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AIM: This article summarizes key research presented at the International AIDS Society (IAS) Conference in Brisbane, held in July 2023. CO-MORBIDITIES: The REPRIEVE Trial as a conference highlight, demonstrating significantly fewer major cardiovascular events amongst people with HIV who were randomized to pitavastatin compared to placebo. Key data on weight, hypertension and incident diabetes are also summarized. ANTIRETROVIRAL THERAPY: Novel data on doravirine and islatravir are described as are trials demonstrating efficacy dolutegravir/lamivudine first-line in people without baseline resistance testing and in suppressed switch amongst people with historic lamivudine resistance. HIV CURE: The sixth case of HIV cure secondary to stem cell transplantation is summarized, as are new insights into the central nervous system as an HIV reservoir.
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Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Humanos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Lamivudina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
To reveal differences in arsenic (As) accumulation among indica rice cultivars and assess the human health risks arising from inorganic arsenic (iAs) intake via rice consumption, a total of 320 field indica rice samples and corresponding soil samples were collected from Fujian Province in China. The results showed that available soil As (0.03 to 3.83 mg/kg) showed a statistically significant positive correlation with total soil As (0.10 to 19.45 mg/kg). The inorganic As content in brown rice was between 0.001 and 0.316 mg/kg. Among the cultivars, ten brown rice samples (3.13%) exceeded the maximum contaminant level (MCL) of iAs in food of 0.2 mg/kg in China. The estimated daily intake (EDI) and calculated individual incremental lifetime cancer risk (ILCR) ranged from 0.337 µg/day to 106.60 µg/day and from 8.18 × 10-6 to 2.59 × 10-3, respectively. Surprisingly, the average EDI and the EDIs of 258 (80.63%) brown rice samples were higher than the maximum daily intake (MDI) of 10 µg/day in drinking water as set by the National Research Council. The mean ILCR associated with iAs was 54.3 per 100,000, which exceeds the acceptable upper limit (AUL) of 10 per 100,000 set by the USEPA. Notably, the cultivars Y-Liang-You 1 and Shi-Ji 137 exhibited significantly higher mean ILCRs compared to the AUL and other cultivars, indicating that they pose more serious cancer risks to the local population. Finally, this study demonstrated that the cultivars Yi-Xiang 2292 and Quan-Zhen 10 were the optimal cultivars to mitigate risks associated with iAs to human health from rice consumption.
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Arsênio , Neoplasias , Oryza , Humanos , Oryza/genética , Monitoramento Ambiental , Medição de Risco , Genótipo , SoloRESUMO
Marine biofouling is a global problem affecting various industries, particularly the shipping industry due to long-distance voyages across various ecosystems. Therein fouled hulls cause increased fuel consumption, greenhouse gas emissions, and the spread of invasive aquatic species. To counteract these issues, biofouling management plans are employed using manual cleaning protocols and protective coatings. This review provides a comprehensive overview of adhesion strategies of marine organisms, and currently available mitigation methods. Further, recent developments and open challenges of antifouling (AF) and fouling release (FR) coatings are discussed with regards to the future regulatory environment. Finally, an overview of the environmental and economic impact of fouling is provided to point out why and when the use of biocidal solutions is beneficial in the overall perspective.
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Incrustação Biológica , Incrustação Biológica/prevenção & controle , Biofilmes , Ecossistema , Organismos AquáticosRESUMO
The recommendations for the general public as well as the tools offered to healthcare professionals for their practices are consistent with the 2022-2025 national strategy for the prevention of infections and antibiotic resistance. They therefore cover both infection prevention and the proper use of antibiotics.
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Antibacterianos , Pessoal de Saúde , Humanos , Antibacterianos/uso terapêutico , Atenção à SaúdeRESUMO
Single nucleotide polymorphisms (SNPs) in insulin and insulin receptor genes may influence the interaction between the two molecules, as may anti-insulin antibodies (IAs), commonly found in patients with type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D) treated with exogenous insulin. We examined the impact of two SNPs in the human insulin gene (INS), rs3842752 and rs689, and two in the insulin receptor gene (INSR) rs2245649 and rs2229429, on disease susceptibility, glycaemic control, and IAs formation in 100 T1D patients and 101 T2D patients treated with insulin. 79 individuals without diabetes were typed as healthy controls. The minor alleles of rs3842752 and rs689 in INS protected against T1D (OR: 0.50, p = 0.01 and OR: 0.44; p = 0.002, respectively). The minor alleles of both rs2245649 and rs2229429 in INSR were risk factors for poor glycaemic control (HbA1c ≥ 80 mmol/mol) in T1D (OR: 5.35, p = 0.009 and OR: 3.10, p = 0.01, respectively). Surprisingly, the minor alleles of rs2245649 and rs2229429 in INSR associated strongly with the absence of IAs in T1D (OR = 0.28, p = 0.008 and OR = 0.30, p = 0.002, respectively). In conclusion, the minor alleles of the investigated INS SNPs protect against T1D, and the minor alleles of the investigated INSR SNPs are associated with poor glycaemic control and the absence of IAs in T1D.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Controle Glicêmico , Humanos , Insulina/genética , Polimorfismo de Nucleotídeo Único , Receptor de Insulina/genéticaRESUMO
Almost all processed food comes packaged in either plastic, glass, metal, or paper and paperboard materials, and many packaging materials are disposed of after a single use (linear economy). Based on the concept of a circular economy, the recycling of food packaging materials has become one of the main targets for industries and regulators around the world. However, recycling presents particular challenges, mainly related to the recycled material composition, which determines its reusability, application, functionality, and chemical safety. In this latter matter, it has been demonstrated that the use of recycled food packaging materials increases the number and possible sources of substances that could be present in the packaging material, which is of concern as substances that can migrate into food and cause health hazards upon consumption. This review compiles information regarding substances detected in non-permanent food packaging materials, focusing mainly on plastics, paper, and paperboards. The compilation of literature studies (110 research articles) on the presence of intentionally added substances (IAS) and non-intentionally added substances (NIAS) in food packaging materials, their migration, toxicity, and dietary exposure has been summarized, evaluated, and discussed. In addition, current sustainable food packaging trends have been mentioned. Finally, approaches to reduce the presence, migration, and potential exposure to substances that have migrated from packaging materials into food have been reviewed.
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Contaminação de Alimentos , Embalagem de Alimentos , Contaminação de Alimentos/análise , Plásticos/análise , ReciclagemRESUMO
Tropical montane grasslands (TMG) support biodiverse and endemic taxa and provide vital ecosystem services to downstream communities. Nevertheless, invasive alien tree species across the world have threatened tropical grasslands and grassland endemic species. In India, TMG in the Shola Sky Islands of the Western Ghats have been reduced due to exotic tree invasions (Acacias, Pines, and Eucalyptus species). The loss of grassland habitat has, in turn, reduced the range sizes of species endemic to grasslands (plants, birds, amphibians, and mammals), driving some populations to local extinction. Grassland conversion to exotic trees has also impacted ecosystem services in the Western Ghats. Conserving existing grassland and restoring invaded habitat is critical to reverse these losses. This research focused on identifying grassland restoration sites using satellite images with a high spatial resolution (RapidEye). We used an object-oriented Random Forest classification to map the area for grassland restoration. We identified an area of 254 sq. km. as suitable for grassland restoration and an area of 362 sq. km. for grassland conservation and preventing invasion by exotic tree species. For restoration, we recommend careful removal of young and isolated exotic trees at the invasion front and restoring grasslands, instead of removing dense stands of mature exotic trees. Although our limited data indicate that areas with low fire frequency tend to be invaded, and areas invaded by exotic trees tend to burn at higher intensities, we recommend a broader investigation of these patterns to critically examine a potential role for the use of fire in invasive species management. We assume that removing exotic tree species in the identified restoration sites and restoring the grassland will help recover lost habitat and ensure the viability of indigenous and endemic species and increase streamflow.
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Espécies Introduzidas , Árvores , Animais , Biodiversidade , Ecossistema , Pradaria , Índia , Ilhas , Tecnologia de Sensoriamento RemotoRESUMO
INTRODUCTION: There is a growing interest in minimally invasive endoscopic gallbladder drainage therapies. Unlike stenting, a technology based on magnetic compression could theoretically produce a durable drainage anastomosis without residual foreign material. This study aimed to evaluate the safety and technical feasibility of a cholecysto-duodenal magnetic compression anastomosis. MATERIAL AND METHODS: We performed a survival study of two Yorkshire pigs. Duodenal magnets were deployed endoscopically; reciprocal gallbladder magnets were placed laparoscopically, and the magnets were coupled. Pigs underwent serial endoscopy documenting magnet expulsion and evolution of cholecysto-duodenal anastomosis creation. Necropsies and histological evaluation were performed. Primary endpoints were technical success and safety. Secondary endpoints included anastomosis integrity, patency, and histologic characteristics. RESULTS: Magnets were successfully delivered and coupled. Patent, leak-free anastomoses formed by day 4. Magnets were expelled by day 10. All anastomoses were widely patent at one month (mean diameter 15 mm). Necropsy showed the absence of adhesions affecting the anastomosis. Histology showed complete re-epithelialization without inflammation or foreign body reaction. CONCLUSIONS: Magnetic cholecysto-duodenal anastomosis for gallbladder drainage appears safe and feasible in the animal model. The anastomoses are patent, leak-free, and without inflammation from the presence of foreign material. Technical modifications for magnet delivery under endoscopic ultrasound (EUS) guidance are currently underway.
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Vesícula Biliar , Magnetismo , Anastomose Cirúrgica , Animais , Vesícula Biliar/cirurgia , Fenômenos Magnéticos , Imãs , SuínosRESUMO
It is known that the chronic intake of arsenic (As) leads to the development of multisystem pathologies. In the case of high levels of As consumption, the risks of negative effects of exposure to inorganic and methylated forms persist for decades. The International Agency for Research on Cancer (IARC) has established that all inorganic forms of As are absolute carcinogens (group 1). Methylated forms of As are classified as substances possibly carcinogenic to humans (group 2b). Not metabolized in the human body forms of organic As are not carcinogenic to humans (group 3). The aim - assessment of health risks of various forms of As contained in food, including seafood. Material and methods. The scientific data regarding the risks associated with As contamination of food obtained by using PubMed, Web of Science, Google Scholar databases, legislative and regulatory acts of the Eurasian Economic Union, the Russian Federation, the Codex Alimentarius Commission, the European Union and other coun tries have been analyzed. Results. The analysis of the available data showed that the degree of As toxicity decreased in the following order: glutathione of dimethylarsonic acid (DMAIIIGl) > methylarsic acid (MMAIII) > dimethylarsic acid (DMAIII) > arsenic hydrocarbons (AsHC) > arsenite (AsIII) > arsenate (AsV) > trimethylarsine (TMAIII) > methylarsonic acid (MMAV) > dimethylarsonic acid (DMAV) > DMAIII-sugar glyceride > DMAV-sugar glyceride > thio compounds of DMAV > arsenosugarsIII > arsenosugarsV > tetramethylarsonium chloride (TETPA) > trimethylarsine oxide (TMAO), arsenocholine (AsC) > arsenobetaine (AB). Consequently, the toxicity of some methylated and organic forms of As (for example, DMAIIIGl, AsHC) may be higher than that of its inorganic forms. It is known that As is found in foods mainly in organic forms. When ingested with food, As organic forms are metabolized and, thus, could cause a number of negative effects in the organism. Conclusion. High levels of organic and inorganic forms of As in food, including seafood, could have a negative impact on the health of the population, which makes it necessary to conduct additional assessments of the health risks of various forms of As entering the body. The insufficient amount of data on the toxicity of organic forms of As indicates the impossibility of separate setting of safety maximum levels for organic and inorganic forms of As in foods.
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Arsênio , Arsênio/análise , Arsênio/toxicidade , Humanos , Federação RussaRESUMO
Nowadays, food packaging is a crucial tool for preserving food quality and has become an inseparable part of our daily life. Strong consumer demand and market trends enforce more advanced and creative forms of food packaging. New packaging development requires safety evaluations that always implicate the application of complex analytical methods. The present work reviews the development and application of new analytical methods for detection of possible food contaminants from the packaging origin on the quality and safety of fresh food. Among food contaminants migrants, set-off migrants from printing inks, polymer degradation products, and aromatic volatile compounds can be found that may compromise the safety and organoleptic properties of food. The list of possible chemical migrants is very wide and includes antioxidants, antimicrobials, intentionally added substances (IAS), non-intentionally added substances (NIAS), monomers, oligomers, and nanoparticles. All this information collected prior to the analysis will influence the type of analyzing samples and molecules (analytes) and therefore the selection of a convenient analytical method. Different analytical strategies will be discussed, including techniques for direct polymer analysis.
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Contaminação de Alimentos/análise , Embalagem de Alimentos , Embalagem de Alimentos/legislação & jurisprudência , Tinta , Nanopartículas/análise , Polímeros/química , Compostos Orgânicos Voláteis/análiseRESUMO
Arsenic is a metalloid found in groundwater as a byproduct of soil/rock erosion and industrial and agricultural processes. This xenobiotic elicits its toxicity through different mechanisms, and it has been identified as a toxicant that affects virtually every organ or tissue in the body. In the central nervous system, exposure to arsenic can induce cognitive dysfunction. Furthermore, iAs has been linked to several neurological disorders, including neurodevelopmental alterations, and is considered a risk factor for neurodegenerative disorders. However, the exact mechanisms involved are still unclear. In this review, we aim to appraise the neurotoxic effects of arsenic and the molecular mechanisms involved. First, we discuss the epidemiological studies reporting on the effects of arsenic in intellectual and cognitive function during development as well as studies showing the correlation between arsenic exposure and altered cognition and mental health in adults. The neurotoxic effects of arsenic and the potential mechanisms associated with neurodegeneration are also reviewed including data from experimental models supporting epidemiological evidence of arsenic as a neurotoxicant. Next, we focused on recent literature regarding arsenic metabolism and the molecular mechanisms that begin to explain how arsenic damages the central nervous system including, oxidative stress, energy failure and mitochondrial dysfunction, epigenetics, alterations in neurotransmitter homeostasis and synaptic transmission, cell death pathways, and inflammation. Outlining the specific mechanisms by which arsenic alters the cell function is key to understand the neurotoxic effects that convey cognitive dysfunction, neurodevelopmental alterations, and neurodegenerative disorders.
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Intoxicação por Arsênico/etiologia , Arsênio/toxicidade , Animais , Apoptose/efeitos dos fármacos , Intoxicação por Arsênico/genética , Autofagia/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Hormone therapy is one of the popular therapeutic methods for prostate cancer. Intermittent androgen suppression (IAS) is the method which stops and resumes hormone therapy repeatedly. The efficacy of IAS differs depending on patients; both the cases have been reported where the relapse of cancer happened and did not happen, for the patients who had undergone IAS. For the patients who cannot avoid the relapse of cancer by IAS, we should delay the relapse of cancer as later as possible. Here we compared some practical methods of determining when to stop and restart hormone therapy for IAS using an existing mathematical model of prostate cancer. The method we suggest is to determine the ratio of on-treatment period and off-treatment period sparsely for each cycle, namely the "sparse search." We also compared the performance of the sparse search with the exhaustive search and the model predictive control. We found that the sparse search can find a good treatment schedule without failure, and the computational cost is not so high compared to the exhaustive method. In addition, we focus on the model predictive control (MPC) method which has been applied to the scheduling of IAS in some existing studies. The MPC is computationary efficient, although it does not always find an optimal schedule in the numerical experiments here. We believe that the MPC method might be also promising because of its reasonable computational costs and its possibility of expanding of the model.
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Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/uso terapêutico , Modelos Biológicos , Modelos Teóricos , Neoplasias da Próstata/tratamento farmacológico , Simulação por Computador , Esquema de Medicação , Humanos , Masculino , Análise Numérica Assistida por Computador , Probabilidade , Antígeno Prostático Específico/metabolismoRESUMO
OBJECTIVE: Despite the prevalence and impact of intracranial aneurysms (IAs), the molecular basis of their pathogenesis remains largely unknown. Moreover, there is a dearth of clinically validated biomarkers to efficiently screen patients with IAs and prognosticate risk for rupture. The aim of this study was to survey the literature to systematically identify the spectrum of genetic aberrations that have been identified in IA formation and risk of rupture. METHODS: A literature search was performed using the Medical Subject Headings (MeSH) system of databases including PubMed, EMBASE, and Google Scholar. Relevant studies that reported on genetic analyses of IAs, rupture risk, and long-term outcomes were included in the qualitative analysis. RESULTS: A total of 114 studies were reviewed and 65 were included in the qualitative synthesis. There are several well-established mendelian syndromes that confer risk to IAs, with variable frequency. Linkage analyses, genome-wide association studies, candidate gene studies, and exome sequencing identify several recurrent polymorphic variants at candidate loci, and genes associated with the risk of aneurysm formation and rupture, including ANRIL (CDKN2B-AS1, 9p21), ARGHEF17 (11q13), ELN (7q11), SERPINA3 (14q32), and SOX17 (8q11). In addition, polymorphisms in eNOS/NOS3 (7q36) may serve as predictive markers for outcomes following intracranial aneurysm rupture. Genetic aberrations identified to date converge on posited molecular mechanisms involved in vascular remodeling, with strong implications for an associated immune-mediated inflammatory response. CONCLUSIONS: Comprehensive studies of IA formation and rupture have identified candidate risk variants and loci; however, further genome-wide analyses are needed to identify high-confidence genetic aberrations. The literature supports a role for several risk loci in aneurysm formation and rupture with putative candidate genes. A thorough understanding of the genetic basis governing risk of IA development and the resultant aneurysmal subarachnoid hemorrhage may aid in screening, clinical management, and risk stratification of these patients, and it may also enable identification of putative mechanisms for future drug development.
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Aneurisma Roto/genética , Aneurisma Intracraniano/genética , Aneurisma Roto/epidemiologia , Progressão da Doença , Predisposição Genética para Doença , Genômica , Humanos , Aneurisma Intracraniano/epidemiologia , Medição de Risco , Hemorragia Subaracnóidea/epidemiologia , Hemorragia Subaracnóidea/genéticaRESUMO
Invasive alien species (IAS) can cause ecological and economic damages. To reduce or prevent these damages different management and prevention strategies aim to impede new establishments or a further spreading of IAS. However, for these measures to be successful, public knowledge of risks and threats of IAS as well as public support for eradication measures are important prerequisites. We conducted a survey to examine (i) public and experts' awareness and knowledge of IAS, (ii) their preferences for six invasive plant species and (iii) their preferences for and trade-offs among management alternatives in Switzerland. In addition, a choice experiment was applied to analyse preferences concerning the intensity, priority and costs of interventions. Both, the Swiss public and the experts have a preference for intervening against invasive alien species. However, the public and the experts differ in their priorities of combatting particular species, resulting in a different ranking of intervention necessities. Further, differences were found in the willingness to pay for interventions between the German-, French- and Italian-speaking parts of Switzerland. The results suggest that a higher problem awareness increases the willingness to pay for countermeasures. We conclude that education programs or information campaigns are promising instruments to raise public awareness and to avoid conflicts concerning the management of invasive alien species.
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Conscientização , Espécies Introduzidas , Ecologia , Plantas , SuíçaRESUMO
Ageing is associated with impaired neuromuscular function of the terminal gastrointestinal (GI) tract, which can result in chronic constipation, faecal impaction and incontinence. Interstitial cells of cajal (ICC) play an important role in regulation of intestinal smooth muscle contraction. However, changes in ICC volume with age in the terminal GI tract (the anal canal including the anal sphincter region and rectum) have not been studied. Here, the distribution, morphology and network volume of ICC in the terminal GI tract of 3- to 4-month-old and 26- to 28-month-old C57BL/6 mice were investigated. ICC were identified by immunofluorescence labelling of wholemount preparations with an antibody against c-Kit. ICC network volume was measured by software-based 3D volume rendering of confocal Z stacks. A significant reduction in ICC network volume per unit volume of muscle was measured in aged animals. No age-associated change in ICC morphology was detected. The thickness of the circular muscle layer of the anal sphincter region and rectum increased with age, while that in the distal colon decreased. These results suggest that ageing is associated with a reduction in the network volume of ICC in the terminal GI tract, which may influence the normal function of these regions.
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Envelhecimento/genética , Constipação Intestinal/genética , Trato Gastrointestinal/metabolismo , Células Intersticiais de Cajal/metabolismo , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Tamanho Celular , Colo/metabolismo , Colo/patologia , Constipação Intestinal/metabolismo , Constipação Intestinal/patologia , Modelos Animais de Doenças , Trato Gastrointestinal/patologia , Humanos , Células Intersticiais de Cajal/patologia , Camundongos , Contração Muscular/genéticaRESUMO
With the establishment by CODEX of a 200 ng/g limit of inorganic arsenic (iAs) in polished rice grain, more analyses of iAs will be necessary to ensure compliance in regulatory and trade applications, to assess quality control in commercial rice production, and to conduct research involving iAs in rice crops. Although analytical methods using high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) have been demonstrated for full speciation of As, this expensive and time-consuming approach is excessive when regulations are based only on iAs. We report a streamlined sample preparation and analysis of iAs in powdered rice based on heated extraction with 0.28 M HNO3 followed by hydride generation (HG) under control of acidity and other simple conditions. Analysis of iAs is then conducted using flow-injection HG and inexpensive ICP-atomic emission spectroscopy (AES) or other detection means. A key innovation compared with previous methods was to increase the acidity of the reagent solution with 4 M HCl (prior to reduction of As5+ to As3+), which minimized interferences from dimethylarsinic acid. An inter-laboratory method validation was conducted among 12 laboratories worldwide in the analysis of six shared blind duplicates and a NIST Standard Reference Material involving different types of rice and iAs levels. Also, four laboratories used the standard HPLC-ICP-MS method to analyze the samples. The results between the methods were not significantly different, and the Horwitz ratio averaged 0.52 for the new method, which meets official method validation criteria. Thus, the simpler, more versatile, and less expensive method may be used by laboratories for several purposes to accurately determine iAs in rice grain. Graphical abstract Comparison of iAs results from new and FDA methods.
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Arsênio/análise , Grão Comestível/química , Análise de Alimentos/métodos , Contaminação de Alimentos/análise , Espectrometria de Massas/métodos , Oryza/química , Cromatografia Líquida de Alta Pressão/métodos , Laboratórios , Limite de DetecçãoRESUMO
Invasive species are one of the main threats to biodiversity. When an alien species is introduced into a new environment, fast identification and definition of management strategies may avoid or minimize impacts. When an invasive species is already established, the most adopted approaches are population control and monitoring. In order to perform such strategies, assessment of characteristics of the invasive population is imperative. This study tested a new method of population size estimation and monitoring in an invasive population of crayfish Procambarus clarkii in a conservation area in the Atlantic Rain Forest (Southeastern Brazil). The population dynamics was studied for 1 year to examine the efficacy of the selected method and to evaluate if the population is stable. Later, the effect of periodical removal of animals on the population size was tested. The method of population estimation used in this study proved to be very effective. We recommend using it to monitor invasive populations of P. clarkii. The population size varied discretely over the year with variable but low growth rate, indicating that the population is already established which introduce a notable threat to native species. The continuous removal of specimens proved to be inefficient since the growth rate was higher after the removal. One intensive removal event might be more effective than a continuous moderate removal as the one applied in this study.
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Astacoidea/crescimento & desenvolvimento , Biodiversidade , Monitoramento Ambiental/métodos , Água Doce , Espécies Introduzidas , Animais , Brasil , Densidade Demográfica , Dinâmica PopulacionalRESUMO
Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC50 values of 1.48µM and 1.61µM, respectively. They were much potent than the reference drug ddI (EC50=76.0µM) and comparable to 3TC (EC50=2.54µM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.
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Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Humanos , Indóis/química , Indóis/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologiaRESUMO
OBJECTIVE: To summarise current knowledge of Internal anal sphincter. BACKGROUND: The internal anal sphincter (IAS) is the involuntary ring of smooth muscle in the anal canal and is the major contributor to the resting pressure in the anus. Structural injury or functional weakness of the muscle results in passive incontinence of faeces and flatus. With advent of new assessment and treatment modalities IAS has become an important topic for surgeons. This review was undertaken to summarise our current knowledge of internal anal sphincter and highlight the areas that need further research. METHOD: The PubMed database was used to identify relevant studies relating to internal anal sphincter. RESULTS: The available evidence has been summarised and advantages and limitations highlighted for the different diagnostic and therapeutic techniques. CONCLUSION: Our understanding of the physiology and pharmacology of IAS has increased greatly in the last three decades. Additionally, there has been a rise in diagnostic and therapeutic techniques specifically targeting the IAS. Although these are promising, future research is required before these can be incorporated into the management algorithm.
Assuntos
Canal Anal , Incontinência Fecal , Canal Anal/anatomia & histologia , Canal Anal/lesões , Canal Anal/patologia , Canal Anal/fisiopatologia , Incontinência Fecal/diagnóstico , Incontinência Fecal/etiologia , Incontinência Fecal/fisiopatologia , Incontinência Fecal/terapia , HumanosRESUMO
BACKGROUND: A minimally invasive method of entero-enteral bypass may be desirable for treatment of obstruction, obesity, or metabolic syndrome. We have developed a technology based on miniature self-assembling magnets which create large-caliber anastomoses (incisionless anastomosis system or IAS). The aim of this study was to assess (a) procedural characteristics of IAS deployment and (b) long-term integrity and patency of the resulting jejuno-ileal dual-path bypass. METHODS: Endoscopic jejuno-ileal bypass creation using IAS magnets was performed in 8 Yorkshire pigs survived 3 months. PROCEDURE: The jejunal magnet was endoscopically deployed. However, the ileal magnet required surgical delivery given restraints of porcine anatomy. A 5-mm enterotomy was created through which the ileal magnet was inserted using a modified laparoscopic delivery tool. Magnets were manually coupled. Pigs underwent serial endoscopies for anastomosis assessment. Three-month necropsies were performed, followed by pressure testing of anastomoses and histological analysis. RESULTS: Jejuno-ileal bypass creation using self-assembling IAS magnets was successful in all 8 pigs (100 %). Patent, leak-free bypasses formed in all animals by day 10. All IAS magnets were expelled by day 12. Anastomoses were widely patent at 3 months, with mean maximal diameter of 30 mm. At necropsy, adhesions were minimal. Pressure testing confirmed superior integrity of anastomotic tissue. Histology showed full epithelialization across the anastomosis with no evidence of submucosal fibrosis or inflammation. CONCLUSIONS: Entero-enteral bypass using self-assembling IAS magnets is safe and technically feasible in the porcine model. IAS magnets can be rapidly delivered endoscopically or through a modified laparoscopic device. Expulsion of fused magnets avoids retention of prosthetic material. Anastomoses are widely patent and fully re-epithelialized. Three-month pressure testing reveals anastomotic tissue to be as robust as native tissue, while necropsy and histology suggests minimal/absent tissue inflammation. In human anatomy, a fully endoscopic jejuno-ileal bypass using IAS magnets may be feasible.