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Today, the emergence of increasingly restrictive treatment and reuse policies make the implementation of full-scale tertiary treatment, capable of improving the quality of water, a priority. Full-scale TiO2 photocatalysis systems are resulting in a promising option, since TiO2 is commercially available. However, questions such as how to work continuously during day/night irradiation cycle, or the removing of TiO2 in outlet flow are still unresolved. In this work, a full-scale system integrating a solar CPC/UV-LED step combined with commercial microfiltration membranes was installed in a conventional WWTP for agricultural reuse purposes. After optimization, 0.5 g/L of catalyst and combined SOLAR + UV-LED showing the highest pharmaceutical removal percentages, while a self-designed UV-LED included in the own reaction tank resulting in higher efficiencies compared with commercial lamps. Longer membrane surface area decreased fouling problems in the system. However, 60 min of irradiation time was necessary to reach the most restrictive water quality values according with (EU 2020/741). After optimization step, total costs were reduced by 45%. However, it was shown that a reduction in operating and maintenance costs, along with the development of more effective and economical commercial filtration membranes is a key factor; therefore, working on these aspects is essential in the treated water cost reduction.
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Purpose: The liver imaging reporting and data system (LI-RADS) is a structured reporting system that categorizes hepatic observations according to major imaging features and lesion size, with an optional ancillary features contribution. This study aimed to evaluate inter-reader agreement of dynamic magnetic resonance imaging (MRI) using LI-RADS v2018 lexicon. Material and methods: Forty-nine patients with 69 hepatic observations were included in our study. The major and ancillary features of each hepatic observation were evaluated by 2 radiologists using LI-RADS v2018, and the interreader agreement was allocated. Results: The inter-reader agreement of major LI-RADS features was substantial; κ of non-rim arterial hyperenhancement, non-peripheral washout appearance, and enhancing capsule was 0.796, 0.799, and 0.772 (p < 0.001), respectively. The agreement of the final LI-RADS category was substantial with κ = 0.651 (p < 0.001), and weighted κ = 0.786 (p < 0.001). The inter-reader agreement of the ancillary features was substantial to almost perfect (k range from 0.718 to 1; p < 0.001). An almost perfect correlation was noted for the hepatic lesion size measurement with ICC = 0.977 (p < 0.001). Conclusions: The major and ancillary features of the LI-RADS v2018, as well as the final category and lesions size, have substantial to almost perfect inter-reader agreement.
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In generating high electroosmotic (EO) flows for use in microfluidic pumps, a limiting factor is faradaic reactions that are more pronounced at high electric fields. These reactions lead to bubble generation at the electrodes and pump efficiency reduction. The onset of gas generation for high current density EO pumping depends on many parameters including applied voltage, working fluid, and pulse duration. The onset of gas generation can be delayed and optimized for maximum volume pumped in the minimum time possible. This has been achieved through the use of a novel numerical model that predicts the onset of gas generation during EO pumping using an optimized pulse voltage waveform. This method allows applying current densities higher than previously reported. Optimal pulse voltage waveforms are calculated based on the previous theories for different current densities and electrolyte molarity. The electroosmotic pump performance is investigated by experimentally measuring the fluid volume displaced and flow rate.
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Eletro-Osmose , Modelos Teóricos , Microfluídica , Água/químicaRESUMO
The applications of smart structures with integrated piezoelectric elements have been expanding in the last few decades due to the abilities of such structures to withstand mechanical loads and operate as sensors or actuators using their electromechanical coupling. The available manufacturing techniques can result in uncertainties in the structure's geometric parameters, which, coupled with uncertainties in material properties, can lead to unexpected failures or unreliable performance. This paper presents a reliability analysis of a smart laminated composite plate made of a graphite/epoxy cross-ply substrate with a piezoelectric fiber-reinforced composite (PFRC) actuator layer under static electrical and mechanical loads. A coupled finite element (FE) model was developed in COMSOL Multiphysics, from which nondimensional stresses and displacements were calculated. To investigate the effects of randomness in the material and geometric properties, an artificial neural network (ANN) model was developed and trained using generated FE data. Monte Carlo Simulation (MCS) and First- and Second-Order Reliability Methods (FORM/SORM) were then used to shed light on the significance of considering randomness in the various material and geometric parameters and the effect of such uncertainty on the resulting nondimensional stresses and displacements. A coefficient of variation (CV) study identified the piezoelectric stress coefficient as the most significant contributing factor to the variation of all nondimensional parameters. Variation in the nondimensional parameters also increases under the application of an electric load. ANN-based FORM, SORM, and MCS all indicate a pattern of low probability of failure until a threshold value of about 3% of input parameter variation is reached, beyond which there is a rapid nonlinear increase in failure probability with increasing input parameter variation.
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PURPOSE: The purpose of this study was to determine the reliability and interobserver agreement of the liver imaging reporting and data system (LI-RADS) treatment response algorithm (LR-TR) v2018 using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and the added value of diffusion-weighted imaging (DWI). MATERIALS AND METHODS: A total of 54 patients who underwent DCE-MRI and DWI after locoregional treatment of 81 hepatocellular carcinoma (HCC) lesions from September 2020 to July 2021 were included. There were 47 men and 7 women, with a mean age of 63.9 ± 9.2 (SD) years (age range: 23-77 years). Locoregional treatments included transarterial chemoembolization (TACE) (53/81; 65.4%), radiofrequency ablation (RFA) (25/81; 30.9%) and microwave ablation (MWA) (3/81; 3.7%). Two independent radiologists retrospectively evaluated DCE-MRI examinations obtained after locoregional treatment using LR-TR, and then three months later both radiologists reevaluated DCE-MRI examinations with DWI. Interobserver agreement was assessed using intraclass correlation coefficient (ICC) and Kappa test. Diagnostic performances were evaluated in term of sensitivity, specificity, and area under ROC curve (AUC) using a composite standard of reference that included results of histopathological examinations and follow-up findings. RESULTS: Using DCE-MRI alone, observer 1 had 83.9% sensitivity (26/31; 95% confidence interval [CI]: 66-95%), 88% specificity (44/50; 95% CI: 76-95%) and 86.4% accuracy (70/81; 95%CI: 77-93%), and observer 2 had 71% sensitivity (22/31; 95% CI: 52-86%), 92% specificity (46/50; 95% CI: 81-98%) and 83.9% accuracy (68/81; 95% CI: 74-91%). For the diagnosis of viable tumors using DCE-MRI with DWI, observer 1 and observer 2 had 87.1% (27/31; 95% CI: 70-96%) and 74.2% (23/31; 95% CI: 55-88%) sensitivity, respectively. The diagnostic performance of DCE-MRI with DWI yielded an AUC (0.875; 95% CI: 0.789-0.962) not different from that of DCE-MRI without DWI (0.859; 95% CI: 0.768-0.951) (P = 0.317). Interobserver agreement for arterial phase hyperenhancement, washout, enhancement similar to pretreatment and DWI findings in all treated HCCs was almost perfect (kappa = 0.815, 0.837, 0.826 and 0.81 respectively). Agreement between observers for LR-TR category was substantial (kappa = 0.795; 95% CI: 0.665-0.924). Interobserver agreement for size of viable HCC was excellent (ICC = 0.938; 95% CI: 0.904-0.960). CONCLUSION: LR-TR using DCE-MRI alone or DCE-MRI with DWI are both accurate for detecting viable HCC lesions after locoregional treatment, with no differences in diagnostic performance and excellent interobserver agreement.
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Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Adulto , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Estudos Retrospectivos , Reprodutibilidade dos Testes , Meios de Contraste , Sensibilidade e Especificidade , Imageamento por Ressonância Magnética/métodosAssuntos
Cerebelo/diagnóstico por imagem , Encefalopatia de Wernicke/diagnóstico por imagem , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Hepatopatias Alcoólicas/complicações , Hepatopatias Alcoólicas/diagnóstico por imagem , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Tiamina/uso terapêutico , Complexo Vitamínico B/uso terapêutico , Encefalopatia de Wernicke/tratamento farmacológicoRESUMO
As phosphorus is a non-renewable resource mainly used to produce fertilizers and helps to provide food all over the world, the proper management of its reserves is a global concern since it is expected to become scarcer in the near future. In this work we assessed two different sludge line configurations aiming for P extraction and recovery before anaerobic digestion and compared them with the classical configuration. This study has been performed by simulation with the model BNRM2 integrated in the software package DESASS 7.1. Configuration 1 was based on the production of a PO4-enriched stream from sludge via elutriation in the primary thickeners, while Configuration 2 was based on the WASSTRIP® process and its PO4-enriched stream was mechanically obtained with dynamic thickeners. In both alternatives recovery was enhanced by promoting poly-phosphate (poly-P) extraction under anaerobic conditions, for which both configurations were fully evaluated in a full-scale WWTP. Both were also optimized to maximize phosphorus extraction. Their costs and life cycles were also analysed. The novelty of this research lies in the lack of literature about the integral evaluation of pre-anaerobic digestion P recovery from wastewaters. This study included a holistic approach and an optimization study of both alternatives plus their economic and environmental aspects. In Configuration 1, the PO4-P load in the recovery stream reached 43.1% of the total influent P load and reduced uncontrolled P-precipitation in the sludge line up to 52.9%. In Configuration 2, extraction was 48.2% of the influent P load and it reduced precipitation by up to 60.0%. Despite Configuration 1's lower phosphorus recovery efficiency, it had a 23.0% lower life cycle cost and a 14.2% lower global warming impact per hm3 of treated influent than Configuration 2. Configuration 1 also reduced the TAEC by 17.6% and global warming impact by 2.0% less than Configuration 0.
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Fósforo , Esgotos , Fertilizantes , Eliminação de Resíduos Líquidos , Águas ResiduáriasRESUMO
The concanavalin A--binding glycoproteins of the rat synaptic junction were isolated by affinity chromatography. These glycoproteins had molecular weights of 160,000, 123,000, 110,000, and 95,000. The tryptic peptide maps of these glycoproteins showed that the three largest glycoproteins contained a high percentage of identical peptides. This indicates that the amino acid sequences of these glycoproteins have a high degree of homology. The 95,000-dalton glycoprotein was unrelated to the other three. These findings suggest that homologous glycoproteins may participate in synapse formation or maintenance, or both.
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Glicoproteínas/análise , Proteínas do Tecido Nervoso/análise , Sinapses/análise , Animais , Peso Molecular , Fragmentos de Peptídeos/análise , Ratos , Receptores de Concanavalina A/análiseRESUMO
Conus venoms contain a remarkable diversity of pharmacologically active small peptides. Their targets are ion channels and receptors in the neuromuscular system. The venom of Conus geographus contains high-affinity peptides that act on voltage-sensitive calcium channels, sodium channels, N-methyl-D-aspartate (NMDA) receptors, acetylcholine receptors, and vasopressin receptors; many more peptides with still uncharacterized receptor targets are present in this venom. It now seems that the Conus species (approximately 500 in number) will each use a distinctive assortment of peptides and that the pharmacological diversity in Conus venoms may be ultimately comparable to that of plant alkaloids or secondary metabolites of microorganisms. The cone snails may generate this diverse spectrum of venom peptides by a "fold-lock-cut" synthetic pathway. These peptides are specific enough to discriminate effectively between closely related receptor subtypes and can be used for structure-function correlations.
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Venenos de Moluscos/genética , Neuropeptídeos/genética , Caramujos/fisiologia , Sequência de Aminoácidos , Animais , Camundongos , Dados de Sequência Molecular , Venenos de Moluscos/isolamento & purificação , Venenos de Moluscos/toxicidade , Receptores de N-Metil-D-Aspartato , Receptores de Neurotransmissores/efeitos dos fármacos , Homologia de Sequência do Ácido Nucleico , Sono/efeitos dos fármacos , Especificidade da EspécieRESUMO
We report 3 cases of an unusual tumor, that is, the giant cell tumor of the tendon sheath. The patients consulted due to the appearance of a well-defined, painless, soft tissue mass with mild-to-moderate inflammation located in the thumbs or toes. These clinical data, together with the bone scan findings, oriented the diagnostic suspicion that was confirmed by a pathology study of the tumor after resection. This work has aimed to review the characteristics of the bone scan (BS) image of this tumor and its correlation with the conventional X-ray imaging and magnetic resonance imaging (MRI).
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Osso e Ossos/diagnóstico por imagem , Tumores de Células Gigantes/diagnóstico por imagem , Tumores de Células Gigantes/patologia , Imageamento por Ressonância Magnética , Tendões , Adolescente , Adulto , Feminino , Humanos , Masculino , CintilografiaRESUMO
INTRODUCTION: Tumors over-expressing the human epithelial receptor 2 (HER2) or exhibiting amplification or mutation of its proto-oncogene have a poorer prognosis. Using trastuzumab and/or other HER2 targeted therapies can increase overall survival in patients with HER2(+) tumors making it critical to accurately identify patients who may benefit. We report on a Phase 0 study of the imaging agent, 111In-CHX-A"-DTPA trastuzumab, in patients with known HER2 status to evaluate its safety and biodistribution and to obtain preliminary data regarding its ability to provide an accurate, whole-body, non-invasive means to determine HER2 status. METHODS: 111In-CHX-A"-DTPA trastuzumab was radiolabeled on-site and slowly infused into 11 patients who underwent single (n=5) or multiple (n=6) ɣ-camera (n=6) and/or SPECT (n=8) imaging sessions. RESULTS: No safety issues were identified. Visual and semi-quantitative imaging data were concordant with tissue HER2 expression profiling in all but 1 patient. The biodistribution showed intense peak liver activity at the initial imaging timepoint (3.3h) and a single-phase clearance fit of the average time-activity curve (TAC) estimated t1/2=46.9h (R2=0.97; 95%CI 41.8 to 53h). This was followed by high gastrointestinal (GI) tract activity peaking by 52h. Linear regression predicted GI clearance by 201.2h (R2 =0.96; 95%CI 188.5 to 216.9h). Blood pool had lower activity with its maximum on the initial images. Non-linear regression fit projected a t1/2=34.2h (R2 =0.96; 95%CI 25.3 to 46.3h). Assuming linear whole-body clearance, linear regression projected complete elimination (x-intercept) at 256.5hr (R2=0.96; 95%CI 186.1 to 489.2h). CONCLUSION: 111In-CHX-A"-DTPA trastuzumab can be safely imaged in humans. The biodistribution allowed for visual and semiquantitative analysis with results concordant with tissue expression profiling in 10 of 11 patients. Advances in Knowledge and Implications for Patient Care Using readily available components and on-site radiolabeling 111In-CHX-A"-DTPA trastuzumab SPECT imaging may provide an economical, non-invasive means to detect HER2 over-expression.
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Latin America, a region composed of a series of neighboring countries that share their history, Latin ancestry and language (Spanish or Portuguese), includes Mexico, Central America, the Spanish Caribbean islands, and South America. The Latin-American Dialysis and Kidney Transplantation Registry, which has been operative since 1991, collects data from 20 countries (Argentina, Brazil, Bolivia, Chile, Colombia, Costa Rica, Cuba, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Paraguay, Peru, Puerto Rico, Dominican Republic, Venezuela and Uruguay), where 97% of Latin Americans live. The prevalence of renal replacement therapy (RRT) has increased from 119 patients per million (pmp) in 1991 to 478.2 in 2005 (147,158 patients [57%] on chronic hemodialysis, 58,251 [23%] on peritoneal dialysis and 52,565 [20%] living with a functioning kidney graft). The incidence rate also increased from 27.8 pmp in 1992 to 167 in 2005. The increment in prevalence and incidence occurred in all Latin- American countries. The transplantation rate increased from 3,7 pmp in 1987 to 15 pmp in 2005 (7,968 kidney transplants performed this year, the cumulative number being 98,415). Access to RRT was available for every patient diagnosed with end-stage renal disease only in Argentina, Brazil, Chile, Cuba, Puerto Rico, Venezuela and Uruguay. In Latin America, the incidence and prevalence of RRT increased year by year. Only in some countries is access to RRT available to 100% of diagnosed patients. Detection and prevention programs for chronic kidney disease are needed in the region. Meanwhile, access to RRT has to be improved for everybody who needs it.
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Falência Renal Crônica/terapia , Transplante de Rim/estatística & dados numéricos , Sistema de Registros , Diálise Renal/estatística & dados numéricos , Humanos , América LatinaRESUMO
The assessment of response to therapy in glioblastoma remains a challenge, because the surrogate measures of survival are subject to radiographic misinterpretation. A solid and reliable definition of progression is needed for both clinical decision-making and for evaluating response within the clinical trials. Historically, assessment criteria have used radiologic and clinical features aimed to correctly classify patients into progressive or non-progressive disease. The widely used RANO criteria are a valuable tool in disease evaluation, both in the clinical setting and in the clinical trials. However, assessment criteria have certain limitations that emerging image techniques have tried to overcome. Differentiating true progression from treatment-related changes (like pseudoprogression or pseudoresponse) is crucial in order not to prematurely discontinue adjuvant chemotherapy or redirect the patient to second-line options. This fact underscores the need for advanced radiologic techniques, like specific diffusion and perfusion MRI sequences, MR spectroscopy and PET, which seem to play a role in distinguishing these phenomena.
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Neoplasias Encefálicas/patologia , Diagnóstico por Imagem/métodos , Glioblastoma/patologia , Lesões por Radiação/patologia , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Progressão da Doença , Glioblastoma/diagnóstico por imagem , Glioblastoma/terapia , Humanos , Lesões por Radiação/diagnóstico por imagem , Resultado do TratamentoRESUMO
Fifty seven suckling lambs (28 males and 29 females) of the Churra da Terra Quente breed were used to evaluate the effects of live weight and sex on carcass composition and meat quality traits. Lambs were slaughtered at three weight classes (<8kg, 8-11kg and >11kg) according to "Borrego Terrincho-PDO" specifications. The left sides of the carcasses were totally dissected. The longissimus thoracis and lumborum muscle was used for meat quality determination. Dressing proportion and carcass fatness were not affected by weight class or sex. Muscle proportion was similar in all carcass joints for the three weight classes. The percentage of bone decreased at the higher weight class, while that of subcutaneous and intermuscular fat increased. Female lambs had higher muscle proportions and greater muscle/bone ratios in the carcass side than males. Muscle pH, colour, cooking losses and tenderness were not affected by gender and weight class. Female lambs and weight classes 8-11kg and >11kg had higher proportions of intramuscular fat.
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OBJECTIVE: Paediatric patients with urinary tract infection (UTI) have risk of developing renal scarrings. Although it is known that vesicoureteral reflux (VUR) predisposes to UTIs and it seems to have an important role in the development of renal lesions, some recent published studies question that relation. The aim of the study was to evaluate renal scarring by using renal scintigraphy 99mTc-DMSA and see the relation with or without the presence of VUR. MATERIAL AND METHODS: We evaluated retrospectively a total of 230 patients (460 renal units), mean age: 11 months (range: 12d-5y), with UTI probed by urinoculture. All were studied with voiding cistourethrography (MCU) to evaluate the presence or absence of VUR. Patients were evaluated with 99mTc-DMSA scan 6 months after UTI to determine if UTI caused renal scarring. RESULTS: Renal scans with 99mTc-DMSA 6 months post-infection were abnormal in 62 renal units, affecting 54 patients (23 %). From all patients studied, 110 were diagnosis of VUR being affected 161 renal units, 43 of them (27 %) presented renal scarrings. From the remaining 120 patients without VUR that is 240 renal units, 19 of them (8 %) presented parenchymatous damage. CONCLUSION: Renal scarring resulting from UTI are in some cases related to VUR, but sometimes are caused by the infection itself. Not all patients with VUR develop renal lesions, and neither the presence of VUR always predispose children to renal lesions. MCU and direct isotopic cystography are useful for diagnosis of VUR but we shouldn't avoid 99mTc-DMSA scan in the management of children with UTI.
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Cicatriz/diagnóstico por imagem , Cicatriz/etiologia , Nefropatias/diagnóstico por imagem , Nefropatias/etiologia , Compostos Radiofarmacêuticos , Ácido Dimercaptossuccínico Tecnécio Tc 99m , Infecções Urinárias/complicações , Refluxo Vesicoureteral/complicações , Refluxo Vesicoureteral/diagnóstico por imagem , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Cintilografia , Estudos RetrospectivosRESUMO
In this work, it is studied the effect of the electric fields (within the range 0.0-1.5 V cm(-1)) on the performance of electrobioremediation with polarity reversal, using a bench scale plant with diesel-spiked kaolinite with 14-d long tests. Results obtained show that the periodic changes in the polarity of the electric field results in a more efficient treatment as compared with the single electro-bioremediation process, and it does not require the addition of a buffer to keep the pH within a suitable range. The soil heating was not very important and it did not cause a change in the temperature of the soil up to values incompatible with the life of microorganisms. Low values of water transported by the electro-osmosis process were attained with this strategy. After only 14 d of treatment, by using the highest electric field studied in this work (1.5 V cm(-1)), up to 35.40% of the diesel added at the beginning of the test was removed, value much higher than the 10.5% obtained by the single bioremediation technology in the same period.
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Eletricidade , Recuperação e Remediação Ambiental/métodos , Gasolina , Microbiologia do Solo , Poluentes do Solo/metabolismo , Biodegradação AmbientalRESUMO
(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (20, CP-101,606) has been identified as a potent and selective N-methyl-D-aspartate (NMDA) antagonist through a structure activity relation (SAR) program based on ifenprodil, a known antihypertensive agent with NMDA antagonist activity. Sites on the threo-ifenprodil skeleton explored in this report include the pendent methyl group (H, methyl, and ethyl nearly equipotent; propyl much weaker), the spacer group connecting the C-4 phenyl group to the piperidine ring (an alternating potency pattern with 0 and 2 carbon atoms yielding the greatest potency), and simple phenyl substitution (little effect). While potent NMDA antagonists were obtained with a two atom spacer, this arrangement also increased alpha 1 adrenergic affinity. Introduction of a hydroxyl group into the C-4 position on these piperidine ring resulted in substantial reduction in alpha 1 adrenergic affinity. The combination of these observations was instrumental in the discovery of 20. This compound potently protects cultured hippocampal neurons from glutamate toxicity (IC50 = 10 nM) while possessing little of the undesired alpha 1 adrenergic affinity (IC50 approximately 20 microM) of ifenprodil. Furthermore, 20 appears to lack the psychomotor stimulant effects of nonselective competitive and channel-blocking NMDA antagonists. Thus, 20 shows great promise as a neuroprotective agent and may lack the side effects of compounds currently in clinical trials.
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N-Metilaspartato/antagonistas & inibidores , Degeneração Neural/efeitos dos fármacos , Piperidinas/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Genes fos/efeitos dos fármacos , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , N-Metilaspartato/farmacologia , Piperidinas/síntese química , Piperidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
A systematic approach to the replacement of acidic groups with potential bioisosteres is described. The strategy involves simple nucleophilic displacement of a common alkyl halide precursor with a variety of mercaptoazoles and related molecules. The mercaptoazoles and their oxidized derivatives (sulfinyl- and sulfonylazoles) represent a series of possible surrogates for acidic groups which span a pKa range from about 4.5-11.5. This simple strategy was extended to include 2-hydroxy- or 2-aminothiophenyl groups which function as relatively nonacidic isosteres for a phosphonic acid. By replacing the phosphonic acid of 2-amino-7-phosphonoheptanoate (AP-7) with these groups, we have synthesized novel N-methyl-d-aspartate (NMDA) antagonists.
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2-Amino-5-fosfonovalerato/análogos & derivados , Aminoácidos/síntese química , Ácido Aspártico/análogos & derivados , Aminoácidos/farmacologia , Animais , Ácido Aspártico/antagonistas & inibidores , Modelos Moleculares , N-Metilaspartato , Ratos , Receptores de N-Metil-D-Aspartato , Receptores de Neurotransmissores/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
1. UK-78,282, a novel piperidine blocker of the T lymphocyte voltage-gated K+ channel, Kv1.3, was discovered by screening a large compound file using a high-throughput 86Rb efflux assay. This compound blocks Kv1.3 with a IC50 of approximately 200 nM and 1:1 stoichiometry. A closely related compound, CP-190,325, containing a benzyl moiety in place of the benzhydryl in UK-78,282, is significantly less potent. 2 Three lines of evidence indicate that UK-78,282 inhibits Kv1.3 in a use-dependent manner by preferentially blocking and binding to the C-type inactivated state of the channel. Increasing the fraction of inactivated channels by holding the membrane potential at - 50 mV enhances the channel's sensitivity to UK-78,282. Decreasing the number of inactivated channels by exposure to approximately 160 mM external K+ decreases the sensitivity to UK-78,282. Mutations that alter the rate of C-type inactivation also change the channel's sensitivity to UK-78,282 and there is a direct correlation between tau(h) and IC50 values. 3. Competition experiments suggest that UK-78,282 binds to residues at the inner surface of the channel overlapping the site of action of verapamil. Internal tetraethylammonium and external charybdotoxin do not compete UK-78,282's action on the channel. 4. UK-78,282 displays marked selectivity for Kv1.3 over several other closely related K+ channels, the only exception being the rapidly inactivating voltage-gated K+ channel, Kv1.4. 5. UK-78,282 effectively suppresses human T-lymphocyte activation.
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Compostos Benzidrílicos/farmacologia , Imunossupressores/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Piperidinas/farmacologia , Bloqueadores dos Canais de Potássio , Linfócitos T/efeitos dos fármacos , Animais , Ligação Competitiva , Células COS , Bovinos , Charibdotoxina/metabolismo , Charibdotoxina/farmacologia , Células HeLa , Humanos , Radioisótopos do Iodo , Ativação do Canal Iônico/fisiologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Canais de Potássio/metabolismo , Canais de Potássio/fisiologia , Ratos , Ratos Endogâmicos Lew , Radioisótopos de Rubídio , Linfócitos T/imunologia , Tetraetilamônio/metabolismo , Tetraetilamônio/farmacologiaRESUMO
We examined the ability of the neurotoxin, L-beta-methylaminoalanine (L-BMAA), to inhibit [3H]glutamate binding to rat brain synaptic junctions. In a tris(hydroxymethyl)aminomethane acetate buffer, L-BMAA did not affect [3H]glutamate binding (IC50 greater than 10 mM). However, in the presence of ammonium bicarbonate (20 mM) L-BMAA blocked [3H]glutamate binding with an IC50 of 1 mM. This inhibition was not caused by ammonium ion since other ammonium salts were inactive. Furthermore, identical inhibition was obtained in the presence of potassium bicarbonate. Bicarbonate ion did not alter the ability of N-methyl-D-aspartic acid to block glutamate binding. These results indicate that bicarbonate ion is required for the interaction of L-BMAA with the glutamate receptor and may account for the observation that beta-methylaminoalanine is neurotoxic in vitro only in the presence of bicarbonate.