Plaques of amyloid-β(Aβ)and neurofibrillary tangles are the main pathological characteristics of Alzheimer’s disease(AD).However,some older adult people with AD pathological hallmarks can retain cognitive function....Plaques of amyloid-β(Aβ)and neurofibrillary tangles are the main pathological characteristics of Alzheimer’s disease(AD).However,some older adult people with AD pathological hallmarks can retain cognitive function.Unraveling the factors that lead to this cognitive resilience to AD offers promising prospects for identifying new therapeutic targets.Our hypothesis focuses on the contribution of resilience to changes in excitatory synapses at the structural and molecular levels,which may underlie healthy cognitive performance in aged AD animals.Utilizing the Morris Water Maze test,we selected resilient(asymptomatic)and cognitively impaired aged Tg2576 mice.While the enzyme-linked immunosorbent assay showed similar levels of Aβ42 in both experimental groups,western blot analysis revealed differences in tau pathology in the pre-synaptic supernatant fraction.To further investigate the density of synapses in the hippocampus of 16-18 month-old Tg2576 mice,we employed stereological and electron microscopic methods.Our findings indicated a decrease in the density of excitatory synapses in the stratum radiatum of the hippocampal CA1 in cognitively impaired Tg2576 mice compared with age-matched resilient Tg2576 and non-transgenic controls.Intriguingly,through quantitative immunoelectron microscopy in the hippocampus of impaired and resilient Tg2576 transgenic AD mice,we uncovered differences in the subcellular localization of glutamate receptors.Specifically,the density of GluA1,GluA2/3,and mGlu5 in spines and dendritic shafts of CA1 pyramidal cells in impaired Tg2576 mice was significantly reduced compared with age-matched resilient Tg2576 and non-transgenic controls.Notably,the density of GluA2/3 in resilient Tg2576 mice was significantly increased in spines but not in dendritic shafts compared with impaired Tg2576 and non-transgenic mice.These subcellular findings strongly support the hypothesis that dendritic spine plasticity and synaptic machinery in the hippocampus play crucial roles in the mechanisms of cognitive resilience in Tg2576 mice.展开更多
Obesity has been growing worldwide, reaching epidemic proportions. Bariatric surgery is the most effective and durable treatment for severe obesity and related diseases. Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gast...Obesity has been growing worldwide, reaching epidemic proportions. Bariatric surgery is the most effective and durable treatment for severe obesity and related diseases. Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG) are the most frequently performed bariatric operations, with long-term good results, in terms of weight loss and comorbidities control. Gastroesophageal Reflux Disease (GERD) is commonly associated with obesity. In general, it precludes the indication of sleeve gastrectomy, since this technique has a refluxogenic potential, as shown in many studies. In such cases, RYGB is considered the best surgery, reaching good weight loss and gastroesophageal reflux disease control. The drawback of this technique is that it leaves the remnant stomach, the duodenum, and the proximal part of the jejunum inaccessible. Besides, RYGB makes transoral endoscopic access to the biliary tree impossible. For all these reasons, this bariatric technique is not indicated in cases of gastric polyposis, gastric dysplasia, or strong family history of cancer, among others. We report a case of a morbidly obese patient with intense GERD, for whom a RYGB was precluded due to her strong family history of cancer, even knowing that it would be the best choice for reflux disease control. Instead, SG was chosen, even knowing it could worsen the gastroesophageal reflux disease. The patient signed an informed consent, after being fully enlightened about the risks. During the surgery, a small subserosal whitish lesion was detected, near the pylorus, on the anterior wall of the antrum. Thinking in a Gastrointestinal Stromal Tumor (GIST), it was resected, with a 2 cm safety margin, leaving a 4 to 5 cm hole on the gastric wall. The decision to maintain the proposed sleeve gastrectomy was made, to avoid leaving a remnant stomach, in a patient with such a strong family history of cancer. In the area of the resected lesion, an intraoperative decision was made not to just close the big gastric hole, being afraid of causing some anatomic or functional disturbance in gastric emptying. Instead, we decided to use the gastric opening to construct a Roux-en-Y antrotrojejunal anastomosis, with a 50 cm alimentary limb and a 200 cm biliopancreatic limb. Accordingly, it was performed a sleeve gastrectomy, associated with an antrojejunostomy in a Roux-en-Y fashion. The patient had an uneventful postoperative course. In the second year, she achieved normal weight and good nutritional status, without gastroesophageal reflux symptoms complaints. Seriography study shows that most of the contrast material passes through the antrojejunal anastomosis, instead of the pylorus, while the duodenum is endoscopically patent. This case report shows an unexpected surgical finding that led to a tactic of adding a Roux-en-Y gastric bypass in the antrum, associated with a sleeve gastrectomy, a strategy that may be adopted in cases of morbidly obese patients with important GERD, for whom gastrointestinal exclusions are contraindicated. To confirm this hypothesis, controlled studies are needed.展开更多
Primary canalicular bile undergoes a process of fluidization and alkalinization along the biliary tract that is influenced by several factors including hormones, innervation/neuropeptides, and biliary constituents. Th...Primary canalicular bile undergoes a process of fluidization and alkalinization along the biliary tract that is influenced by several factors including hormones, innervation/neuropeptides, and biliary constituents. The excretion of bicarbonate at both the canaliculi and the bile ducts is an important contributor to the generation of the so-called bile-salt independent flow. Bicarbonate is secreted from hepatocytes and cholangiocytes through parallel mechanisms which involve chloride efflux through activation of Cl- channels, and further bicarbonate secretion via AE2/SLC4A2-mediated Cl-/HCO3- exchange. Glucagon and secretin are two relevant hormones which seem to act very similarly in their target cells (hepatocytes for the former and cholangiocytes for the latter). These hormones interact with their specific G protein-coupled receptors, causing increases in intracellular levels of cAMP and activation of cAMP-dependent Cl- and HCO3- secretory mechanisms. Both hepatocytes and cholangiocytes appear to have cAMP-responsive intracellular vesicles in which AE2/SLC4A2 colocalizes with cell specific Cl- channels (CFTR in cholangiocytes and not yet determined in hepatocytes) and aquaporins (AQP8 in hepatocytes and AQP1 in cholangiocytes), cAMP-induced coordinated trafficking of these vesicles to either canalicular or cholangiocyte lumenal membranes and further exocytosis results in increased osmotic forces and passive movement of water with net bicarbonate-rich hydrocholeresis.展开更多
AIM: To review the initial presentation and demonstrate the importance of Takotsubo cardiomyopathy. METHODS: A PubMed search using the terms "Takotsubo cardiomyopathy (TC)" and "apical ballooning syndro...AIM: To review the initial presentation and demonstrate the importance of Takotsubo cardiomyopathy. METHODS: A PubMed search using the terms "Takotsubo cardiomyopathy (TC)" and "apical ballooning syndrome" yield 211 publications. Only those that were relevant were fully reviewed. The gender, age, precipitating stressor, main complaint at presentation, electrocardiogram (ECG) at admission and serum cardiac markers of patients diagnosed with TC, were extracted as available. The data were organized in tables and graphics, and the incidence of the disorder was calculated and analyzed. RESULTS: A total of 250 clinical cases were examined. The predominant gender that was affected was female, with a prevalence of 87.5%. The mean age of presentation was 64±14 years. The cases were divided by age into 10-year intervals. The age interval of 60-69 years showed the highest frequency of TC, accounting for 79 cases. The most common precipitating stressor was physical (50% of cases). Chest pain wasthe primary complaint at presentation (58.8% of cases) followed by dyspnea (30% of cases). The ST segment changes category was the most common (60%), followed by T wave changes (39.6%). Of the 60% of cases with ST segment changes, 12% had concomitant T wave changes. This means that for 27.6% of the cases, the primary abnormality in the ECG was T wave changes; 87.6% of cases with TC had a change in the ST segment, in the T wave or in both. The percentage of ECGs presenting with changes in the anterior wall was 54.4% (35.6% of ST segment elevation +1.6% of ST segment depression +17.2% of T wave inversion). The percentage of patients presenting with changes in the lateral segment of the heart was 46.8%, while the percentage of patients with changes in the inferior heart was 21.6% and the percentage of patients with changes in the apical region was only 16%. The prevalence of elevated creatinine kinase and/or troponin on initial presentation was 89.3%. CONCLUSION: It is essential that every physician consider Takotsubo cardiomyopathy as a possible differential diagnosis when a patient is classified with acute coronary syndrome. To do so, it is necessary to know the clinical presentation of this syndrome in its early stages.展开更多
Gene therapy offers a new approach for treatment of cancer. Transfer of genes encoding immunostimulatory cytokines has been used with remarkable success to eliminate cancer in animals. However, clinical trials in pati...Gene therapy offers a new approach for treatment of cancer. Transfer of genes encoding immunostimulatory cytokines has been used with remarkable success to eliminate cancer in animals. However, clinical trials in patients with this strategy had limited efficacy. Therefore, improvement ofgene transfer vector system is necessary. A hybrid viral vector, consisting of SFV replicon with either murine IL-12 or reporter LacZ gene, was constructed. This hybrid vector showed specificity and high level of expression in HCC both in vitro and in vivo. In a rat orthotropic liver tumor model, treatment of established tumors by the hybrid vector with raiL- 12 gene resulted in a strong anti-tumor activity without accompanying toxicity. Subsequently, a helper-dependent adenovirus vectors containing a mifepristone (RU486) inducible system was constructed for controlled and liver-specific expression of human interleukin 12 (hIL- 12) (HD-Ad/RUhIL- 12) and mouse IL-12 (mIL-12) (HD-Ad/RUmIL-12). Data showed that high and sustained serum levels of hlL-12 could be attained by continuing administration of RU486 every 12 or 24 h. Repetitive induction ofhlL-12 could be obtained over, at least, a period of 48 weeks after a single injection of HD-Ad/RUhlL-12. Treatment of liver metastases with of HD-Ad/RUmIL- 12 plus RU846 resulted in complete tumor regression in all animals. Then, different cytokine genes were inserted into conditional replicative adenoviruses vectors (also called oncolytic adenovirus). Replication ofadenovirus in tumor cells would kill tumor cells and release viruses, which infect surrounding tumor cells. The combination of cytopathic effect by oncolytic adenovirus and biological effect of transgene would exert strong antitumor activity. These new types of vectors may provide a potent and safe tool for cancer gene therapy.展开更多
Wilson's disease(WD), which results from the defective ATP7 B protein product, is characterized by impaired copper metabolism and its clinical consequences vary from an asymptomatic state to fulminant hepatic fail...Wilson's disease(WD), which results from the defective ATP7 B protein product, is characterized by impaired copper metabolism and its clinical consequences vary from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurological, and psychiatric manifestations. A high grade of suspicion is warranted to not miss cases of WD, especially less florid cases with only mild elevation of transaminases, or isolated neuropsychiatric involvement. Screening in first and second relatives of index cases is mandatory, and treatment must commence upon establishment of diagnosis. Treatment strategies include chelators such as D-penicillamine and trientine, while zinc salts act as inductors of methallothioneins, which favor a negative copper balance and a reduction of free plasmatic copper. As an orphan disease, research is lacking in this field, especially regarding therapeutic strategies which are associated with better patient compliance and which could eventually also reverse established injury.展开更多
Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal ofintrons and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that...Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal ofintrons and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that allows the alternative usage of exons, the retention ofintronic sequences and the generation of exonic sequences of variable length. Most human genes undergo splicing events, and disruptions of this process have been associated with a variety of diseases, including cancer. Hepatocellular carcinoma (HCC) is a molecularly heterogeneous type of tumor that usually develops in a cirrhotic liver. Alterations in pre-mRNA splicing of some genes have been observed in liver cancer, and although still scarce, the available data suggest that splicing defects may have a role in hepatocarcinogenesis. Here we briefly review the general mechanisms that regulatepre-mRNA splicing, and discuss some examples that illustrate how this process is impaired in liver tumorigenesis, and may contribute to HCC development. We believe that a more thorough examination of pre-mRNA splicing is still needed to accurately draw the molecular portrait of liver cancer. This will surely contribute to a better understanding of the disease and to the development of new effective therapies.展开更多
Hepatitis delta virus(HDV) seems to strongly suppress hepatitis B virus(HBV)replication, although little is known about the mechanism of this interaction. Both these viruses show a dynamic distribution of mutants, res...Hepatitis delta virus(HDV) seems to strongly suppress hepatitis B virus(HBV)replication, although little is known about the mechanism of this interaction. Both these viruses show a dynamic distribution of mutants, resulting in viral quasispecies. Next-generation sequencing is a viable approach for analyzing the composition of these mutant spectra. As the regulatory hepatitis B X protein(HBx) is essential for HBV replication, determination of HBV X gene(HBX)quasispecies complexity in HBV/HDV infection compared to HBV monoinfection may provide information on the interactions between these two viruses.AIM To compare HBV quasispecies complexity in the HBX 5' region between chronic hepatitis delta(CHD) and chronic HBV mono-infected patients.METHODS Twenty-four untreated patients were included: 7/24(29.2%) with HBeAgnegative chronic HBV infection(CI, previously termed inactive carriers), 8/24(33.3%) with HBeAg-negative chronic hepatitis B(CHB) and 9/24(37.5%) with CHD. A serum sample from each patient was first tested for HBV DNA levels.The HBX 5' region [nucleotides(nt) 1255-1611] was then PCR-amplified for subsequent next-generation sequencing(MiSeq, Illumina, United States). HBV quasispecies complexity in the region analyzed was evaluated using incidencebased indices(number of haplotypes and number of mutations), abundancebased indices(Hill numbers of order 1 and 2), and functional indices(mutation frequency and nucleotide diversity). We also evaluated the pattern of nucleotide changes to investigate which of them could be the cause of the quasispecies complexity.RESULTS CHB patients showed higher median HBV-DNA levels [5.4 logIU/mL,interquartile range(IQR) 3.5-7.9] than CHD(3.4 logIU/mL, IQR 3-7.6)(P = n.s.)or CI(3.2 logIU/mL, IQR 2.3-3.5)(P < 0.01) patients. The incidence and abundance indices indicated that HBV quasispecies complexity was significantly greater in CI than CHB. A similar trend was observed in CHD patients, although only Hill numbers of order 2 showed statistically significant differences(CHB2.81, IQR 1.11-4.57 vs CHD 8.87, 6.56-11.18, P = 0.038). There were no significant differences in the functional indices, but CI and CHD patients also showed a trend towards greater complexity than CHB. No differences were found for any HBV quasispecies complexity indices between CHD and CI patients. G-to-A and C-to-T nucleotide changes, characteristic of APOBEC3 G, were higher in CHD and CI than in CHB in genotype A haplotypes, but not in genotype D. The proportion of nt G-to-A vs A-to-G changes and C-to-T vs T-to-C changes in genotype A and D haplotypes in CHD patients showed no significant differences. In CHB and CI the results of these comparisons were dependent on HBV genotype.CONCLUSION The lower-replication CHD and CI groups show a trend to higher quasispecies complexity than the higher-replication CHB group. The mechanisms associated with this greater complexity require elucidation.展开更多
Colorectal cancer constitutes one of the most common malignancies and the second leading cause of death from cancer in the western world representing one million new cases and half a million deaths annually worldwide....Colorectal cancer constitutes one of the most common malignancies and the second leading cause of death from cancer in the western world representing one million new cases and half a million deaths annually worldwide. The treatment of patients with metastatic colon cancer comprises different regimens of chemotherapeutic compounds (fluoropyrimidines, irinotecan and oxaliplatin) and new targeted therapies. Interestingly, most recent trials that attempt to expose patients to all five-drug classes (fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and cetuximab) achieve an overall survival well over 2 years. In this review we will focus on the main epidermal growth factor receptor inhibitors demonstrating clinical benefit for colorectal cancer mainly cetuximab, panitumumab, erlotinib and gefltinib. We will also describe briefly the molecular steps that lie beneath them and the different clinical or molecular mechanisms that are reported for resistance and response.展开更多
Abundances of the fireworm Hermodice carunculata were counted through a monitoring assessment study of fish cages in Barranco Hondo(NE Tenerife). Seven campaigns were conducted from November 2007 to June 2010 and te...Abundances of the fireworm Hermodice carunculata were counted through a monitoring assessment study of fish cages in Barranco Hondo(NE Tenerife). Seven campaigns were conducted from November 2007 to June 2010 and temporal variations were found, as well as differences among sampling stations. The polychaete H. carunculata obtained its highest abundance in sediments beneath fish cages throughout the study period. Thus, the assemblages of this omnivorous species were favoured by the presence of fish cages.展开更多
The prolonged mei-yu/baiu system with anomalous precipitation in the year 2020 has swollen many rivers and lakes,caused flash flooding,urban flooding and landslides,and consistently wreaked havoc across large swathes ...The prolonged mei-yu/baiu system with anomalous precipitation in the year 2020 has swollen many rivers and lakes,caused flash flooding,urban flooding and landslides,and consistently wreaked havoc across large swathes of China,particularly in the Yangtze River basin.Significant precipitation and flooding anomalies have already been seen in magnitude and extension so far this year,which have been exerting much higher pressure on emergency responses in flood control and mitigation than in other years,even though a rainy season with multiple ongoing serious flood events in different provinces is not that uncommon in China.Instead of delving into the causes of the uniqueness of this year’s extreme precipitation-flooding situation,which certainly warrants in-depth exploration,in this article we provide a short view toward a more general hydrometeorological solution to this annual nationwide problem.A“glocal”(global to local)hydrometeorological solution for floods(GHS-F)is considered to be critical for better preparedness,mitigation,and management of different types of significant precipitation-caused flooding,which happen extensively almost every year in many countries such as China,India and the United States.Such a GHS-F model is necessary from both scientific and operational perspectives,with the strength in providing spatially consistent flood definitions and spatially distributed flood risk classification considering the heterogeneity in vulnerability and resilience across the entire domain.Priorities in the development of such a GHS-F are suggested,emphasizing the user’s requirements and needs according to practical experiences with various flood response agencies.展开更多
Throughout the shores of the world, a confluence of different sources of pollution is common, e.g., through outlets releasing brine, industrial, and domestic sewage. In this study, we assessed whether a combined dispo...Throughout the shores of the world, a confluence of different sources of pollution is common, e.g., through outlets releasing brine, industrial, and domestic sewage. In this study, we assessed whether a combined disposal of domestic sewage and brine altered the patterns of abundance and assemblage structure of sub- tidal macrofauna inhabiting sandy seabeds on the south coast of Gran Canaria (Canary Islands, NE Atlantic Ocean). Samples were collected in two surveys (May 2008 and January 2009) at three distances (0, 15, and 30 m) away from the discharge point. Macrofaunal abundances showed different patterns with varying proximity from the disposal point in the two surveys. In May 2008, lower abundances were observed at 0 m (53.89±46.82 ind.) than at 15 m (120±91.7 ind.) and 30 m (283.89±189.33 ind.) away from the dis- posal point. In January 2009, however, higher abundances were observed at 0 m (131.33±58.69 ind.) than at 30 m (100±24.44 ind.) and 15 m (84.78±58.39 ind.) away from the disposal point. Significant differ- ences in macrofaunal assemblage structure were found with varying proximity from the discharge point in both surveys. The effect of proximity from the disposal point was confounded by changes in sedimen- tary composition between surveys, which contributed to explain differences in macrofaunal abundances and assemblage structure with varying proximity from the discharge point. As a result, confounding driver- s of macrofaunal assemblage structure, here, changes in sediment composition, accounted for changes in macrofaunal abundances and assemblage structure with varying proximity from a combined disposal point of brine and sewage.展开更多
A shallow subtidal (3 m deep) meiofaunal assemblage in Los Abrigos Bay, Tenerife, Canary Islands was sam- pled during May 2000-April 2001. The main aims were to (1) find temporal variations in meiofaunal assem- bl...A shallow subtidal (3 m deep) meiofaunal assemblage in Los Abrigos Bay, Tenerife, Canary Islands was sam- pled during May 2000-April 2001. The main aims were to (1) find temporal variations in meiofaunal assem- blage structure and overall abundance, as well as in the most abundant meiofaunal species throughout the study period, and (2) identify environmental variables (sedimentary composition, organic matter content, and total nitrogen) that better explain meiofaunal assemblage structure during the study year. The most abundant species were the nematodes Siphonolaimus sp. 2 and Catanema sp., which represented 46.2% of the overall meiofaunal abundances and varied significantly throughout the study duration. Overall meio- faunal abundance and the most abundant taxonomic groups (nematodes, copepods, and oligochaetes) showed significant temporal variations during the study period. Nematodes overwhelmingly dominated during the study period, ranging from 78% in May to 97.34% in February. Multivariate analyses showed seasonality in meiofaunal community structure during the study year, with the lowest abundances in May. Keywords: Meiofauna, assemblage structure, subtidal, Canary Islands, Atlantic Ocean展开更多
This study contributes with the first data on physical and taxonomical structure of macrofaunal assemblages of maerl beds from the Canary Islands. Maerl beds and Cymodocea nodosa meadows of the Canary Islands are cons...This study contributes with the first data on physical and taxonomical structure of macrofaunal assemblages of maerl beds from the Canary Islands. Maerl beds and Cymodocea nodosa meadows of the Canary Islands are considered biodiversity hot-spots in terms of taxonomic and functional biodiversity with a broad geographical and depth ranges. The authors have studied the structure of the macrofaunal assemblages on different habitat types (Cymodocea, Caulerpa, sabellid field, garden eel and maerl beds). Samples were taken at a range of depths between 14 and 46 m. Correlations were performed among abiotic variables (granulometry, organic matter, nitrogen and phosphates) and the most abundant taxa. Similarity analysis was performed to explore the patchiness of seabeds at a local scale. Significant differences were found in macrofaunal assemblages among seabed types, with highest abundances and lowest biodiversity in sabellid fields, where the sabellid Bispira viola dominated. The polychaetes Aponuphis bilineata and Chone filicauda and the mollusc Turritella brochii were the most abundant taxa on maerl beds. The mosaic of granulometric conditions would explain the associated macroinfaunal community structure and contribute to the creation of diversity on these relatively well preserved seabeds at a local scale.展开更多
Research was done with the objective of evaluating the quality of water supplied to the potable water system in Hidalgo Del Parral, which comes from two main supply sources: wells from "Valle del Verano", which pro...Research was done with the objective of evaluating the quality of water supplied to the potable water system in Hidalgo Del Parral, which comes from two main supply sources: wells from "Valle del Verano", which provide water to the east side of the city, and the Water Treatment Plant, which receives water from different mines and supplies the west side of the city. When this plant is overcome on its capacity of treatment, a part of the water from the mines is fed directly to the northwest part of the city. The metals lead (Pb), chromium (Cr), cadmium (Cd), zinc (Zn), and arsenic (As) were analyzed by atomic absorption (AA) technique, based on the United States Environmental Protection Agency (EPA) Method 7000B (Revision 2, February 2007). The digestion process was done according to the guidelines established in Method NMX-AA-051-SCFI-2001, Analysis of Water-Determination of Metals by Atomic Absorption, developed by the National Standardization Technical Committee for Environmental Protection (Mexico). The samples were collected from the following points: 13 wells and 2 re-pumping stations of "Valle del Verano", the inlet and outlet of the Water Treatment Plant, and domestic faucets. The east side of the city, supplied by the wells of "Valle del Verano", is metal-pollution free. The water that comes from the mines contains high concentrations of As, Zn, Cd and Pb, with levels that can get to 0.12, 32.6, 0.26 and 3.5 mg/L, respectively. This water pollution generated by mining can be concluded from the high levels found in the domestic samples in which, for several points, the concentrations exceed the parameters set by the current guideline. According to the results, it is vital to set a plan of remediation for the water that comes from the mines, because there is a great risk for health in the consumotion of this water.展开更多
基金supported by grant PID2021-125875OB-I00 funded by MCIN/AEI/10.13039/501100011033 and by"ERDF A way of making Europe"(to RL)supported by a grant from Junta de Comunidades de Castilla-La Mancha (SBPLY/21/180501/000064)+3 种基金Universidad de Castilla-La Mancha (2023-GRIN-34187)(to RL).Grant PID201 9-104921RB-I00/MCI/AEI/10.13039/501100011033 (to AGO)the Foundation for Applied Medical Research,the University of Navarra (Pamplona,Spain)for financial supporthe Asociación de Amigos of the University of Navarra for the grant (to SB)Margarita Salas fellowship from Ministerio de Universidades and Universidad de Castilla-La Mancha (to AMB)
文摘Plaques of amyloid-β(Aβ)and neurofibrillary tangles are the main pathological characteristics of Alzheimer’s disease(AD).However,some older adult people with AD pathological hallmarks can retain cognitive function.Unraveling the factors that lead to this cognitive resilience to AD offers promising prospects for identifying new therapeutic targets.Our hypothesis focuses on the contribution of resilience to changes in excitatory synapses at the structural and molecular levels,which may underlie healthy cognitive performance in aged AD animals.Utilizing the Morris Water Maze test,we selected resilient(asymptomatic)and cognitively impaired aged Tg2576 mice.While the enzyme-linked immunosorbent assay showed similar levels of Aβ42 in both experimental groups,western blot analysis revealed differences in tau pathology in the pre-synaptic supernatant fraction.To further investigate the density of synapses in the hippocampus of 16-18 month-old Tg2576 mice,we employed stereological and electron microscopic methods.Our findings indicated a decrease in the density of excitatory synapses in the stratum radiatum of the hippocampal CA1 in cognitively impaired Tg2576 mice compared with age-matched resilient Tg2576 and non-transgenic controls.Intriguingly,through quantitative immunoelectron microscopy in the hippocampus of impaired and resilient Tg2576 transgenic AD mice,we uncovered differences in the subcellular localization of glutamate receptors.Specifically,the density of GluA1,GluA2/3,and mGlu5 in spines and dendritic shafts of CA1 pyramidal cells in impaired Tg2576 mice was significantly reduced compared with age-matched resilient Tg2576 and non-transgenic controls.Notably,the density of GluA2/3 in resilient Tg2576 mice was significantly increased in spines but not in dendritic shafts compared with impaired Tg2576 and non-transgenic mice.These subcellular findings strongly support the hypothesis that dendritic spine plasticity and synaptic machinery in the hippocampus play crucial roles in the mechanisms of cognitive resilience in Tg2576 mice.
文摘Obesity has been growing worldwide, reaching epidemic proportions. Bariatric surgery is the most effective and durable treatment for severe obesity and related diseases. Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG) are the most frequently performed bariatric operations, with long-term good results, in terms of weight loss and comorbidities control. Gastroesophageal Reflux Disease (GERD) is commonly associated with obesity. In general, it precludes the indication of sleeve gastrectomy, since this technique has a refluxogenic potential, as shown in many studies. In such cases, RYGB is considered the best surgery, reaching good weight loss and gastroesophageal reflux disease control. The drawback of this technique is that it leaves the remnant stomach, the duodenum, and the proximal part of the jejunum inaccessible. Besides, RYGB makes transoral endoscopic access to the biliary tree impossible. For all these reasons, this bariatric technique is not indicated in cases of gastric polyposis, gastric dysplasia, or strong family history of cancer, among others. We report a case of a morbidly obese patient with intense GERD, for whom a RYGB was precluded due to her strong family history of cancer, even knowing that it would be the best choice for reflux disease control. Instead, SG was chosen, even knowing it could worsen the gastroesophageal reflux disease. The patient signed an informed consent, after being fully enlightened about the risks. During the surgery, a small subserosal whitish lesion was detected, near the pylorus, on the anterior wall of the antrum. Thinking in a Gastrointestinal Stromal Tumor (GIST), it was resected, with a 2 cm safety margin, leaving a 4 to 5 cm hole on the gastric wall. The decision to maintain the proposed sleeve gastrectomy was made, to avoid leaving a remnant stomach, in a patient with such a strong family history of cancer. In the area of the resected lesion, an intraoperative decision was made not to just close the big gastric hole, being afraid of causing some anatomic or functional disturbance in gastric emptying. Instead, we decided to use the gastric opening to construct a Roux-en-Y antrotrojejunal anastomosis, with a 50 cm alimentary limb and a 200 cm biliopancreatic limb. Accordingly, it was performed a sleeve gastrectomy, associated with an antrojejunostomy in a Roux-en-Y fashion. The patient had an uneventful postoperative course. In the second year, she achieved normal weight and good nutritional status, without gastroesophageal reflux symptoms complaints. Seriography study shows that most of the contrast material passes through the antrojejunal anastomosis, instead of the pylorus, while the duodenum is endoscopically patent. This case report shows an unexpected surgical finding that led to a tactic of adding a Roux-en-Y gastric bypass in the antrum, associated with a sleeve gastrectomy, a strategy that may be adopted in cases of morbidly obese patients with important GERD, for whom gastrointestinal exclusions are contraindicated. To confirm this hypothesis, controlled studies are needed.
基金the "UTE for CIMA project" as well as by a grant from the "Institute de Salud CarlosⅢ" (PI051098). J. M. B. has a grant from the Spanish Ministry of Science and Technology
文摘Primary canalicular bile undergoes a process of fluidization and alkalinization along the biliary tract that is influenced by several factors including hormones, innervation/neuropeptides, and biliary constituents. The excretion of bicarbonate at both the canaliculi and the bile ducts is an important contributor to the generation of the so-called bile-salt independent flow. Bicarbonate is secreted from hepatocytes and cholangiocytes through parallel mechanisms which involve chloride efflux through activation of Cl- channels, and further bicarbonate secretion via AE2/SLC4A2-mediated Cl-/HCO3- exchange. Glucagon and secretin are two relevant hormones which seem to act very similarly in their target cells (hepatocytes for the former and cholangiocytes for the latter). These hormones interact with their specific G protein-coupled receptors, causing increases in intracellular levels of cAMP and activation of cAMP-dependent Cl- and HCO3- secretory mechanisms. Both hepatocytes and cholangiocytes appear to have cAMP-responsive intracellular vesicles in which AE2/SLC4A2 colocalizes with cell specific Cl- channels (CFTR in cholangiocytes and not yet determined in hepatocytes) and aquaporins (AQP8 in hepatocytes and AQP1 in cholangiocytes), cAMP-induced coordinated trafficking of these vesicles to either canalicular or cholangiocyte lumenal membranes and further exocytosis results in increased osmotic forces and passive movement of water with net bicarbonate-rich hydrocholeresis.
文摘AIM: To review the initial presentation and demonstrate the importance of Takotsubo cardiomyopathy. METHODS: A PubMed search using the terms "Takotsubo cardiomyopathy (TC)" and "apical ballooning syndrome" yield 211 publications. Only those that were relevant were fully reviewed. The gender, age, precipitating stressor, main complaint at presentation, electrocardiogram (ECG) at admission and serum cardiac markers of patients diagnosed with TC, were extracted as available. The data were organized in tables and graphics, and the incidence of the disorder was calculated and analyzed. RESULTS: A total of 250 clinical cases were examined. The predominant gender that was affected was female, with a prevalence of 87.5%. The mean age of presentation was 64±14 years. The cases were divided by age into 10-year intervals. The age interval of 60-69 years showed the highest frequency of TC, accounting for 79 cases. The most common precipitating stressor was physical (50% of cases). Chest pain wasthe primary complaint at presentation (58.8% of cases) followed by dyspnea (30% of cases). The ST segment changes category was the most common (60%), followed by T wave changes (39.6%). Of the 60% of cases with ST segment changes, 12% had concomitant T wave changes. This means that for 27.6% of the cases, the primary abnormality in the ECG was T wave changes; 87.6% of cases with TC had a change in the ST segment, in the T wave or in both. The percentage of ECGs presenting with changes in the anterior wall was 54.4% (35.6% of ST segment elevation +1.6% of ST segment depression +17.2% of T wave inversion). The percentage of patients presenting with changes in the lateral segment of the heart was 46.8%, while the percentage of patients with changes in the inferior heart was 21.6% and the percentage of patients with changes in the apical region was only 16%. The prevalence of elevated creatinine kinase and/or troponin on initial presentation was 89.3%. CONCLUSION: It is essential that every physician consider Takotsubo cardiomyopathy as a possible differential diagnosis when a patient is classified with acute coronary syndrome. To do so, it is necessary to know the clinical presentation of this syndrome in its early stages.
文摘Gene therapy offers a new approach for treatment of cancer. Transfer of genes encoding immunostimulatory cytokines has been used with remarkable success to eliminate cancer in animals. However, clinical trials in patients with this strategy had limited efficacy. Therefore, improvement ofgene transfer vector system is necessary. A hybrid viral vector, consisting of SFV replicon with either murine IL-12 or reporter LacZ gene, was constructed. This hybrid vector showed specificity and high level of expression in HCC both in vitro and in vivo. In a rat orthotropic liver tumor model, treatment of established tumors by the hybrid vector with raiL- 12 gene resulted in a strong anti-tumor activity without accompanying toxicity. Subsequently, a helper-dependent adenovirus vectors containing a mifepristone (RU486) inducible system was constructed for controlled and liver-specific expression of human interleukin 12 (hIL- 12) (HD-Ad/RUhIL- 12) and mouse IL-12 (mIL-12) (HD-Ad/RUmIL-12). Data showed that high and sustained serum levels of hlL-12 could be attained by continuing administration of RU486 every 12 or 24 h. Repetitive induction ofhlL-12 could be obtained over, at least, a period of 48 weeks after a single injection of HD-Ad/RUhlL-12. Treatment of liver metastases with of HD-Ad/RUmIL- 12 plus RU846 resulted in complete tumor regression in all animals. Then, different cytokine genes were inserted into conditional replicative adenoviruses vectors (also called oncolytic adenovirus). Replication ofadenovirus in tumor cells would kill tumor cells and release viruses, which infect surrounding tumor cells. The combination of cytopathic effect by oncolytic adenovirus and biological effect of transgene would exert strong antitumor activity. These new types of vectors may provide a potent and safe tool for cancer gene therapy.
文摘Wilson's disease(WD), which results from the defective ATP7 B protein product, is characterized by impaired copper metabolism and its clinical consequences vary from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurological, and psychiatric manifestations. A high grade of suspicion is warranted to not miss cases of WD, especially less florid cases with only mild elevation of transaminases, or isolated neuropsychiatric involvement. Screening in first and second relatives of index cases is mandatory, and treatment must commence upon establishment of diagnosis. Treatment strategies include chelators such as D-penicillamine and trientine, while zinc salts act as inductors of methallothioneins, which favor a negative copper balance and a reduction of free plasmatic copper. As an orphan disease, research is lacking in this field, especially regarding therapeutic strategies which are associated with better patient compliance and which could eventually also reverse established injury.
基金Supported by The Agreement between FIMA and the "UTE project CIMA"Red Temática de Investigación Cooperativa en Cáncer RD06 00200061 (to Berasain C and ávila MA)Ciberehd (to Prieto J) from Instituto de Salud Carlos Ⅲ,Grants FIS PI070392 and PI070402 from Ministerio de Sanidad y Con-sumo
文摘Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal ofintrons and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that allows the alternative usage of exons, the retention ofintronic sequences and the generation of exonic sequences of variable length. Most human genes undergo splicing events, and disruptions of this process have been associated with a variety of diseases, including cancer. Hepatocellular carcinoma (HCC) is a molecularly heterogeneous type of tumor that usually develops in a cirrhotic liver. Alterations in pre-mRNA splicing of some genes have been observed in liver cancer, and although still scarce, the available data suggest that splicing defects may have a role in hepatocarcinogenesis. Here we briefly review the general mechanisms that regulatepre-mRNA splicing, and discuss some examples that illustrate how this process is impaired in liver tumorigenesis, and may contribute to HCC development. We believe that a more thorough examination of pre-mRNA splicing is still needed to accurately draw the molecular portrait of liver cancer. This will surely contribute to a better understanding of the disease and to the development of new effective therapies.
基金Supported by the Instituto de Salud Carlos Ⅲ,grants PI15/00856 and PI17/02233co-financed by the European Regional Development Fund(ERDF)
文摘Hepatitis delta virus(HDV) seems to strongly suppress hepatitis B virus(HBV)replication, although little is known about the mechanism of this interaction. Both these viruses show a dynamic distribution of mutants, resulting in viral quasispecies. Next-generation sequencing is a viable approach for analyzing the composition of these mutant spectra. As the regulatory hepatitis B X protein(HBx) is essential for HBV replication, determination of HBV X gene(HBX)quasispecies complexity in HBV/HDV infection compared to HBV monoinfection may provide information on the interactions between these two viruses.AIM To compare HBV quasispecies complexity in the HBX 5' region between chronic hepatitis delta(CHD) and chronic HBV mono-infected patients.METHODS Twenty-four untreated patients were included: 7/24(29.2%) with HBeAgnegative chronic HBV infection(CI, previously termed inactive carriers), 8/24(33.3%) with HBeAg-negative chronic hepatitis B(CHB) and 9/24(37.5%) with CHD. A serum sample from each patient was first tested for HBV DNA levels.The HBX 5' region [nucleotides(nt) 1255-1611] was then PCR-amplified for subsequent next-generation sequencing(MiSeq, Illumina, United States). HBV quasispecies complexity in the region analyzed was evaluated using incidencebased indices(number of haplotypes and number of mutations), abundancebased indices(Hill numbers of order 1 and 2), and functional indices(mutation frequency and nucleotide diversity). We also evaluated the pattern of nucleotide changes to investigate which of them could be the cause of the quasispecies complexity.RESULTS CHB patients showed higher median HBV-DNA levels [5.4 logIU/mL,interquartile range(IQR) 3.5-7.9] than CHD(3.4 logIU/mL, IQR 3-7.6)(P = n.s.)or CI(3.2 logIU/mL, IQR 2.3-3.5)(P < 0.01) patients. The incidence and abundance indices indicated that HBV quasispecies complexity was significantly greater in CI than CHB. A similar trend was observed in CHD patients, although only Hill numbers of order 2 showed statistically significant differences(CHB2.81, IQR 1.11-4.57 vs CHD 8.87, 6.56-11.18, P = 0.038). There were no significant differences in the functional indices, but CI and CHD patients also showed a trend towards greater complexity than CHB. No differences were found for any HBV quasispecies complexity indices between CHD and CI patients. G-to-A and C-to-T nucleotide changes, characteristic of APOBEC3 G, were higher in CHD and CI than in CHB in genotype A haplotypes, but not in genotype D. The proportion of nt G-to-A vs A-to-G changes and C-to-T vs T-to-C changes in genotype A and D haplotypes in CHD patients showed no significant differences. In CHB and CI the results of these comparisons were dependent on HBV genotype.CONCLUSION The lower-replication CHD and CI groups show a trend to higher quasispecies complexity than the higher-replication CHB group. The mechanisms associated with this greater complexity require elucidation.
文摘Colorectal cancer constitutes one of the most common malignancies and the second leading cause of death from cancer in the western world representing one million new cases and half a million deaths annually worldwide. The treatment of patients with metastatic colon cancer comprises different regimens of chemotherapeutic compounds (fluoropyrimidines, irinotecan and oxaliplatin) and new targeted therapies. Interestingly, most recent trials that attempt to expose patients to all five-drug classes (fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and cetuximab) achieve an overall survival well over 2 years. In this review we will focus on the main epidermal growth factor receptor inhibitors demonstrating clinical benefit for colorectal cancer mainly cetuximab, panitumumab, erlotinib and gefltinib. We will also describe briefly the molecular steps that lie beneath them and the different clinical or molecular mechanisms that are reported for resistance and response.
基金To the company Cultivos Marinos del Atlántico SL for logistic facilities and financial support throughout the present study
文摘Abundances of the fireworm Hermodice carunculata were counted through a monitoring assessment study of fish cages in Barranco Hondo(NE Tenerife). Seven campaigns were conducted from November 2007 to June 2010 and temporal variations were found, as well as differences among sampling stations. The polychaete H. carunculata obtained its highest abundance in sediments beneath fish cages throughout the study period. Thus, the assemblages of this omnivorous species were favoured by the presence of fish cages.
基金This study was supported by the National Key R&D Program of China(Grant No.2017YFA0604300)the National Natural Science Foundation of China(Grant Nos.41861144014,41775106 and U1811464)+1 种基金the Program for Guangdong Introducing Innovative and Entrepreneurial Teams(Grant No.2017ZT07X355)the project of the Chinese Ministry of Emergency Management on“Catastrophe Evaluation Modeling Study”.
文摘The prolonged mei-yu/baiu system with anomalous precipitation in the year 2020 has swollen many rivers and lakes,caused flash flooding,urban flooding and landslides,and consistently wreaked havoc across large swathes of China,particularly in the Yangtze River basin.Significant precipitation and flooding anomalies have already been seen in magnitude and extension so far this year,which have been exerting much higher pressure on emergency responses in flood control and mitigation than in other years,even though a rainy season with multiple ongoing serious flood events in different provinces is not that uncommon in China.Instead of delving into the causes of the uniqueness of this year’s extreme precipitation-flooding situation,which certainly warrants in-depth exploration,in this article we provide a short view toward a more general hydrometeorological solution to this annual nationwide problem.A“glocal”(global to local)hydrometeorological solution for floods(GHS-F)is considered to be critical for better preparedness,mitigation,and management of different types of significant precipitation-caused flooding,which happen extensively almost every year in many countries such as China,India and the United States.Such a GHS-F model is necessary from both scientific and operational perspectives,with the strength in providing spatially consistent flood definitions and spatially distributed flood risk classification considering the heterogeneity in vulnerability and resilience across the entire domain.Priorities in the development of such a GHS-F are suggested,emphasizing the user’s requirements and needs according to practical experiences with various flood response agencies.
基金The Spanish Ministry of the Environment and Rural and Marine Affairs (Project:"Minimisation of environmental impacts from brine disposals over marine seabed biodiversity,with special reference to Cymodocea nodosa seagrass meadows"2007–2010) under contract No.056/SGTB/2007/2.4
文摘Throughout the shores of the world, a confluence of different sources of pollution is common, e.g., through outlets releasing brine, industrial, and domestic sewage. In this study, we assessed whether a combined disposal of domestic sewage and brine altered the patterns of abundance and assemblage structure of sub- tidal macrofauna inhabiting sandy seabeds on the south coast of Gran Canaria (Canary Islands, NE Atlantic Ocean). Samples were collected in two surveys (May 2008 and January 2009) at three distances (0, 15, and 30 m) away from the discharge point. Macrofaunal abundances showed different patterns with varying proximity from the disposal point in the two surveys. In May 2008, lower abundances were observed at 0 m (53.89±46.82 ind.) than at 15 m (120±91.7 ind.) and 30 m (283.89±189.33 ind.) away from the dis- posal point. In January 2009, however, higher abundances were observed at 0 m (131.33±58.69 ind.) than at 30 m (100±24.44 ind.) and 15 m (84.78±58.39 ind.) away from the disposal point. Significant differ- ences in macrofaunal assemblage structure were found with varying proximity from the discharge point in both surveys. The effect of proximity from the disposal point was confounded by changes in sedimen- tary composition between surveys, which contributed to explain differences in macrofaunal abundances and assemblage structure with varying proximity from the discharge point. As a result, confounding driver- s of macrofaunal assemblage structure, here, changes in sediment composition, accounted for changes in macrofaunal abundances and assemblage structure with varying proximity from a combined disposal point of brine and sewage.
文摘A shallow subtidal (3 m deep) meiofaunal assemblage in Los Abrigos Bay, Tenerife, Canary Islands was sam- pled during May 2000-April 2001. The main aims were to (1) find temporal variations in meiofaunal assem- blage structure and overall abundance, as well as in the most abundant meiofaunal species throughout the study period, and (2) identify environmental variables (sedimentary composition, organic matter content, and total nitrogen) that better explain meiofaunal assemblage structure during the study year. The most abundant species were the nematodes Siphonolaimus sp. 2 and Catanema sp., which represented 46.2% of the overall meiofaunal abundances and varied significantly throughout the study duration. Overall meio- faunal abundance and the most abundant taxonomic groups (nematodes, copepods, and oligochaetes) showed significant temporal variations during the study period. Nematodes overwhelmingly dominated during the study period, ranging from 78% in May to 97.34% in February. Multivariate analyses showed seasonality in meiofaunal community structure during the study year, with the lowest abundances in May. Keywords: Meiofauna, assemblage structure, subtidal, Canary Islands, Atlantic Ocean
文摘This study contributes with the first data on physical and taxonomical structure of macrofaunal assemblages of maerl beds from the Canary Islands. Maerl beds and Cymodocea nodosa meadows of the Canary Islands are considered biodiversity hot-spots in terms of taxonomic and functional biodiversity with a broad geographical and depth ranges. The authors have studied the structure of the macrofaunal assemblages on different habitat types (Cymodocea, Caulerpa, sabellid field, garden eel and maerl beds). Samples were taken at a range of depths between 14 and 46 m. Correlations were performed among abiotic variables (granulometry, organic matter, nitrogen and phosphates) and the most abundant taxa. Similarity analysis was performed to explore the patchiness of seabeds at a local scale. Significant differences were found in macrofaunal assemblages among seabed types, with highest abundances and lowest biodiversity in sabellid fields, where the sabellid Bispira viola dominated. The polychaetes Aponuphis bilineata and Chone filicauda and the mollusc Turritella brochii were the most abundant taxa on maerl beds. The mosaic of granulometric conditions would explain the associated macroinfaunal community structure and contribute to the creation of diversity on these relatively well preserved seabeds at a local scale.
文摘Research was done with the objective of evaluating the quality of water supplied to the potable water system in Hidalgo Del Parral, which comes from two main supply sources: wells from "Valle del Verano", which provide water to the east side of the city, and the Water Treatment Plant, which receives water from different mines and supplies the west side of the city. When this plant is overcome on its capacity of treatment, a part of the water from the mines is fed directly to the northwest part of the city. The metals lead (Pb), chromium (Cr), cadmium (Cd), zinc (Zn), and arsenic (As) were analyzed by atomic absorption (AA) technique, based on the United States Environmental Protection Agency (EPA) Method 7000B (Revision 2, February 2007). The digestion process was done according to the guidelines established in Method NMX-AA-051-SCFI-2001, Analysis of Water-Determination of Metals by Atomic Absorption, developed by the National Standardization Technical Committee for Environmental Protection (Mexico). The samples were collected from the following points: 13 wells and 2 re-pumping stations of "Valle del Verano", the inlet and outlet of the Water Treatment Plant, and domestic faucets. The east side of the city, supplied by the wells of "Valle del Verano", is metal-pollution free. The water that comes from the mines contains high concentrations of As, Zn, Cd and Pb, with levels that can get to 0.12, 32.6, 0.26 and 3.5 mg/L, respectively. This water pollution generated by mining can be concluded from the high levels found in the domestic samples in which, for several points, the concentrations exceed the parameters set by the current guideline. According to the results, it is vital to set a plan of remediation for the water that comes from the mines, because there is a great risk for health in the consumotion of this water.