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ABSTRACT: Hemojuvelin (HJV) is a glycosylphosphatidylinositol-anchored protein of the repulsive guidance molecule family acting as a bone morphogenetic protein (BMP) coreceptor to induce the hepatic iron regulatory protein hepcidin. Hepcidin causes ubiquitination and degradation of the sole known iron exporter ferroportin, thereby limiting iron availability. The detailed signaling mechanism of HJV in vivo has yet to be investigated. In the current manuscript, we used an established model of adeno-associated virus (AAV)-mediated liver-specific overexpression of HJV in murine models of hepatocyte-specific deficiency of the BMP type I receptors Alk2 or Alk3. In control mice, HJV overexpression increased hepatic Hamp messenger RNA (mRNA) levels, soluble HJV (sHJV), splenic iron content (SIC), as well as phosphorylated small mothers against decapentaplegic protein (pSMAD1/5/8) levels. In contrast, in Alk2fl/fl;Alb-Cre and Alk3fl/fl;Alb-Cre mice, which present with moderate and severe iron overload, respectively, the administration of AAV-HJV induced HJV and sHJV. However, it did not rescue the iron overload phenotypes of those mice. Serum iron levels were induced in Alk2fl/fl;Alb-Cre mice after HJV overexpression. In phosphate-buffered saline-injected Alk3fl/fl;Alb-Cre mice, serum iron levels and the expression of duodenal ferroportin remained high, whereas Hamp mRNA levels were decreased to 1% to 5% of the levels detected in controls. This was reduced even further by AAV-HJV overexpression. SIC remained low in mice with hepatocyte-specific Alk2 or Alk3 deficiency, reflecting disturbed iron homeostasis with high serum iron levels and transferrin saturation and an inability to induce hepcidin by HJV overexpression. The data indicate that ALK2 and ALK3 are both required in vivo for the HJV-mediated induction of hepcidin.

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Metal-derived platinum complexes are widely used to treat solid tumors. However, systemic toxicity and tumor resistance to these drugs encourage further research into similarly effective compounds. Among others, organotin compounds have been shown to inhibit cell growth and induce cell death and autophagy. Nevertheless, the impact of the ligand structure and mechanisms involved in the toxicity of organotin compounds have not been clarified. In the present study, the biological activities of commercially available bis(tributyltin) oxide and tributyltin chloride, in comparison to those of specially synthesized tributyltin trifluoroacetate (TBT-OCOCF3) and of cisplatin, were assessed using cells with different levels of tumorigenicity. The results show that tributyltins were more cytotoxic than cisplatin in all the tested cell lines. NMR revealed that this was not related to the interaction with DNA but to the inhibition of glucose uptake into the cells. Moreover, highly tumorigenic cells were less susceptible than nontumorigenic cells to the nonunique pattern of death induced by TBT-OCOCF3. Nevertheless, tumorigenic cells became sensitive when cotreated with wortmannin and TBT-OCOCF3, although no concomitant induction of autophagy by the compound was detected. Thus, TBT-OCOCF3 might be the prototype of a family of potential anticancer agents.

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Rupture of Achilles tendon is a common accident affecting professional and recreational athletes. Acute and chronic pain are symptoms commonly observed in patients with rupture. However, few studies have investigated whether Achilles tendon rupture is able to promote disorders in the central nervous system (CNS). Therefore, the current study aimed to evaluate nociceptive alterations and inflammatory response in the L5 lumbar segment of Balb/c mice spinal cord after Achilles tendon rupture. We found increased algesia in the paw of the ruptured group on the 7th and 14th days post-tenotomy compared with the control group. This phenomenon was accompanied by overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase-2 (NOS-2) as well as hyperactivation of astrocytes and microglia in nociceptive areas of L5 spinal cord as evidenced by intense GFAP and IBA-1 immunostaining, respectively. Biochemical studies also demonstrated increased levels of nitrite in the L5 spinal cord of tenotomized animals compared with the control group. Thus, we have demonstrated for the first time that total rupture of the Achilles tendon induced inflammatory response and nitrergic and glial activation in the CNS in the L5 spinal cord region.

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OBJECTIVE: Thoracic calcifications are frequently found in chest radiographs and CTs, occurring in a wide variety of disorders. Although most calcifications are harmless sequelae of previous disease, they provide important information to establish the diagnosis. This article reviews the different types of calcified lesions found in the chest, focusing on lesions outside the lung parenchyma. A location-based approach to the differential diagnosis is used, while providing the reader with diagnostic pearls and discussing the clinical importance of the different types of calcifications. CONCLUSION: Chest calcifications are a common finding in routine chest imaging. Understanding the different etiologies and radiologic manifestations provide the radiologist with the necessary tools to elaborate a differential diagnosis, as well as to correctly differentiate the findings that need further work-up from the ones that can be dismissed.

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Microcystins constitute a group of over 200 variants and are increasingly considered as emerging toxins in food and feed safety, particularly with regards to sea-food and fish consumption. Toxicity of MCs is congener-specific, being characterised by different acute potencies, likely related to the differential activity of metabolic enzymes and transporters proteins involved in their cellular uptake. However, the active transport of MCs across intestinal membranes has not been fully elucidated. Our results, obtained using a fit for purpose 3D human reconstructed intestinal epithelium, provide new information on the complex mechanisms involved in the absorption of 5 MC variants': it is indeed characterised by the equilibrium between uptake and extrusion, since the selected congeners are substrates of both influx and efflux proteins. In the range of tested nominal concentrations (10-40 µM) fully representative of relevant exposure scenarios, none of the active tested transporters were saturated. The comparison of permeability (Papp) values of MCs variants highlighted a dose independent relationship for MC-LR, -YR and -RR (Papp x 10-7 ranged from 2.95 to 3.54 cm/s), whereas -LW and-LF showed a dose dependent increase in permeability reaching Papp values which were similar to the other congeners at 40 µM. MC-RR, -LR, -YR show absorption values around 5% of the administered dose. Due to their lipophilicity, MC-LW and -LF were also detected within the cellular compartment. The intestinal uptake was only partially attributable to OATPs, suggesting the involvement of additional transporters. Regarding the efflux proteins, MCs are not P-gp substrates whereas MRP2 and to a lesser extent Breast cancer resistance protein are active in their extrusion. Despite the presence of GST proteins, as an indication of metabolic competence, in the intestinal tissue, MC-conjugates were never detected in our experimental settings.

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BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex, progressive respiratory condition characterized by heterogeneous clinical presentations (phenotypes). The aim of this study was to assess the prevalence of the main COPD phenotypes and match of each phenotype to the most fitting clinical and lung function profile. METHODS: the CLIMA (Clinical Phenotypes in Actual Clinical Practice) study was an observational, cross-sectional investigation involving twenty-four sites evenly distributed throughout Italy. Patients were tentatively grouped based on their history and claimed prevailing symptoms at recruitment: chronic cough (CB, suggesting chronic bronchitis); dyspnoea (possible emphysema components, E); recurrent wheezing (presuming asthma components, A). Variables collected were: anagraphics; smoking habit; history of asthma; claim of >1 exacerbations in the previous year; blood eosinophil count; total blood IgE and alpha1 anti-trypsin (α1-AT) levels; complete lung function, and the chest X-ray report. mMRC, CAT, BCS, EQ5d-5L were also used. The association between variables and phenotypes were checked by Chi-square test and multinomial logistic regression. RESULTS: The CB phenotype was prevalent (48.3%), followed by the E and the A phenotypes (38.8% and 12.8%, respectively). When dyspnoea was the prevailing symptom, the probability of belonging to the COPD-E phenotype was 3.40 times higher. Recurrent wheezing was mostly related to the COPD-A phenotype. Lung function proved more preserved in the COPD-CB phenotype. Smoke; n. exacerbations/year; VR, and BODE index were positively correlated with the COPD-E phenotype, while SpO2, FEV1/FVC, FEV1/VC, and FEV1 reversibility were negatively correlated. Lower DLco values were highly probative for the COPD-E phenotype (p<0.001). Conversely, smoke, wheezing, plasma eosinophils, FEV1 reversibility, and DLco were positively correlated with the COPD-A phenotype. The probability of belonging to the COPD-A phenotype raised by 2.71 times for any increase of one unit in % plasma eosinophils (p<0.001). Also multiparametrical scores contributed to discriminate the three phenotypes. CONCLUSION: The recognition of the main phenotypes of COPD can be effectively pursued by means of a few clinical and instrumental parameters, easy to obtain also in current daily practice. The phenotypical approach is crucial in the management of COPD as it allows to individualize the therapeutic strategy and to obtain more effective clinical outcomes.

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La infección por COVID-19 presenta una elevada mortalidad respecto a otros virus respiratorios. En este artículo buscamos definir las comorbilidades que están asociadas a la elevada mortalidad o a las complicaciones que requieren mayor soporte ventilatorio en unidades de cuidados intensivos. Se ha diseñado una búsqueda bibliográfica con respecto a las comorbilidades y/o alteraciones en los exámenes de laboratorio y los estudios radiológicos que se han asociado a la presencia de mortalidad, especialmente en los casos descritos en China.

Mortality due to SARS-CoV-2 is high compared to that caused by other respiratory viruses. This article aims to define the comorbidities associated with high mortality rates or complications that require ventilatory support in intensive care units. A bibliographic search has been performed with respect to comorbidities and/or alterations in laboratory tests and radiographic exams that have been associated with mortality, especially those described in China.

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BACKGROUND: This paper fills a gap in the applied research field, for a local context, by addressing the topics of describing cataract surgery' clinical outcomes; quality of life (QoL); and costs of the patients treated after the implementation of the ICHOM standard set. METHODS: This is a retrospective observational study using real-world data (RWD). We included all patients subjected to cataract surgery at the Portuguese Institute of oncology - Porto (IPO-Porto), Portugal, after 3 months follow up period completed between 5th June 2017 and 21st May 2018. The following inclusion criteria: corrected visual acuity of ≤ 6/10 or other significant visual disturbance due to lens opacity or the existence of a large anisometropia. A circuit was implemented based on the ICHOM standard for cataract, to measure clinical variables (e.g. visual acuity) and QoL (CATQUEST-9SF) before and after surgery, and cost of treatment. The results were explored by means of a paired-sample t-test, considering normality assumptions. RESULTS: Data refers to 268 patients (73 P25-P75:32-95 years old), regarding 374 eyes. The cataract surgery had a positive effect on visual acuity (p < 0.001), refraction (right and left cylinder; p < 0.001) and all QoL dimensions. The vast majority of patients, around 98%, reported improvements in QoL. Based on IPO-Porto administrative records, the direct cost of treating cataracts (per eye) is of 500€, representing a total cost of 187,000€ for the number of patients operated herein. CONCLUSION: This study reports the successful implementation of the ICHOM standard set for cataracts in a Portuguese institution and confirms that cataract surgery provides a rapid visual recovery, with excellent visual outcomes and minimal complications in most patients, while also having a positive impact on patients' quality of life.

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Imaging has not only an established role in screening and diagnosis of hepatocellular carcinoma (HCC) in patients with chronic liver inflammatory diseases, but also a crucial importance for patient stratification and treatment allocation, as well as for assessing treatment response. In the setting of increasing therapeutic options for HCC, the Barcelona Clinic Liver Cancer (BCLC) system still remains the most appropriate way to select candidate cohorts for best treatments. This classification takes into account the imaging information on tumor burden and extension, liver function, and cancer-related symptoms, stratifying patients in five risk categories (Stages 0, A, B, C and D) associated with different treatment options. Still now, there are no clear roles for biomarkers use in treatment allocation. The increasing use of locoregional non-surgical therapies in the different stages is highly dependent on reliable evaluation of treatment response, in particular when they are used with curative intention or for downstaging at liver transplantation re-assessment. Moreover, objective response (OR) has emerged as an important imaging biomarker, providing information on tumor biology, which can contribute for further prognostic assessment. Current guidelines for OR assessment recommend only the measurement of viable tumor according to mRECIST criteria, with further classification into complete response, partial response, stable disease or progressive disease. Either computed tomography (CT) or magnetic resonance (MR) imaging can be used for this purpose, and the Liver Imaging Reporting and Data System (LI-RADS) committee has recently provided some guidance for reporting after locoregional therapies. Nevertheless, imaging pitfalls resulting from treatment-related changes can impact with the correct evaluation of treatment response, especially after transarterial radioembolization (TARE). Volume criteria and emerging imaging techniques might also contribute for a better refinement in the assessment of treatment response and monitoring. As the role of imaging deeply expands in the multidisciplinary assessment of HCC, our main objective in this review is to discuss state-of-the-art decision-making aspects for treatment allocation and provide guidance for treatment response evaluation.

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AIM: To compare pancreatic and hepatic steatosis quantified by proton density fat fraction (PDFF) on magnetic resonance imaging (MRI) in patients with chronic liver disease. MATERIAL AND METHODS: This cross-sectional study included 46 adult patients who underwent liver biopsy for chronic viral hepatitis (n=19) or other chronic non-alcoholic liver diseases (NALD) (n=27). Liver biopsy was used as the gold standard for diagnosing and grading hepatic steatosis. All patients underwent clinical evaluation and MRI with a multi-echo chemical shift-encoded (MECSE) gradient-echo sequence for liver and pancreas PDFF quantification. We used Spearman's correlation coefficient to determine the degree of association between hepatic PDFF and steatosis grade, and between pancreatic PDFF and steatosis grade and hepatic PDFF. To compare the chronic viral hepatitis group and the NALD group, we used t-tests for continuous or ordinal variables and chi-square tests for categorical variables. RESULTS: Hepatic PDFF measurements correlated with steatosis grades (RS=0.875, p<0.001). Pancreatic PDFF correlated with hepatic steatosis grades (RS=0.573, p<0.001) and hepatic PDFF measurements (RS=0.536, p<0.001). In the subgroup of patients with chronic NALD, the correlations remained significant between pancreatic PDFF and hepatic PDFF (RS=0.632, p<0.001) and between pancreatic PDFF and liver steatosis (RS=0.608, p<0.001); however, in the subgroup of patients with viral hepatitis these correlations were no longer significant. CONCLUSION: Pancreatic fat deposition correlates with hepatic steatosis in patients with chronic NALD, but not in those with chronic viral hepatitis.

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BACKGROUND: Pulmonary metastasectomy is considered a potentially curative treatment for selected patients with metastatic colorectal cancer (CRC). Several prognostic factors have been analysed, but to date, it is still not well defined which is the optimal resection margin during lung metastasectomy (LM). This study analyses the long-term results and prognostic factors after LM in CRC patients with particular attention to the resection margins. Primary endpoint of this study is to assess the correlation between resection margins and long-term outcomes. METHODS: Observational cohort study on all proven cases of CRC lung metastases (2000-2016) resected with curative intent in a single centre. RESULTS: The series included 210 consecutive patients (M/F 133/77) with a mean age of 65.4 (± 9.96) years, 75% (159/210) of them with a solitary metastasis. Mean size of metastasis was 2.57 cm (± 1.45). One hundred sixty-eight patients underwent wedge resections (80%) and lymphadenectomy was carried out in 90 cases (42.9%). With a mean follow-up of 56 months (range 5-192), we observed a 1-, 3- and 5-year overall survival (OS) of 95%, 74% and 54%, respectively. The patients were divided into three groups according to the resection margin distance from the tumour: (a) ≥ 2 cm (145 cases); (b) < 2, ≥ 1 cm (37 cases); and (c) < 1 cm (12 cases). The OS was significantly different between the three groups (p = 0,020); univariate and multivariate analyses showed that a narrow resection margin was an independent prognostic factor of worse survival (p = 0.006 and HR 3.4 p = 0.009). CONCLUSIONS: Long-term survival of patients after LM is strongly associated with a greater distance between the lesion and the resection margin.

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The original version of this article, unfortunately, contained an error. In Fig. 2 - panel d, incorrect image was published and this is now presented correctly in this article.

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INTRODUCTION: Insulinomas are neuroendocrine tumors characterized by an excessive secretion of insulin, and its most common primary site is the pancreas. PRESENTATION OF THE CASE: Female, 31 years old, who underwent surgical resection of a pancreatic insulinoma measuring 0.5 × 0.5 cm during the third trimester of pregnancy. The patient started to present characteristic symptoms (hypoglycemia, adrenergic and neuroglycopenic symptoms) 18 months before being referred to our center. It was decided to resect the lesion due to the intensity of the symptoms and failure of the clinical treatment. The postoperative course was uneventful, and the fetus presented good vitality, as evidenced by the obstetric ultrasound. The patient was discharged from the hospital on the 6th postoperative day. The neonate was born at term, 38 weeks, with appropriate weight for gestational age. Today, around 12 months after surgery, the patient and the infant are in good health conditions and have no complaints. CONCLUSION: The moment of the surgical intervention in our case reflects the importance of this report, since it reinforces the feasibility of this procedure during pregnancy.

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Environmental cadmium (Cd) sources have increased in mangrove sediments in recent decades, inducing cellular damage to many plants. Avicennia schaueriana is abundant in mangrove sites and has been subject to Cd contamination. The possible effects of Cd toxicity and the structural and physiological disturbances to this plant were studied. Can this plant express early cellular tolerance mechanisms to such metal contamination? Seedlings of A. schaueriana were collected from sites of their natural occurrence, placed in plastic pots containing nutrient solution for 60 days, and subsequently exposed to increasing Cd concentrations for 5 days under experimental conditions. The anatomical, ultrastructural and physiological changes induced by Cd were analysed. Cd accumulated mainly in the root system and in pneumatophores, stems and leaves, induced differential accumulation of mineral nutrients, but did not induce necrosis or changes in leaf anatomy. However, there was a decrease in starch grains and an increase in deposited electron-dense material in the cortex and vascular bundles. Cd induced both increases in calcium (Ca) content in shoots and Ca oxalate crystal precipitation in leaf mesophyll and was detected in crystals and in the secretion of salt glands. Our observations and experimental results provide evidence of Cd tolerance in A. schaueriana. As a new feature, despite the clear cellular physiological disorders, this plant is able to eliminate Cd through leaf salt glands and immobilise it in Ca crystals, representing fast mechanisms for Cd exclusion and complexation in leaves in heavy metal coastal polluted marine ecosystems.

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Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.

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BACKGROUND AND PURPOSE: SPAST mutations are the most common cause of hereditary spastic paraplegia (SPG4-HSP), which is characterized by progressive lower limb weakness, spasticity and hyperreflexia. There are few studies about non-motor manifestations in this disease and none about autonomic involvement. Therefore, the aim was to determine the frequency and pattern of autonomic complaints in patients with SPG4-HSP, as well as to determine the clinical relevance and the possible factors associated with these manifestations. METHODS: Thirty-four molecularly confirmed SPG4 patients were recruited in a multicenter cross-sectional study, of whom 26 underwent detailed neurophysiological testing (heart rate variability, sympathetic skin response and the Quantitative Sudomotor Axonal Reflex Test). The Scales for Outcomes in Parkinson's Disease - Autonomic Questionnaire (SCOPA-AUT) was applied to quantify the severity of autonomic symptoms. Results were compared with 44 age- and gender-matched healthy controls using non-parametric tests. P values <0.05 were considered significant. RESULTS: In the SPG4-HSP group, there were 18 men with a mean age of 47.7 ± 12.6 years. SCOPA-AUT scores were similar between patients and controls (P = 0.238). Only the urinary domain subscore was significantly higher amongst patients (4 vs. 2.5, P = 0.05). Absent sympathetic skin response in the hands and feet was more frequent amongst patients (20% vs. 0%, P < 0.001, and 64% vs. 0%, P = 0.006, respectively). Quantitative Sudomotor Axonal Reflex Test responses were also smaller throughout all recording regions in the SPG4-HSP group. CONCLUSION: Our results indicate that SPG4-HSP patients have sudomotor dysfunction caused by damaged small post-ganglionic cholinergic fibers. Damage in SPG4-HSP extends to the peripheral nervous system.

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The bioengineering of a replacement kidney has been proposed as an approach to address the growing shortage of donor kidneys for the treatment of chronic kidney disease. One approach being investigated is the recellularization of kidney scaffolds. In this study, we present several key advances toward successful re-endothelialization of whole kidney matrix scaffolds from both rodents and humans. Based on the presence of preserved glycosoaminoglycans within the decelullarized kidney scaffold, we show improved localization of delivered endothelial cells after preloading of the vascular matrix with vascular endothelial growth factor and angiopoietin 1. Using a novel simultaneous arteriovenous delivery system, we report the complete re-endothelialization of the kidney vasculature, including the glomerular and peritubular capillaries, using human inducible pluripotent stem cell -derived endothelial cells. Using this source of endothelial cells, it was possible to generate sufficient endothelial cells to recellularize an entire human kidney scaffold, achieving efficient cell delivery, adherence, and endothelial cell proliferation and survival. Moreover, human re-endothelialized scaffold could, in contrast to the non-re-endothelialized human scaffold, be fully perfused with whole blood. These major advances move the field closer to a human bioengineered kidney.

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Leaf gas exchanges, carbohydrate metabolism and growth of three Brazilian Cerrado invasive African grasses were evaluated after growing for 75 days under doubled CO2 concentration and temperature elevated by 3 °C. Results showed that although the species presented photosynthetic C4 metabolism, they all had some kind of positive response to increased CO2. Urochloa brizantha and Megathyrsus maximus showed increased height for all induced environmental conditions. Urochloa decumbens showed only improvement in water use efficiency (WUE), while U. brizantha showed increased CO2 assimilation and M. maximus presented higher biomass accumulation under doubled CO2 concentration. The most significant improvement of increased CO2 in all three species appears to be the increase in WUE. This improvement probably explains the positive increase of photosynthesis and biomass accumulation presented by U. brizantha and M. maximus, respectively. The increase in temperature affected leaf carbohydrate content of M. maximus by reducing sucrose, glucose and fructose content. These reductions were not related to thermal stress since photosynthesis and growth were not harmed. Cellulose content was not affected in any of the three species, just the lignin content in U. decumbens and M. maximus. All treatments promoted lignin content reduction in U. brizantha, suggesting a delay in leaf maturation of this species. Together, the results indicate that climate change may differentially promote changes in leaf gas exchanges, carbohydrate content and growth in C4 plant species studied and all of them could benefit in some way from these changes, constituting a threat to the native Cerrado biodiversity.

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Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure disorder linked predominantly to ribosomal protein gene mutations. Here the European DBA consortium reports novel mutations identified in the RPL15 gene in 6 unrelated individuals diagnosed with DBA. Although point mutations have not been previously reported for RPL15, we identified 4 individuals with truncating mutations p.Tyr81* (in 3 of 4) and p.Gln29*, and 2 with missense variants p.Leu10Pro and p.Lys153Thr. Notably, 75% (3 of 4) of truncating mutation carriers manifested with severe hydrops fetalis and required intrauterine transfusions. Even more remarkable is the observation that the 3 carriers of p.Tyr81* mutation became treatment-independent between four and 16 months of life and maintained normal blood counts until their last follow up. Genetic reversion at the DNA level as a potential mechanism of remission was not observed in our patients. In vitro studies revealed that cells carrying RPL15 mutations have pre-rRNA processing defects, reduced 60S ribosomal subunit formation, and severe proliferation defects. Red cell culture assays of RPL15-mutated primary erythroblast cells also showed a severe reduction in cell proliferation, delayed erythroid differentiation, elevated TP53 activity, and increased apoptosis. This study identifies a novel subgroup of DBA with mutations in the RPL15 gene with an unexpected high rate of hydrops fetalis and spontaneous, long-lasting remission.