Spontaneously ruptured hepatocellular carcinoma on non-cirrhotic liver: A prospective case series.

BACKGROUND AND AIMS: Spontaneous ruptured hepatocellular carcinoma is an uncommon complication, and there are scarce data about non-cirrhotic patients. Tumor treatment is not standardized and the risk of peritoneal dissemination is unclear. AIM: we analyzed the treatment and survival in patients with rHCC on non-cirrhotic liver. METHODS: One hundred and forty-one non-cirrhotic patients with hepatocellular carcinoma diagnosed by histology were included in a multicenter prospective registry (2018-2022). Seven of them (5%) presented with hemoperitoneum due to spontaneous rupture. RESULTS: Liver disease was associated in three patients (42.9%). A single nodule was detected in three cases (42.9%). One patient had vascular invasion and none extrahepatic spread. Initial hemostatic therapy and sequential treatment was individualized. Patients with single nodule were treated: resection (one case) with recurrence at 4 months treated with TACE and sorafenib. TACE/TAE followed by surgery (two cases) one in remission 43 months later, the other had liver recurrence at 18 months and was transplanted. Patients with multiple lesions were treated: TAE/emergency surgery and subsequent systemic therapy (two cases), one received lenvatinib (1-year survival) and the other sorafenib (5-month survival). TAE and surgery with subsequent systemic therapy (one case). Initial hemostatic surgery, dying on admission (one case). No patient developed intraperitoneal metastasis. All patients with multiple lesions died by tumor. The 3-year survival rate was 42.9%. CONCLUSIONS: Initial hemostasis was achieved in all patients by TAE/TACE or surgery. Subsequent treatment was individualized, based on tumor characteristics, regardless of rupture. Long-time remission could be achieved in single nodule patients.

Phosphorus scarcity contributes to nitrogen limitation in lowland tropical rainforests.

There is increasing evidence to suggest that soil nutrient availability can limit the carbon sink capacity of forests, a particularly relevant issue considering today's changing climate. This question is especially important in the tropics, where most part of the Earth's plant biomass is stored. To assess whether tropical forest growth is limited by soil nutrients and to explore N and P limitations, we analyzed stem growth and foliar elemental composition of the five stem widest trees per plot at two sites in French Guiana after 3 years of nitrogen (N), phosphorus (P), and N + P addition. We also compared the results between potential N-fixer and non-N-fixer species. We found a positive effect of N fertilization on stem growth and foliar N, as well as a positive effect of P fertilization on stem growth, foliar N, and foliar P. Potential N-fixing species had greater stem growth, greater foliar N, and greater foliar P concentrations than non-N-fixers. In terms of growth, there was a negative interaction between N-fixer status, N + P, and P fertilization, but no interaction with N fertilization. Because N-fixing plants do not show to be completely N saturated, we do not anticipate N providing from N-fixing plants would supply non-N-fixers. Although the soil-age hypothesis only anticipates P limitation in highly weathered systems, our results for stem growth and foliar elemental composition indicate the existence of considerable N and P co-limitation, which is alleviated in N-fixing plants. The evidence suggests that certain mechanisms invest in N to obtain the scarce P through soil phosphatases, which potentially contributes to the N limitation detected by this study.

From Dyspnea to Skin Grafting: The Difficulties of Managing a Patient with Extreme Obesity.

While the prevalence of severe obesity is increasing worldwide, caregivers are often challenged with the management of patients with extreme weight. A 30-year-old woman (weight 245 kg, body mass index 85 kg/m2) presented with dyspnea, for which investigations led to suspect pulmonary embolism. The patient's weight made it impossible to perform adapted imaging; thus, an empirical anticoagulant treatment was initiated. A hematoma of the thigh occurred as a consequence of a transient antivitamin K overdose, leading to a 15-cm necrotic wound worsened by a state of malnutrition. Multidisciplinary and comprehensive care was performed including wound trimming, antibiotics, skin grafting, treatment of malnutrition, and psychological support, but with marked difficulties due to the lack of adapted medical equipment and facilities as well as appropriate medical guidelines. Overall, 7 months of hospitalization including 4 months of physiotherapy and rehabilitation were needed before the patient could return home. This case highlights how difficult managing patients with extreme obesity can be and points to the importance for healthcare systems to adapt to the specific needs of these patients and to design specific guidelines for treatment dosage and malnutrition prevention and treatment in this setting.

Nivolumab after selective internal radiation therapy for the treatment of hepatocellular carcinoma: a phase 2, single-arm study.

PURPOSE: To evaluate the safety and efficacy of selective internal radiation therapy (SIRT) in combination with a PD-1 inhibitor in patients with unresectable hepatocellular carcinoma (uHCC) and liver-only disease ineligible for chemoembolization. PATIENTS AND METHODS: NASIR-HCC is a single-arm, multicenter, open-label, phase 2 trial that recruited from 2017 to 2019 patients who were naïve to immunotherapy and had tumors in the BCLC B2 substage (single or multiple tumors beyond the up-to-7 rule), or unilobar tumors with segmental or lobar portal vein invasion (PVI); no extrahepatic spread; and preserved liver function. Patients received SIRT followed 3 weeks later by nivolumab (240 mg every 2 weeks) for up to 24 doses or until disease progression or unacceptable toxicity. Safety was the primary endpoint. Secondary objectives included objective response rate (ORR), time to progression (TTP), and overall survival (OS). RESULTS: 42 patients received SIRT (31 BCLC-B2, 11 with PVI) and were followed for a median of 22.2 months. 27 patients discontinued and 1 never received Nivolumab. 41 patients had any-grade adverse events (AE) and 21 had serious AEs (SAE). Treatment-related AEs and SAEs grade 3-4 occurred in 8 and 5 patients, respectively. Using RECIST 1.1 criteria, ORR reported by investigators was 41.5% (95% CI 26.3% to 57.9%). Four patients were downstaged to partial hepatectomy. Median TTP was 8.8 months (95% CI 7.0 to 10.5) and median OS was 20.9 months (95% CI 17.7 to 24.1). CONCLUSIONS: The combination of SIRT and nivolumab has shown an acceptable safety profile and signs of antitumor activity in the treatment of patients with uHCC that were fit for SIRT. TRIAL REGISTRATION NUMBER: NCT03380130.

Seroprevalence of Trypanosoma cruzi in Eight Blood Banks in Mexico.

BACKGROUND: The true prevalence of Chagas disease in Mexico is unknown. However, it has been estimated that 1.1-4 million people are infected with Trypanosoma cruzi, which represents a potential risk for transmission of the disease via contaminated blood. AIM OF THE STUDY: To determine the Chagas disease seroprevalence in donors from eight blood banks in the north of Mexico City, and the northeast of the State of Mexico. STUDY DESIGN AND METHODS: Serum samples from blood donors (n = 515,038) were tested to detect the presence of anti-Trypanosoma cruzi antibodies in eight blood banks. The serologic screening test was performed in each of the blood banks. To confirm the seropositive blood donors, only two out of the eight blood banks used a test with a different principle with the aim of identifying anti-Trypanosoma cruzi antibodies. All tests were validated by the Mexican Institute for Epidemiological Diagnosis and Reference. RESULTS: One thousand two hundred and ten blood donors were seropositive for Trypanosoma cruzi, which represents a 0.23% seroprevalence (95% CI 0.22-0.25%). Of the seropositive blood donors, 97.03 % resided in the northeast area of the State of Mexico, Mexico City, and southern part of the State of Hidalgo. CONCLUSIONS: Active transmission of Chagas disease may be occurring in non-endemic regions in the northeast of the State of Mexico.

Hepatitis C eradication improves cognitive function in patients with or without cirrhosis: A prospective real-life study.

BACKGROUND AND PURPOSE: Hepatitis C virus (HCV) infection is associated with neuropsychiatric disturbances that impact on functioning and health-related quality of life (HRQoL). Reversibility at different liver disease stages is unknown, particularly in cirrhosis. We aimed to evaluate cognition, functioning, and HRQoL following HCV eradication at different liver disease stages. METHODS: A random sample (n = 152) of consecutive patients treated with direct-acting antiviral agents (DAAs) between April 2015 and March 2017 were included. A comprehensive neuropsychological assessment, functioning and HRQoL questionnaires were applied at baseline, and 12 and 48 weeks after the end of antivirals. RESULTS: One-hundred thirty-five patients who achieved virological response completed the follow-up, of whom 44 had cirrhosis (27% decompensated). Twenty-one percent had cognitive impairment before starting DAAs (34.1% cirrhotic vs. 14.4% noncirrhotic, p < 0.011). Viral eradication was associated with a decrease in cognitive impairment to 23% of cirrhotic and 6% of noncirrhotic patients (p < 0.05). Interestingly, older patients (B = 0.11, 95% confidence interval [CI] = 0.03-0.19) with baseline cognitive impairment (B = 3.58, 95% CI = 1.54-5.62) were those with higher cognitive benefit, regardless of liver disease. Persistent cognitive impairment was associated with having higher cardiovascular risk, cirrhosis, lower education, and higher anxiety and depression scores. Functioning and HRQoL also improved after eradication but remained worse in the cirrhotic group. CONCLUSIONS: Viral eradication decreases the prevalence of cognitive impairment and improves functioning and HRQoL. Patients with lower brain reserve (older patients) and baseline cognitive impairment may benefit the most. Identification and treatment of HCV patients through screening programs may reduce the burden of cognitive disturbances beyond the prevention of liver disease progression.

Does timing matter on tocilizumab administration? Clinical, analytical and radiological outcomes in COVID-19.

INTRODUCTION: While there are no pharmacological treatments with proven efficacy for coronavirus disease 2019 (COVID-19), tocilizumab has emerged as a candidate therapy. Some aspects of this therapy are still unknown, including the optimal timing of administration. OBJECTIVE: This observational study aimed to compare the 90-day mortality in two cohorts of patients when the drug was administered within the first 10 days from onset of symptoms or after day 11. METHODS: Patients hospitalised with severe COVID-19 pneumonia who had received tocilizumab were divided into two groups according to when the medication was administered. The primary outcome was 90-day mortality. Secondary outcomes were 30-day mortality, clinical improvement on a 6-item scale by day 6, biomarker improvement by day 6, radiological image improvement by day 10 and SaO2 quotient by day 6. The results in the two groups were compared. Additionally, adverse events relating to tocilizumab were recorded. RESULTS: A total of 112 patients were analysed. Both groups were epidemiologically comparable. The results obtained in the primary efficacy variable of the study (90-day mortality) showed a statistically significant difference in the subgroups according to the time of administration of tocilizumab (18.6% vs 5.0%, p=0.048). There was clinical improvement in 24.1% of patients at 6 days, with similar behaviour in both subgroups. No statistically significant differences were found in the percentage of patients who achieved radiological improvement at 10 days or in the other inflammatory parameters, with the exception of significant reductions in lactate dehydrogenase and C-reactive protein. Administration of tocilizumab was not associated with relevant adverse events. CONCLUSION: To our knowledge, this is the first report of data regarding the timing of administration of tocilizumab in patients with COVID-19 pneumonia. A strategy involving tocilizumab administration after 10 days from onset of symptoms may decrease mortality. Further randomised controlled trials are needed to confirm this emerging hypothesis.

Long-term effects of gasification biochar application on soil functions in a Mediterranean agroecosystem: Higher addition rates sequester more carbon but pose a risk to soil faunal communities.

Biochar applications can have important implications for many of the soil functions upon which agroecosystems rely, particularly regarding organic carbon storage. This study evaluated the impacts of adding a highly aromatic gasification biochar at different rates (0, 12 and 50 t ha-1) to a barley crop on the provision of crucial soil functions (carbon sequestration, water content, greenhouse gas emissions, nutrient cycling, soil food web functioning, and food production). After natural ageing in the field for six years, a wide range of soil properties representative of the studied soil functions were measured and integrated into a soil quality index. Results showed that C sequestration increased with biochar rate (23 and 68% higher than in the control for the 12 and 50 t biochar ha-1 treatments, respectively). Water content was enhanced at the 50 t ha-1 treatment depending on the sampling date. Despite biochar additions neither abating nor increasing CO2 equivalent emissions (carbon dioxide plus nitrous oxide and methane), the system shifted from being a methane sink (-0.017 ± 0.01 mg CH4-C m-2 h-1 at the 12 t ha-1 treatment), to a net source (0.025 ± 0.02 mg CH4-C m-2 h-1 at the 50 t ha-1 treatment). In addition, biochar ageing provoked a loss of nitrate mitigation potential, and indeed ammonium production was stimulated at the 50 t ha-1 rate. The 50 t ha-1 treatment also adversely affected nematode and collembolan functional diversity. Lastly, biochar did not affect barley yield. The results of the soil quality index indicated that no biochar treatment provided more benefits to our agricultural soil, and, although the 50 t ha-1 treatment increased C sequestration, this was potentially offset by its harmful effects on soil faunal communities. Therefore, application of this biochar at high rates should be avoided to prevent risks to soil biological communities.

Radiological response to nivolumab in patients with hepatocellular carcinoma: A multicenter analysis of real-life practice.

BACKGROUND AND AIMS: Immune-checkpoint inhibitors are effective in many advanced tumors. However, there is scarce information regarding the radiological response to these agents in hepatocellular carcinoma outside clinical trials. We aimed to describe the radiological response in a retrospective cohort of hepatocellular carcinoma patients treated with nivolumab and to analyze the radiological evolution according to tumor response at first post-treatment radiological assessment. METHODS: We reviewed pre-treatment and post-treatment images (CT or MRI) obtained at different time-points in patients with hepatocellular carcinoma treated with nivolumab outside clinical trials at seven Spanish centers, assessing the response according to RECIST 1.1 and iRECIST and registering atypical responses. We also analyzed the imaging findings on subsequent assessments according to tumor status on the first posttreatment imaging assessment. RESULTS: From the 118 patients with hepatocellular carcinoma treated with nivolumab, we finally analyzed data from 31 patients (71 % Child-Pugh A; 74 % BCLC-C). Median follow-up was 8.39 months [IQR 5.00-10.92]; median overall survival was 12.82 months (95 %CI 10.92-34.79). According to RECIST 1.1, the objective response rate was 16 % and according to iRECIST, the objective response rate was 22.6 %. Findings at the first post-treatment assessment varied, showing stable disease in 44.8 % of patients; findings during follow-up also varied widely, including 4 hyperprogressions and 3 pseudoprogressions. CONCLUSION: Imaging findings during nivolumab treatment are heterogeneous between and within patients. Progression of disease does not always signify treatment failure, and surrogate end-points may not reflect survival outcomes, making the management of hepatocellular carcinoma patients under immunotherapy challenging.

A Model Based on Noninvasive Markers Predicts Very Low Hepatocellular Carcinoma Risk After Viral Response in Hepatitis C Virus-Advanced Fibrosis.

BACKGROUND AND AIMS: Patients with hepatitis C virus (HCV) and advanced fibrosis remain at risk of hepatocellular carcinoma (HCC) after sustained viral response (SVR) and need lifelong surveillance. Because HCC risk is not homogenous and may decrease with fibrosis regression, we aimed to identify patients with low HCC risk based on the prediction of noninvasive markers and its changes after SVR. APPROACH AND RESULTS: This is a multicenter cohort study, including patients with HCV and compensated advanced fibrosis that achieved SVR after direct antivirals. Clinical and transient elastography (TE) data were registered at baseline, 1 year, and 3 years after the end of treatment (EOT). All patients underwent liver ultrasound scan every 6 months. Patients with clinical evaluation 1 year after EOT were eligible. Univariate and multivariate Cox regression analysis were performed, and predictive models were constructed. HCC occurrence rates were evaluated by Kaplan-Meier. Nine hundred and ninety-three patients were eligible (56% male; 44% female; median age 62 years), 35 developed HCC (3.9%), and the median follow-up was 45 months (range 13-53). Baseline liver stiffness measurement (LSM) (HR 1.040; 95% CI 1.017-1.064), serum albumin (HR 0.400; 95% CI 0.174-0.923), 1-year DeltaLSM (HR 0.993; 95% CI 0.987-0.998), and 1-year FIB-4 score (HR 1.095; 95% CI 1.046-1.146) were independent factors associated with HCC. The TE-based HCC risk model predicted 0% of HCC occurrence at 3 years in patients with score 0 (baseline LSM ≤ 17.3 kPa, albumin >4.2 g/dL, and 1-year DeltaLSM > 25.5%) versus 5.2% in patients with score 1-3 (Harrell's C 0.779; log-rank 0.002). An alternative model with FIB-4 similarly predicted HCC risk. CONCLUSIONS: A combination of baseline and dynamic changes in noninvasive markers may help to identify patients with a very low risk of HCC development after SVR.

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment.

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aß1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aß1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

Nutrient scarcity strengthens soil fauna control over leaf litter decomposition in tropical rainforests.

Soil fauna is a key control of the decomposition rate of leaf litter, yet its interactions with litter quality and the soil environment remain elusive. We conducted a litter decomposition experiment across different topographic levels within the landscape replicated in two rainforest sites providing natural gradients in soil fertility to test the hypothesis that low nutrient availability in litter and soil increases the strength of fauna control over litter decomposition. We crossed these data with a large dataset of 44 variables characterizing the biotic and abiotic microenvironment of each sampling point and found that microbe-driven carbon (C) and nitrogen (N) losses from leaf litter were 10.1 and 17.9% lower, respectively, in the nutrient-poorest site, but this among-site difference was equalized when meso- and macrofauna had access to the litterbags. Further, on average, soil fauna enhanced the rate of litter decomposition by 22.6%, and this contribution consistently increased as nutrient availability in the microenvironment declined. Our results indicate that nutrient scarcity increases the importance of soil fauna on C and N cycling in tropical rainforests. Further, soil fauna is able to equalize differences in microbial decomposition potential, thus buffering to a remarkable extent nutrient shortages at an ecosystem level.

FGFR4 increases EGFR oncogenic signaling in lung adenocarcinoma, and their combined inhibition is highly effective.

OBJECTIVES: Lung adenocarcinoma accounts for approximately half of lung cancer cases. Twenty to 50% of tumors of this type harbor mutations affecting epidermal growth factor receptor (EGFR) expression or activity, which can be therapeutically targeted. EGFR inhibitors in this context exhibit high efficacy and are currently used in the clinical setting. However, not all adenocarcinomas harboring EGFR mutations respond to therapy, so predictive biomarkers of therapeutic outcomes, as well as novel therapies sensitizing these tumors to EGFR inhibition, are needed. MATERIALS AND METHODS: We performed in vitro gene overexpression/silencing and tumorigenic surrogate assays, as well as in vitro and in vivo combination treatments with Fibroblast Growth Factor Receptor (FGFR)/EGFR inhibitors. At the clinical level, we determined FGFR4 expression levels in tumors from patients treated with EGFR inhibitors and correlated these with treatment response. RESULTS: We describe a cooperative interaction between EGFR and FGFR4, which results in their reciprocal activation with pro-oncogenic consequences in vitro and in vivo. This cooperation is independent of EGFR activating mutations and increases resistance to different EGFR inhibitors. At the therapeutic level, we provide evidence of the synergistic effects of the combination of EGFR and FGFR inhibitors in high FGFR4-expressing, EGFR-activated tumors in vitro and in vivo. Correlated with these results, we found that patients treated with EGFR inhibitors relapse earlier when their tumors exhibit high FGFR4 expression. CONCLUSIONS: We propose a novel predictive biomarker for EGFR-targeted therapy, and a highly efficacious combinatory therapeutic strategy to treat EGFR-dependent; this may may extend the use of appropriate inhibitors beyond EGFR-mutated adenocarcinoma patients.

FGFR1 Cooperates with EGFR in Lung Cancer Oncogenesis, and Their Combined Inhibition Shows Improved Efficacy.

INTRODUCTION: There is substantial evidence for the oncogenic effects of fibroblast growth factor receptor 1 (FGFR1) in many types of cancer, including lung cancer, but the role of this receptor has not been addressed specifically in lung adenocarcinoma. METHODS: We performed FGFR1 and EGFR overexpression and co-overexpression assays in adenocarcinoma and in inmortalized lung cell lines, and we also carried out surrogate and interaction assays. We performed monotherapy and combination EGFR/FGFR inhibitor sensitivity assays in vitro and in vivo in cell line- and patient-derived xenografts. We determined FGFR1 mRNA expression in a cohort of patients with anti-EGFR therapy-treated adenocarcinoma. RESULTS: We have reported a cooperative interaction between FGFR1 and EGFR in this context, resulting in increased EGFR activation and oncogenic signaling. We have provided in vitro and in vivo evidence indicating that FGFR1 expression increases tumorigenicity in cells with high EGFR activation in EGFR-mutated and EGFR wild-type models. At the clinical level, we have shown that high FGFR1 expression levels predict higher resistance to erlotinib or gefitinib in a cohort of patients with tyrosine kinase inhibitor-treated EGFR-mutated and EGFR wild-type lung adenocarcinoma. Dual EGFR and FGFR inhibition in FGFR1-overexpressing, EGFR-activated models shows synergistic effects on tumor growth in vitro and in cell line- and patient-derived xenografts, suggesting that patients with tumors bearing these characteristics may benefit from combined EGFR/FGFR inhibition. CONCLUSION: These results support the extended the use of EGFR inhibitors beyond monotherapy in the EGFR-mutated adenocarcinoma setting in combination with FGFR inhibitors for selected patients with increased FGFR1 overexpression and EGFR activation.

Fiebre de origen oscuro como manifestación de lupus eritematoso sistémico / Fever of unknown origin as manifestation of systemic lupus erythematosus

Resumen: La fiebre de origen oscuro se caracteriza por un espectro clínico de pacientes que consultan por padecer fiebre como manifestación única o predominante, mayor o igual a 38.3ºC, de más de tres semanas de evolución y en quienes los resultados de la evaluación clínica y estudios paraclínicos iniciales no han identificado su causa. Se han agrupado cinco categorías que engloban las causas de la fiebre de origen oscuro, entre las que se encuentran las enfermedades infecciosas, neoplásicas, inflamatorias no infecciosas, misceláneas y de origen desconocido. El lupus eritematoso sistémico es una enfermedad de tipo autoinmunitario que afecta el tejido conectivo y tiene amplio rango de manifestaciones clínicas, entre las que destacan al inicio poliartritis, úlceras mucocutáneas y el eritema malar; el lupus eritematoso sistémico es una de las causas inflamatorias no infecciosas de fiebre de origen oscuro. Se comunica el caso clínico de una paciente de 51 años de edad, quien consultó al servicio de Medicina interna, por padecer un cuadro clínico de 30 días de evolución, con fiebre intermitente, diaria y cuantificada entre 38.5 y 39°C, asociada con pérdida significativa de peso; en quien se diagnosticó por hallazgos clínicos y paraclínicos lupus eritematoso sistémico, fue tratada con hidroxicloroquina y prednisolona, con desaparición de la fiebre y mejoría del estado general.

Abstract: Fever of unknown origin is defined as a clinical spectrum of patients who consulted for presenting fever as a single or predominant manifestation, greater or equal to 38.3ºC, more than 3 weeks of evolution, and in whom clinical evaluation results and initial paraclinical studies have not identified its cause. Five categories group the causes of fever of unknown origin which include infectious, neoplastic, inflammatory non-infectious, miscellaneous and of unknown origin. Systemic lupus erythematosus is an autoimmune disease that affects connective tissue and has a wide range of clinical manifestations, among which the presence of polyarthritis, mucocutaneous ulcers and malar erythema stand out at the beginning; systemic lupus erythematosus is one of the non-infectious inflammatory causes of fever of unknown origin. A clinical case report is made, of a 51-year-old woman, who consulted to Internal Medicine, with a clinical picture of 30 days of evolution, with intermittent fever, daily and quantified between 38.5 and 39ºC, associated with significant weight loss; to which it was diagnosed by clinical and paraclinical findings systemic lupus erythematosus, treated with hydroxychloroquine and prednisolone, achieving disappearance of the fever and improvement of the general state of the patient.

Carotenoid-based skin ornaments reflect foraging propensity in a seabird, Sula leucogaster.

Carotenoid-based ornaments are common signalling features in animals. It has long been proposed that such ornaments communicate information about foraging abilities to potential mates. However, evidence linking foraging with ornamentation is largely missing from unmanipulated, free-ranging populations. To investigate this relationship, we studied a coastal population of brown booby (Sula leucogaster brewsteri), a seabird with a carotenoid-based gular skin ornament. δ13C values from both feathers and blood plasma were negatively correlated with male gular colour, indicating birds that consumed more pelagic prey in offshore locations had more ornamented skin than those that fed on nearshore, benthic prey. This relationship was supported by our GPS tracking results, which revealed longer, more offshore foraging trips among highly ornamented males. Our data show that brown booby ornaments are honest indicators of foraging propensity; a link consistent with the rarity hypothesis and potentially driven by the concentration of carotenoids found in phytoplankton versus benthic algae. Carotenoid-based ornaments may reflect foraging tendencies in animals such as coastal predators that use food webs with distinct carotenoid profiles.

The FGFR4-388arg Variant Promotes Lung Cancer Progression by N-Cadherin Induction.

The FGFR4-388Arg variant has been related to poor prognosis in several types of cancer, including lung cancer. The mechanism underlying this association has not been addressed in detail in patients with this pathology. Here, we report that this FGFR4 variant induces MAPK and STAT3 activation and causes pro-oncogenic effects in NSCLC in vitro and in vivo. This variant induces the expression of EMT-related genes, such as N-cadherin, vimentin, Snail1 and Twist1. Indeed, the induction of N-cadherin protein expression by this variant is essential for its pro-tumorigenic role. The presence of the FGFR4-388Arg variant correlates with higher N-cadherin expression levels in clinical NSCLC samples and with poorer outcome in patients with FGFR expression. These results support the prognostic role of this FGFR variant in lung cancer and show that these effects may be mediated by the induction of N-cadherin expression and an EMT phenotype.

Orthodontic fixed retainers: a systematic review / Retenedores fijos en ortodoncia: revisión sistemática

ABSTRACT Introduction: the objective of this study was to evaluate the periodontal effects of fixed retainers in the long term. Methods: a search in electronic databases (PubMed, Cochrane Library, Science Direct, Embase, ProQuest, Ebsco, Biomed Central, Medline, Lilacs, and Google Scholar) and a manual search with no language restrictions. The inclusion criteria were: randomized clinical trials and meta-analysis, prospective and retrospective studies, studies in humans, clinical and radiographical studies evaluating the periodontium, performed during the 1987-2014 period, up to 10 years of follow-up. Four authors extracted data from the selected studies independently. Results: after applying the inclusion criteria, we selected 4 studies in which a total of 405 patients were evaluated. All the studies were longitudinal and retrospective. There was a greater prevalence of gingival recessions, especially in mandibular incisors, which are more vulnerable. There were no significant changes in terms of alveolar bone index or calculus index. The survival rate of fixed retainers was 50% or higher. Due to the heterogeneity of the selected studies, including difference in study population, differences in methods to assess the intervention, and follow-up periods, it was impossible to quantify the variables to perform a meta-analysis. Conclusions: the selected studies had a middle level of evidence. The greatest gingival recessions occurred with the use of fixed retainers in a long time; however, there is no alteration of the alveolar bone level. The studies recommend encouraging patients to maintain good oral hygiene. The findings of this review should be cautiously taken due to the resulting level of evidence, and the general recommendation for clinicians is that, in the long run, these retainers appear to be safe to maintain the alignment of mandibular incisors, although more studies with greater scientific rigor are required. There were no conflicts of interest and this study did not have any kind of financial support.

RESUMEN. Introducción: el objetivo del presente estudio consistió en evaluar los efectos periodontales de los retenedores fijos a largo plazo. Métodos: se realizó una búsqueda en bases de datos electrónicas (PubMed, Cochrane Library, Science Direct, Embase, ProQuest, Ebsco, Biomed Central, Medline, Lilacs y Google Scholar) y una búsqueda manual sin restricción de lenguaje. Los criterios de inclusión fueron: ensayos clínicos aleatorizados y metaanálisis, estudios prospectivos y retrospectivos, estudios en humanos, estudios en los que se evaluara clínica y radiográficamente el periodonto, periodo comprendido entre 1987 y 2014, seguimiento hasta 10 años. Cuatro autores extrajeron independientemente los datos de los estudios seleccionados. Resultados: después de aplicar los criterios de inclusión, se seleccionaron 4 estudios en los que se evaluaron un total de 405 pacientes. Todos los estudios fueron longitudinales retrospectivos. Se encontró una mayor prevalencia de recesiones gingivales, especialmente de los incisivos mandibulares, que son más vulnerables. No mostraron cambios significativos ni el índice de hueso alveolar ni el índice de cálculo. La tasa de supervivencia de los retenedores fijos fue mayor del 50%. Debido a la heterogeneidad de los estudios seleccionados, entre los cuales se encuentra la diferencia en la población de estudio, diferencias en los métodos para evaluar la intervención y el tiempo de seguimiento, fue imposible cuantificar las variables para realizar un metaanálisis. Conclusiones: los estudios seleccionados tuvieron un nivel de evidencia medio. Se presentan mayores recesiones gingivales con el uso de los retenedores fijos a largo plazo; sin embargo, no hay alteración del nivel óseo alveolar. Los estudios recomiendan incentivar al paciente para que mantenga una buena higiene oral. Los resultados de esta revisión se deben tomar con cautela por el nivel de evidencia que arrojaron, y la recomendación general para el clínico es que, a largo plazo, estos retenedores parecen ser seguros para mantener el alineamiento de incisivos mandibulares, aunque se requieren más estudios con mayor rigor científico. No hubo conflictos de intereses y la investigación no contó con ningún tipo de financiamiento.

Effects of shiga toxin 2 on cellular regeneration mechanisms in primary and three-dimensional cultures of human renal tubular epithelial cells.

Shiga toxin (Stx)-producing Escherichia coli (STEC) causes post-diarrheal Hemolytic Uremic Syndrome (HUS), which is one of the most common causes of acute renal failure in children in Argentine. The aim of the present work was to study the effects of Shiga toxin type 2 (Stx2) on regenerative mechanisms of primary cultures of human cortical renal tubular epithelial cells (HRTEC) and three-dimensional (3D) cultures of HRTEC. Primary cultures of HRTEC were able to develop tubular structures when grown in matrigel, which showed epithelial cells surrounding a central lumen resembling the original renal tubules. Exposure to Stx2 inhibited tubulogenesis in 3D-HRTEC cultures. Moreover, a significant increase in apoptosis, and decrease in cell proliferation was observed in tubular structures of 3D-HRTEC exposed to Stx2. A significant reduction in cell migration and vimentin expression levels was observed in HRTEC primary cultures exposed to Stx2, demonstrating that the holotoxin affected HRTEC dedifferentiation. Furthermore, a decreased number of cells expressing CD133 progenitor marker was found in HRTEC cultures treated with Stx2. The CD133 positive cells also expressed the Stx receptor globotriaosylceramide, which may explain their sensitivity to Stx2. In conclusion, Stx2 affects the regenerative processes of human renal tubular epithelial cells in vitro, by inhibiting cell dedifferentiation mechanisms, as well as tubules restoration. The development of 3D-HRTEC cultures that resemble original human renal proximal tubules is a novel in vitro model to study renal epithelial repair mechanisms after injury.

El papel de los hermanos en el logro de objetivos en los programas de acogimiento residencial infantil / The role of siblings in goal achievement in residential child care programs

Dentro del sistema de protección infantil, cuando existen grupos de hermanos se recomienda mantenerlos juntos cuando son acogidos. El objetivo de este trabajo es comprobar si mantener a los grupos de hermanos juntos en acogimiento residencial es beneficioso y en qué aspectos. La muestra está compuesta por 167 niños y adolescentes que vivían en hogares de protección, de los que 105 (62.9%) estaban con hermanos y 62 (37.1%) estaban solos. Se analizó la evolución de las puntuaciones en la escala mensual de observación de objetivos del SERAR (Del Valle y Bravo, 2007). Los resultados indican que, en general, los que están con los hermanos obtienen más ventajas que los que están solos, adaptándose mejor al contexto residencial. No obstante, cuando las estancias se alargan demasiado empeora la interacción social dentro de la residencia en los grupos de hermanos. Estos resultados se discuten en relación a la investigación previa y a sus implicaciones prácticas

Within the child welfare system, when groups of siblings are placed in residential care it is recommended to keep them together. The goal of this work is to verify whether keeping groups of siblings together in residential care is beneficial. The sample was made up of 167 children and adolescents who lived in supervised homes; 105 (62.9%) were with siblings and 62 (37.1%) were alone. We analyzed the evolution of their scores on the monthly goal observation scale of the SERAR (Del Valle & Bravo, 2007). The results indicate that, in general, children who are with their siblings obtain more benefits than children who are alone, especially in the dimensions of the residential setting. Nevertheless, when stays are too long, social interaction within the residence worsens in the groups of siblings. These results are discussed with regard to prior research and its practical implications