer. The aims of this work are to discuss the causes and mechanisms of hypointensity of liver lesions on T2-weighted images and proposing an algorithm for classification that may be useful as a quick reminder for the interested reader.

National audience

Deux cas d'hemangiopericytome congenital sont rapportes. Dans le premier cas, la tumeur etait situee au niveau de la paroi abdominale, dans le deuxieme au niveau du cuir chevelu. Le traitement des deux cas a consiste en la resection complete de la masse tumorale. Apres 2 et 4 ans, ces enfants demeurent asymptomatiques. L'extraordinaire interet de ces cas est du a la tres grande rarete de l'hemangiopericytome congenital et aussi a la constatation que ces tumeurs etaient pour la premiere fois observees chez deux freres.

International audience

Supernovae (SNe) that have been multiply imaged by gravitational lensing are rare and powerful probes for cosmology. Each detection is an opportunity to develop the critical tools and methodologies needed as the sample of lensed SNe increases by orders of magnitude with the upcoming Vera C. Rubin Observatory and Nancy Grace Roman Space Telescope. The latest such discovery is of the quadruply imaged Type Ia SN 2022qmx (aka, “SN Zwicky”) at z = 0.3544. SN Zwicky was discovered by the Zwicky Transient Facility in spatially unresolved data. Here we present follow-up Hubble Space Telescope observations of SN Zwicky, the first from the multicycle “LensWatch (www.lenswatch.org)” program. We measure photometry for each of the four images of SN Zwicky, which are resolved in three WFC3/UVIS filters (F475W, F625W, and F814W) but unresolved with WFC3/IR F160W, and present an analysis of the lensing system using a variety of independent lens modeling methods. We find consistency between lens-model-predicted time delays (≲1 day), and delays estimated with the single epoch of Hubble Space Telescope colors (≲3.5 days), including the uncertainty from chromatic microlensing (∼1–1.5 days). Our lens models converge to an Einstein radius of θ E = ( 0.168 − 0.005 + 0.009 ) ″ , the smallest yet seen in a lensed SN system. The “standard candle” nature of SN Zwicky provides magnification estimates independent of the lens modeling that are brighter than predicted by ∼ 1.7 − 0.6 + 0.8 mag and ∼ 0.9 − 0.6 + 0.8 mag for two of the four images, suggesting significant microlensing and/or additional substructure beyond the flexibility of our image-position mass models.

In certain contexts, and historical moments, the press has become an instrument of a dominant group that turns media discourse into a weapon, in order to carry out ideological manipulation of the recipient (Charaudeau 2003: 42 ). This is the case in the magazines that are the subject of this work: Legiones y Falanges (1940-1943) and Y, Revista para la mujer nacionalsindicalista (1938-1945), two exemplary publications in which the power elites propose to extol the ideological basis of the young Francoist dictatorship and to build the identity of the woman that the regime needs. With this objective, institutional locutors adopt a wide range of argumentative strategies, legal and not, forging a clearly populist discourse, in which the denunciation of evil (Charaudeau 2011) and the exaltation of the saviour (Franco and his institutions) stand out, generating a highly emotive language (evaluative lexicon, metaphors ...), often based on irrationality. I have used the theoretical framework of pragmatic linguistics (Fuentes Rodríguez 2013 and 2017), the theory of argumentation (Anscombre and Ducrot 1994) and its grammar (Lo Cascio 1991 and 2009; Fuentes Rodríguez and Alcaide Lara 2002), the instruments of critical discourse analysis, as well as Van Dijk's studies on ideology, discourse, and manipulation (especially 2003, 2005, 2006, 2008, 2009 y 2010). En determinados contextos y momentos históricos la prensa ha llegado a identificarse con un instrumento de orientación y coacción, como una instancia de un grupo dominante que convierte el discurso mediático en un arma destinada al servicio de la manipulación ideológica del blanco receptor (Charaudeau, 2003: 42). Es este, como me propongo demostrar, el caso de las revistas objeto de este trabajo: Legiones y Falanges (1940-1943) e Y, Revista para la mujer nacionalsindicalista (1938-1945). Se trata de dos publicaciones ejemplares en las que las élites del poder se proponen ensalzar los fundamentos ideológicos de la joven dictadura franquista y construir la identidad de la mujer que necesita el régimen. Con este objetivo, los locutores institucionales adoptan una amplia gama de estrategias argumentativas, lícitas y no, forjando un discurso claramente populista, en el que sobresalen la denuncia del mal (Charaudeau, 2011) y la exaltación del salvador (Franco y sus instituciones), que se verbalizan en un lenguaje altamente emotivo (léxico valorativo, metáforas…), a menudo basado en la irracionalidad. Desde el punto de vista metodológico, he trabajado de forma transversal, recurriendo a la lingüística pragmática (Fuentes Rodríguez, 2013 y 2015), a la teoría de la argumentación (Anscombre y Ducrot, 1994) y a su gramática (Lo Cascio, 1991 y 2009; Fuentes Rodríguez y Alcaide Lara, 2002 y 2007), a los instrumentos del análisis crítico del discurso, así como a los estudios sobre ideología, discurso y manipulación de Van Dijk (sobre todo 1996, 2003, 2006, 2008, 2009 y 2010).