Preliminary exploration of the metabolic profile and metabolic pathways in newly diagnosed multiple myeloma / 中华肿瘤杂志

Objective: To explore the metabolite profile and metabolic pathways of newly diagnosed multiple myeloma (MM). Methods: Gas chromatography-mass spectrometry (GC-MS) was employed for the high-throughput detection and identification of serum samples from 55 patients with MM and 37 healthy controls matched for age and sex from 2016 to 2017 collected at the First Affiliated Hospital of Soochow University. The relative standard deviation (RSD) of quality control (QC) samples was employed to validate the reproducibility of GC-MS approach. The differential metabolites between patients with MM and healthy controls were detected by partial least squares discrimination analysis (PLS-DA), and t-test with false discovery rate (FDR) correction. Metabolomics pathway analysis (MetPA) was employed to construct metabolic pathways. Results: There were 55 MM patients, including 34 males and 21 females. The median age was 60 years old (42-73 years old). There were 30 cases of IgG type, 9 cases of IgA type, 1 case of IgM type, 2 cases of non-secreted type, 1 case of double clone type and 12 cases of light chain type, including 3 cases of kappa light chain type and 9 cases of lambda light chain type. The result of QC sample test showed that the proportion of compounds with the RSD of the relative content of metabolites < 15% was 70.21% obtained by the reproducibility of GC-MS experimental data, which implied that the experimental data were reliable. A total of 17 metabolites were screened differently with the healthy control group, including myristic acid, hydroxyproline, cysteine, palmitic acid, L-leucine, stearic acid, methionine, phenylalanine, glycerin, serine, isoleucine, tyrosine, valine, citric acid, inositol, threonine, and oxalic acid (VIP>1, P<0.05). Metabolic pathway analysis suggested that metabolic disorders in MM patients comprised mainly phenylalanine metabolism, glyoxylic acid and dicarboxylic acid metabolism, phosphoinositide metabolism, cysteine and methionine metabolism, glycerolipid metabolism, glycine, serine, and threonine metabolism. Conclusion: Compared with normal people, patients with newly diagnosed MM have obvious differences in metabolic profiles and metabolic pathways.

Molecular cloning and characterization of three phenylalanine ammonia-lyase genes from Schisandra chinensis / 中国天然药物

Phenylalanine ammonia-lyase (PAL), which catalyzes the conversion from L-phenylalanine to trans-cinnamic acid, is a well-known key enzyme and a connecting step between primary and secondary metabolisms in the phenylpropanoid biosynthetic pathway of plants and microbes. Schisandra chinensis, a woody vine plant belonging to the family of Magnoliaceae, is a rich source of dibenzocyclooctadiene lignans exhibiting potent activity. However, the functional role of PAL in the biosynthesis of lignan is relatively limited, compared with those in lignin and flavonoids biosynthesis. Therefore, it is essential to clone and characterize the PAL genes from this valuable medicinal plant. In this study, molecular cloning and characterization of three PAL genes (ScPAL1-3) from S. chinensis was carried out. ScPALs were cloned using RACE PCR. The sequence analysis of the three ScPALs was carried out to give basic characteristics followed by docking analysis. In order to determine their catalytic activity, recombinant protein was obtained by heterologous expression in pCold-TF vector in Escherichia coli (BL21-DE3), followed by Ni-affinity purification. The catalytic product of the purified recombinant proteins was verified using RP-HPLC through comparing with standard compounds. The optimal temperature, pH value and effects of different metal ions were determined. Vmax, Kcat and Km values were determined under the optimal conditions. The expression of three ScPALs in different tissues was also determined. Our work provided essential information for the function of ScPALs.

Estratégias terapêuticas e atualizações no tratamento de vitiligo / Therapeutic strategies and updates for treatment of vitiligo

O vitiligo é uma desordem dermatológica complexa, cuja patogênese ainda não é totalmente esclarecida. Apesar de não apresentar complicações funcionais no organismo dos pacientes acometidos, o vitiligo pode resultar em um grande impacto psicossocial. Desse modo, é importante que os médicos saibam como conduzir o tratamento dessa patologia. O objetivo deste estudo foi documentar as terapias disponíveis para o tratamento do vitiligo, assim como apontar pesquisas que relataram a utilização dessas opções terapêuticas e os dados resultantes. As terapias abordadas foram corticoides tópicos e sistêmicos, fototerapia e fotoquimioterapias, antioxidantes, imunomoduladores, fenilalanina, despigmentação, procedimentos cirúrgicos e novas abordagens. A monoterapia parece ser menos eficaz no tratamento do vitiligo. A associação de medicação tópica e/ou sistêmica com o uso da fototerapia ultravioleta B de banda estreita parece ser o padrão-ouro para a repigmentação da pele dos pacientes. Medicamentos novos estão em estudo, porém sua eficácia e o estudo dos possíveis efeitos colaterais, principalmente a longo prazo, têm que ser melhores investigados. É necessário que o médico dermatologista, em conjunto com o paciente, escolha a melhor terapia dentre as disponíveis, de acordo com critérios clínicos e a possibilidade de acesso ao tratamento pelo portador. O acompanhamento e a abordagem por uma equipe multiprofissional também são importantes. (AU)

Vitiligo is a complex dermatological disorder, whose pathogenesis has not yet been fully elucidated. Although it does not present functional complications in the affected patients' body, vitiligo can result in a great psychosocial impact. Therefore, it is important that physicians know how to conduct its treatment. This study aimed at documenting the available therapies for the treatment of vitiligo, as well as pointing out studies reporting the use of these therapeutic options and their resulting data. The therapies addressed were topical and systemic corticosteroids, phototherapy, and photochemotherapies, antioxidants, immunomodulators, phenylalanine, depigmentation, surgical procedures, and new approaches. Monotherapy appears to be less effective in the treatment of vitiligo. The combination of topical and/or systemic medication with the use of narrowband ultraviolet B phototherapy seems to be the gold standard for the patients' skin repigmentation. New drugs are under study, but their effectiveness and study of possible side effects, especially in the long run, have to be better investigated. It is necessary that the dermatologist, together with the patient, choose the best therapy among those available, according to clinical criteria and the possibility of access to treatment by the patient. Monitoring and approach by a multiprofessional team is also important. (AU)

A abordagem metabolômica na indicação do tratamento de estenose de junção ureteropélvica em crianças / Metabolomics approach in the treatment of ureteropelvic junction stenosis in children

Estenose de Junção Ureteropélvica (JUP) é uma doença caracterizada pelo bloqueio do fluxo de urina da pelve renal (porção proximal do ureter no rim) ao ureter, tubo que liga o rim à bexiga. Essa formação congênita é uma das maiores causas de dilatação do rim (hidronefrose) em recém-nascidos e, em alguns casos, pode causar danos mais severos ao órgão. A hidronefrose causada pela estenose de JUP pode desaparecer espontaneamente sem perda da função renal, entretanto, é preciso um acompanhamento clínico. Por outro lado, em casos mais severos, onde a dilatação pode causar danos maiores ao rim, um tratamento cirúrgico se faz necessário. Embora existam métodos para o diagnóstico da estenose de JUP, como ultrassonografia, tomografia computadorizada, ressonância e cintilografia, é um grande desafio diferenciar os pacientes que requerem um tratamento cirúrgico e os que necessitam apenas de um acompanhamento convencional. A metabolômica global, que investiga de modo comparativo o conjunto de metabólitos de baixa massa molecular expressos em indivíduos em condições pré-selecionadas, tem o potencial de servir como ferramenta diagnóstica para os pacientes com estenose de JUP e, consequentemente, auxiliar na tomada de decisão entre um acompanhamento clínico ou tratamento cirúrgico. Assim sendo, no presente trabalho, três grupos de pacientes com estenose de JUP, pré-diagnosticados por métodos convencionais, foram investigados sob a perspectiva da metabolômica global, por meio de análises de urina, utilizando cromatografia gasosa e cromatografia líquida, ambas acoplada à espectrometria de massas (GC-MS e RPLC10 MS, respectivamente): pacientes que requerem tratamento cirúrgico (CIR), pacientes que requerem acompanhamento clínico (CLI), e indivíduos sãos (CON). Os resultados mostram que é possível encontrar metabólitos discriminantes entre todas as comparações (CON x CLI, CON x CIR e CLI x CIR); os metabólitos encontrados nas análises multivariada e univariada foram utilizados para construção da curva ROC, para confirmar a possibilidade de utilização desses compostos como biomarcadores. Foram observadas alterações em rotas metabólicas importantes para o bom funcionamento das funções renais, principalmente entre a comparação mais desafiadora (CLI x CIR), como o metabolismo da fenilalanina, da tirosina, da beta-alanina, dos aminoaçúcares e dos nucleotídeos. Há indícios de que o ciclo de Krebs também sofre alteração. Os resultados obtidos podem servir como ponto de partida para uma futura análise alvo e validação biológica

Ureteropelvic junction (UPJ) stenosis is a disease characterized by the interruption of the flow of urine from the renal pelvis (proximal part of ureter in the kidney) to the ureter, tube that links the kidney to bladder. That congenital formation is one of the main causes of kidney dilation (hydronephrosis) in newborns and, sometimes, can cause more serious damage to the organ. The hydronephrosis caused by UPJ stenosis can disappear spontaneously without compromising renal function, although a clinical follow-up is required. On the other hand, in more serious cases, when dilation can induce larger damage to the kidney, surgery intervention is necessary. Although there are methods to diagnose UPJ stenosis, such as ultrasound, computed tomography, resonance and scintigraphy, it is still a great challenge to distinguish patients that require surgery from those whose a clinical follow-up suffices. Global metabolomics, a method that investigates in a comparative manner the set of low molecular mass metabolites expressed by an individual in pre-selected conditions, has the potential to function as a diagnostic tool for patients with UPJ stenosis to support decisions about patient treatment, i.e., surgery versus clinical follow-up. In this work, three groups of UPJ stenosis patients were investigated with the aid of global metabolomics using urine analysis by gas chromatography and liquid chromatography coupled to mass spectrometry (GC-MS and RPLC-MS, respectively): one group consisted of UPJ stenosis patients requiring clinical follow-up (CLI), other group UPJ stenosis patients requiring surgery intervention (CIR) and a third group comprising healthy individuals, the control group (CON).12 The results show that it was possible to find discriminant metabolites among all pairwise comparisons (CON versus CLI, CON versus CIR and CLI versus CIR). The metabolites found by multivariate and univariate analyses were used to build ROC curves, to confirm whether it is possible to use them as biomarkers. Alterations in metabolic pathways that are important for the good maintenance of kidney functions were found, especially in the most challenged comparison (CLI versus CIR), such as the metabolism of phenylalanine, tyrosine, beta-alanine, amino acids and nucleotides. There are evidences that Krebs cycle was also impacted. The results obtained here can serve as a starting point to future targeted analysis and biological validation

Metabolic control and body composition of children and adolescents with phenylketonuria / Controle metabólico e composição corporal de crianças e adolescentes com diagnóstico neonatal de fenilcetonúria

ABSTRACT Objective: To characterize metabolic control and verify whether it has any relation with socioeconomic, demographic, and body composition variables in children and adolescents with phenylketonuria (PKU) diagnosed in the neonatal period. Methods: This cohort study collected retrospective data of 53 phenylketonuric children and adolescents. Data on family income, housing, and mother's age and schooling level were collected, and anthropometric measures of body composition and distribution were taken. All dosages of phenylalanine (Phe) from the last five years (2015-2019) were evaluated and classified regarding their adequacy (cutoffs: 0-12 years: 2-6 mg/dL; 12-19 years: 2-10 mg/dL). Adequate metabolic control was considered if ≥7%) of the dosages were within desired ranges. Results: The mean (±standard deviation) age in the last year was 10.1±4.6 years. Most of them were under 12 years old (33/53; 62.3%) and had the classic form of the disease (39/53; 73.6%). Better metabolic control was observed among adolescents (68.4 versus 51.4%; p=0.019). Overweight was found in 9/53 (17%) and higher serum Phe levels (p<0.001) were found in this group of patients. Metabolic control with 70% or more Phe level adequacy decreased along with the arm muscle area (AMA) (ptendency=0.042), being 70.0% among those with low reserve (low AMA), and 18.5% among those with excessive reserve (high AMA). Conclusions: Adequate metabolic control was observed in most patients. The findings suggest that, in this sample, the levels of phenylalanine may be related to changes in body composition.

RESUMO Objetivo: Caracterizar o controle metabólico e verificar se existe relação entre ele, variáveis socioeconômicas, demográficas e composição corporal de crianças e adolescentes com fenilcetonúria (FNC) diagnosticada no período neonatal. Métodos: Coorte com coleta retrospectiva de dados de 53 crianças e adolescentes fenilcetonúricos. Foram coletados dados de renda familiar, moradia, idade e escolaridade materna e realizaram-se medidas antropométricas de composição e distribuição corporal. Todas as dosagens de fenilalanina (Fal) dos últimos cinco anos (2015-2019) foram avaliadas e classificadas quanto à adequação (cortes: 0-12 anos: 2-6 mg/dL; 12-19 anos: 2-10 mg/dL). A proporção de dosagens adequadas ≥70% foi considerada como controle metabólico adequado. Resultados: A média (±desvio padrão) de idade, no último ano, foi de 10,1±4,6 anos. A maioria tinha menos de 12 anos (33/53; 62,3%) e apresentava a forma clássica da doença (39/53; 73,6%). Observou-se melhor controle metabólico entre os adolescentes (68,4 vs. 51,4%; p=0,019). Excesso de peso foi encontrado em 9/53 (17%) e maiores níveis séricos de Fal foram descritos nesse grupo (p<0,001). O percentual de controle metabólico com 70% ou mais de adequação dos níveis de Fal foi decrescente de acordo com a área muscular do braço (AMB; ptendência=0,042), sendo de 70% entre os de baixa reserva (AMB reduzida) e de 18,5% entre os com excesso (AMB elevada). Conclusões: Observou-se controle metabólico adequado na maioria dos avaliados e os achados sugerem que, nesta amostra, os níveis de fenilalanina podem estar relacionados com alterações da composição corporal.

Dietary intake of tyrosine and phenylalanine, and p-cresyl sulfate plasma levels in non-dialyzed patients with chronic kidney disease / Ingestão dietética de tirosina e fenilalanina e níveis plasmáticos de p-cresil sulfato em pacientes com doença renal crônica não dialisados

ABSTRACT Background: Patients with chronic kidney disease (CKD) present an imbalance of the gut microbiota composition, leading to increased production of uremic toxins like p-cresyl sulfate (PCS), product from bacterial fermentation of the amino acids tyrosine (Tyr) and phenylalanine (Phe) from the diet. Thus, diet may be a determinant in the uremic toxins levels produced by the gut microbiota. The aim of this study was to evaluate the possible relationship between Tyr and Phe intake and PCS plasma levels in non-dialysis CKD patients. Methods: Twenty-seven non-dialysis CKD patients (stages 3 and 4) without previous nutritional intervention were evaluated. The dietary intake was evaluated using a 24-hour recall, 3-day food record and protein intake was also estimated by Protein Nitrogen Appearance (PNA). The plasma levels of PCS were measured using reverse phase high performance liquid chromatography. Results: The evaluated patients (GRF, 34.8 ± 12.4 mL/min, 54.2 ± 14.3 years, BMI, 29.3 ± 6.1 kg/m2) presented mean protein intake of 1.1 ± 0.5 g/kg/day), Tyr of 4.5 ± 2.4 g/day and Phe of 4.6 ± 2.5 g/day. PCS plasma levels (20.4 ± 15.5 mg/L) were elevated and positively associated with both, Tyr (r = 0.58, p = 0.002) and Phe intake (r = 0.53, p = 0.005), even after adjustments for eGFR and age. Conclusion: This study suggests that the diet is an important modulator of the uremic toxins plasma levels produced by the gut microbiota, in non-dialysis CKD patients.

RESUMO Introdução: Pacientes com doença renal crônica (DRC) apresentam desequilíbrio na composição da microbiota intestinal, gerando toxinas urêmicas, como o p-cresil sulfato (PCS), pela fermentação bacteriana dos aminoácidos tirosina (Tyr) e fenilalanina (Phe) da dieta. Assim, a dieta pode ser determinante nos níveis de toxinas urêmicas produzidos pela microbiota intestinal. O objetivo deste estudo foi avaliar a possível relação entre a ingestão de Tyr e Phe e os níveis plasmáticos de PCS em pacientes com DRC não dialisados. Métodos: Foram avaliados 27 pacientes com DRC em tratamento conservador (estágios 3 e 4), sem intervenção nutricional prévia. A ingestão alimentar foi avaliada pelo recordatório alimentar de 24h (R-24h) de 3 dias, e a ingestão proteica também foi verificada através do Protein Nitrogen Appearance (PNA). Os níveis plasmáticos de PCS foram determinados por cromatografia líquida de fase reversa. Resultados: Os pacientes avaliados (TFG, 34,8 ± 12,4 mL/min, 54,2 ± 14,3 anos, IMC 29,3 ± 6,1 kg/m2) apresentaram ingestão média de proteína de 1,1 ± 0,5 g/kg/dia, Tyr de 4,5 ± 2,4 g/dia e Phe de 4,6 ± 2,5 g/dia. Os níveis plasmáticos de PCS (20,4 ± 15,5 mg/L) foram elevados e positivamente associados à ingestão de Tyr (r = 0,58, p = 0,002) e Phe (r = 0,53, p = 0,005), mesmo após ajustes pela TFG e idade. Conclusão: Este estudo sugere que a dieta é um importante modulador dos níveis plasmáticos de toxinas urêmicas produzidas pela microbiota intestinal em pacientes com DRC não dialisados.

Effect of Salinity Stress on Various Growth and Physiological Attributes of Two Contrasting Maize Genotypes

Abstract The response of two local maize (Zea mays L.) genotypes designated as Sahwal-2002 (salt-tolerant) and Sadaf (salt-sensitive) to salt stress was investigated under controlled growth conditions. The role of phenylalanine and seed priming under salt stress in maize with different morphological parameters were studied. The genotype Sadaf, being salt-tolerant, experienced more oxidative damage than the Sahiwall-2002 genotype under salt stress. The salinity affected both growth and physiological attributes of the maize species whereas the phenylalanine successfully increased the salinity tolerance in maize species at the seedling stage.

Fenilcetonuria de diagnóstico precoz: Bases fisiopatológicas del daño neuronal y opciones terapéuticas / Early diagnosis of phenylketonuria. Physiopathology of the neuronal damage and therapeutic options

La fenilcetonuria, también conocida como PKU, es el error congénito más frecuente del metabolismo de los aminoácidos. La forma grave o PKU clásica no tratada, causa una discapacidad intelectual, aunque los programas de detección en el período neonatal, el diagnóstico y el tratamiento evitan la aparición de los síntomas. A pesar de un diagnóstico y tratamiento temprano hemos observado cierta neurotoxicidad en los pacientes con PKU tratados. Analizamos los demás factores implicados, aparte de la toxicidad por las elevadas concentraciones cerebrales de fenilalanina (Phe), se revisan los defectos de síntesis de neurotransmisores, las alteración de la mielinización cerebral, el efecto de la elevación de Phe en los procesos de transporte y distribución de los aminoácidos neutros con una síntesis anómala de proteínas cerebrales, la deficiencia plasmática y cerebral de tirosina, la neurotoxicidad de los metabolitos de Phe, el defecto de la biosíntesis del colesterol o el aumento del estrés oxidativo. Las alteraciones de la sustancia blanca en los pacientes con PKU tienen un papel importante en las manifestaciones neurológicas. El tratamiento de la PKU es para toda la vida y se basa en la reducción del aporte de alimentos que contienen Phe combinado con la administración de una fórmula especial, o en el tratamiento con tetrahidrobiopterina (BH4). Se analizan nuevas opciones terapéuticas.

Phenylketonuria, also known as PKU, is the most frequent congenital inborn error of metabolism. The severe form or classic PKU untreated causes intellectual disability, although with the early detection programs in the neonatal period, diagnosis and treatment prevent the appearance of the symptoms. Despite early diagnosis and treatment we have observed some neurotoxicity in treated PKU patients. We analyzed the factors involved apart from the toxicity due to the high cerebral concentrations of phenylalanine (Phe), the defects of synthesis of neurotransmitters, the alteration of cerebral myelination, the effect of the elevation of Phe in the processes of transport and distribution of neutral amino acids with an abnormal synthesis of brain proteins, plasma and cerebral tyrosine deficiency, the neurotoxicity of Phe metabolites, the defect of cholesterol biosynthesis or the increase of oxidative stress. White matter alterations in early treated PKU patients have an important role in neurological manifestations. The treatment of PKU is for life and is based on the reduction of foods containing Phe combined with the administration of a special formula or tetrahydrobiopterin (BH4) treatment. New therapeutic options will be analyzed.

Obesity-Associated Metabolic Signatures Correlate to Clinical and Inflammatory Profiles of Asthma: A Pilot Study

PURPOSE: Obesity is associated with metabolic dysregulation, but the underlying metabolic signatures involving clinical and inflammatory profiles of obese asthma are largely unexplored. We aimed at identifying the metabolic signatures of obese asthma. METHODS: Eligible subjects with obese (n = 11) and lean (n = 22) asthma underwent body composition and clinical assessment, sputum induction, and blood sampling. Sputum supernatant was assessed for interleukin (IL)-1β, -4, -5, -6, -13, and tumor necrosis factor (TNF)-α, and serum was detected for leptin, adiponectin and C-reactive protein. Untargeted gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolic profiles in sputum, serum and peripheral blood monocular cells (PBMCs) were analyzed by orthogonal projections to latent structures-discriminate analysis (OPLS-DA) and pathway topology enrichment analysis. The differential metabolites were further validated by correlation analysis with body composition, and clinical and inflammatory profiles. RESULTS: Body composition, asthma control, and the levels of IL-1β, -4, -13, leptin and adiponectin in obese asthmatics were significantly different from those in lean asthmatics. OPLS-DA analysis revealed 28 differential metabolites that distinguished obese from lean asthmatic subjects. The validation analysis identified 18 potential metabolic signatures (11 in sputum, 4 in serum and 2 in PBMCs) of obese asthmatics. Pathway topology enrichment analysis revealed that cyanoamino acid metabolism, caffeine metabolism, alanine, aspartate and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, pentose phosphate pathway in sputum, and glyoxylate and dicarboxylate metabolism, glycerolipid metabolism and pentose phosphate pathway in serum are suggested to be significant pathways related to obese asthma. CONCLUSIONS: GC-TOF-MS-based metabolomics indicates obese asthma is characterized by a metabolic profile different from lean asthma. The potential metabolic signatures indicated novel immune-metabolic mechanisms in obese asthma with providing more phenotypic and therapeutic implications, which needs further replication and validation.

Quality of life and adherence to treatment in early-treated Brazilian phenylketonuria pediatric patients

Early dietary treatment of phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, results in normal cognitive development. Although health-related quality of life (HRQoL) of PKU patients has been reported as unaffected in high-income countries, there are scarce data concerning HRQoL and adherence to treatment of PKU children and adolescents from Brazil. The present study compared HRQoL scores in core dimensions of Brazilian early-treated PKU pediatric patients with those of a reference population, and explored possible relationships between adherence to treatment and HRQoL. Early-treated PKU pediatric patient HRQoL was evaluated by self- and parent-proxy reports of the Pediatric Quality of Life Inventory (PedsQL) core scales. Adherence to treatment was evaluated by median Phe levels and percentage of results within the therapeutic target range in two periods. Means for total and core scales scores of PedsQL self- and parent proxy-reports of PKU patients were significantly lower than their respective means for controls. Adequacy of median Phe concentrations and the mean percentage of values in the target range fell substantially from the first year of life to the last year of this study. There was no significant difference in mean total and core scale scores for self- and parent proxy-reports between patients with adequate and those with inadequate median Phe concentrations. The harmful consequences for intellectual capacity caused by poor adherence to dietary treatment could explain the observed decrease in all HRQoL scales, especially in school functioning. Healthcare system and financial difficulties may also have influenced negatively all HRQoL dimensions.

Evaluación neuropsicológica en niños y adolescentes con fenilcetonuria e hiperfenilalaninemia y su relación con los niveles de fenilalanina plasmática / Neuropsychological assessment among children and adolescents with phenylketonuria and hyperphenylalaninemia and its relationship with plasma phenylalanine levels

Aunque, con tratamiento precoz, los pacientes con fenilcetonuria pueden presentar niveles de inteligencia normales, es importante optimizar el control dietético para mantener niveles de fenilalanina adecuados y poder desarrollar su potencial intelectual sin alteraciones en sus tareas diarias por déficits en las funciones ejecutivas. Se presenta una serie de 26 pacientes, diagnosticados y tratados precozmente, a quienes se realizó una evaluación psicométrica junto con determinaciones de fenilalanina a lo largo de su vida y en el momento de realización de los tests. Se observa una tendencia a la relación inversa entre el cociente intelectual y la fenilalanina concurrente, la mediana de fenilalanina y el cociente fenilalanina/tirosina, así como una tendencia a la relación negativa entre las funciones ejecutivas y los valores de fenilalanina concurrentes y durante la vida.

Although with early treatment phenylketonuria patients may have average intelligence levels, it is important to optimize the nutritional management to maintain adequate phenylalanine levels, so that patients can develop their intellectual potential free of abnormalities in their daily activities due to deficits of cognitive executive functions. This study presents a series of 26 patients, diagnosed and treated early, who underwent a psychometric evaluation together with phenylalanine determinations along their lives, and at the time of doing the tests. A trend is observed towards a reverse relationship between IQ and concurrent phenylalanine concentration, phenylalanine median and phenylalanine/tyrosine ratio. Likewise, a trend towards a negative relationship is observed between executive functions and concurrent phenylalanine values along patients' lives.

Correlation Between Gastric Emptying and Gastric Adaptive Relaxation Influenced by Amino Acids

BACKGROUND/AIMS: Amino acids have many physiological activities. We report the correlation between gastric emptying and gastric adaptive relaxation using tryptophan and amino acids with a straight alkyl chain, hydroxylated chain, and branched chain. Here we sought to further clarify the correlation between gastric emptying and gastric adaptive relaxation by using other amino acids. METHODS: In Sprague-Dawley rats, gastric emptying was evaluated by a breath test using [1-¹³C] acetic acid. The expired ¹³CO₂ pattern, T(max), C(max), and AUC(120min) values were used as evaluation items. Gastric adaptive relaxation was evaluated in a barostat experiment. Individual amino acids (1 g/kg) were administered orally 30 minutes before each breath test or barostat test. RESULTS: L-phenylalanine and L-tyrosine did not influence gastric emptying. All other amino acids, ie, L-proline, L-histidine, L-cysteine, L-methionine, L-aspartic acid, L-glutamic acid, L-asparagine, L-arginine, L-glutamine, and L-lysine significantly delayed and inhibited gastric emptying. L-Cysteine and L-aspartic acid significantly enhanced and L-methionine and L-glutamine significantly inhibited gastric adaptive relaxation. L-Phenylalanine moved the balloon toward the antrum, suggesting strong contraction of the fundus. T(max) showed a significant positive correlation (r = 0.709), and C(max) and AUC(120min) each showed negative correlations (r = 0.613 and 0.667, respectively) with gastric adaptive relaxation. CONCLUSION: From the above findings, it was found that a close correlation exists between gastric emptying and adaptive relaxation, suggesting that enhanced gastric adaptive relaxation inhibits gastric emptying.

Uso de fórmula nutricional libre de fenilalanina en pacientes con diagnóstico de fenilcetonuria / Use of phenylalanine-free nutritional formula in patients diagnosed with phenylketonuria

INTRODUCCIÓN: Antecedentes: El presente informe expone la evaluación del producto Fórmula nutricional libree de fenilalanina respecto a su uso en pacientes con diagnóstico de fenilcetonuria (PKU). Aspectos Generales: La fenilcetonuria (PKU) es un error innato del metabolismo provocado por mutaciones en el gen fenilalanina hidroxilasa (PAH), encargado de codificar la enzima PAH. La enzima PAH participa en la vía metabólica principal de la fenilalanina, un aminoácido esencial. La función de la enzima es hidroxilar la fenilalanina en tirosina en conjunto con el cofactor BH4, y oxigenio. Las mutaciones en el gen de PAH provocan una disminución o eliminación de la actividad enzimática de la PAH, por onde, niveles elevados de fenilalanina sérica, conocido como hiperfenilalaninemia. Tecnología Sanitaria de Interés: Formula nutricional libre de fenilalanina: Las fórmulas nutricionales libres de fenilalanina son alimentos médicos que forman parte del grupo de sustitutos o equivalentes de proteínas destinados para pacientes con PKU. Los alimentos médicos se definen como "un alimento formulado para ser consumido o adminitrado vía enteral bajo supervisión médica, y está dirigido para el manejo dietético de una enfermedad o condición para la cual los requerimientos nutricionales son establecidos por una evaluación médica. Los alimentos médicos para pacientes con PKU han sido modificados para elimiar el aminoácido fenilalanina de su composición a través de hidrólisis enzimáticas y procesos bioquímicos que incluyen el uso de filtraciones por gel, resinas de poliestireno, ultrafiltración, entre otros. METODOLOGIA: Estrategia de Búsqueda: Se realizó una búsqueda de literatura científica en relación al uso de fórmulas nutricionales libre de fenilalanina en pacientes menores de 15 años con diagnóstico de fenilcetonuria. Se dio preferencia a guías de práctica clínica, revisiones sistemáticas con o sin meta-análisis y ensayos clínicos aleatorizados. Asimismo, se consideró extraer información con una estrategia de "bola de nieve" mediante la revisión de listas de referencias de las guías de práctica clínica, revisiones sistemáticas, estudios primarios y revisiones narrativas seleccionadas. RESULTADOS: Se realizó la búsqueda bibliográfica y de evidencia científica que sustende el uso de una formula libre de fenilalanina en pacientes menores de 15 años con diagnóstico de PKU. Luego de revisar un total de 1073 referencias resultados de la búsqueda bibliográfica, logramos filtrar 29 estudios. Luego, tres referencias fueron finalmente seleccionadas para ser analizadas. Sinopsos de la Evidencia: Se sintetiza la evidencia considerada para el presente dictamen que sustenta el uso de fórmulas nutricionales libres de fenilalanina en pacientes menores de 15 años con PKU, en las Guías de Práctica Clínica, Revisiones Sistemáticas, Ensayos Clínicos, Ensayos Clínicos no publicados, Estudios observacionales. CONCLUSIONES: En la presente evaluación de tecnología sanitaria se presenta la evidencia recabada sobre el benefício de las fórmulas nutricionales libres de fenilalanina en pacientes menores de 15 años con Fenilcetonuria (PKU). No se encontró evidencia que compara el uso de fórmulas libres de fenilalanina con fórmulas estándar en pacientes menores de 15 años; sin embargo, se hallaron dos GPC, de alta y baja calidad metodológica, y un artículo de recomendación tipo revisión sistemática que recomiendan su uso en pacientes con PKU. El Instituto de Evaluación de Tecnologías en Salud e Investigación-IETSI, aprueba el uso de la fórmula libre de fenilalanina en pacientes menores de 15 años con diagnóstico de PKU. El presenta Dictamen Preliminar tiene una vigencia de dos años a partir de la fecha de publicación.

Deficiência de vitamina B12 e fenilcetonúria / Vitamin B 12 deficiency and phenylketonuria

A fenilcetonúria, doença metabólica hereditária, autossômica recessiva, é a mais frequente das aminoacidopatias. Quando não diagnosticada e tratada precocemente, causa retardo mental grave. Os programas de triagem neonatal transformaram a histó- ria natural dessa doença, possibilitando o diagnóstico neonatal e a instituição imediata do tratamento dietético. Atualmente, os pacientes com controle adequado têm vida normal. Nas últimas décadas, alterações nutricionais têm sido relacionadas ao tratamento dietético e aos seus desvios, especialmente após a primeira década de vida. Neste artigo apresenta-se o caso de um adolescente que desenvolveu anemia megaloblástica por deficiente ingestão de vitamina B12 e uma revisão da literatura sobre o tema.(AU)

Phenylketonuria, inherited metabolic disease, autosomal recessive, is the most common of aminoacidopathies. If not diagnosed and treated early, causes severe mental retardation. The newborn screening programs have transformed the natural history of this disease, allowing the neonatal diagnosis and the immediate institution of dietary treatment. Currently, patients with adequate control have normal life. In recent decades, nutritional changes have been related to dietary treatment and its deviations, especially after the first decade of life. In this article we present the case of a teenager who developed megaloblastic anemia due to poor intake of vitamin B12 and a literature review on the topic(AU)

Effect of glycemic index on obesity control

Objective Evaluate the effect of glycemic index (GI) on biochemical parameters, food intake, energy metabolism, anthropometric measures and body composition in overweight subjects.Materials and methods Simple blind study, in which nineteen subjects were randomly assigned to consume in the laboratory two daily low GI (n = 10) or high GI (n = 9) meals, for forty-five consecutive days. Habitual food intake was assessed at baseline. Food intake, anthropometric measures and body composition were assessed at each 15 days. Energy metabolism and biochemical parameters were evaluated at baseline and the end of the study.Results Low GI meals increased fat oxidation, and reduced waist circumference and HOMA-IR, while high GI meals increased daily dietary fiber and energy intake compared to baseline. There was a higher reduction on waist circumference and body fat, and a higher increase on postprandial fat oxidation in response to the LGI meals than after high GI meals. High GI meals increased fasting respiratory coefficient compared to baseline and low GI meals.Conclusion The results of the present study showed that the consumption of two daily low GI meals for forty-five consecutive days has a positive effect on obesity control, whereas, the consumption of high GI meals result has the opposite effect. Arch Endocrinol Metab. 2015;59(3):245-51.

¿Qué debe saber el pediatra de las hiperfenilalaninemias? / What should the paediatrician know about hyperphenylalaninaemia?

Las hiperfenilalaninemias se definen por un nivel sanguíneo de fenilalanina sobre 2 mg/dl. La principal causa es una mutación en el gen que codifica la fenilalanina hidroxilasa que cataliza la reacción que transforma la fenilalanina en tirosina. Las hiperfenilalaninemias se clasifican en benignas o leves, y las fenilcetonurias en leves, moderadas y clásicas. Debido a que su detección más allá del periodo neonatal causa retardo mental severo, desde 1992 en Chile su detección, junto con la del hipotirodismo congénito, es parte del Programa Nacional de Pesquisa Neonatal. Este artículo pretende responder las preguntas más comunes que se puede hacer el pediatra cuando enfrenta a un paciente con hiperfenilalaninemias.

Hyperphenylalaninaemias are defined by a blood phenylalanine over 2 mg/dl. The main cause is due to a mutation in the gene that codes the phenylalanine hydroxylase that catalyses the reaction that converts phenylalanine into tyrosine. The hyperphenylalaninaemias are classified into benign or mild hyperphenylalaninaemias, or mild, moderate or classic phenylketonurias. Due to its delayed detection outside the neonatal period it causes severe mental retardation. Its detection along with congenital hypothyroidism has been part of the National Neonatal Screening Program since 1992 in Chile. This article aims to answer the most common questions asked by the paediatrician when faced with a patient with hyperphenylalaninaemias.

Metabolic syndrome in children and adolescents with phenylketonuria / Síndrome metabólica em crianças e adolescentes com fenilcetonúria

OBJECTIVE: This study aimed to identify markers of metabolic syndrome (MS) in patients with phenylketonuria (PKU). METHODS: This was a cross-sectional study consisting of 58 PKU patients (ages of 4-15 years): 29 patients with excess weight, and 29 with normal weight. The biochemical variables assessed were phenylalanine (phe), total cholesterol, HDL-c, triglycerides, glucose, and basal insulin. The patients had Homeostasis Model Assessment (HOMA) and waist circumference assessed. RESULTS: No inter-group difference was found for phe. Overweight patients had higher levels of triglycerides, basal insulin, and HOMA, but lower concentrations of HDL-cholesterol, when compared to the eutrophic patients. Total cholesterol/HDL-c was significantly higher in the overweight group. A positive correlation between basal insulin level and HOMA with waist circumference was found only in the overweight group. CONCLUSION: The results of this study suggest that patients with PKU and excess weight are potentially vulnerable to the development of metabolic syndrome. Therefore, it is necessary to conduct clinical and laboratory monitoring, aiming to prevent metabolic changes, as well as excessive weight gain and its consequences, particularly cardiovascular risk. .

OBJETIVO: Determinar marcadores bioquímicos da síndrome metabólica em pacientes com PKU. MÉTODOS: Foram avaliados dois grupos de pacientes com PKU, de quatro a 15 anos, com excesso de peso (29) e eutróficos (29). As variáveis bioquímicas avaliadas foram fenilalanina (phe), colesterol total, HDL-c, triglicérides, glicose e insulina basal. Foi determinado o Homa e mensurada a circunferência da cintura. RESULTADOS: As concentrações de phe, de colesterol total e de glicose foram equivalentes entre os grupos. Os pacientes com excesso de peso apresentaram maiores concentrações de triglicérides, de insulina basal, maiores valores da determinação do Homa, menores concentrações de HDL colesterol e valores mais elevados da relação do colesterol total/HDL-c. Houve correlação positiva entre a dosagem de insulina basal e do Homa com a circunferência da cintura nos pacientes do grupo com excesso de peso. CONCLUSÕES: Os resultados deste estudo sugerem que pacientes com PKU e excesso de peso são potencialmente vulneráveis ao desenvolvimento da síndrome metabólica. Há, portanto, necessidade de acompanhamento clínico-laboratorial que previna as alterações metabólicas, o ganho excessivo de peso e as suas consequências, em especial o risco cardiovascular. .

Polymorphisms of SLC22A9 (hOAT7) in Korean Females with Osteoporosis

Among solute carrier proteins, the organic anion transporters (OATs) play an important role for the elimination or reabsorption of endogenous and exogenous negatively charged anionic compounds. Among OATs, SLC22A9 (hOAT7) transports estrone sulfate with high affinity. The net decrease of estrogen, especially in post-menopausal women induces rapid bone loss. The present study was performed to search the SNP within exon regions of SLC22A9 in Korean females with osteoporosis. Fifty healthy controls and 50 osteoporosis patients were screened for the genetic polymorphism in the coding region of SLC22A9 using GC-clamped PCR and denaturing gradient gel electrophoresis (DGGE). Six SNPs were found on the SLC22A9 gene from Korean women with/without osteoporosis. The SNPs were located as follows: two SNPs in the osteoporosis group (A645G and T1277C), three SNPs in the control group (G1449T, C1467T and C1487T) and one SNP in both the osteoporosis and control groups (G767A). The G767A, T1277C and C1487T SNPs result in an amino acid substitution, from synonymous vs nonsynonymous substitution arginine to glutamine (R256Q), phenylalanine to serine (F426S) and proline to leucine (P496L), respectively. The Km values and Vmax of the wild type, R256Q, P496L and F426S were 8.84, 8.87, 9.83 and 12.74 microM, and 1.97, 1.96, 2.06 and 1.55 pmol/oocyte/h, respectively. The present study demonstrates that the SLC22A9 variant F426S is causing inter-individual variation that is leading to the differences in transport of the steroid sulfate conjugate (estrone sulfate) and, therefore this could be used as a marker for certain disease including osteoporosis.

Cloning and Expression Analysis of Phenylalanine Ammonia-Lyase Gene in the Mycelium and Fruit Body of the Edible Mushroom Flammulina velutipes

Phenylalanine ammonia-lyase (PAL) gene is known to be expressed in plants, and is involved in the differentiation, growth and synthesis of secondary metabolites. However, its expression in fungi remains to be explored. To understand its expression in mushroom fungi, the PAL gene of the edible mushroom Flammulina velutipes (Fvpal) was cloned and characterized. The cloned Fvpal consists of 2,175 bp, coding for a polypeptide containing 724 amino acids and having 11 introns. The translated amino acid sequence of Fvpal shares a high identity (66%) with that of ectomycorrhizal fungus Tricholoma matsutake. Distinctively, the Fvpal expression in the mycelium was higher in minimal medium supplemented with L-tyrosine than with other aromatic amino acids. During cultivation of the mushroom on sawdust medium, Fvpal expression in the fruit body correspondingly increased as the mushroom grew. In the fruiting body, Fvpal was expressed more in the stipe than in the pileus. These results suggest that F. velutipes PAL activity differs in the different organs of the mushroom. Overall, this is first report to show that the PAL gene expression is associated with mushroom growth in fungi.