PERK inhibition in zebrafish mimics human Wolcott-Rallison syndrome phenotypes.

Wolcott-Rallison Syndrome (WRS) is the most common cause of permanent neonatal diabetes mellitus among consanguineous families. The diabetes associated with WRS is non-autoimmune, insulin-requiring and associated with skeletal dysplasia and growth retardation. The therapeutic options for WRS patients rely on permanent insulin pumping or on invasive transplants of liver and pancreas. WRS has a well identified genetic cause: loss-of-function mutations in the gene coding for an endoplasmic reticulum kinase named PERK (protein kinase R-like ER kinase). Currently, WRS research is facilitated by cellular and rodent models with PERK ablation. While these models have unique strengths, cellular models incompletely replicate the organ/system-level complexity of WRS, and rodents have limited scalability for efficiently screening potential therapeutics. To address these challenges, we developed a new in vivo model of WRS by pharmacologically inhibiting PERK in zebrafish. This small vertebrate displays high fecundity, rapid development of organ systems and is amenable to highly efficient in vivo drug testing. PERK inhibition in zebrafish produced typical WRS phenotypes such as glucose dysregulation, skeletal defects, and impaired development. PERK inhibition in zebrafish also produced broad-spectrum WRS phenotypes such as impaired neuromuscular function, compromised cardiac function and muscular integrity. These results show that zebrafish holds potential as a versatile model to study WRS mechanisms and contribute to the identification of promising therapeutic options for WRS.

Deep inspirational breast hold (DIBH) for right breast irradiation: Improved sparing of liver and lung tissue.

Objective: To reduce liver and lung dose during right breast irradiation while maintaining optimal dose to the target volume. This dose reduction has the potential to decrease acute side effects and long-term toxicity. Materials and Methods: 16 patients treated with radiation therapy for localized carcinoma of the right breast were included retrospectively. For the planning CT, each patient was immobilised on an indexed board with the arms placed above the head. CT scans were acquired in free-breathing (FB) as well as with deep inspiration breath hold (DIBH). Both scans were acquired with the same length. Planning target volumes (PTV's) were created with a 5 mm margin from the respective clinical target volumes (CTV's) on both CT datasets. The liver was outlined as scanned. Dose metrics evaluated were as follows: differences in PTV coverage, dose to the liver (max, mean, V90%, V50%, V30%), dose to lung (mean, V20Gy, relative electron density) and dose to heart (Dmax). The p-values were calculated using Wilcoxon signed-rank tests. A p-value was significant when <0.05. Results: Differences in PTV coverage between plans using FB and DIBH were less than 2 %. Maximum liver dose was significantly less using DIBH: 17.5 Gy versus FB: 40.3 Gy (p < 0.001). The volume of the liver receiving 10 % of the dose was significantly less using DIBH with 1.88 cm3 versus 72.2 cm3 under FB (p < 0.001). The absolute volume receiving 20 Gy in the right lung was larger using DIBH: 291 cm3 versus 230 cm3 under FB (p < 0.001) and the relative volume of lung receiving dose greater than 20 Gy was smaller with DIBH: 11.5 % versus 14 % in FB (p = 0.007). The relative electron density of lung was significantly less with DIBH: 0.59 versus 0.62 with FB, (p < 0.001). This suggests that the lung receives less dose due to its lower density when using DIBH. Conclusion: Radiation of the right breast using DIBH spares liver and lung tissue significantly and thus carries the potential of best practice for right sided breast cancer.

Esophageal Stenting: How I Do It.

Endoscopic esophageal stent placement is an effective palliative treatment for malignant strictures and has also been successfully used for benign indications, including esophageal refractory strictures and iatrogenic leaks and perforations. Despite several decades of evolution and the wide variety of esophageal stents available to choose from, an ideal stent that is both effective and without adverse events such as stent migration, tissue ingrowth, or pressure necrosis has yet to be developed. This paper is an overview of how this evolution happened, and it also addresses the characteristics of some of the currently available stents, like their material and construction, delivery device, radial and axial force pattern, covering and size which may help to understand and avoid the occurrence of adverse events. The insertion delivery systems and techniques of placement of an esophageal self-expandable metal stent are reviewed, as well as some tips and tricks regarding placement and management of adverse events.

A colocação endoscópica de próteses esofágicas metálicas auto-expansíveis é um tratamento paliativo eficaz da estenose maligna, tendo também sido usada com sucesso em indicações benignas, como no caso de estenoses refratárias do esófago ou de perfurações e deiscências iatrogénicas. Apesar de várias décadas de evolução e não obstante existir uma grande variedade de escolha de próteses esofágicas, ainda está por desenvolver a prótese ideal que apresente simultaneamente uma eficácia elevada e uma incidência reduzida de complicações como migração, crescimento tecidular ou necrose por pressão. Este artigo fornece uma visão global de como esta evolução ocorreu e aborda as características de algumas das próteses atualmente existentes no mercado, como o seu material e tipo de construção, padrão de força axial e radial, cobertura e dimensões, que poderão ajudar a compreender e a evitar a ocorrência desses eventos adversos. São analisados os sistemas de libertação e técnicas de introdução das próteses metálicas auto-expansíveis, com alguns truques e dicas relativas à colocação das próteses e abordagem de eventos adversos.

Genetic landscape of homologous recombination repair genes in early-onset/familial prostate cancer patients.

Prostate cancer (PrCa) is one of the three most frequent and deadliest cancers worldwide. The discovery of PARP inhibitors for the treatment of tumors with deleterious variants in homologous recombination repair (HRR) genes has placed PrCa on the roadmap of precision medicine. However, the overall contribution of HRR genes to the 10%-20% of carcinomas arising in men with early-onset/familial PrCa has not been fully clarified. We used targeted next-generation sequencing (T-NGS) covering eight HRR genes (ATM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PALB2, and RAD51C) and an analysis pipeline querying both small and large genomic variations to clarify their global and relative contribution to hereditary PrCa predisposition in a series of 462 early-onset/familial PrCa cases. Deleterious variants were found in 3.9% of the patients, with CHEK2 and ATM being the most frequently mutated genes (38.9% and 22.2% of the carriers, respectively), followed by PALB2 and NBN (11.1% of the carriers, each), and finally by BRCA2, RAD51C, and BRIP1 (5.6% of the carriers, each). Using the same NGS data, exonic rearrangements were found in two patients, one pathogenic in BRCA2 and one of unknown significance in BRCA1. These results contribute to clarify the genetic heterogeneity that underlies PrCa predisposition in the early-onset and familial disease, respectively.

Anastomotic Leakages after Surgery for Gastroesophageal Cancer: A Systematic Review and Meta-Analysis on Endoscopic versus Surgical Management.

Introduction: With the increase of esophageal and gastric cancer, surgery will be more often performed. Anastomotic leakage (AL) is one of the most feared postoperative complications of gastroesophageal surgery. It can be managed by conservative, endoscopic (such as endoscopic vacuum therapy and stenting), or surgical methods, but optimal treatment remains controversial. The aim of our meta-analysis was to compare (a) endoscopic and surgical interventions and (b) different endoscopic treatments for AL following gastroesophageal cancer surgery. Methods: Systematic review and meta-analysis, with search in three online databases for studies evaluating surgical and endoscopic treatments for AL following gastroesophageal cancer surgery. Results: A total of 32 studies comprising 1,080 patients were included. Compared with surgical intervention, endoscopic treatment presented similar clinical success, hospital length of stay, and intensive care unit length of stay, but lower in-hospital mortality (6.4% [95% CI: 3.8-9.6%] vs. 35.8% [95% CI: 23.9-48.5%]. Endoscopic vacuum therapy was associated with a lower rate of complications (OR 0.348 [95% CI: 0.127-0.954]), shorter ICU length of stay (mean difference -14.77 days [95% CI: -26.57 to -2.98]), and time until AL resolution (17.6 days [95% CI: 14.1-21.2] vs. 39.4 days [95% CI: 27.0-51.8]) when compared with stenting, but there were no significant differences in terms of clinical success, mortality, reinterventions, or hospital length of stay. Conclusions: Endoscopic treatment, in particular endoscopic vacuum therapy, seems safer and more effective when compared with surgery. However, more robust comparative studies are needed, especially for clarifying which is the best treatment in specific situations (according to patient and leak characteristics).

Introdução: Com o aumento da incidência de cancro esofágico e gástrico, a cirurgia será mais frequentemente realizada. As deiscências anastomóticas (DA) são uma das complicações pós-operatórias mais temidas da cirurgia gastroesofágica. Podem ser tratadas com métodos conservadores, endoscópicos (como terapêutica endoscópica por vácuo e colocação de próteses) ou cirúrgicos, mas a melhor abordagem ainda é controversa. O objetivo da nossa meta-análise foi a comparação a) entre intervenções endoscópicas e cirúrgicas e b) entre diferentes tratamentos endoscópicos para a DA após cirurgia oncológica gastroesofágica. Métodos: Revisão sistemática e meta-análise, com pesquisa em 3 bases de dados online de estudos que avaliassem tratamentos cirúrgicos e endoscópicos da DA após cirurgia oncológica gastroesofágica. Resultados: Um total de 32 estudos englobando 1,080 pacientes foram incluídos. Comparativamente à intervenção cirúrgica, o tratamento endoscópico apresentou sucesso clínico, duração do internamento hospitalar e do internamento na unidade de cuidados intensivos semelhantes, mas menor mortalidade intra-hospitalar (6.4% [95% CI: 3.8­9.6%] vs. 35.8% [95% CI: 23.9­48.5%]). A terapêutica endoscópica por vácuo associou-se a menor taxa de complicações (OR 0.348 [95% CI: 0.127­0.954]), menor duração do internamento na UCI (diferença média −14.77 dias [95% CI: −26.57 to −2.98]) e do tempo até resolução da DA (17.6 dias [95% CI: 14.1­21.2] vs. 39.4 dias [95% CI: 27.0­51.8]) quando comparada com as próteses endoscópicas, mas não houve diferenças significativas em termos de sucesso clínico, mortalidade, reintervenções ou duração do internamento hospitalar. Conclusões: O tratamento endoscópico, em particular a terapêutica endoscópica por vácuo parece ser mais segura e efetiva em comparação com a cirurgia. Porém, estudos comparativos mais robustos são necessários, especialmente para clarificar qual o melhor tratamento em situações específicas (consoante as caraterísticas do paciente e da deiscência).

Anastomotic Leaks following Esophagectomy for Esophageal and Gastroesophageal Junction Cancer: The Key Is the Multidisciplinary Management.

Introduction: Anastomotic leakage after esophagectomy is associated with high mortality and impaired quality of life. Aim: The objective of this work was to determine the effectiveness of management of esophageal anastomotic leakage (EAL) after esophagectomy for esophageal and gastroesophageal junction (GEJ) cancer. Methods: Patients submitted to esophagectomy for esophageal and GEJ cancer at a tertiary oncology hospital between 2014 and 2019 (n = 119) were retrospectively reviewed and EAL risk factors and its management outcomes determined. Results: Older age and nodal disease were identified as independent risk factors for anastomotic leak (adjusted OR 1.06, 95% CI 1.00-1.13, and adjusted OR 4.89, 95% CI 1.09-21.8). Patients with EAL spent more days in the intensive care unit (ICU; median 14 vs. 4 days) and had higher 30-day mortality (15 vs. 2%) and higher in-hospital mortality (35 vs. 4%). The first treatment option was surgical in 13 patients, endoscopic in 10, and conservative in 3. No significant differences were noticeable between these patients, but sepsis and large leakages were tendentially managed by surgery. At follow-up, 3 patients in the surgery group (23%) and 9 in the endoscopic group (90%) were discharged under an oral diet (p = 0.001). The in-hospital mortality rate was 38% in the surgical group, 33% in the conservative group, and 10% in endoscopic group (p = 0.132). In patients with EAL, the presence of septic shock at leak diagnosis was the only predictor of mortality (p = 0.004). ICU length-of-stay was non-significantly lower in the endoscopic therapy group (median 4 days, vs. 16 days in the surgical group, p = 0.212). Conclusion: Risk factors for EAL may help change pre-procedural optimization. The results of this study suggest including an endoscopic approach for EAL.

Introdução: A deiscência anastomótica após esofagectomia está associada a uma elevada taxa de mortalidade e qualidade de vida comprometida. Objetivo: Avaliar a eficácia da abordagem da deiscência de anastomose esofágica após esofagectomia por neoplasia do esófago e da junção esofagogastrica (JEG). Métodos: Foram revistos retrospetivamente todos os doentes submetidos a esofagectomia por neoplasia do esófago e da JEG num hospital terciário entre 2014 e 2019 (n = 119) e analisados os fatores de risco e as diferentes abordagens na deiscência anastomótica. Resultados: A idade avançada e a presença de metastização ganglionar foram identificados como fatores de risco independentes para deiscência anastomótica (OR 1.06, 95% IC 1.00­1.13 e 4.89, IC 1.09­21.8). Os doentes com deiscência anastomótica estiveram mais dias internados na unidade de cuidados intensivos (UCI) (mediana 14 vs. 4 dias) e tiveram uma mortalidade aos 30 dias e intra-hospitalar mais elevada (15% vs. 2% e 35% vs. 4%, respectivamente). A primeira abordagem terapêutica foi cirúrgica em 13 doentes, endoscópica em 10 e conservadora em 3. Não foram encontradas diferenças estatisticamente significativas entre estes doentes, com uma tendência para a presença de sépsis e de deiscências de maior dimensão nos doentes abordados cirurgicamente. Durante o seguimento, 3 doentes do grupo cirúrgico (23%) e 9 do grupo endoscópico (90%) tiveram alta hospitalar sob dieta oral (p = 0.001). A taxa de mortalidade intra-hospitalar foi de 38% no grupo cirúrgico, 33% no grupo conservador e 10% no grupo endoscópico (p = 0.132). Nos doentes com deiscência anastomótica, a presença de choque sético ao diagnóstico foi o único preditor de mortalidade (p = 0.004). O tempo de internamento na UCI não foi significativamente menor no grupo submetido a tratamento endoscópico (mediana de 4 dias vs. 16 dias no grupo cirúrgico, p = 0.212). Conclusão: A identificação de fatores de risco para deiscência anastomótica após esofagectomia pode ajudar a alterar a optimização pré-procedimento. Os resultados deste estudo sugerem incluir uma abordagem endoscópica nos doentes com deiscência anastomótica.

Engineering graphene-based electrodes for optical neural stimulation.

Graphene-based materials (GBMs) have been investigated in recent years with the aim of developing flexible interfaces to address a range of neurological disorders, where electrical stimulation may improve brain function and tissue regeneration. The recent discovery that GBM electrodes can generate an electrical response upon light exposure has inspired the development of non-genetic approaches capable of selectively modulating brain cells without genetic manipulation (i.e., optogenetics). Here, we propose the conjugation of graphene with upconversion nanoparticles (UCNPs), which enable wireless transcranial activation using tissue-penetrating near-infrared (NIR) radiation. Following a design of experiments approach, we first investigated the influence of different host matrices and dopants commonly used to synthesize UCNPs in the electrical response of graphene. Two UCNP formulations achieving optimal enhancement of electrical conductivity upon NIR activation at λ = 780 or 980 nm were identified. These formulations were then covalently attached to graphene nanoplatelets following selective hydroxyl derivatization. The resulting nanocomposites were evaluated in vitro using SH-SY5Y human neuroblastoma cells. NIR activation at λ = 980 nm promoted cell proliferation and downregulated neuronal and glial differentiation markers, suggesting the potential application of GBMs in minimally invasive stimulation of cells for tissue regeneration.

Efficacy and safety after posterior chamber Implantable Collamer Lens implantation according to preoperative anterior chamber depth: Short-term comparative study.

PURPOSE: To compare visual, refractive, and safety outcomes of posterior chamber Implantable Collamer Lens (ICL) implantation for the correction of myopia according to the preoperative anterior chamber depth (ACD). METHODS: Retrospective, comparative study, patients submitted to implantation of myopic posterior-chamber phakic Implantable Collamer Lens (ICL), model V4C/V5, minimum follow-up of 12 months; two groups were created: Group 1 (ACD 2.80 to 2.99 mm) and Group 2 (ACD equal to or greater than 3.00 mm). The parameters evaluated were uncorrected and corrected visual acuity, subjective refraction, efficacy and safety index, predictability, endothelial cell density, central vault, anterior chamber angle and postoperative complications. A total of 558 eyes from 298 patients were evaluated: 111 eyes (19.9%) in group 1 and 447 eyes (80.1%) in group 2. RESULTS: At 12 months, the efficacy index was similar in both groups (p = 0.264); the safety index was higher in group 1 (p = 0.031); the mean central Vault was significantly lower in group 1 (212.8 vs 410.6 µm; p < 0.001). Respectively, 93 (83.8%) and 366 (84.1%) eyes were within ±0.50 D of targeted refraction. Anterior chamber angle significantly decreased during follow-up in both groups (p < 0.001; p < 0.001). Intraocular pressure did not change significantly (p = 0.310 and p = 0.446, respectively). There were no significant differences in endothelial cell density loss (p = 0.278) or in the rate of complications observed (p = 0.733). CONCLUSIONS: ICL implantation is an effective and safe procedure in eyes with shallow anterior chambers, with visual and refractive results and complication rates identical to those obtained in deeper anterior chambers.

DNA methylation is a comprehensive marker for pediatric adrenocortical tumors.

Children diagnosed with pediatric adrenocortical tumors (pACT) have variable outcomes, and, to date, the disease lacks robust prognostic biomarkers. The prognostic potential of tumor methylation has been demonstrated in several cancers. We aimed to evaluate the pACT methylation profile and its association with disease presentation and survival. In this cross-sectional study, we accessed the DNA methylation (MethylationEPIC Array, Illumina) of 57 primary pACT from Southeastern Brazil and the respective patients' clinicopathological features. We also applied our analysis in an independent 48 pACT methylation dataset. Unsupervised learning whole-methylome analysis showed two groups with distinct methylation signatures: pACT-1 and pACT-2. Compared to pACT-2, pACT-1 tumors were enriched with higher methylation in CpG islands, mainly in gene promoter regions. The topmost hypermethylated gene in these samples was shown to be underexpressed. Patients in the pACT-1 group were older at diagnosis and were more likely to have carcinomas and nonlocalized/advanced and recurrent/metastatic disease. Univariate and bivariate regressions showed that pACT-1 methylation signature confers superior hazard ratio of disease progression and death than known prognostic features. The methylation groups had similar frequencies of germline mutations in the TP53 gene, including the regionally frequent p.R337H. Our analysis replication validated our findings and reproduced those recently described in pACT. We demonstrated the existence of different tumor methylation signatures associated with pACT presentation and clinical evolution, even in the context of germline TP53 mutations. Our data support tumor methylation profiling as a robust and independent prognostic biomarker for pACT and suggest a list of candidate genes for further validation.

Shaping of Hepatic Ischemia/Reperfusion Events: The Crucial Role of Mitochondria.

Hepatic ischemia reperfusion injury (HIRI) is a major hurdle in many clinical scenarios, including liver resection and transplantation. Various studies and countless surgical events have led to the observation of a strong correlation between HIRI induced by liver transplantation and early allograft-dysfunction development. The detrimental impact of HIRI has driven the pursuit of new ways to alleviate its adverse effects. At the core of HIRI lies mitochondrial dysfunction. Various studies, from both animal models and in clinical settings, have clearly shown that mitochondrial function is severely hampered by HIRI and that its preservation or restoration is a key indicator of successful organ recovery. Several strategies have been thus implemented throughout the years, targeting mitochondrial function. This work briefly discusses some the most utilized approaches, ranging from surgical practices to pharmacological interventions and highlights how novel strategies can be investigated and implemented by intricately discussing the way mitochondrial function is affected by HIRI.

PEG35 as a Preconditioning Agent against Hypoxia/Reoxygenation Injury.

Pharmacological conditioning is a protective strategy against ischemia/reperfusion injury, which occurs during liver resection and transplantation. Polyethylene glycols have shown multiple benefits in cell and organ preservation, including antioxidant capacity, edema prevention and membrane stabilization. Recently, polyethylene glycol 35 kDa (PEG35) preconditioning resulted in decreased hepatic injury and protected the mitochondria in a rat model of cold ischemia. Thus, the study aimed to decipher the mechanisms underlying PEG35 preconditioning-induced protection against ischemia/reperfusion injury. A hypoxia/reoxygenation model using HepG2 cells was established to evaluate the effects of PEG35 preconditioning. Several parameters were assessed, including cell viability, mitochondrial membrane potential, ROS production, ATP levels, protein content and gene expression to investigate autophagy, mitochondrial biogenesis and dynamics. PEG35 preconditioning preserved the mitochondrial function by decreasing the excessive production of ROS and subsequent ATP depletion, as well as by recovering the membrane potential. Furthermore, PEG35 increased levels of autophagy-related proteins and the expression of genes involved in mitochondrial biogenesis and fusion. In conclusion, PEG35 preconditioning effectively ameliorates hepatic hypoxia/reoxygenation injury through the enhancement of autophagy and mitochondrial quality control. Therefore, PEG35 could be useful as a potential pharmacological tool for attenuating hepatic ischemia/reperfusion injury in clinical practice.

Relationships between type and duration of training and well-being status of volleyball athletes / Relações entre tipo e duração do treinamento e status de bem-estar de atletas de voleibol

ABSTRACT The purpose of this study was to describe weekly variations in the type and duration of training, as well as wellness-related parameters, in elite volleyball players. Twenty-four youth elite volleyball players from the French national team (age: 17.8 ± 1.0 y.o.) were monitored daily, and the type of training, training duration, participation in matches, and wellness status were measured over 22 weeks. Volleyball training duration varied from 100 to 510 minutes per week, while strength and conditioning training duration varied from 97 to 262 minutes per week. Fatigue levels varied from 1.5 to 2.8 A.U., and delayed onset muscle soreness (DOMS) varied from 1.5 to 2.5 A.U. Large positive correlation were found between sleep and match duration (r = 0.64) and between stress and weekly volume (r = 0.52). Additionally, moderate positive correlation were found between fatigue and match duration (r = 0.36); between sleep and weekly volume (r = 0.35); between DOMS and match duration (r = 0.43); between stress and strength training (r = 0.42), volleyball training (r = 0.35), and match duration (r = 0.47). The present study revealed natural variations in training volume across the season and moderate dependency between weekly training/match durations and wellness status.

RESUMO O objetivo deste estudo foi descrever as variações semanais no tipo e duração do treinamento, bem como parâmetros relacionados ao bem-estar, em jogadores de elite de voleibol. Vinte e quarto jovens jogadores de elite de voleibol da seleção Francesa (idade: 17,8 ± 1,0 anos) foram monitorados diariamente, e o tipo de treinamento, a duração do treinamento, a participação em partidas e o status de bem-estar foram medidos durante 22 semanas. A duração do treinamento de voleibol variou de 100 a 510 minutos por semana, enquanto a duração do treinamento de força e condicionamento variou de 97 a 262 minutos por semana. Os níveis de fadiga variaram de 1,5 a 2,8 A.U., e a dor muscular tardia (DMT) variou de 1,5 a 2,5 A.U. Correlação positiva grande foi encontrada entre sono e duração do jogo (r = 0,64) e entre estresse e volume semanal (r = 0,52). Além disso, uma correlação positiva moderada foi encontrada entre fadiga e duração da partida (r = 0,36), entre sono e volume semanal (r = 0,35), entre DMT e duração da partida (r = 0,43), entre estresse e treinamento de força (r = 0,42), treinamento de voleibol (r = 0,35), e duração da partida (r = 0,47). O presente estudo revelou variações naturais no volume de treinamento ao longo da temporada e dependência moderada entre treinamento semanal/duração da partida e status de bem-estar.

Neuroprotective Properties of Food-Borne Polyphenols in Neurodegenerative Diseases.

Fruits and vegetables are the richest source of polyphenols in the regular human diet [...].

Localisation in focal epilepsy: a practical guide.

The semiology of epileptic seizures reflects activation, or dysfunction, of areas of brain (often termed the symptomatogenic zone) as a seizure begins and evolves. Specific semiologies in focal epilepsies provide an insight into the location of the seizure onset zone, which is particularly important for presurgical epilepsy assessment. The correct diagnosis of paroxysmal events also depends on the clinician being familiar with the spectrum of semiologies. Here, we summarise the current literature on localisation in focal epilepsies using illustrative cases and discussing possible pitfalls in localisation.

Role of PEG35, Mitochondrial ALDH2, and Glutathione in Cold Fatty Liver Graft Preservation: An IGL-2 Approach.

The total damage inflicted on the liver before transplantation is associated with several surgical manipulations, such as organ recovery, washout of the graft, cold conservation in organ preservation solutions (UW, Celsior, HTK, IGL-1), and rinsing of the organ before implantation. Polyethylene glycol 35 (PEG35) is the oncotic agent present in the IGL-1 solution, which is an alternative to UW and Celsior solutions in liver clinical transplantation. In a model of cold preservation in rats (4 °C; 24 h), we evaluated the effects induced by PEG35 on detoxifying enzymes and nitric oxide, comparing IGL-1 to IGL-0 (which is the same as IGL-1 without PEG). The benefits were also assessed in a new IGL-2 solution characterized by increased concentrations of PEG35 (from 1 g/L to 5 g/L) and glutathione (from 3 mmol/L to 9 mmol/L) compared to IGL-1. We demonstrated that PEG35 promoted the mitochondrial enzyme ALDH2, and in combination with glutathione, prevented the formation of toxic aldehyde adducts (measured as 4-hydroxynonenal) and oxidized proteins (AOPP). In addition, PEG35 promoted the vasodilator factor nitric oxide, which may improve the microcirculatory disturbances in steatotic grafts during preservation and revascularization. All of these results lead to a reduction in damage inflicted on the fatty liver graft during the cold storage preservation. In this communication, we report on the benefits of IGL-2 in hypothermic static preservation, which has already been proved to confer benefits in hypothermic oxygenated dynamic preservation. Hence, the data reported here reinforce the fact that IGL-2 is a suitable alternative to be used as a unique solution/perfusate when hypothermic static and preservation strategies are used, either separately or combined, easing the logistics and avoiding the mixture of different solutions/perfusates, especially when fatty liver grafts are used. Further research regarding new therapeutic and pharmacological insights is needed to explore the underlying mitochondrial mechanisms exerted by PEG35 in static and dynamic graft preservation strategies for clinical liver transplantation purposes.

Advanced Carbon-Nickel Sulfide Hybrid Nanostructures: Extending the Limits of Battery-Type Electrodes for Redox-Based Supercapacitor Applications.

Transition-metal sulfides combined with conductive carbon nanostructures are considered promising electrode materials for redox-based supercapacitors due to their high specific capacity. However, the low rate capability of these electrodes, still considered "battery-type" electrodes, presents an obstacle for general use. In this work, we demonstrate a successful and fast fabrication process of metal sulfide-carbon nanostructures ideal for charge-storage electrodes with ultra-high capacity and outstanding rate capability. The novel hybrid binder-free electrode material consists of a vertically aligned carbon nanotube (VCN), terminated by a nanosized single-crystal metallic Ni grain; Ni is covered by a nickel nitride (Ni3N) interlayer and topped by trinickel disulfide (Ni3S2, heazlewoodite). Thus, the electrode is formed by a Ni3S2/Ni3N/Ni@NVCN architecture with a unique broccoli-like morphology. Electrochemical measurements show that these hybrid binder-free electrodes exhibit one of the best electrochemical performances compared to the other reported Ni3S2-based electrodes, evidencing an ultra-high specific capacity (856.3 C g-1 at 3 A g-1), outstanding rate capability (77.2% retention at 13 A g-1), and excellent cycling stability (83% retention after 4000 cycles at 13 A g-1). The remarkable electrochemical performance of the binder-free Ni3S2/Ni3N/Ni@NVCN electrodes is a significant step forward, improving rate capability and capacity for redox-based supercapacitor applications.

Paraneoplastic giant cell arteritis and prostate cancer: A case report of a not common association.

GCA is not always a linear diagnosis. Rarely reported as a paraneoplastic condition when associated with solid tumors, the available cases are associated with poor response to corticosteroids.

Epidural blood patch for the treatment of liquor hypotension after intrathecal chemotherapy in a 10-year-old: case report.

BACKGROUND AND OBJECTIVES: An epidural blood patch is used to treat postdural puncture and liquor hypotension headache. We report the use of an epidural blood patch in a critical pediatric patient. CASE REPORT: A 10-year-old girl with acute leukemia developed venous cerebral thrombosis with hemorrhagic transformation one month after intrathecal chemotherapy. Given the unusual clinical and imagiological evolution even after decompressive craniectomy, we suspected cerebrospinal fluid hypotension. Spine imaging revealed signs of post-lumbar puncture fistula; we hence performed a blind blood patch. CONCLUSIONS: Recognizing cerebrospinal fluid hypotension in critical pediatric patients is important. Less-conventional life-saving measures, such as a blind blood patch, may be considered in such patients.

Development and application of an HPLC-DAD technique for human plasma concentration monitoring of perampanel and lamotrigine in drug-resistant epileptic patients.

Perampanel is a third-generation antiepileptic drug (AED), while lamotrigine is a second-generation AED. Both drugs are subject to extensive pharmacokinetic variability between different patients. Furthermore, it has been reported that perampanel and lamotrigine may be implied in pharmacokinetic drug-drug interactions with other AEDs such as carbamazepine or valproate, with consequent alterations of plasma concentrations. This emphasizes the relevance of therapeutic drug monitoring of perampanel and lamotrigine with appropriate bioanalytical methods. Herein, the development and validation of a bioanalytical techique for the simultaneous quantification of perampanel and lamotrigine in human plasma samples is described. The reported method is based on high-performance liquid chromatography coupled with diode-array detection (HPLC-DAD) and sample preparation consists of liquid-liquid extraction. Chromatographic separation of the analytes (lamotrigine and perampanel) and the internal standard (entacapone) was achieved in 12 min on a reversed-phase C18 column at 40 °C by applying a gradient elution program with a mobile phase composed of 0.1% ortho-phosphoric acid pH 2.79 (A) and acetonitrile (B) pumped at 1.0 mL/min. Perampanel was quantified at 320 nm while lamotrigine and the internal standard were monitored at 306 nm. Calibration curves were linear in the concentration range of 0.03-4.5 µg/mL (r2 = 0.9978) for perampanel and in the concentration range of 0.25-30 µg/mL (r2 = 0.9981) for lamotrigine. Overall precision did not exceed 14.3% and accuracy ranged from -6.08 to 12.66%. Some drugs potentially co-prescribed with perampanel and lamotrigine were tested and did not interfere with the retention times of the analytes and internal standard. The method was then successfully applied for the quantification of perampanel and lamotrigine in plasma samples obtained from 42 drug-resistant epileptic patients admitted to the Coimbra University Hospital Centre (CHUC.EPE, Coimbra, Portugal). In conclusion, it is a suitable method for the therapeutic drug monitoring of lamotrigine and perampanel in drug-resistant epileptic patients, as well as, for the assessment of drug-drug interactions. It can also be adopted by hospitals and laboratories, when HPLC with fluorescence and mass spectrometry detections are unavailable.

Label-Free Iron Oxide Nanoparticles as Multimodal Contrast Agents in Cells Using Multi-Photon and Magnetic Resonance Imaging.

INTRODUCTION: The inherent fluorescence properties of iron oxide nanoparticles (IONPs) were characterized, and their applicability for multiphoton imaging in cells was tested in combination with their magnetic resonance imaging (MRI) capabilities. METHODS: Superparamagnetic iron oxide nanoparticles were synthesized and subsequently coated with polyethylene glycol to make them water-dispersible. Further characterization of the particles was performed using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), dynamic light scattering (DLS), superconducting quantum interference device (SQUID) and magnetic resonance relaxivity measurements. MRI and fluorescence properties of bare IONPs were first studied in solution and subsequently in A549-labeled cells. RESULTS: The particles, with a core size of 11.3 ± 4.5 nm, showed a good negative MRI contrast in tissue-mimicking phantoms. In vitro studies in mammalian A549 cells demonstrate that these IONPs are biocompatible and can also produce significant T2/T2* contrast enhancement in IONPs-labeled cells. Furthermore, excitation-wavelength dependent photoluminescence was observed under one- and two-photon excitation. DISCUSSION: The obtained results indicated that IONPs could be used for fluorescence label-free bioimaging at multiple wavelengths, which was proven by multiphoton imaging of IONPs internalization in A549 cancer cells.