Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-32165542

RESUMO

Acid-sensing ion channels (ASICs) are proton-gated cation channels that contribute to neurotransmission, as well as initiation of pain and neuronal death following ischemic stroke. As such, there is a great interest in understanding the in vivo regulation of ASICs, especially by endogenous neuropeptides that potently modulate ASICs. The most potent endogenous ASIC modulator known to date is the opioid neuropeptide big dynorphin (BigDyn). BigDyn is up-regulated in chronic pain and increases ASIC-mediated neuronal death during acidosis. Understanding the mechanism and site of action of BigDyn on ASICs could thus enable the rational design of compounds potentially useful in the treatment of pain and ischemic stroke. To this end, we employ a combination of electrophysiology, voltage-clamp fluorometry, synthetic BigDyn analogs, and noncanonical amino acid-mediated photocrosslinking. We demonstrate that BigDyn binding results in an ASIC1a closed resting conformation that is distinct from open and desensitized states induced by protons. Using alanine-substituted BigDyn analogs, we find that the BigDyn modulation of ASIC1a is primarily mediated through electrostatic interactions of basic amino acids in the BigDyn N terminus. Furthermore, neutralizing acidic amino acids in the ASIC1a extracellular domain reduces BigDyn effects, suggesting a binding site at the acidic pocket. This is confirmed by photocrosslinking using the noncanonical amino acid azidophenylalanine. Overall, our data define the mechanism of how BigDyn modulates ASIC1a, identify the acidic pocket as the binding site for BigDyn, and thus highlight this cavity as an important site for the development of ASIC-targeting therapeutics.

3.
JAMA Netw Open ; 3(3): e200663, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32154887

RESUMO

Importance: Inflammation is a key driver of malnutrition during illness and is often accompanied by metabolic effects, including insulin resistance and reduction of appetite. However, it still remains unclear if inflammation influences the response to nutritional support among patients with disease-related malnutrition. Objective: To examine whether patients' baseline inflammatory status is associated with the effect of nutritional support on 30-day mortality. Design, Setting, and Participants: This is a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a randomized clinical trial conducted in 8 Swiss hospitals from April 2014 to February 2018. A total of 1950 participants who had C-reactive protein measurements at the time of admission were included in this secondary analysis. Data analysis was conducted between June and July 2019. Interventions: Hospitalized patients at risk for malnutrition were randomly assigned to receive protocol-guided individualized nutritional support to reach protein and energy goals (intervention group) or standard hospital food (control group). Main Outcomes and Measures: The primary end point was 30-day mortality. Based on C-reactive protein levels at admission, patients were stratified into groups with low, moderate, or high inflammation (<10 mg/L, 10-100 mg/L, and >100 mg/L, respectively). Results: A total of 1950 patients (median [interquartile range] age, 75 [65-83] years; 1025 [52.6%] men) were included; 533 (27.3%) had low levels of inflammation, 894 (45.9%) had moderate levels of inflammation, and 523 (26.8%) had high levels of inflammation. Compared with the control group, patients receiving nutritional support showed a significant reduction in 30-day mortality, regardless of C-reactive protein level (adjusted odds ratio, 0.61; 95% CI, 0.43-0.86; P = .005). In the subgroup of patients with high inflammation, there was no beneficial effect of nutritional support (adjusted odds ratio, 1.32; 95% CI, 0.70-2.50; P = .39), providing evidence that inflammation has a significant modifying association (P for interaction = .005). Conclusions and Relevance: Based on this secondary analysis of a multicenter randomized trial, a patient's admission inflammatory status was associated with their response to nutritional support. If validated in future clinical trials, nutritional support may need to be individualized based on a patient's initial presentation and markers of inflammation. These results may also help to explain some of the heterogeneity in treatment effects of nutrition seen in previous critical care trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02517476.

4.
Clin Nutr ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32061370

RESUMO

Evidence-based medicine is the art of combining "best external evidence", "clinical judgement" and "patient values" for improved daily clinical decision making and is the ultimate goal in modern medicine. Historically, in the field of medical nutrition, there had been a lack of strong evidence from large and high-quality trials resulting in often weak guideline recommendations and therefore insufficient implementation in clinical practice. Particularly in the field of malnutrition, the medical community has long struggled to find evidence-based approaches for effective management by means of screening, assessment and treatment of patients. With recent trials showing that individual medical nutrition therapy has strong effects on clinical outcomes, we should now aim to practice "evidence-based medical nutrition" (EBMN) by combining clinical judgement (e.g., thorough clinical assessment of the malnourished patient), patient preferences (e.g., integration of perspectives of patients and relatives, consideration of comorbidities to define specific energy/protein goals and appropriate route of medical nutrition therapy) and the most current scientific evidence (e.g., trial-supported use of nutritional interventions for individual patients). Such an approach may certainly be helpful to improve clinical outcomes of the vulnerable population of malnourished medical inpatients.

5.
Clin Nutr ; 2019 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-31882232

RESUMO

INTRODUCTION: The Nutritional Risk Screening 2002 (NRS 2002) identifies patients at risk of malnutrition. We studied the prognostic implications of this score with regard to short-term and long-term clinical outcomes in a well-characterised cohort of medical inpatients from a previous trial. METHODS: This is a secondary analysis of an investigator-initiated, prospective randomised controlled multicenter trial in Switzerland (EFFORT) that compared the effects of an individualised nutritional support intervention with standard of care. We investigated associations between admission NRS and several short-term and long-term outcomes using multivariable regression analyses. RESULTS: Of the 2028 patients, 31% had an NRS of 3, 38% of 4 and 31% of ≥5 points, and 477 (24%) died during the 180 days of follow-up. For each point increase in NRS, we found a stepwise increase in risk of 30-day mortality (adjusted Hazard Ratio (HR) 1.22 (95% CI 1.00 to 1.48), p = 0.048) and 180-day mortality (adjusted HR 1.37 (95% CI 1.22 to 1.55), p < 0.001). NRS was associated with length of hospital stay (adjusted difference of 0.60 days per NRS point increase, 95%CI 0.23 to 0.97, p = 0.002) and functional outcomes at 180 days (adjusted decrease in Barthel index of -4.49 points per NRS point increase, 95%CI -6.54 to -2.45, p < 0.001). In a subgroup analysis, associations of NRS and short-term adverse outcomes were less pronounced in patients receiving nutritional support (intervention group) compared to control group patients (adjusted HR for 30-day mortality 1.12 [95%CI 0.83 to 1.52, p = 0.454] vs. 1.33 [95%CI 1.02 to 1.72, p = 0.032]). CONCLUSION: The NRS is a strong and independent risk score for malnutrition-associated mortality and adverse outcomes over 180 days. Our data provide strong evidence that the nutritional risk, however, is modifiable and can be reduced by the provision of adequate nutritional support.

6.
Medicine (Baltimore) ; 98(48): e18113, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770235

RESUMO

The impact of vitamin D deficiency on the recovery of patients with malnutrition remains undefined. Our aim was to study the prevalence of vitamin D deficiency in a well-characterized cohort of patients with malnutrition and its association with outcomes.Within this secondary analysis of a randomized controlled trial, we examined the association of vitamin D deficiency and adverse clinical outcomes over a follow-up of 180 days in hospitalized patients at risk for malnutrition. We measured 25-hydroxyvitamin D levels upon admission and defined Vitamin D deficiency when levels were <50nmol/l. The primary endpoint was 180-day mortality.The prevalence of vitamin D deficiency in our cohort of 828 patients was 58.2% (n = 482). Patients with vitamin D deficiency had increased 180-day mortality rates from 23.1% to 29.9% (odds ratio 1.42, 95% confidence interval [CI] 1.03-1.94, P = .03). When adjusting the analysis for demographics, comorbidities, and randomization, this association remained significant for the subgroup of patients not receiving vitamin D treatment (adjusted odds ratio 1.63, 95% CI 1.01-2.62, P = .04). There was no significantly lower risk for mortality in the subgroup of vitamin D deficient patients receiving vitamin D treatment compared to not receiving treatment (adjusted odds ratio 0.74, 95% CI 0.48-1.13, P = .15).Vitamin D deficiency is highly prevalent in the population of malnourished inpatients and is negatively associated with long-term mortality particularly when patients are not receiving vitamin D treatment. Our findings suggest that malnourished patients might benefit from vitamin D screening and treatment in case of deficiency.


Assuntos
Idoso Fragilizado/estatística & dados numéricos , Fragilidade/mortalidade , Desnutrição/mortalidade , Deficiência de Vitamina D/mortalidade , Deficiência de Vitamina D/terapia , Idoso , Idoso de 80 Anos ou mais , Suplementos Nutricionais , Feminino , Fragilidade/sangue , Fragilidade/complicações , Humanos , Pacientes Internados/estatística & dados numéricos , Masculino , Desnutrição/sangue , Desnutrição/complicações , Prevalência , Estudos Prospectivos , Qualidade de Vida , Resultado do Tratamento , Vitamina D/análogos & derivados , Vitamina D/sangue , Vitamina D/uso terapêutico , Deficiência de Vitamina D/complicações , Vitaminas/uso terapêutico
7.
Lancet ; 393(10188): 2312-2321, 2019 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-31030981

RESUMO

BACKGROUND: Guidelines recommend the use of nutritional support during hospital stays for medical patients (patients not critically ill and not undergoing surgical procedures) at risk of malnutrition. However, the supporting evidence for this recommendation is insufficient, and there is growing concern about the possible negative effects of nutritional therapy during acute illness on recovery and clinical outcomes. Our aim was thus to test the hypothesis that protocol-guided individualised nutritional support to reach protein and caloric goals reduces the risk of adverse clinical outcomes in medical inpatients at nutritional risk. METHODS: The Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT) is a pragmatic, investigator-initiated, open-label, multicentre study. We recruited medical patients at nutritional risk (nutritional risk screening 2002 [NRS 2002] score ≥3 points) and with an expected length of hospital stay of more than 4 days from eight Swiss hospitals. These participants were randomly assigned (1:1) to receive either protocol-guided individualised nutritional support to reach protein and caloric goals (intervention group) or standard hospital food (control group). Randomisation was done with variable block sizes and stratification according to study site and severity of malnutrition using an interactive web-response system. In the intervention group, individualised nutritional support goals were defined by specialist dietitians and nutritional support was initiated no later than 48 h after admission. Patients in the control group received no dietary consultation. The composite primary endpoint was any adverse clinical outcome defined as all-cause mortality, admission to intensive care, non-elective hospital readmission, major complications, and decline in functional status at 30 days, and it was measured in all randomised patients who completed the trial. This trial is registered with ClinicalTrials.gov, number NCT02517476. FINDINGS: 5015 patients were screened, and 2088 were recruited and monitored between April 1, 2014, and Feb 28, 2018. 1050 patients were assigned to the intervention group and 1038 to the control group. 60 patients withdrew consent during the course of the trial (35 in the intervention group and 25 in the control group). During the hospital stay, caloric goals were reached in 800 (79%) and protein goals in 770 (76%) of 1015 patients in the intervention group. By 30 days, 232 (23%) patients in the intervention group experienced an adverse clinical outcome, compared with 272 (27%) of 1013 patients in the control group (adjusted odds ratio [OR] 0·79 [95% CI 0·64-0·97], p=0·023). By day 30, 73 [7%] patients had died in the intervention group compared with 100 [10%] patients in the control group (adjusted OR 0·65 [0·47-0·91], p=0·011). There was no difference in the proportion of patients who experienced side-effects from nutritional support between the intervention and the control group (162 [16%] vs 145 [14%], adjusted OR 1·16 [0·90-1·51], p=0·26). INTERPRETATION: In medical inpatients at nutritional risk, the use of individualised nutritional support during the hospital stay improved important clinical outcomes, including survival, compared with standard hospital food. These findings strongly support the concept of systematically screening medical inpatients on hospital admission regarding nutritional risk, independent of their medical condition, followed by a nutritional assessment and introduction of individualised nutritional support in patients at risk. FUNDING: The Swiss National Science Foundation and the Research Council of the Kantonsspital Aarau, Switzerland.


Assuntos
Desnutrição/prevenção & controle , Apoio Nutricional/métodos , Assistência Centrada no Paciente/métodos , Doença Aguda/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Doença Crônica/epidemiologia , Comorbidade , Ingestão de Energia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Medição de Risco
8.
Sci Rep ; 8(1): 1598, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29371615

RESUMO

The major cow's milk allergen Bos d 5 belongs to the lipocalin protein family, with an intramolecular pocket for hydrophobic ligands. We investigated whether Bos d 5 when loaded with the active vitamin A metabolite retinoic acid (RA), would elicit differential immune responses compared to the unloaded state. By in silico docking an affinity energy of -7.8 kcal/mol was calculated for RA into Bos d 5. Loading of RA to Bos d 5 could be achieved in vitro, as demonstrated by ANS displacement assay, but had no effect on serum IgE binding in tolerant or challenge-positive milk allergic children. Bioinformatic analysis revealed that RA binds to the immunodominant T-cell epitope region of Bos d 5. In accordance, Bos d 5 significantly suppressed the CD3+ CD4+ cell numbers, proliferative response and IL-10, IL-13 and IFN-γ secretion from stimulated human PBMCs only when complexed with RA. This phenomenon was neither associated with apoptosis of T-cells nor with the activation of Foxp3+ T-cells, but correlated likely with enhanced stability to lysosomal digestion due to a predicted overlap of Cathepsin S cleavage sites with the RA binding site. Taken together, proper loading of Bos d 5 with RA may suppress its immunogenicity and prevent its allergenicity.


Assuntos
Alérgenos/imunologia , Alérgenos/metabolismo , Epitopos de Linfócito T/metabolismo , Fatores Imunológicos/metabolismo , Lipocalinas/imunologia , Lipocalinas/metabolismo , Tretinoína/metabolismo , Animais , Bovinos , Proliferação de Células/efeitos dos fármacos , Humanos , Imunoglobulina E/metabolismo , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-13/metabolismo , Leucócitos Mononucleares/imunologia , Lisossomos/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Proteólise
9.
Nutrition ; 33: 304-310, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27742103

RESUMO

OBJECTIVE: Positive associations between body mass index (BMI) and clinical outcomes have been found and are called "the obesity survival paradox." However, whether obesity has protective effects or if this paradox is because of confounding remains unclear. Herein, we analyzed the effects of weight on long-term mortality in a large cohort of patients with community-acquired pneumonia (CAP) and investigated whether the differential effects of obesity on inflammation pathways accounted for mortality differences. METHODS: For this secondary analysis, we followed prospectively for 6 y 763 CAP patients who were previously included in a multicenter trial (the ProHOSP Trial). To assess associations of BMI with mortality and with several inflammatory biomarker levels, we calculated three regression models adjusted for severity: the pneumonia severity index (PSI); fully adjusted for PSI, age, sex, metabolic factors, cardiovascular diseases, and other comorbidities; and fully adjusted including biomarker levels. RESULTS: Within the 763 patients studied, all-cause 6-y mortality was significantly lower in obese patients (BMI >30 kg/m2) compared with normal-weight patients (BMI 18.5-25 kg/m2), with a severity-adjusted hazard ratio of 0.641 (95% confidence interval 0.462-0.889) and robust results in fully adjusted and fully adjusted plus biomarker models. No associations of increased BMI and C-reactive protein, procalcitonin, or white blood cell count were found, but BMI > 30 kg/m2 was associated with higher proadrenomedullin levels. CONCLUSIONS: Over a 6-y long-term follow-up, we found obesity to be associated with lower all-cause mortality in CAP patients, confirming the obesity paradox in this population. However, differences in inflammatory pathways did not explain these findings.


Assuntos
Infecções Comunitárias Adquiridas/imunologia , Modelos Imunológicos , Obesidade/imunologia , Pneumonia/imunologia , Adrenomedulina/sangue , Biomarcadores/sangue , Índice de Massa Corporal , Proteína C-Reativa/análise , Calcitonina/sangue , Estudos de Coortes , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/mortalidade , Infecções Comunitárias Adquiridas/fisiopatologia , Comorbidade , Seguimentos , Humanos , Mediadores da Inflamação/sangue , Contagem de Leucócitos , Mortalidade , Obesidade/sangue , Obesidade/epidemiologia , Obesidade/fisiopatologia , Pneumonia/epidemiologia , Pneumonia/mortalidade , Pneumonia/fisiopatologia , Estudos Prospectivos , Precursores de Proteínas/sangue , Risco , Índice de Gravidade de Doença , Análise de Sobrevida , Suíça/epidemiologia
10.
Ann Nutr Metab ; 68(3): 164-72, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26855046

RESUMO

BACKGROUND AND AIMS: Malnutrition is associated with poor clinical outcomes. Whether there is a causal relationship or it merely mirrors a severe patient condition remains unclear. We examined the association of malnutrition with biomarkers characteristic of different pathophysiological states to better understand the underlying etiological mechanisms. METHODS: We prospectively followed consecutive adult medical inpatients. Multivariable regression models were used to investigate the associations between malnutrition - as assessed using the Nutritional Risk Screening (NRS 2002) - and biomarkers linked to inflammation, stress, renal dysfunction, nutritional status and hematologic function. RESULTS: A total of 529 patients were included. In a fully adjusted model, malnutrition was significantly associated with the inflammatory markers procalcitonin (0.20, 95% CI 0.03-0.37), proadrenomedullin (0.28, 95% CI 0.12-0.43) and albumin (-0.39, 95% CI -0.57 to -0.21), the stress marker copeptin (0.34, 95% CI 0.17-0.51), the renal function marker urea (0.23, 95% CI 0.07-0.38), the nutritional markers vitamin D25 (-0.22, 95% CI -0.41 to -0.02) and corrected calcium (0.29, 95% CI 0.10-0.49) and the hematological markers hemoglobin (-0.27, 95% CI -0.43 to -0.10) and red blood cell distribution width (0.26, 95% CI 0.07-0.44). Subgroup analysis suggested that acute malnutrition rather than chronic malnutrition was associated with elevated biomarker levels. CONCLUSION: Acute malnutrition was associated with a pronounced inflammatory response and an alteration in biomarkers associated with different pathophysiological states. Interventional trials are needed to prove causality.


Assuntos
Biomarcadores/sangue , Desnutrição Aguda Grave/sangue , Regulação para Cima , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Terapia Combinada , Comorbidade , Serviço Hospitalar de Emergência , Feminino , Seguimentos , Humanos , Masculino , Desnutrição/sangue , Desnutrição/diagnóstico , Desnutrição/epidemiologia , Desnutrição/terapia , Pessoa de Meia-Idade , Avaliação Nutricional , Avaliação de Resultados da Assistência ao Paciente , Estudos Prospectivos , Risco , Desnutrição Aguda Grave/diagnóstico , Desnutrição Aguda Grave/epidemiologia , Desnutrição Aguda Grave/terapia , Suíça/epidemiologia , Centros de Atenção Terciária , Triagem
11.
ACS Chem Neurosci ; 7(3): 339-48, 2016 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-26764897

RESUMO

Cys-loop receptors mediate fast synaptic transmission in the nervous system, and their dysfunction is associated with a number of diseases. While some sequence variability is essential to ensure specific recognition of a chemically diverse set of ligands, other parts of the underlying amino acid sequences show a high degree of conservation, possibly to preserve the overall structural fold across the protein family. In this study, we focus on the only two absolutely conserved residues across the Cys-loop receptor family, two Trp side chains in the WXD motif of Loop D and in the WXPD motif of Loop A. Using a combination of conventional mutagenesis, unnatural amino acid incorporation, immunohistochemistry and MD simulations, we demonstrate the crucial contributions of these two Trp residues to receptor expression and function in two prototypical Cys-loop receptors, the anion-selective GlyR α1 and the cation-selective nAChR α7. Specifically, our results rule out possible electrostatic contributions of these Trp side chains and instead suggest that the overall size and shape of this aromatic pair is required in stabilizing the Cys-loop receptor extracellular domain.


Assuntos
Modelos Moleculares , Receptores da Glicina/química , Triptofano/química , Receptor Nicotínico de Acetilcolina alfa7/química , Animais , Humanos , Imuno-Histoquímica , Técnicas de Patch-Clamp , Domínios Proteicos , Xenopus laevis
12.
Swiss Med Wkly ; 145: w14265, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26709887

RESUMO

Although obesity and the associated metabolic syndrome negatively impact on health outcomes, a paradoxical relationship between obesity and mortality has been reported for specific patient populations - the "obesity paradox". However, underlying mechanisms remain unclear and several possible explanations are being discussed. First, a true protective effect of obesity is possible, mediated through differences in the immune response and more metabolic reserves. Although there is a growing body of evidence supporting this hypothesis, the influence of obesity on immune function is complex and not completely understood. Second, a statistical bias is possible, owing to confounding, selection bias, performance bias and measurement bias of most observational studies reporting the obesity paradox. Within this article, we summarise current concepts regarding the underlying pathophysiology and possible explanation for the obesity paradox, and discuss open questions such as whether age is an effect modifier on the relationship of obesity and mortality.


Assuntos
Síndrome Metabólica/epidemiologia , Mortalidade , Obesidade/epidemiologia , Viés , Biomarcadores/análise , Índice de Massa Corporal , Humanos , Síndrome Metabólica/mortalidade , Obesidade/mortalidade , Pneumonia/epidemiologia , Pneumonia/mortalidade , Fatores de Proteção
13.
J Food Sci ; 75(6): S308-11, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20722953

RESUMO

Olive leaf extract (OLE) contains high amounts of oleuropein and hydroxytyrosol. The antioxidant capacity of these polyphenols makes OLE a promising ingredient for functional food. OLE causes very strong bitterness perception and can therefore only be formulated in low concentrations. In this research, bitter detection and recognition thresholds of OLE-fortified fruit smoothies were determined by a trained sensory panel (n = 11). Masking of the OLE's bitter taste was investigated with addition of sodium cyclamate, sodium chloride, and sucrose by means of a standardized ranking method and a scale test. Detection (5.78 mg/100 g) and recognition thresholds (8.05 mg/100 g) of OLE polyphenols confirmed the low formulation limits when bitterness was not masked by other substances. At higher polyphenol levels of 20 mg/100 g, sodium cyclamate and sucrose were able to reduce bitter taste perception by 39.9% and 24.9%, respectively, whereas sodium chloride could not effectively mask bitterness. Practical Application: Development of functional food poses new challenges for the food industry. A major problem in this field is the high bitterness of natural polyphenol-containing extracts with potential health benefits. This research was conducted to understand the sensory impact of olive leaf extract (OLE), a novel food ingredient with very bitter taste. In product development, the data of this research can be considered for formulation limits and the general sensory quality of OLE-fortified food and beverages.


Assuntos
Bebidas/análise , Alimentos Fortificados/análise , Frutas , Olea/química , Extratos Vegetais , Folhas de Planta/química , Percepção Gustatória , Adulto , Antioxidantes/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Sensação , Cloreto de Sódio na Dieta , Edulcorantes , Limiar Gustativo , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA