The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cereb...The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cerebral organoids have emerged as valuable tools offering a more complex,versatile,and human-relevant system than traditional animal models,which are often unable to replicate the intricate architecture and functionality of the human brain.Since human cerebral organoids are a state-of-the-art model for the study of neurodevelopment and different pathologies affecting the brain,this field is currently under constant development,and work in this area is abundant.In this review,we give a complete overview of human cerebral organoids technology,starting from the different types of protocols that exist to generate different human cerebral organoids.We continue with the use of brain organoids for the study of brain pathologies,highlighting neurodevelopmental,psychiatric,neurodegenerative,brain tumor,and infectious diseases.Because of the potential value of human cerebral organoids,we describe their use in transplantation,drug screening,and toxicology assays.We also discuss the technologies available to study cell diversity and physiological characteristics of organoids.Finally,we summarize the limitations that currently exist in the field,such as the development of vasculature and microglia,and highlight some of the novel approaches being pursued through bioengineering.展开更多
Data-driven drug repositioning using olfactory omics profiles-challenges and perspectives in neurodegeneration:Neurodegenerative diseases are characterized by progressive degeneration and loss of neuronal function in ...Data-driven drug repositioning using olfactory omics profiles-challenges and perspectives in neurodegeneration:Neurodegenerative diseases are characterized by progressive degeneration and loss of neuronal function in the central nervous system.These diseases are often characterized as proteinopathies,which are disorders primarily driven by the aggregation or misfolding of specific amyloid proteins within cells,leading to their dysfunction and eventual death.Despite the gain-of-function hypothesis related to the aggregation of these proteins,recently,an alternative hypothesis regarding the loss-of-function of the soluble monomeric proteins during the process of aggregation into amyloids is gaining currency.This last event is called proteinopenia and refers to conditions characterized by a deficiency or decrease in the levels of specific soluble proteins in the body(Ezzat et al.,2023).It has been demonstrated that levels of soluble proteins involved in neurodegenerative diseases are decreased.展开更多
Gastric cancer(GC)is both the fifth most common cancer worldwide and the fifth in mortality.Owing to a lack of symptoms in the early stages and unspecific cli-nical presentation in the later stages,GC is usually diagn...Gastric cancer(GC)is both the fifth most common cancer worldwide and the fifth in mortality.Owing to a lack of symptoms in the early stages and unspecific cli-nical presentation in the later stages,GC is usually diagnosed at advanced stages.This means that only approximately 60%of patients are eligible for curative treat-ment,and overall,GC patients have a 5-year survival rate of only 28.3%,under-scoring the importance of developing new treatment strategies.Drug repurposing involves identifying new therapeutic uses for approved drugs and is a promising strategy for cancer treatment because of its lower cost and faster development time.A variety of targetable pathways are involved in GC progression,including the mitogen-activated protein kinase,phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin,p53,Janus kinase 2/signal transducer and activator of transcription 3,hypoxia-inducible factor-1α,wingless-type mouse mammary tumor virus integration site family/beta-catenin(Wnt/β-catenin),nuclear factor kappa B,and Hippo pathways.Therefore,the repurposing of drugs targeting these pathways represents an interesting option in the search for new treatments for GC.In this review,we explore some relevant pathways involved in the development of GC and the possibilities of repurposing drugs that target them.展开更多
BACKGROUND Despite advances in the treatment of ulcerative colitis(UC),some patients remain refractory to the currently available treatments.Dual biologic therapy(DBT)has emerged as a promising strategy for these pati...BACKGROUND Despite advances in the treatment of ulcerative colitis(UC),some patients remain refractory to the currently available treatments.Dual biologic therapy(DBT)has emerged as a promising strategy for these patients.CASE SUMMARY A patient with extensive UC presented with steroid dependence and contraindications(past medical history included breast cancer and previous myocardial infarction)to treatment with tumor necrosis factor and Janus kinase inhibitors.DBT ofα4β7 integrin antagonist(vedolizumab)and interleukin 23p19 inhibitor(mirikizumab)resulted in a sustained clinical and biochemical remission.No adverse events were recorded during the follow-up.CONCLUSION This case highlighted the challenge of managing refractory UC,especially in frail patients.展开更多
BACKGROUND Hypoxia in oral cancer promotes tumoral invasion by inducing epithelial-mesenchymal transition,leading to aggressive tumor progression.AIM To characterize the expression of hypoxia-inducible factor 1-alpha(...BACKGROUND Hypoxia in oral cancer promotes tumoral invasion by inducing epithelial-mesenchymal transition,leading to aggressive tumor progression.AIM To characterize the expression of hypoxia-inducible factor 1-alpha(HIF-1α)at the invasive tumor front(ITF)in comparison to tumor islands(TI)in oral squamous cell carcinoma(OSCC)and to explore its relationship with E-cadherin and Vimentin expression.METHODS Thirty-eight cases of OSCC and five cases of normal oral mucosa(NOM)were included in this study.The ITF was identified based on the region and immune expression of AE1/AE3.Immunohistochemistry was performed to assess the expression of HIF-1α,Vimentin,and E-cadherin.The immunostaining was analyzed using an immunoreactive score,and the results were illustrated using immunofluorescence.RESULTS HIF-1αexpression was significantly higher in the TI region compared to the ITF region(P=0.0134).Additionally,a significant difference was observed between TI and NOM(P=0.0115).In the ITF regions,HIF-1αexpression showed a significant correlation with Vimentin expression,with higher levels of HIF-1αassociated with increased Vimentin expression(P=0.017).CONCLUSION Based on the results of this study,HIF-1αappears to play a distinct role in OSCC tumor progression,underscoring the importance of exploring hypoxia-driven changes in cellular phenotype at the ITF of OSCC.Further research is needed to better understand their impact on OSCC prognosis.展开更多
Infrastructure in mountainous regions is particularly vulnerable when exposed to socio-natural hazards associated with extreme events,especially flood events involving the transport of large volumes of sediment and wo...Infrastructure in mountainous regions is particularly vulnerable when exposed to socio-natural hazards associated with extreme events,especially flood events involving the transport of large volumes of sediment and woody debris.In this context,understanding how such processes affect the structural stability of bridges is crucial for effective risk management and the planning of resilient infrastructure.This study examines the impacts of river floods,including large wood and sediment transport,on the“El Blanco Bridge”over the Blanco River in Chaitén,Chilean Patagonia,and the resulting susceptibility of the structure.The 2D Iber model,which solves the shallow water equations,was employed to simulate different flood scenarios as bi-phasic flows(i.e.,water,inorganic and organic sediments,the latter are referred to as large wood,LW),evaluating the hydrodynamic loadings(i.e.pressure distributions and forces)on piers and their susceptibility to sliding,overturning and scouring.Critical flood scenarios that could pose a potential risk of infrastructure failure were identified by separately determining the associated peak discharge,sediment transport rates,LW loads and bed elevation changes.Compared to clear water flows,LW transport resulted in a reduction of the factor of safety against overturning and sliding,indicating higher hydrodynamic loads on the exposed structure.When sediment transport was considered,increasing flood flows slightly augmented maximum scour depth at the base of the piers.This study underscores the significance of hydrodynamic modeling of the Blanco River for natural risk management,and highlights the importance of considering LW transport when quantifying the safety of structures,especially in catchments where easily transportable LW sources may be found(e.g.,in catchments following fires or volcanic eruptions).展开更多
BACKGROUND Previous studies have shown that individuals with type 1 diabetes(T1D)frequently present with reduced fecal elastase levels,suggesting exocrine pancreatic insufficiency.However,the underlying determinants a...BACKGROUND Previous studies have shown that individuals with type 1 diabetes(T1D)frequently present with reduced fecal elastase levels,suggesting exocrine pancreatic insufficiency.However,the underlying determinants and the longitudinal trajectory of these changes remain poorly understood.AIM To evaluate longitudinal changes in fecal elastase among individuals with T1D,identify associated factors,and determine clinical implications.METHODS Pancreatic exocrine function was evaluated in a cohort of patients with T1D by measuring fecal elastase concentrations(FECs).After a mean follow-up of 8.5±0.5 years,participants were recontacted,and a second stool sample was obtained.At both time points,detailed medical histories were collected,including information on diabetes progression,metabolic control,complications,gastrointestinal symptoms,and nutritional status.The study was approved by the institutional ethics committee,and written informed consent was obtained from all participants.RESULTS A total of 106 individuals with T1D(mean age=46.2 years;50%male)were enrolled.At baseline,the median FEC was 239.5μg/g,with 44 participants(41.5%)demonstrating abnormally low levels(<200μg/g).Reduced fecal elastase was significantly associated with male sex,diabetes-related complications,particularly retinopathy,and higher glycated hemoglobin levels.No significant differences in gastrointestinal symptoms,body mass index,nor most serum nutritional markers were observed between individuals with normal vs reduced fecal elastase levels.Sixty-six participants completed follow-up.Their median fecal elastase was 171.5μg/g,with 59.1%presenting levels below 200μg/g.Paired analysis showed a non-significant decline in FEC s over time.No clinical nor metabolic variables predicted longitudinal changes in FEC independently.CONCLUSION Fecal elastase levels are frequently reduced in individuals with T1D and may show a gradual decline over time.The clinical impact of these changes appears to be limited.展开更多
This study presents the microwave-assisted synthesis and characterization of a series of heterometal lic coordination polymers(HMCPs)with a 4-methyl-2,6-di[(1H-1,2,4-triazol-1-yl)]phenoxo ligand with varying Eu^(Ⅲ)/T...This study presents the microwave-assisted synthesis and characterization of a series of heterometal lic coordination polymers(HMCPs)with a 4-methyl-2,6-di[(1H-1,2,4-triazol-1-yl)]phenoxo ligand with varying Eu^(Ⅲ)/Tb^(Ⅲ)ratios.Single crystal X-ray diffraction reveals a double-chain structure bridged by triazolyl groups.Powder X-ray diffraction confirms the isostructural nature of the synthesized HMCPs.The photophysical properties depend on lanthanide ion concentration and excitation wavelength,leading to a color shift from green to blue as the proportion of Tb^(Ⅲ)decreases and Eu^(Ⅲ)increases.White light generation is achieved in the 8/2 Eu^(Ⅲ)/Tb^(Ⅲ)HMCP(CIE:0.293,0.326)under 335 nm excitation.The study suggests energy transfer from Tb^(Ⅲ)to Eu^(Ⅲ),but both experimental and theoretical calculations indicate that this transfer is orders of magnitude lower than the sensitization through ligand states.展开更多
Multifocal epithelial hyperplasia(MEH),also known as Heck’s disease,is a rare and benign condition of the oral mucosa that is strongly associated with low-risk human papillomavirus(HPV)genotypes 13 and 32.This narrat...Multifocal epithelial hyperplasia(MEH),also known as Heck’s disease,is a rare and benign condition of the oral mucosa that is strongly associated with low-risk human papillomavirus(HPV)genotypes 13 and 32.This narrative review synthesizes recent findings regarding the epidemiology,viral mechanisms,clinical and histopathological features,diagnostic strategies-including molecular and immunohistochemical methods-and therapeutic approaches to MEH.This disease predominantly affects children and adolescents from Indigenous American countries,although cases have been increasingly reported in nonendemic regions.MEH manifests clinically as multiple,asymptomatic papules or nodules,typically exhibiting a characteristic cobblestone-like appearance.Histologically,it presents with epithelial hyperplasia,koilocytosis,and altered cytokeratin expression.Molecular techniques such as polymerase chain reaction and in situ hybridization are pivotal for accurate viral genotyping,while immunohistochemical markers such as CK4/13,Ki-67,and the absence of p16 can be useful adjuncts in differential diagnosis.Despite its self-limiting nature in most cases,treatment may be warranted in symptomatic or immunocompromised patients.This review highlights the need to improve diagnostic access,develop targeted vaccines,and implement public health strategies in vulnerable communities.It also highlights existing gaps in knowledge,particularly regarding host-virus interactions and the absence of standardized treatment protocols.展开更多
Objective:To investigate mutations in the Chikungunya(CHIKV)envelope genome region and evaluate their potential impact on B lymphocyte epitopes via in silico analysis.Methods:E1,E2 and 6K protein genes were sequenced ...Objective:To investigate mutations in the Chikungunya(CHIKV)envelope genome region and evaluate their potential impact on B lymphocyte epitopes via in silico analysis.Methods:E1,E2 and 6K protein genes were sequenced from viral RNA isolated from 13 CHIKV-positive serum samples from Alagoas State,Brazil,during the 2016 outbreak.Phylogenetic analysis,experimental epitope identification in the immune epitope database(IEDB)and in silico approaches were employed to predict the potential impact of the detected mutations.Results:The sequences were clustered via phylogenetic analysis.The CHIKV isolates belong to the ECSA genotype,with 13 detected amino acid mutations.Five mutations are located on the surface of the viral particle in regions critical for cellular receptor interaction.Nine mutations are known experimentally validated epitopes for B and T cells.In B-cell epitope predictions,mutations affect sequences within three conformational epitopes in E2 and one in E1,as well as linear epitopes.Notably,the E2-G60D mutation found in the Alagoas strain has been previously reported to influence the vector competence of Aedes aegypti,the primary vector in Brazil.Conclusions:Genomic surveillance and an in-depth understanding of viral mutations are crucial for adapting public health strategies and improving the outbreak response.These findings could have significant public health implications,such as the development of more effective vaccines,diagnostic tests,and antiviral therapies.展开更多
Emerging infectious diseases are a major threat to biodiversity and an important public health issue.Flaviviruses are the cause of several emerging vector-borne zoonotic arboviruses whose distribution is currently inc...Emerging infectious diseases are a major threat to biodiversity and an important public health issue.Flaviviruses are the cause of several emerging vector-borne zoonotic arboviruses whose distribution is currently increasing in Europe.The evidence that West Nile virus(WNV)circulates in resident and migratory species has implications for both animal and public health and should therefore be studied in depth.USUTU(USUV),Bagaza(BAGV)and tick-borne encephalitis virus(TBEV)are other viruses that are beginning to spread more widely.An integrated surveillance program,namely in birds,is essential for reducing the risk of infection in human populations within the One Health principles.In the present study,wild birds admitted to wildlife rehabilitation centers in Portugal were sampled.Two hundred eight blood samples were assayed serologically for antibodies to flaviviruses by using a commercial ELISA kit.An over-all seroprevalence of 19.6%(95%confidence interval[CI]:13.7-26.7%)was observed.Antibodies against flaviviruses were detected in 13(35.1%)different species of wild birds.Accipitriformes(26.7%;95%CI:18.5-36.2%)and Strigi-formes(26.7%;95%CI:14.6-42.0%)were the orders with the highest seroprevalence rates recorded.There were no statistically significant differences(p=0.725)between the geographical regions(NUTSⅡ)studied,but a statistically significant difference(p=0.017)was found between sex(male:34.4%;female:4.8%).A higher seroprevalence was detected in adults(32.1%)than in juvenile birds(9.3%)(p=0.014),and age was considered a risk factor for flavivirus infection in wild birds(odds ratio 1.4;95%CI:0.5-4.0).More epidemiological studies are needed in Portugal since the actual spread of the genus Flavivirus throughout the country is unknown.展开更多
Multiparent advanced generation inter-cross(MAGIC)populations improve the accuracy of quantitative trait loci mapping compared to biparental populations by increasing diversity and reducing linkage disequilibrium betw...Multiparent advanced generation inter-cross(MAGIC)populations improve the accuracy of quantitative trait loci mapping compared to biparental populations by increasing diversity and reducing linkage disequilibrium between variants.Here we describe the development of two MAGIC populations derived from a cross of 11 founder lines from the INTA(National Institute for Agricultural Technology in Argentina)sunflower breeding program.The founder lines are fertility maintainer inbred lines that exhibit genetic diversity in several traits,including flowering cycle,plant architecture,disease resistance,oil content and oil quality.The crossing scheme applied follows the design of two-way,four-way and eight-way crosses with a modification to increase the number of recombinations and shorten the linkage disequilibrium.Phenotyping a subset of F_(2)families and F_5 lines for different traits shows an increase in the diversity of the analyzed traits compared to the parental lines.In addition,we identified lines with transgressive segregation for Sunflower Verticillium Wilt resistance.These results confirm that the MAGIC populations will serve as unique genetic and genomic resources to better characterize the genetics of complex traits and identify potentially superior alleles for sunflower breeding.It will also enrich the gene pool of fertility maintainers(A/B line)of the sunflower germplasm and facilitate the introduction of new breeding methods to select female parents for use in AxR combinations to obtain superior sunflower hybrids.展开更多
Background There is insufficient evidence to provide recommendations for leisure-time physical activity among workers across various occupational physical activity levels.This study aimed to assess the association of ...Background There is insufficient evidence to provide recommendations for leisure-time physical activity among workers across various occupational physical activity levels.This study aimed to assess the association of leisure-time physical activity with cardiovascular and all-cause mortality across occupational physical activity levels.Methods This study utilized individual participant data from 21 cohort studies,comprising both published and unpublished data.Eligibility criteria included individual-level data on leisure-time and occupational physical activity(categorized as sedentary,low,moderate,and high)along with data on all-cause and/or cardiovascular mortality.A 2-stage individual participant data meta-analysis was conducted,with separate analysis of each study using Cox proportional hazards models(Stage 1).These results were combined using random-effects models(Stage 2).Results Higher leisure-time physical activity levels were associated with lower all-cause and cardiovascular mortality risk across most occupational physical activity levels,for both males and females.Among males with sedentary work,high compared to sedentary leisure-time physical activity was associated with lower all-cause(hazard ratios(HR)=0.77,95%confidence interval(95%CI):0.70-0.85)and cardiovascular mortality(HR=0.76,95%CI:0.66-0.87)risk.Among males with high levels of occupational physical activity,high compared to sedentary leisure-time physical activity was associated with lower all-cause(HR=0.84,95%CI:0.74-0.97)and cardiovascular mortality(HR=0.79,95%CI:0.60-1.04)risk,while HRs for low and moderate levels of leisure-time physical activity ranged between 0.87 and 0.97 and were not statistically significant.Among females,most effects were similar but more imprecise,especially in the higher occupational physical activity levels.Conclusion Higher levels of leisure-time physical activity were generally associated with lower mortality risks.However,results for workers with moderate and high occupational physical activity levels,especially women,were more imprecise.Our findings suggests that workers may benefit from engaging in high levels of leisure-time physical activity,irrespective of their level of occupational physical activity.展开更多
Cervical cancer is a worldwide disease that constitutes a significant public health problem, especially in developing countries, not only due to its high incidence but also because the most affected population compris...Cervical cancer is a worldwide disease that constitutes a significant public health problem, especially in developing countries, not only due to its high incidence but also because the most affected population comprises women who belong to marginalized socio-economic classes. Clinical and molecular research has identified immunological impairment in squamous intraepithelial cervical lesions and cervical cancer patients. Human Papillomavirus(HPV) has several mechanisms for avoiding the immune system: it down-regulates the expression of interferon and upregulates interleukin(IL)-10and transforming growth factor(TGF)-β1 to produce a local immunosuppressive environment, which, along with altered tumor surface antigens, forms an immunosuppressive network that inhibits the antitumor immune response. In this review we analyzed the available data on several deregulated cellular immune functions in patients with NIC Ⅰ, NIC Ⅱ and NIC Ⅲ and cervical cancer. The effects of immunosuppressive cytokines on innate immune response, T-cell activation and cellular factors that promote tumor cell proliferation in cervical cancer patients are summarized. We discuss the functional consequences of HPV E2, E6, and E7 protein interactions with IL-10 and TGF-β1 promoters in the induction of these cytokines and postulate its effect on the cellular immune response in squamous intraepithelial cervical lesions and cervical cancer patients. This review provides a comprehensive picture of the immunological functions of IL-10 and TGF-β1 in response to HPV in humans.展开更多
Geological,geochronological and isotopic data are integrated in order to present a revised model for the Neoproterozoic evolution of Western Gondwana.Although the classical geodynamic scenario assumed for the period 8...Geological,geochronological and isotopic data are integrated in order to present a revised model for the Neoproterozoic evolution of Western Gondwana.Although the classical geodynamic scenario assumed for the period 800-700 Ma is related to Rodinia break-up and the consequent opening of major oceanic basins,a significantly different tectonic evolution can be inferred for most Western Gondwana cratons.These cratons occupied a marginal position in the southern hemisphere with respect to Rodinia and recorded subduction with back-arc extension,island arc development and limited formation of oceanic crust in internal oceans.This period was thus characterized by increased crustal growth in Western Gondwana,resulting from addition of juvenile continental crust along convergent margins.In contrast,crustal reworking and metacratonization were dominant during the subsequent assembly of Gondwana.The Rio de la Plata,Congo-Sao Francisco,West African and Amazonian cratons collided at ca.630-600 Ma along the West Gondwana Orogen.These events overlap in time with the onset of the opening of the Iapetus Ocean at ca.610-600 Ma,which gave rise to the separation of Baltica,Laurentia and Amazonia and resulted from the final Rodinia break-up.The East African/Antarctic Orogen recorded the subsequent amalgamation of Western and Eastern Gondwana after ca.580 Ma,contemporaneously with the beginning of subduction in the Terra Australis Orogen along the southern Gondwana margin.However,the Kalahari Craton was lately incorporated during the Late Ediacaran-Early Cambrian.The proposed Gondwana evolution rules out the existence of Pannotia,as the final Gondwana amalgamation postdates latest connections between Laurentia and Amazonia.Additionally,a combination of introversion and extroversion is proposed for the assembly of Gondwana.The contemporaneous record of final Rodinia break-up and Gondwana assembly has major implications for the supercontinent cycle,as supercontinent amalgamation and break-up do not necessarily represent alternating episodic processes but overlap in time.展开更多
Helicobacter pylori(H. pylori) is a successful pathogen that can persist in the stomach of an infected person for their entire life. It provokes chronic gastric inflammation that leads to the development of serious ga...Helicobacter pylori(H. pylori) is a successful pathogen that can persist in the stomach of an infected person for their entire life. It provokes chronic gastric inflammation that leads to the development of serious gastric diseases such as peptic ulcers, gastric cancer and Mucosa associated lymphoid tissue lymphoma. It is known that these ailments can be avoided if the infection by the bacteria can be prevented or eradicated. Currently, numerous antibiotic-based therapies are available. However, these therapies have several inherent problems, including the appearance of resistance to the antibiotics used and associated adverse effects, the risk of re-infection and the high cost of antibiotic therapy. The delay in developing a vaccine to prevent or eradicate the infection has furthered research into new therapeutic approaches. This review summarises the most relevant recent studies on vaccine development and new treatments using natural resources such as plants, probiotics and nutraceuticals. In addition, novel alternatives based on microorganisms, peptides, polysaccharides, and intragastric violet light irradiation are presented. Alternative therapies have not been effective in eradicating the bacteria but have been shown to maintain low bacterial levels. Nevertheless, some of them are useful in preventing the adverse effects of antibiotics, modulating the immune response, gastroprotection, and the general promotion of health. Therefore, those agents can be used as adjuvants of allopathic anti-H. pylori eradication therapy.展开更多
There has been significant progress in our understanding of the pathobiology, epidemiology and prognosis of pulmonary vascular disease and, over the past few years, there has been an explosion of clinical therapeutic ...There has been significant progress in our understanding of the pathobiology, epidemiology and prognosis of pulmonary vascular disease and, over the past few years, there has been an explosion of clinical therapeutic trials for pulmonary arterial hypertension (PAH). The increasing number of different conditions now associated with PAH and the appearance of new diagnostic techniques have led to a need for a systematic diagnostic approaches and a new disease classification, which has resulted in notable improvements in the quality and efficacy of clinical care. We appreciate traditional resting right heart catheterization techniques (which still remain the gold standard for diagnosing PAH and managing patients on therapy) and look forward to novel invasive techniques (e.g. intravascular ultrasound) that add greatly to our understanding of right ventricle and pulmonary circulation, and for the interpretation of data from clinical trials as well.展开更多
AIM:To ascertain the role of cardiovascular risk factors,cardiovascular diseases,standard treatments and other diseases in the development of ischemic colitis(IC).METHODS:A retrospective,case-control study was designe...AIM:To ascertain the role of cardiovascular risk factors,cardiovascular diseases,standard treatments and other diseases in the development of ischemic colitis(IC).METHODS:A retrospective,case-control study was designed,using matched data and covering 161 incident cases of IC who required admission to our hospital from 1998 through 2003.IC was diagnosed on the basis of endoscopic findings and diagnostic or compatible his-tology.Controls were randomly chosen from a cohort of patients who were admitted in the same period and required a colonoscopy,excluding those with diagnosis of colitis.Cases were matched with controls(ratio 1:2),by age and sex.A conditional logistic regression was performed.RESULTS:A total of 483 patients(161 cases,322 con-trols)were included;mean age 75.67±10.03 years,55.9%women.The principal indications for colonos-copy in the control group were lower gastrointestinal hemorrhage(35.4%),anemia(33.9%),abdominal pain(19.9%)and diarrhea(9.6%).The endoscopic findings in this group were hemorrhoids(25.5%),diverticular disease(30.4%),polyps(19.9%)and colorectal cancer(10.2%).The following variables were associated with IC in the univariate analysis:arterial hypertension(P= 0.033);dyslipidemia(P<0.001);diabetes mellitus(P =0.025);peripheral arterial disease(P=0.004);heart failure(P=0.026);treatment with hypotensive drugs(P=0.023);angiotensin-converting enzyme inhibitors;(P=0.018);calcium channel antagonists(P=0.028);and acetylsalicylic acid(ASA)(P<0.001).Finally,the following variables were independently associated with the development of IC:diabetes mellitus[odds ratio(OR)1.76,95%confidence interval(CI):1.001-3.077,P=0.046];dyslipidemia(OR 2.12,95%CI:1.26-3.57,P=0.004);heart failure(OR 3.17,95%CI:1.31-7.68,P=0.01);peripheral arterial disease(OR 4.1,95%CI:1.32-12.72,P=0.015);treatment with digoxin(digitalis)(OR 0.27,95%CI:0.084-0.857,P=0.026);and ASA(OR 1.97,95%CI:1.16-3.36,P=0.012).CONCLUSION:The development of an episode of IC was independently associated with diabetes,dyslipid-emia,presence of heart failure,peripheral arterial dis-ease and treatment with digoxin or ASA.展开更多
Pulmonary vein stenosis(PVS) is rare condition characterized by a challenging diagnosis and unfavorable prognosis at advance stages. At present, injury from radiofrequency ablation for atrial fibrillation has become t...Pulmonary vein stenosis(PVS) is rare condition characterized by a challenging diagnosis and unfavorable prognosis at advance stages. At present, injury from radiofrequency ablation for atrial fibrillation has become the main cause of the disease. PVS is characterized by a progressive lumen size reduction of one or more pulmonary veins that, when hemodynamically significant, may raise lobar capillary pressure leading to signs and symptoms such as shortness of breath, cough, and hemoptysis. Image techniques(transesophageal echocardiography, computed tomography, magnetic resonance and perfusion imaging) are essential to reach a final diagnosis and decide an appropriate therapy. In this regard, series from referral centers have shown that surgical and transcatheter interventions may improve prognosis. The purpose of this article is to review the etiology, assessment and management of PVS.展开更多
Hepatitis C virus(HCV) has infected over 170 million people worldwide and creates a huge disease burden due to chronic, progressive liver disease. HCV is a singlestranded, positive sense, RNA virus, member of the Flav...Hepatitis C virus(HCV) has infected over 170 million people worldwide and creates a huge disease burden due to chronic, progressive liver disease. HCV is a singlestranded, positive sense, RNA virus, member of the Flaviviridae family. The high error rate of RNA-dependent RNA polymerase and the pressure exerted by the host immune system, has driven the evolution of HCV into 7 different genotypes and more than 67 subtypes. HCV evolves by means of different mechanisms of genetic variation. On the one hand, its high mutation rates generate the production of a large number of different but closely related viral variants during infection, usually referred to as a quasispecies. The great quasispecies variability of HCV has also therapeutic implications since the continuous generation and selection of resistant or fitter variants within the quasispecies spectrum might allow viruses to escape control by antiviral drugs. On the other hand HCV exploits recombination to ensure its survival. This enormous viral diversity together with some host factors has made it difficult to control viral dispersal. Current treatment options involve pegylated interferon-α and ribavirin as dual therapy or in combination with a direct-acting antiviral drug, depending on the country. Despite all the efforts put into antiviral therapy studies, eradication of the virus or the development of a preventive vaccine has been unsuccessful so far. This review focuses on current available data reported to date on the genetic mechanisms driving the molecular evolution of HCV populations and its relation with the antiviral therapies designed to control HCV infection.展开更多
基金supported by the Grant PID2021-126715OB-IOO financed by MCIN/AEI/10.13039/501100011033 and"ERDFA way of making Europe"by the Grant PI22CⅢ/00055 funded by Instituto de Salud CarlosⅢ(ISCⅢ)+6 种基金the UFIECPY 398/19(PEJ2018-004965) grant to RGS funded by AEI(Spain)the UFIECPY-396/19(PEJ2018-004961)grant financed by MCIN (Spain)FI23CⅢ/00003 grant funded by ISCⅢ-PFIS Spain) to PMMthe UFIECPY 328/22 (PEJ-2021-TL/BMD-21001) grant to LM financed by CAM (Spain)the grant by CAPES (Coordination for the Improvement of Higher Education Personnel)through the PDSE program (Programa de Doutorado Sanduiche no Exterior)to VSCG financed by MEC (Brazil)
文摘The brain is the most complex human organ,and commonly used models,such as two-dimensional-cell cultures and animal brains,often lack the sophistication needed to accurately use in research.In this context,human cerebral organoids have emerged as valuable tools offering a more complex,versatile,and human-relevant system than traditional animal models,which are often unable to replicate the intricate architecture and functionality of the human brain.Since human cerebral organoids are a state-of-the-art model for the study of neurodevelopment and different pathologies affecting the brain,this field is currently under constant development,and work in this area is abundant.In this review,we give a complete overview of human cerebral organoids technology,starting from the different types of protocols that exist to generate different human cerebral organoids.We continue with the use of brain organoids for the study of brain pathologies,highlighting neurodevelopmental,psychiatric,neurodegenerative,brain tumor,and infectious diseases.Because of the potential value of human cerebral organoids,we describe their use in transplantation,drug screening,and toxicology assays.We also discuss the technologies available to study cell diversity and physiological characteristics of organoids.Finally,we summarize the limitations that currently exist in the field,such as the development of vasculature and microglia,and highlight some of the novel approaches being pursued through bioengineering.
基金funded by grants from the Spanish Ministry of Science,Innovation and Universities(Ref.PID2019-110356RB-I00/AEI/10.13039/501100011033)to JFI and ESthe Department of Economic and Business Development from Government of Navarra(Ref.0011-1411-2023-000028 to ES)+2 种基金supported by a predoctoral fellowship from the Public University of Navarra(UPNA)supported by a postdoctoral fellowship from Miguel Servet Foundation-Navarrabiomedsupported by“Programa MRR Investigo 2023”in the framework of the European Union recovery and resilience facility。
文摘Data-driven drug repositioning using olfactory omics profiles-challenges and perspectives in neurodegeneration:Neurodegenerative diseases are characterized by progressive degeneration and loss of neuronal function in the central nervous system.These diseases are often characterized as proteinopathies,which are disorders primarily driven by the aggregation or misfolding of specific amyloid proteins within cells,leading to their dysfunction and eventual death.Despite the gain-of-function hypothesis related to the aggregation of these proteins,recently,an alternative hypothesis regarding the loss-of-function of the soluble monomeric proteins during the process of aggregation into amyloids is gaining currency.This last event is called proteinopenia and refers to conditions characterized by a deficiency or decrease in the levels of specific soluble proteins in the body(Ezzat et al.,2023).It has been demonstrated that levels of soluble proteins involved in neurodegenerative diseases are decreased.
基金Supported by the Instituto de Salud Carlos III,No.PI24/00784,No.PI24/00737,No.PI21/01181,No.PI21/00333 and No.INT22/00112Departamento de Universidad,Innovación y Transformación Digital Gobierno de Navarra,No.0011-1408-2024-000011,No.0011-1408-2022-000010.
文摘Gastric cancer(GC)is both the fifth most common cancer worldwide and the fifth in mortality.Owing to a lack of symptoms in the early stages and unspecific cli-nical presentation in the later stages,GC is usually diagnosed at advanced stages.This means that only approximately 60%of patients are eligible for curative treat-ment,and overall,GC patients have a 5-year survival rate of only 28.3%,under-scoring the importance of developing new treatment strategies.Drug repurposing involves identifying new therapeutic uses for approved drugs and is a promising strategy for cancer treatment because of its lower cost and faster development time.A variety of targetable pathways are involved in GC progression,including the mitogen-activated protein kinase,phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin,p53,Janus kinase 2/signal transducer and activator of transcription 3,hypoxia-inducible factor-1α,wingless-type mouse mammary tumor virus integration site family/beta-catenin(Wnt/β-catenin),nuclear factor kappa B,and Hippo pathways.Therefore,the repurposing of drugs targeting these pathways represents an interesting option in the search for new treatments for GC.In this review,we explore some relevant pathways involved in the development of GC and the possibilities of repurposing drugs that target them.
文摘BACKGROUND Despite advances in the treatment of ulcerative colitis(UC),some patients remain refractory to the currently available treatments.Dual biologic therapy(DBT)has emerged as a promising strategy for these patients.CASE SUMMARY A patient with extensive UC presented with steroid dependence and contraindications(past medical history included breast cancer and previous myocardial infarction)to treatment with tumor necrosis factor and Janus kinase inhibitors.DBT ofα4β7 integrin antagonist(vedolizumab)and interleukin 23p19 inhibitor(mirikizumab)resulted in a sustained clinical and biochemical remission.No adverse events were recorded during the follow-up.CONCLUSION This case highlighted the challenge of managing refractory UC,especially in frail patients.
基金Supported by Comisión Sectorial de Investigación Científica(CSIC-Research Group 88180)The Agencia Nacional de Investigación e Innovación/Sistema Nacional de Investigadores(ANII/SNI)The Programa de Desarrollo de las Ciencias Básicas(PEDECIBA),Uruguay.
文摘BACKGROUND Hypoxia in oral cancer promotes tumoral invasion by inducing epithelial-mesenchymal transition,leading to aggressive tumor progression.AIM To characterize the expression of hypoxia-inducible factor 1-alpha(HIF-1α)at the invasive tumor front(ITF)in comparison to tumor islands(TI)in oral squamous cell carcinoma(OSCC)and to explore its relationship with E-cadherin and Vimentin expression.METHODS Thirty-eight cases of OSCC and five cases of normal oral mucosa(NOM)were included in this study.The ITF was identified based on the region and immune expression of AE1/AE3.Immunohistochemistry was performed to assess the expression of HIF-1α,Vimentin,and E-cadherin.The immunostaining was analyzed using an immunoreactive score,and the results were illustrated using immunofluorescence.RESULTS HIF-1αexpression was significantly higher in the TI region compared to the ITF region(P=0.0134).Additionally,a significant difference was observed between TI and NOM(P=0.0115).In the ITF regions,HIF-1αexpression showed a significant correlation with Vimentin expression,with higher levels of HIF-1αassociated with increased Vimentin expression(P=0.017).CONCLUSION Based on the results of this study,HIF-1αappears to play a distinct role in OSCC tumor progression,underscoring the importance of exploring hypoxia-driven changes in cellular phenotype at the ITF of OSCC.Further research is needed to better understand their impact on OSCC prognosis.
基金funded by the ANID Fondecyt Nr.1200091"Unravelling the dynamics and impacts of sediment-laden flows in urban areas in southern Chile as a basis for innovative adaptation(SEDIMPACT)"by principal investigator Bruno Mazzorana.
文摘Infrastructure in mountainous regions is particularly vulnerable when exposed to socio-natural hazards associated with extreme events,especially flood events involving the transport of large volumes of sediment and woody debris.In this context,understanding how such processes affect the structural stability of bridges is crucial for effective risk management and the planning of resilient infrastructure.This study examines the impacts of river floods,including large wood and sediment transport,on the“El Blanco Bridge”over the Blanco River in Chaitén,Chilean Patagonia,and the resulting susceptibility of the structure.The 2D Iber model,which solves the shallow water equations,was employed to simulate different flood scenarios as bi-phasic flows(i.e.,water,inorganic and organic sediments,the latter are referred to as large wood,LW),evaluating the hydrodynamic loadings(i.e.pressure distributions and forces)on piers and their susceptibility to sliding,overturning and scouring.Critical flood scenarios that could pose a potential risk of infrastructure failure were identified by separately determining the associated peak discharge,sediment transport rates,LW loads and bed elevation changes.Compared to clear water flows,LW transport resulted in a reduction of the factor of safety against overturning and sliding,indicating higher hydrodynamic loads on the exposed structure.When sediment transport was considered,increasing flood flows slightly augmented maximum scour depth at the base of the piers.This study underscores the significance of hydrodynamic modeling of the Blanco River for natural risk management,and highlights the importance of considering LW transport when quantifying the safety of structures,especially in catchments where easily transportable LW sources may be found(e.g.,in catchments following fires or volcanic eruptions).
文摘BACKGROUND Previous studies have shown that individuals with type 1 diabetes(T1D)frequently present with reduced fecal elastase levels,suggesting exocrine pancreatic insufficiency.However,the underlying determinants and the longitudinal trajectory of these changes remain poorly understood.AIM To evaluate longitudinal changes in fecal elastase among individuals with T1D,identify associated factors,and determine clinical implications.METHODS Pancreatic exocrine function was evaluated in a cohort of patients with T1D by measuring fecal elastase concentrations(FECs).After a mean follow-up of 8.5±0.5 years,participants were recontacted,and a second stool sample was obtained.At both time points,detailed medical histories were collected,including information on diabetes progression,metabolic control,complications,gastrointestinal symptoms,and nutritional status.The study was approved by the institutional ethics committee,and written informed consent was obtained from all participants.RESULTS A total of 106 individuals with T1D(mean age=46.2 years;50%male)were enrolled.At baseline,the median FEC was 239.5μg/g,with 44 participants(41.5%)demonstrating abnormally low levels(<200μg/g).Reduced fecal elastase was significantly associated with male sex,diabetes-related complications,particularly retinopathy,and higher glycated hemoglobin levels.No significant differences in gastrointestinal symptoms,body mass index,nor most serum nutritional markers were observed between individuals with normal vs reduced fecal elastase levels.Sixty-six participants completed follow-up.Their median fecal elastase was 171.5μg/g,with 59.1%presenting levels below 200μg/g.Paired analysis showed a non-significant decline in FEC s over time.No clinical nor metabolic variables predicted longitudinal changes in FEC independently.CONCLUSION Fecal elastase levels are frequently reduced in individuals with T1D and may show a gradual decline over time.The clinical impact of these changes appears to be limited.
基金Project supported by Fondo Nacional de Desarrollo Científico y Tecnologico,FONDECYT(1200033)the National Doctoral Scholarship(21192195)+2 种基金Chile,Conselho Nacional de Desenvolvimento Científico e Tecnologico(CNPq,427164/2018-4 and 310307/2021-0)Funda?āo de AmparoàPesquisa do Estado de Goiás(FAPEG),Brazil,developed within the scope of the project CICECO-Aveiro Institute of Materials(UIDB/50011/2020,UIDP/50011/2020,LA/P/0006/2020)LogicALL(PTDC/CTMCTM/0340/2021)financed through the FCT-Foundation for Science and Technology/Ministry of Education(PIDDAC-Central Government Investment and Development Expenditure Program),Portugal。
文摘This study presents the microwave-assisted synthesis and characterization of a series of heterometal lic coordination polymers(HMCPs)with a 4-methyl-2,6-di[(1H-1,2,4-triazol-1-yl)]phenoxo ligand with varying Eu^(Ⅲ)/Tb^(Ⅲ)ratios.Single crystal X-ray diffraction reveals a double-chain structure bridged by triazolyl groups.Powder X-ray diffraction confirms the isostructural nature of the synthesized HMCPs.The photophysical properties depend on lanthanide ion concentration and excitation wavelength,leading to a color shift from green to blue as the proportion of Tb^(Ⅲ)decreases and Eu^(Ⅲ)increases.White light generation is achieved in the 8/2 Eu^(Ⅲ)/Tb^(Ⅲ)HMCP(CIE:0.293,0.326)under 335 nm excitation.The study suggests energy transfer from Tb^(Ⅲ)to Eu^(Ⅲ),but both experimental and theoretical calculations indicate that this transfer is orders of magnitude lower than the sensitization through ligand states.
文摘Multifocal epithelial hyperplasia(MEH),also known as Heck’s disease,is a rare and benign condition of the oral mucosa that is strongly associated with low-risk human papillomavirus(HPV)genotypes 13 and 32.This narrative review synthesizes recent findings regarding the epidemiology,viral mechanisms,clinical and histopathological features,diagnostic strategies-including molecular and immunohistochemical methods-and therapeutic approaches to MEH.This disease predominantly affects children and adolescents from Indigenous American countries,although cases have been increasingly reported in nonendemic regions.MEH manifests clinically as multiple,asymptomatic papules or nodules,typically exhibiting a characteristic cobblestone-like appearance.Histologically,it presents with epithelial hyperplasia,koilocytosis,and altered cytokeratin expression.Molecular techniques such as polymerase chain reaction and in situ hybridization are pivotal for accurate viral genotyping,while immunohistochemical markers such as CK4/13,Ki-67,and the absence of p16 can be useful adjuncts in differential diagnosis.Despite its self-limiting nature in most cases,treatment may be warranted in symptomatic or immunocompromised patients.This review highlights the need to improve diagnostic access,develop targeted vaccines,and implement public health strategies in vulnerable communities.It also highlights existing gaps in knowledge,particularly regarding host-virus interactions and the absence of standardized treatment protocols.
基金supported by Decit/SCTIE-Ministério da Saúde,Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq),Fundação de AmparoàPesquisa do Estado de Alagoas(FAPEAL)and Secretaria de Estado da Saúde de Alagoas(SESAU-AL)[PPSUS 60030000841/2016].
文摘Objective:To investigate mutations in the Chikungunya(CHIKV)envelope genome region and evaluate their potential impact on B lymphocyte epitopes via in silico analysis.Methods:E1,E2 and 6K protein genes were sequenced from viral RNA isolated from 13 CHIKV-positive serum samples from Alagoas State,Brazil,during the 2016 outbreak.Phylogenetic analysis,experimental epitope identification in the immune epitope database(IEDB)and in silico approaches were employed to predict the potential impact of the detected mutations.Results:The sequences were clustered via phylogenetic analysis.The CHIKV isolates belong to the ECSA genotype,with 13 detected amino acid mutations.Five mutations are located on the surface of the viral particle in regions critical for cellular receptor interaction.Nine mutations are known experimentally validated epitopes for B and T cells.In B-cell epitope predictions,mutations affect sequences within three conformational epitopes in E2 and one in E1,as well as linear epitopes.Notably,the E2-G60D mutation found in the Alagoas strain has been previously reported to influence the vector competence of Aedes aegypti,the primary vector in Brazil.Conclusions:Genomic surveillance and an in-depth understanding of viral mutations are crucial for adapting public health strategies and improving the outbreak response.These findings could have significant public health implications,such as the development of more effective vaccines,diagnostic tests,and antiviral therapies.
基金funded by the Portuguese Foundation for Science and Technology(FCT)sup-ported by the projects UIDB/00772/2020(https://doi.org/10.54499/UIDB/00772/2020)。
文摘Emerging infectious diseases are a major threat to biodiversity and an important public health issue.Flaviviruses are the cause of several emerging vector-borne zoonotic arboviruses whose distribution is currently increasing in Europe.The evidence that West Nile virus(WNV)circulates in resident and migratory species has implications for both animal and public health and should therefore be studied in depth.USUTU(USUV),Bagaza(BAGV)and tick-borne encephalitis virus(TBEV)are other viruses that are beginning to spread more widely.An integrated surveillance program,namely in birds,is essential for reducing the risk of infection in human populations within the One Health principles.In the present study,wild birds admitted to wildlife rehabilitation centers in Portugal were sampled.Two hundred eight blood samples were assayed serologically for antibodies to flaviviruses by using a commercial ELISA kit.An over-all seroprevalence of 19.6%(95%confidence interval[CI]:13.7-26.7%)was observed.Antibodies against flaviviruses were detected in 13(35.1%)different species of wild birds.Accipitriformes(26.7%;95%CI:18.5-36.2%)and Strigi-formes(26.7%;95%CI:14.6-42.0%)were the orders with the highest seroprevalence rates recorded.There were no statistically significant differences(p=0.725)between the geographical regions(NUTSⅡ)studied,but a statistically significant difference(p=0.017)was found between sex(male:34.4%;female:4.8%).A higher seroprevalence was detected in adults(32.1%)than in juvenile birds(9.3%)(p=0.014),and age was considered a risk factor for flavivirus infection in wild birds(odds ratio 1.4;95%CI:0.5-4.0).More epidemiological studies are needed in Portugal since the actual spread of the genus Flavivirus throughout the country is unknown.
基金supported by a doctoral grant from the National Scientific and Technical Research Council(Consejo Nacional de Investigaciones Científicas y T ecnicas,CONICET)the National Institute of Agricultural Technology(INTA)+1 种基金by projects funded by INTA(CP_2019–2023 I-114,I-127,I-090/2023–2025 I-111,I-87)Agencia Nacional de Promocio n Científica y T ecnica(PICT 2017N?2523)。
文摘Multiparent advanced generation inter-cross(MAGIC)populations improve the accuracy of quantitative trait loci mapping compared to biparental populations by increasing diversity and reducing linkage disequilibrium between variants.Here we describe the development of two MAGIC populations derived from a cross of 11 founder lines from the INTA(National Institute for Agricultural Technology in Argentina)sunflower breeding program.The founder lines are fertility maintainer inbred lines that exhibit genetic diversity in several traits,including flowering cycle,plant architecture,disease resistance,oil content and oil quality.The crossing scheme applied follows the design of two-way,four-way and eight-way crosses with a modification to increase the number of recombinations and shorten the linkage disequilibrium.Phenotyping a subset of F_(2)families and F_5 lines for different traits shows an increase in the diversity of the analyzed traits compared to the parental lines.In addition,we identified lines with transgressive segregation for Sunflower Verticillium Wilt resistance.These results confirm that the MAGIC populations will serve as unique genetic and genomic resources to better characterize the genetics of complex traits and identify potentially superior alleles for sunflower breeding.It will also enrich the gene pool of fertility maintainers(A/B line)of the sunflower germplasm and facilitate the introduction of new breeding methods to select female parents for use in AxR combinations to obtain superior sunflower hybrids.
基金The Trùndelag Health Study (HUNT) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology), Trùndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public HealthThe coordination of European Prospective Investigation into Cancer and Nutrition - Spain study (EPIC) is financially supported by the International Agency for Research on Cancer (IARC)+7 种基金by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC)supported by Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andaluc 1a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain)funded by The Netherlands Organisation for Health Research and DevelopmentZon Mw (Grant No.: 531-00141-3)Funding for the SHIP study has been provided by the Federal Ministry for Education and Research (BMBFidentification codes 01 ZZ96030, 01 ZZ0103, and 01 ZZ0701)support from the Swedish Research Council (2018-02527 and 2019-00193)financed by the Helmholtz Zentrum München - German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria.
文摘Background There is insufficient evidence to provide recommendations for leisure-time physical activity among workers across various occupational physical activity levels.This study aimed to assess the association of leisure-time physical activity with cardiovascular and all-cause mortality across occupational physical activity levels.Methods This study utilized individual participant data from 21 cohort studies,comprising both published and unpublished data.Eligibility criteria included individual-level data on leisure-time and occupational physical activity(categorized as sedentary,low,moderate,and high)along with data on all-cause and/or cardiovascular mortality.A 2-stage individual participant data meta-analysis was conducted,with separate analysis of each study using Cox proportional hazards models(Stage 1).These results were combined using random-effects models(Stage 2).Results Higher leisure-time physical activity levels were associated with lower all-cause and cardiovascular mortality risk across most occupational physical activity levels,for both males and females.Among males with sedentary work,high compared to sedentary leisure-time physical activity was associated with lower all-cause(hazard ratios(HR)=0.77,95%confidence interval(95%CI):0.70-0.85)and cardiovascular mortality(HR=0.76,95%CI:0.66-0.87)risk.Among males with high levels of occupational physical activity,high compared to sedentary leisure-time physical activity was associated with lower all-cause(HR=0.84,95%CI:0.74-0.97)and cardiovascular mortality(HR=0.79,95%CI:0.60-1.04)risk,while HRs for low and moderate levels of leisure-time physical activity ranged between 0.87 and 0.97 and were not statistically significant.Among females,most effects were similar but more imprecise,especially in the higher occupational physical activity levels.Conclusion Higher levels of leisure-time physical activity were generally associated with lower mortality risks.However,results for workers with moderate and high occupational physical activity levels,especially women,were more imprecise.Our findings suggests that workers may benefit from engaging in high levels of leisure-time physical activity,irrespective of their level of occupational physical activity.
基金Supported by The Instituto Nacional de Salud PúblicaMexicoby the grant from CONACYT-FOSISS SALUD2008-C01-494 87701,Mexico
文摘Cervical cancer is a worldwide disease that constitutes a significant public health problem, especially in developing countries, not only due to its high incidence but also because the most affected population comprises women who belong to marginalized socio-economic classes. Clinical and molecular research has identified immunological impairment in squamous intraepithelial cervical lesions and cervical cancer patients. Human Papillomavirus(HPV) has several mechanisms for avoiding the immune system: it down-regulates the expression of interferon and upregulates interleukin(IL)-10and transforming growth factor(TGF)-β1 to produce a local immunosuppressive environment, which, along with altered tumor surface antigens, forms an immunosuppressive network that inhibits the antitumor immune response. In this review we analyzed the available data on several deregulated cellular immune functions in patients with NIC Ⅰ, NIC Ⅱ and NIC Ⅲ and cervical cancer. The effects of immunosuppressive cytokines on innate immune response, T-cell activation and cellular factors that promote tumor cell proliferation in cervical cancer patients are summarized. We discuss the functional consequences of HPV E2, E6, and E7 protein interactions with IL-10 and TGF-β1 promoters in the induction of these cytokines and postulate its effect on the cellular immune response in squamous intraepithelial cervical lesions and cervical cancer patients. This review provides a comprehensive picture of the immunological functions of IL-10 and TGF-β1 in response to HPV in humans.
基金S.Oriolo thanks DAAD for a long-term PhD scholarship(A/12/75051)
文摘Geological,geochronological and isotopic data are integrated in order to present a revised model for the Neoproterozoic evolution of Western Gondwana.Although the classical geodynamic scenario assumed for the period 800-700 Ma is related to Rodinia break-up and the consequent opening of major oceanic basins,a significantly different tectonic evolution can be inferred for most Western Gondwana cratons.These cratons occupied a marginal position in the southern hemisphere with respect to Rodinia and recorded subduction with back-arc extension,island arc development and limited formation of oceanic crust in internal oceans.This period was thus characterized by increased crustal growth in Western Gondwana,resulting from addition of juvenile continental crust along convergent margins.In contrast,crustal reworking and metacratonization were dominant during the subsequent assembly of Gondwana.The Rio de la Plata,Congo-Sao Francisco,West African and Amazonian cratons collided at ca.630-600 Ma along the West Gondwana Orogen.These events overlap in time with the onset of the opening of the Iapetus Ocean at ca.610-600 Ma,which gave rise to the separation of Baltica,Laurentia and Amazonia and resulted from the final Rodinia break-up.The East African/Antarctic Orogen recorded the subsequent amalgamation of Western and Eastern Gondwana after ca.580 Ma,contemporaneously with the beginning of subduction in the Terra Australis Orogen along the southern Gondwana margin.However,the Kalahari Craton was lately incorporated during the Late Ediacaran-Early Cambrian.The proposed Gondwana evolution rules out the existence of Pannotia,as the final Gondwana amalgamation postdates latest connections between Laurentia and Amazonia.Additionally,a combination of introversion and extroversion is proposed for the assembly of Gondwana.The contemporaneous record of final Rodinia break-up and Gondwana assembly has major implications for the supercontinent cycle,as supercontinent amalgamation and break-up do not necessarily represent alternating episodic processes but overlap in time.
基金Supported by DGAPA-UNAM IN225711 MéxicoCONACYT,Grant 2011-CO1-162358,México
文摘Helicobacter pylori(H. pylori) is a successful pathogen that can persist in the stomach of an infected person for their entire life. It provokes chronic gastric inflammation that leads to the development of serious gastric diseases such as peptic ulcers, gastric cancer and Mucosa associated lymphoid tissue lymphoma. It is known that these ailments can be avoided if the infection by the bacteria can be prevented or eradicated. Currently, numerous antibiotic-based therapies are available. However, these therapies have several inherent problems, including the appearance of resistance to the antibiotics used and associated adverse effects, the risk of re-infection and the high cost of antibiotic therapy. The delay in developing a vaccine to prevent or eradicate the infection has furthered research into new therapeutic approaches. This review summarises the most relevant recent studies on vaccine development and new treatments using natural resources such as plants, probiotics and nutraceuticals. In addition, novel alternatives based on microorganisms, peptides, polysaccharides, and intragastric violet light irradiation are presented. Alternative therapies have not been effective in eradicating the bacteria but have been shown to maintain low bacterial levels. Nevertheless, some of them are useful in preventing the adverse effects of antibiotics, modulating the immune response, gastroprotection, and the general promotion of health. Therefore, those agents can be used as adjuvants of allopathic anti-H. pylori eradication therapy.
基金Supported by Programa de Desarrollo de las Ciencias Básicas,Ministry of Education and Culture
文摘There has been significant progress in our understanding of the pathobiology, epidemiology and prognosis of pulmonary vascular disease and, over the past few years, there has been an explosion of clinical therapeutic trials for pulmonary arterial hypertension (PAH). The increasing number of different conditions now associated with PAH and the appearance of new diagnostic techniques have led to a need for a systematic diagnostic approaches and a new disease classification, which has resulted in notable improvements in the quality and efficacy of clinical care. We appreciate traditional resting right heart catheterization techniques (which still remain the gold standard for diagnosing PAH and managing patients on therapy) and look forward to novel invasive techniques (e.g. intravascular ultrasound) that add greatly to our understanding of right ventricle and pulmonary circulation, and for the interpretation of data from clinical trials as well.
文摘AIM:To ascertain the role of cardiovascular risk factors,cardiovascular diseases,standard treatments and other diseases in the development of ischemic colitis(IC).METHODS:A retrospective,case-control study was designed,using matched data and covering 161 incident cases of IC who required admission to our hospital from 1998 through 2003.IC was diagnosed on the basis of endoscopic findings and diagnostic or compatible his-tology.Controls were randomly chosen from a cohort of patients who were admitted in the same period and required a colonoscopy,excluding those with diagnosis of colitis.Cases were matched with controls(ratio 1:2),by age and sex.A conditional logistic regression was performed.RESULTS:A total of 483 patients(161 cases,322 con-trols)were included;mean age 75.67±10.03 years,55.9%women.The principal indications for colonos-copy in the control group were lower gastrointestinal hemorrhage(35.4%),anemia(33.9%),abdominal pain(19.9%)and diarrhea(9.6%).The endoscopic findings in this group were hemorrhoids(25.5%),diverticular disease(30.4%),polyps(19.9%)and colorectal cancer(10.2%).The following variables were associated with IC in the univariate analysis:arterial hypertension(P= 0.033);dyslipidemia(P<0.001);diabetes mellitus(P =0.025);peripheral arterial disease(P=0.004);heart failure(P=0.026);treatment with hypotensive drugs(P=0.023);angiotensin-converting enzyme inhibitors;(P=0.018);calcium channel antagonists(P=0.028);and acetylsalicylic acid(ASA)(P<0.001).Finally,the following variables were independently associated with the development of IC:diabetes mellitus[odds ratio(OR)1.76,95%confidence interval(CI):1.001-3.077,P=0.046];dyslipidemia(OR 2.12,95%CI:1.26-3.57,P=0.004);heart failure(OR 3.17,95%CI:1.31-7.68,P=0.01);peripheral arterial disease(OR 4.1,95%CI:1.32-12.72,P=0.015);treatment with digoxin(digitalis)(OR 0.27,95%CI:0.084-0.857,P=0.026);and ASA(OR 1.97,95%CI:1.16-3.36,P=0.012).CONCLUSION:The development of an episode of IC was independently associated with diabetes,dyslipid-emia,presence of heart failure,peripheral arterial dis-ease and treatment with digoxin or ASA.
文摘Pulmonary vein stenosis(PVS) is rare condition characterized by a challenging diagnosis and unfavorable prognosis at advance stages. At present, injury from radiofrequency ablation for atrial fibrillation has become the main cause of the disease. PVS is characterized by a progressive lumen size reduction of one or more pulmonary veins that, when hemodynamically significant, may raise lobar capillary pressure leading to signs and symptoms such as shortness of breath, cough, and hemoptysis. Image techniques(transesophageal echocardiography, computed tomography, magnetic resonance and perfusion imaging) are essential to reach a final diagnosis and decide an appropriate therapy. In this regard, series from referral centers have shown that surgical and transcatheter interventions may improve prognosis. The purpose of this article is to review the etiology, assessment and management of PVS.
基金Agencia Nacional de Investigación e Innovación(ANII)through project FMV_2_2011_1_6971 and PEDECIBA,Uruguay
文摘Hepatitis C virus(HCV) has infected over 170 million people worldwide and creates a huge disease burden due to chronic, progressive liver disease. HCV is a singlestranded, positive sense, RNA virus, member of the Flaviviridae family. The high error rate of RNA-dependent RNA polymerase and the pressure exerted by the host immune system, has driven the evolution of HCV into 7 different genotypes and more than 67 subtypes. HCV evolves by means of different mechanisms of genetic variation. On the one hand, its high mutation rates generate the production of a large number of different but closely related viral variants during infection, usually referred to as a quasispecies. The great quasispecies variability of HCV has also therapeutic implications since the continuous generation and selection of resistant or fitter variants within the quasispecies spectrum might allow viruses to escape control by antiviral drugs. On the other hand HCV exploits recombination to ensure its survival. This enormous viral diversity together with some host factors has made it difficult to control viral dispersal. Current treatment options involve pegylated interferon-α and ribavirin as dual therapy or in combination with a direct-acting antiviral drug, depending on the country. Despite all the efforts put into antiviral therapy studies, eradication of the virus or the development of a preventive vaccine has been unsuccessful so far. This review focuses on current available data reported to date on the genetic mechanisms driving the molecular evolution of HCV populations and its relation with the antiviral therapies designed to control HCV infection.
