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INTRODUCTION: Protein nutrition disorder in alkaptonuria (AKU), resulting in increased homogentisic acid (HGA) before nitisinone therapy and increased tyrosine (TYR) during nitisinone therapy, may benefit from dietetic intervention. The aim of this study was to characterise the diet and their effects prospectively in those who received formal dietetic intervention in the nitisinone-receiving National Alkaptonuria Centre (NAC) patients with those who did not in no-nitisinone Suitability of Nitisinone in Alkaptonuria 2 (SN2 N-) and nitisinone-treated SN2 (SN2 N+) randomised study groups. PATIENTS AND METHODS: A total of 63, 69, and 69 AKU patients from the NAC, SN2 N-, and SN2 N+ were studied for anthropometric (weight, BMI), body composition (including muscle mass, %body fat, hand grip strength), chemical characteristics (serum TYR, serum phenylalanine, urine urea or uUREA, and urine creatinine or uCREAT), and corneal keratopathy. Nitisinone 2 mg and 10 mg were employed in the NAC and SN2 N+ groups, respectively. Dieticians managed protein intake in the NAC, while the SN2 N- and SN2 N+ groups only received advice on self-directed protein restriction during four years of study duration. RESULTS: uUREA decreased in the NAC, SN2 N-, and SN2 N+ groups, showing that protein restriction was achieved in these groups. Body weight and BMI increased in the NAC and SN2 N+ groups. uCREAT decreased significantly in SN2 N- and SN2 N+ compared with the NAC over four years of study. Corneal keratopathy was less frequent in the NAC than in the SN2 N+ group. Active dietetic intervention in NAC stabilised lean body mass (muscle mass, hand grip strength) despite a decrease in uUREA and uCREAT, as well as sTYR. CONCLUSION: Ongoing dietetic intervention prevented loss of lean body mass despite protein restriction and moderated serum tyrosine increase, leading to less prevalent corneal keratopathy. Protein restriction risks fat mass gain.
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Alcaptonuria , Composición Corporal , Ciclohexanonas , Nitrobenzoatos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Composición Corporal/efectos de los fármacos , Anciano , Tirosina/sangre , Tirosina/análogos & derivados , Adulto , Estudios Prospectivos , Índice de Masa Corporal , Estado Nutricional , Fenilalanina/sangre , Antropometría , Ácido Homogentísico/orina , Fuerza de la ManoRESUMEN
L-tyrosine is a recognized biomarker of albinism, whose endogenous level in human bodies is directly linked to melanin synthesis while no attention has been paid to its specific diagnosis. To this end, we have developed an electrochemical point-of-care testing device based on a molecularly imprinted gel prepared by a universal paradigm shift design to achieve the enhanced specific recognition of the L-tyrosine. Interestingly, this theoretically optimized molecularly imprinted gel validates the recognition pattern of L-tyrosine and optimizes the structure of the polymer itself with the aid of computational chemistry. Besides, modified extended-layer MXene and Au nanoclusters have significantly improved the sensing activity. As a result, the linear diagnostic range of this electrochemical point-of-care testing device for L-tyrosine is 0.1-100 µM in actual human fluids, which fully covers the L-tyrosine levels of healthy individuals and people with albinism. The diagnosis is completed in 90 s and then the results are transmitted by Bluetooth low energy to the smart mobile terminal. Therefore, we are convinced that this electrochemical point-of-care testing device is a promising tool in the future smart medical system.
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Albinismo , Biomarcadores , Técnicas Biosensibles , Técnicas Electroquímicas , Oro , Pruebas en el Punto de Atención , Tirosina , Humanos , Técnicas Biosensibles/instrumentación , Técnicas Biosensibles/métodos , Biomarcadores/análisis , Biomarcadores/sangre , Técnicas Electroquímicas/instrumentación , Técnicas Electroquímicas/métodos , Tirosina/análisis , Tirosina/sangre , Oro/química , Albinismo/diagnóstico , Diseño de Equipo , Impresión Molecular/métodos , Nanopartículas del Metal/química , Límite de Detección , Sistemas de Atención de PuntoRESUMEN
INTRODUCTION: Tyrosinaemia type I is a rare hereditary metabolic disease caused by deficiency of the enzyme involved in the breakdown of tyrosine. Since the use of nitisinone in addition to diet in 1992, survival rates have increased significantly, but more and more socio-emotional problems have become apparent. The aim of the study was the assessment the relationship between variations in serum tyrosine and phenylalanine levels and measurements of socio-emotional functioning and determination of patients' IQs. THE AIM OF THE STUDY: was the assessment the relationship between variations in serum tyrosine and phenylalanine levels and measurements of socio-emotional functioning and determination of patients' IQs. MATERIAL AND METHODS: Twelve children were studied, from a single centre, born between 1994 and 2012, treated with nitisinone and a low-phenylalanine and -tyrosine diet. The psychological evaluation was conducted using the parent form of the Child Behaviour Checklist (CBCL)/4-18. Additionally, the patients' IQs were measured using the Stanford-Binet 5 (SB5) Intelligence Scale. Statistical analyses were performed using PAWS software suite version 26. We found that phenylalanine variability over time correlated with measures of emotional and behavioural functioning. This relationship holds true for externalising behaviour, associated with the experience of maladjustment and aggression. Total score intellectual and cognitive function was within the norm for all patients. CONCLUSIONS: To maintain better quality of life for patients and their families in terms of emotional and behavioural functioning, it may be important to avoid spikes (significant fluctuations) in phenylalanine levels. Regular, detailed psychological evaluations are recommended to detect potential problems and implement interventions aimed at achieving the best possible individual development and realise the intellectual and behavioural potential, thereby improving the patient's and her family's quality of life.
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Fenilalanina , Tirosinemias , Humanos , Tirosinemias/sangre , Tirosinemias/psicología , Niño , Masculino , Femenino , Fenilalanina/sangre , Preescolar , Adolescente , Tirosina/sangre , Ciclohexanonas/uso terapéutico , Emociones , Calidad de Vida , Nitrobenzoatos/uso terapéutico , Conducta Infantil/psicologíaRESUMEN
BACKGROUND: Despite enormous advances in diabetes treatment, women with type 1 diabetes mellitus (DM) still experience delayed menarche, menstrual irregularities, fewer pregnancies, and a higher rate of stillbirths compared to women without the disease. Due to the fact that type 1 DM occurs at a young age, the preservation of reproductive health is one of the most important goals of treatment. AIMS: The aim of this study was to evaluate the relationship between different glycemic profiles and changes in the pro-oxidant-antioxidant balance and ovarian follicular apparatus in reproductive-age patients with type 1 DM. METHODS: We examined 50 reproductive-age (19-38 years) women with type 1 DM with a disease duration of at least ten years. Carbohydrate metabolism was assessed with the continuous glucose monitoring (CGM) system and glycated hemoglobin (HbA1c) concentration measurement. CGM was performed using the FreeStyle Libre flash glucose monitoring system (Abbott Diabetes Care, Witney, UK). In each patient, malondialdehyde level, catalase activity and 3-nitrotyrosine level in the blood serum were determined. To assess the ovarian function, we measured the ovarian volume, the antral follicle count, and the serum levels of anti-Müllerian hormone and follicle-stimulating hormone. All patients were divided into four groups (glucotypes) based on the CGM results. Group 1 included type 1 DM patients with satisfactory compensation of carbohydrate metabolism; group 2 consisted of patients with frequent hypoglycemic conditions and pathological glucose variability; group 3 included individuals with prolonged hyperglycemic conditions and maximum HbA1c levels; and group 4 comprised patients with the glycemic profile characterized by all the presented types of dysglycemia (intermittent glycemia). RESULTS: We revealed a negative correlation between serum catalase activity and time of hypoglycemic conditions in patients with type 1 DM based on the CGM results (rs = -0.47, p < 0.01). In group 4 (intermittent glycemia), patients demonstrated the lowest serum catalase activity and increased serum 3-nitrotyrosine level, while in group 3, women with chronic hyperglycemia (HbA1c 8.4 [8.1; 9.9]%; 68 [65; 85] mmol/mol) had a moderate change in antioxidant defense and oxidative stress parameters. Correlation analysis of ovarian volume, the antral follicle count, and the serum anti-Müllerian hormone level in type 1 DM women with different glycemic profiles established a negative relationship (rs = -0.82, p < 0.05) between the antral follicle count and glucose variability in group 1, a positive relationship (rs = 0.68, p < 0.05) between ovarian volume and glucose variability in group 2, and a positive relationship (rs = 0.88, p < 0.05) between ovarian volume and time of hypoglycemic conditions, which, according to the CGM results, amounted to a critical value of 57.5 [40.0; 82.0]%. CONCLUSIONS: The data obtained indicate the relationship between the ovarian volume, serum anti-Müllerian hormone level, the antral follicle count and oxidative stress parameters not only in patients with hyperglycemia, but also in those with hypoglycemic conditions, as well as with pathological glucose variability.
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Glucemia , Diabetes Mellitus Tipo 1 , Hemoglobina Glucada , Folículo Ovárico , Estrés Oxidativo , Humanos , Femenino , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Estrés Oxidativo/fisiología , Adulto , Adulto Joven , Glucemia/análisis , Hemoglobina Glucada/análisis , Catalasa/sangre , Hormona Antimülleriana/sangre , Malondialdehído/sangre , Tirosina/análogos & derivados , Tirosina/sangreRESUMEN
BACKGROUND: Acute kidney injury (AKI) is a serious complication of cirrhosis. This study analyzed the prognostic effect of AKI in patients with cirrhosis and its risk factors, particularly in relation to amino acid imbalance. METHODS: This retrospective study reviewed 808 inpatients with cirrhosis at two institutes in Gifu, Japan. AKI was diagnosed according to the recommendations of the International Club of Ascites. Amino acid imbalance was assessed by measuring serum branched-chain amino acid (BCAA) levels, tyrosine levels, and the BCAA-to-tyrosine ratio (BTR). Factors associated with mortality and AKI development were assessed using the Cox proportional hazards regression model with AKI as a time-dependent covariate and the Fine-Gray competing risk regression model, respectively. RESULTS: Of the 567 eligible patients without AKI at baseline, 27% developed AKI and 25% died during a median follow-up period of 4.7 years. Using a time-dependent covariate, AKI development (hazard ratio [HR], 6.25; 95% confidence interval [CI], 3.98-9.80; p < 0.001) was associated with mortality in patients with cirrhosis independent of potential covariates. In addition, alcohol-associated/-related liver disease, metabolic dysfunction-associated steatohepatitis, Child-Pugh score, and BTR (subdistribution HR 0.78; 95% CI 0.63-0.96; p = 0.022) were independently associated with AKI development in patients with cirrhosis. Similar results were obtained in the multivariate model that included BCAA and tyrosine levels instead of BTR. CONCLUSIONS: AKI is common and associated with mortality in Japanese patients with cirrhosis. An amino acid imbalance is strongly associated with the development of AKI in patients with cirrhosis.
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Lesión Renal Aguda , Aminoácidos de Cadena Ramificada , Cirrosis Hepática , Humanos , Lesión Renal Aguda/mortalidad , Lesión Renal Aguda/etiología , Lesión Renal Aguda/sangre , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/mortalidad , Anciano , Japón/epidemiología , Factores de Riesgo , Aminoácidos de Cadena Ramificada/sangre , Pronóstico , Tirosina/sangre , Tirosina/análogos & derivados , Modelos de Riesgos Proporcionales , Estudios de Seguimiento , Pueblos del Este de AsiaRESUMEN
This study examined if the amino acids phenylalanine or tyrosine contribute to risk of hip fracture or frailty in older adults. We determined that neither phenylalanine nor tyrosine are important predictors of hip fracture or frailty. We suggest advice on protein intake for skeletal health consider specific amino acid composition. PURPOSE: Protein is essential for skeletal health, but the specific amino acid compositions of protein may have differential associations with fracture risk. The aim of this study was to determine the association of serum levels of the aromatic amino acids phenylalanine and tyrosine with risk for incident hip fractures over twelve years of follow-up and cross sectional associations with frailty. METHODS: We included 131 older men and women from the Cardiovascular Health Study (CHS) who sustained a hip fracture over twelve years of follow-up and 131 men and women without an incident hip fracture over this same period of time. 42% of this cohort were men and 95% were Caucasian. Weighted multivariable Cox hazards molecules were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of incident hip fracture associated with a one standard deviation (SD) higher serum level of phenylalanine or tyrosine. Relative risk regression was used to determine the cross-sectional association of these amino acids with Freid's frailty index. RESULTS: Neither serum levels of phenylalanine (HR 0.85 (95% CI 0.62-1.16) or tyrosine (HR 0.82 (95% CI 0.62-1.1) were significantly associated with incident hip fractures or cross sectionally with frailty (frail compared with prefrail/not frail) (HR 0.92 (95% CI 0.48-1.76) and HR (0.86 (95% CI 0.46-1.61) respectively. CONCLUSION: Phenylalanine and tyrosine are not significant contributors to hip fractures or frailty in older men and women.
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Fragilidad , Fracturas de Cadera , Fenilalanina , Tirosina , Humanos , Masculino , Fenilalanina/sangre , Femenino , Tirosina/sangre , Fracturas de Cadera/sangre , Fracturas de Cadera/epidemiología , Anciano , Fragilidad/sangre , Fragilidad/epidemiología , Anciano de 80 o más Años , Estudios Transversales , Anciano Frágil/estadística & datos numéricos , Factores de RiesgoRESUMEN
Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines. In this study, we used ultra-performance liquid chromatography (UPLC)/quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients. We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla. Through conducting two steps of metabolomics analysis, we identified 111 differential metabolites between the healthy group and the patient group, among which 53 metabolites were validated. By integrating the information of differential metabolites and differentially expressed genes, we inferred that the cysteine-methionine, pyrimidine, and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm. The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma, whereas the pyrimidine pathway showed no significant difference. Finally, we developed an optimized diagnostic model of two metabolites, L-dihydroorotic acid and vanylglycol. Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.
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Neoplasias de las Glándulas Suprarrenales , Cisteína , Metionina , Feocromocitoma , Pirimidinas , Tirosina , Feocromocitoma/metabolismo , Feocromocitoma/sangre , Humanos , Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasias de las Glándulas Suprarrenales/sangre , Pirimidinas/metabolismo , Metionina/metabolismo , Tirosina/metabolismo , Tirosina/sangre , Cisteína/metabolismo , Masculino , Metabolómica/métodos , Femenino , Persona de Mediana Edad , Adulto , Redes y Vías MetabólicasRESUMEN
Nitrosative stress promotes protein glycoxidation, and both processes can occur during an infection with the SARS-CoV-2 virus. Therefore, the aim of this study was to assess selected nitrosative stress parameters and protein glycoxidation products in COVID-19 patients and convalescents relative to healthy subjects, including in reference to the severity of COVID-19 symptoms. The diagnostic utility of nitrosative stress and protein glycoxidation biomarkers was also evaluated in COVID-19 patients. The study involved 218 patients with COVID-19, 69 convalescents, and 48 healthy subjects. Nitrosative stress parameters (NO, S-nitrosothiols, nitrotyrosine) and protein glycoxidation products (tryptophan, kynurenine, N-formylkynurenine, dityrosine, AGEs) were measured in the blood plasma or serum with the use of colorimetric/fluorometric methods. The levels of NO (p = 0.0480), S-nitrosothiols (p = 0.0004), nitrotyrosine (p = 0.0175), kynurenine (p < 0.0001), N-formylkynurenine (p < 0.0001), dityrosine (p < 0.0001), and AGEs (p < 0.0001) were significantly higher, whereas tryptophan fluorescence was significantly (p < 0.0001) lower in COVID-19 patients than in the control group. Significant differences in the analyzed parameters were observed in different stages of COVID-19. In turn, the concentrations of kynurenine (p < 0.0001), N-formylkynurenine (p < 0.0001), dityrosine (p < 0.0001), and AGEs (p < 0.0001) were significantly higher, whereas tryptophan levels were significantly (p < 0.0001) lower in convalescents than in healthy controls. The ROC analysis revealed that protein glycoxidation products can be useful for diagnosing infections with the SARS-CoV-2 virus because they differentiate COVID-19 patients (KN: sensitivity-91.20%, specificity-92.00%; NFK: sensitivity-92.37%, specificity-92.00%; AGEs: sensitivity-99,02%, specificity-100%) and convalescents (KN: sensitivity-82.22%, specificity-84.00%; NFK: sensitivity-82,86%, specificity-86,00%; DT: sensitivity-100%, specificity-100%; AGE: sensitivity-100%, specificity-100%) from healthy subjects with high sensitivity and specificity. Nitrosative stress and protein glycoxidation are intensified both during and after an infection with the SARS-CoV-2 virus. The levels of redox biomarkers fluctuate in different stages of the disease. Circulating biomarkers of nitrosative stress/protein glycoxidation have potential diagnostic utility in both COVID-19 patients and convalescents.
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Biomarcadores , COVID-19 , Quinurenina/análogos & derivados , Estrés Nitrosativo , SARS-CoV-2 , Tirosina , Tirosina/análogos & derivados , Humanos , COVID-19/diagnóstico , COVID-19/sangre , COVID-19/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Biomarcadores/sangre , Adulto , Tirosina/sangre , Tirosina/metabolismo , Anciano , Quinurenina/sangre , Quinurenina/metabolismo , S-Nitrosotioles/sangre , S-Nitrosotioles/metabolismo , Óxido Nítrico/sangre , Óxido Nítrico/metabolismo , Triptófano/sangre , Triptófano/análogos & derivados , Triptófano/metabolismo , Productos Finales de Glicación Avanzada/sangre , Productos Finales de Glicación Avanzada/metabolismo , Curva ROCRESUMEN
BACKGROUND: The branched-chain amino acids (BCAAs) to tyrosine (Tyr) ratio (BTR) test is used to evaluate the progression of chronic liver disease (CLD). However, the differences across sex, age, body mass index (BMI) and etiologies are still unclear. METHODS: We retrospectively reviewed data from 2,529 CLD cases with free amino acids (FAAs) in peripheral blood from four hospitals and 16,421 general adults with FAAs data from a biobank database. In total, 1,326 patients with CLD (covering seven etiologies) and 8,086 healthy controls (HCs) were analyzed after exclusion criteria. We investigated the change of BTR in HCs by sex, age and BMI and then compared these to patients divided by modified ALBI (mALBI) grade after propensity score matching. RESULTS: BTR is significantly higher in males than females regardless of age or BMI and decreases with aging in HCs. In 20 types of FAAs, 7 FAAs including BCAAs were significantly decreased, and 11 FAAs including Tyr were significantly increased by mALBI grade in total CLD. The decreasing timings of BTR were at mALBI grade 2b in all CLD etiologies compared to HCs, however in chronic hepatitis C (CHC), chronic hepatitis B (CHB) and alcoholic liver disease (ALD), BTR started to decrease at 2a. There was a positive correlation between BCAAs and albumin among parameters in BTR and mALBI. The correlation coefficients in PBC, ALD and MASLD were higher than those of other etiologies. CONCLUSIONS: BTR varies by sex and age even among healthy adults, and decreasing process and timing of BTR during disease progression is different among CLD etiologies.
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Aminoácidos de Cadena Ramificada , Progresión de la Enfermedad , Hepatopatías , Tirosina , Humanos , Masculino , Femenino , Aminoácidos de Cadena Ramificada/sangre , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Anciano , Tirosina/sangre , Hepatopatías/etiología , Hepatopatías/sangre , Factores Sexuales , Índice de Masa Corporal , Enfermedad Crónica , Factores de Edad , Adulto Joven , Estudios de Casos y Controles , Hepatopatías Alcohólicas/complicaciones , Hepatopatías Alcohólicas/sangre , Biomarcadores/sangreRESUMEN
L-Tyrosine (L-Tyr), a critical amino acid whose aberrant levels impact melanin and dopamine levels in human body while also increasing insulin resistance thereby increasing the risk of type 2 diabetes. The objective of this study was to detect the amount of L-Tyr in human fluids by tailored electrochemical synthesis of well adhered, homogenous and thin molecularly imprinted polymers (MIPs) by the electro-polymerization of pyrrole on glassy carbon electrode modified functionalized multi-walled carbon nanotubes. The key benefits of this procedure over previous imprinting techniques were the elimination of expensive materials like Au and tedious multi-step synthesis, for L-Tyr detection using a handheld potentiostat. The developed particles were characterized using Fourier Transform Infrared Spectroscopy, Scanning Electron Microscope, Chronoamperometry, and Cyclic Voltammetry. With strong reproducibility and stability, this optimized approach provides a rapid and effective method of preparing and sensing MIPs for the target analyte with a broad linear range of [Formula: see text] to [Formula: see text]. The Limit of Detection and Limit of Quantification were [Formula: see text] and [Formula: see text], respectively. The engineered sensor was validated for quantifying the concentrations of L-Tyr in human blood and serum samples, yielding satisfactory recovery and can be expanded in future to detect analytes simultaneous.
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Técnicas Electroquímicas , Polímeros Impresos Molecularmente , Nanotubos de Carbono , Tirosina , Tirosina/química , Tirosina/sangre , Tirosina/análisis , Humanos , Técnicas Electroquímicas/métodos , Polímeros Impresos Molecularmente/química , Nanotubos de Carbono/química , Límite de Detección , Reproducibilidad de los Resultados , Impresión Molecular/métodos , Polímeros/químicaRESUMEN
AIMS: We aim to explore the associations between serum tyrosine (Tyr) to threonine (Thr) ratio and chronic heart failure (HF) with reduced or mildly reduced ejection fraction (EF) (HFrEF or HFmrEF). METHODS AND RESULTS: The study recruited 418 subjects (77.5% males, mean age 65.2 ± 12.5 years), including 318 HF subjects (HFrEF or HFmrEF) and 100 cardiovascular subjects without acute or chronic HF [including heart failure with preserved ejection fraction (HFpEF)] as controls. Serum levels of 21 kinds of amino acids (AAs) were measured by mass spectrometry. Logistic regression analysis was conducted to measuring the association between the AAs levels and the presence of HF. Event-free survival was determined by Kaplan-Meier curves and differences in survival were assessed using log-rank tests. Cox regression analysis was used to assess the prognostic value of AAs in HF. Receiver-operating characteristic (ROC) curve was performed to further confirm regression analysis. Along with the control, HFmrEF, and HFrEF subjects, serum tyrosine (Tyr) gradually increased (64.43 ± 15.28 µmol/L vs. 71.79 ± 18.74 µmol/L vs. 77.32 ± 25.90 µmol/L, P < 0.001) while serum threonine (Thr) decreased (165.21 ± 40.09 µmol/L vs. 144.93 ± 44.56 µmol/L vs. 135.25 ± 41.25 µmol/L, P < 0.001). Tyr/Thr ratio was the independent risk factor for the presence of HF in all subjects [odds ratio (OR), 3.510; 95% confidence interval (CI): 2.445-5.040; P < 0.001]. After following up for a mean year (11.10 ± 2.80 months) in 269 HF subjects (75.1% males, mean age 65.2 ± 12.8 years), the higher Tyr/Thr ratio was associated with a higher risk of HF endpoint events in HF subjects [hazard ratio (HR), 2.901; 95% CI: 1.228-6.851; P = 0.015]. By comparing the area under the receiver-operating characteristic curve (AUC), Tyr/Thr ratio was superior to Fischer's ratio (FR) in predicting HF occurrence (0.767:0.573, P < 0.001) or cardiovascular (CV) death (0.715:0.550, P = 0.047). CONCLUSIONS: Circulating elevated Tyr/Thr ratio confer an increased risk for the presence of HF and poor prognosis. Tyr/Thr index outweighs FR index in predicting HF occurrence or CV death.
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Insuficiencia Cardíaca , Volumen Sistólico , Treonina , Tirosina , Humanos , Masculino , Femenino , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Volumen Sistólico/fisiología , Anciano , Treonina/sangre , Tirosina/sangre , Pronóstico , Biomarcadores/sangre , Persona de Mediana Edad , Estudios de Seguimiento , Curva ROC , Estudios Retrospectivos , Función Ventricular Izquierda/fisiologíaRESUMEN
INTRODUCTION: Management of phenylketonuria (PKU) is mainly achieved through dietary control with limited intake of phenylalanine (Phe) from food, supplemented with low protein (LP) food and a mixture of free synthetic (FS) amino acids (AA) (FSAA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese making by the action of the enzyme chymosin. Because CGMP in its pure form does not contain Phe, it is nutritionally suitable as a supplement in the diet for PKU when enriched with specific AAs. Lacprodan® CGMP-20 (= CGMP) used in this study contained only trace amounts of Phe due to minor presence of other proteins/peptides. OBJECTIVE: The aims were to address the following questions in a classical PKU mouse model: Study 1, off diet: Can pure CGMP or CGMP supplemented with Large Neutral Amino Acids (LNAA) as a supplement to normal diet significantly lower the content of Phe in the brain compared to a control group on normal diet, and does supplementation of selected LNAA results in significant lower brain Phe level?. Study 2, on diet: Does a combination of CGMP, essential (non-Phe) EAAs and LP diet, provide similar plasma and brain Phe levels, growth and behavioral skills as a formula which alone consist of FSAA, with a similar composition?. MATERIAL AND METHODS: 45 female mice homozygous for the Pahenu2 mutation were treated for 12 weeks in five different groups; G1(N-CGMP), fed on Normal (N) casein diet (75%) in combination with CGMP (25%); G2 (N-CGMP-LNAA), fed on Normal (N) casein diet (75%) in combination with CGMP (19,7%) and selected LNAA (5,3% Leu, Tyr and Trp); G3 (N), fed on normal casein diet (100%); G4 (CGMP-EAA-LP), fed on CGMP (70,4%) in combination with essential AA (19,6%) and LP diet; G5 (FSAA-LP), fed on FSAA (100%) and LP diet. The following parameters were measured during the treatment period: Plasma AA profiles including Phe and Tyr, growth, food and water intake and number of teeth cut. At the end of the treatment period, a body scan (fat and lean body mass) and a behavioral test (Barnes Maze) were performed. Finally, the brains were examined for content of Phe, Tyr, Trp, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindole-acetic acid (5-HIAA), and the bone density and bone mineral content were determined by dual-energy x-ray absorptiometry. RESULTS: Study 1: Mice off diet supplemented with CGMP (G1 (N-CGMP)) or supplemented with CGMP in combination with LNAA (G2 (N-CGMP-LNAA)) had significantly lower Phe in plasma and in the brain compared to mice fed only casein (G3 (N)). Extra LNAA (Tyr, Trp and Leu) to CGMP did not have any significant impact on Phe levels in the plasma and brain, but an increase in serotonin was measured in the brain of G2 mice compared to G1. Study 2: PKU mice fed with mixture of CGMP and EAA as supplement to LP diet (G4 (CGMP-EAA-LP)) demonstrated lower plasma-Phe levels but similar brain- Phe levels and growth as mice fed on an almost identical combination of FSAA (G5 (FSAA-LP)). CONCLUSION: CGMP can be a relevant supplement for the treatment of PKU.
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Aminoácidos/uso terapéutico , Caseínas/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Fenilcetonurias/dietoterapia , Aminoácidos/sangre , Aminoácidos/síntesis química , Animales , Densidad Ósea , Huesos/diagnóstico por imagen , Huesos/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Suplementos Dietéticos , Modelos Animales de Enfermedad , Femenino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Fenilalanina/análisis , Fenilalanina/sangre , Fenilalanina Hidroxilasa/deficiencia , Fenilalanina Hidroxilasa/genética , Serotonina/sangre , Tirosina/sangreRESUMEN
BACKGROUND: Measurement of quantitative levels of phenylalanine and tyrosine in blood is an essential test for the diagnosis of and monitoring genetic disorders associated with phenylalanine metabolism, such as phenylketonuria (PKU), tyrosinemia, and defects of tetrahydrobiopterin synthesis and recycling. We developed a highly accurate and fast liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for the quantification of phenylalanine and tyrosine on dried blood spot (DBS). We also designed a performance score system to evaluate various calibration methods in matrix matched material. METHODS: Phenylalanine/tyrosine-free whole blood was used to make accurate and stable DBS calibrators. Six calibrators cover the range of 0-1000 µmol/L. Underivatized phenylalanine and tyrosine were extracted and measured by LC-MS/MS. Precision, accuracy, limit of quantification, recovery and carryover were validated. External quality assurance materials were also used to evaluate performance of multi-point calibrations and single-point calibrations. RESULTS: The run time was 4.5-minute. Accuracy analysis showed good agreement with reference materials. Precision, recovery, and the lower and upper limit of quantification met the criteria. When phenylalanine and tyrosine concentrations were less than 150 µmol/L, the 5-point calibration without the calibrator of 1000 µmol/L had the best performance. When the concentrations were > 250 µmol/L, the single-point calibration of 500 µmol/L had the best performance. CONCLUSION: We developed a simple, fast and highly accurate method for the detection of phenylalanine and tyrosine on DBS, with chromatographic separation and underivatized analysis. Based on the calibration performance, a 6-point calibration method is satisfying for this test. An optional dynamic calibration method, which includes 6-point calibration, 5-point calibration and single-point calibration, can further increase test reliability.
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Pruebas con Sangre Seca/métodos , Fenilalanina/sangre , Tirosina/sangre , Cromatografía Liquida , Humanos , Espectrometría de Masas en TándemRESUMEN
The mainstay of phenylketonuria treatment is a low protein diet, supplemented with phenylalanine (Phe)-free protein substitutes and micronutrients. Adhering to this diet is challenging, and even patients with good metabolic control who follow the dietary prescriptions in everyday life ignore the recommendations occasionally. The present study explores the ability of slow-release large neutral amino acids (srLNAAs) to prevent Phe increase following a Phe dietary load. Fourteen phenylketonuric patients aged ≥13 years were enrolled in a 6-week protocol. Oral acute Phe loads of 250 and 500 mg were added to the evening meal together with srLNAAs (0.5 gr/kg). Phe and tyrosine were dosed before dinner, 2h-after dinner, and after the overnight fast. After oral Phe loads, mean plasma Phe remained stable and below 600 µmol/L. No Phe peaks were registered. Tyrosine levels significantly increased, and Phe/Tyrosine ratio decreased. No adverse events were registered. In conclusion, a single oral administration of srLNAAs at the dose of 0.5 gr/kg is effective in maintaining stable plasma Phe during acute oral loads with Phe-containing food and may be added to the dietetic scheme in situations in which patients with generally good adherence to diet foresee a higher than prescribed Phe intake due to their commitments.
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Aminoácidos Neutros/administración & dosificación , Suplementos Dietéticos , Fenilalanina/administración & dosificación , Fenilcetonurias/tratamiento farmacológico , Adolescente , Adulto , Aminoácidos/administración & dosificación , Aminoácidos Neutros/sangre , Aminoácidos Neutros/uso terapéutico , Dieta , Femenino , Humanos , Italia , Masculino , Micronutrientes/uso terapéutico , Fenilalanina/sangre , Fenilalanina/uso terapéutico , Fenilcetonurias/sangre , Tirosina/sangre , Tirosina/uso terapéutico , Adulto JovenRESUMEN
5-hydroxytryptophan (5HTP) and 3-O-methyldopa (3OMD) are CSF diagnostic biomarkers of the defect of aromatic L-amino acid decarboxylase (AADC), a rare inherited disorder of neurotransmitter synthesis which, if untreated, results in severely disabling neurological impairment. In the last few years, different methods to detect 3OMD in dried blood spot (DBS) were published. We developed and validated a fast and specific diagnostic tool to detect 5HTP alongside 3OMD. After extraction from DBS, 3OMD and 5HTP were separated by ultra-performance liquid chromatography (UPLC) and detected by tandem mass spectrometry (MS/MS). Instrument parameters were optimized to obtain the best sensitivity and specificity. Chromatographic separation was accomplished in 13 min. The limit of detection was 2.4 and 1.4 nmol/L of blood for 3OMD and 5HTP respectively, and response was linear over the blood range of 25-5000 nmol/L. Between-run imprecision was less than 9% for 3OMD and <13% for 5HTP. An age-specific continuous reference range was established, revealing a marked and continuous 3OMD decline with aging. The effect of age on 5HTP was less evident, showing only a slight decrease with age after the first week of life. A marked increase of both 3OMD and 5HTP was found in four patients affected by AADC deficiency (1780.6 ± 773.1 nmol/L, rv 71.0-144.9; and 94.8 ± 19.0 nmol/L, rv 15.2-42.8, respectively) while an isolated increase of 3OMD (6159.6 ± 3449.1 nmol/L, rv 73.2-192.2) was detected in three subjects affected by inherited disorders of dopamine synthesis under levodopa/carbidopa treatment (a marginal increase of 5HTP was detected in one of them). Simultaneous measurement of 5HTP and 3OMD in DBS leads to an improvement in specificity and sensitivity for the biochemical diagnosis of AADC deficiency.
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5-Hidroxitriptófano/sangre , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Descarboxilasas de Aminoácido-L-Aromático/deficiencia , Cromatografía Líquida de Alta Presión/métodos , Pruebas con Sangre Seca/métodos , Espectrometría de Masas en Tándem/métodos , Tirosina/análogos & derivados , Adolescente , Adulto , Errores Innatos del Metabolismo de los Aminoácidos/sangre , Errores Innatos del Metabolismo de los Aminoácidos/enzimología , Descarboxilasas de Aminoácido-L-Aromático/sangre , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Tirosina/sangre , Adulto JovenRESUMEN
Tyrosinemia type I (HTI) is treated with nitisinone, a tyrosine (Tyr) and phenylalanine (Phe)-restricted diet, and supplemented with a Tyr/Phe-free protein substitute (PS). Casein glycomacropeptide (CGMP), a bioactive peptide, is an alternative protein source to traditional amino acids (L-AA). CGMP contains residual Tyr and Phe and requires supplementation with tryptophan, histidine, methionine, leucine, cysteine and arginine. AIMS: a 2-part study assessed: (1) the tolerance and acceptability of a low Tyr/Phe CGMP-based PS over 28 days, and (2) its long-term impact on metabolic control and growth over 12 months. METHODS: 11 children with HTI were recruited and given a low Tyr/Phe CGMP to supply all or part of their PS intake. At enrolment, weeks 1 and 4, caregivers completed a questionnaire on gastrointestinal symptoms, acceptability and ease of PS use. In study part 1, blood Tyr and Phe were assessed weekly; in part 2, weekly to fortnightly. In parts 1 and 2, weight and height were assessed at the study start and end. RESULTS: Nine of eleven children (82%), median age 15 years (range 8.6-17.7), took low Tyr/Phe CGMP PS over 28 days; it was continued for 12 months in n = 5 children. It was well accepted by 67% (n = 6/9), tolerated by 100% (n = 9/9) and improved gastrointestinal symptoms in 2 children. The median daily dose of protein equivalent from protein substitute was 60 g/day (range 45-60 g) with a median of 20 g/day (range 15 to 30 g) from natural protein. In part 2 (n = 5), a trend for improved blood Tyr was observed: 12 months pre-study, median Tyr was 490 µmol/L (range 200-600) and Phe 50 µmol/L (range 30-100); in the 12 months taking low Tyr/Phe CGMP PS, median Tyr was 430 µmol/L (range 270-940) and Phe 40 µmol/L (range 20-70). Normal height, weight and BMI z scores were maintained over 12 months. CONCLUSIONS: In HTI children, CGMP was well tolerated, with no deterioration in metabolic control or growth when studied over 12 months. The efficacy of CGMP in HTI needs further investigation to evaluate the longer-term impact on blood Phe concentrations and its potential influence on gut microflora.
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Caseínas/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Tirosinemias/dietoterapia , Adolescente , Aminoácidos/administración & dosificación , Aminoácidos/sangre , Niño , Preescolar , Ciclohexanonas/administración & dosificación , Dieta/métodos , Proteínas en la Dieta/administración & dosificación , Suplementos Dietéticos , Femenino , Humanos , Masculino , Nitrobenzoatos/administración & dosificación , Fenilalanina/administración & dosificación , Fenilalanina/sangre , Estudios Prospectivos , Tirosina/administración & dosificación , Tirosina/sangreRESUMEN
Background Phenylketonuria is the most common inborn error of amino acid metabolism, where oxidative stress and collateral metabolic abnormalities are likely to cause cardiac structural and functional modifications. We aim herein to characterize the cardiac phenotype of adult subjects with phenylketonuria using advanced cardiac imaging. Methods and Results Thirty-nine adult patients with phenylketonuria (age, 30.5±8.7 years; 10-year mean phenylalanine concentration, 924±330 µmol/L) and 39 age- and sex-matched healthy controls were investigated. Participants underwent a comprehensive cardiac magnetic resonance and echocardiography examination. Ten-year mean plasma levels of phenylalanine and tyrosine were used to quantify disease activity and adherence to treatment. Patients with phenylketonuria had thinner left ventricular walls (septal end-diastolic thickness, 7.0±17 versus 8.8±1.7 mm [P<0.001]; lateral thickness, 6.1±1.4 versus 6.8±1.2 mm [P=0.004]), more dilated left ventricular cavity (end-diastolic volume, 87±14 versus 80±14 mL/m2 [P=0.0178]; end-systolic volume, 36±9 versus 29±8 mL/m2 [P<0.001]), lower ejection fraction (59±6% versus 64±6% [P<0.001]), reduced systolic deformation (global circumferential strain, -29.9±4.2 % versus -32.2±5.0 % [P=0.027]), and lower left ventricular mass (38.2±7.9 versus 47.8±11.0 g/m2 [P<0.001]). T1 native values were decreased (936±53 versus 996±26 ms [P<0.001]), with particular low values in patients with phenylalanine >1200 µmol/L (909±48 ms). Both mean phenylalanine (P=0.013) and tyrosine (P=0.035) levels were independently correlated with T1; and in a multiple regression model, higher phenylalanine levels and higher left ventricular mass associate with lower T1. Conclusions Cardiac phenotype of adult patients with phenylketonuria reveals some traits of an early-stage cardiomyopathy. Regular cardiology follow-up, tighter therapeutic control, and prophylaxis of cardiovascular risk factors, in particular dyslipidemia, are recommended.
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Cardiomiopatías , Fenilcetonurias , Adulto , Cardiomiopatías/diagnóstico por imagen , Humanos , Espectroscopía de Resonancia Magnética , Fenotipo , Fenilalanina/sangre , Fenilcetonurias/complicaciones , Tirosina/sangre , Adulto JovenRESUMEN
Aging causes oxidative stress, endothelial dysfunction and a reduction in the bioavailability of nitric oxide. The study aim was to determine whether, as a result of repeated whole-body exposure to cryogenic temperature (3 min -130 °C), there is an increase of inducible nitric oxide synthase (iNOS) concentration in senior subjects (59 ± 6 years), and if this effect is stronger in athletes. In 10 long-distance runners (RUN) and 10 untraining (UTR) men, 24 whole-body cryotherapy (WBC) procedures were performed. Prior to WBC, after 12th and 24th treatments and 7 days later, the concentration of iNOS, asymmetric dimethylarginine (ADMA), 3-nitrotyrosine (3-NTR), homocysteine (HCY), C-reactive protein (CRP) and interleukins such as: IL-6, IL-1ß, IL-10 were measured. In the RUN and UTR groups, after 24 WBC, iNOS concentration was found to be comparable and significantly higher (F = 5.95, p < 0.01) (large clinical effect size) compared to before 1st WBC and after 12th WBC sessions. There were no changes in the concentration of the remaining markers as a result of WBC (p > 0.05). As a result of applying 24 WBC treatments, using the every-other-day model, iNOS concentration increased in the group of older men, regardless of their physical activity level. Along with this increase, there were no changes in nitro-oxidative stress or inflammation marker levels.
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Crioterapia/métodos , Óxido Nítrico Sintasa de Tipo II/sangre , Anciano , Arginina/análogos & derivados , Arginina/sangre , Atletas , Índice de Masa Corporal , Ejercicio Físico , Humanos , Interleucinas/sangre , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Resistencia Física , Tirosina/análogos & derivados , Tirosina/sangreRESUMEN
The aim of this study was to investigate drug interactions of L-dopa/carbidopa with catechin and green tea essence in rabbits following the simultaneous administration via an intramuscular injection of catechin or via an intragastric route for green tea essence with L-dopa/carbidopa. The results indicated that catechin at doses of 10, 20 and 50 mg/kg increased the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-t ) of L-dopa by about 69, 78 and 42%, respectively. The metabolic ratios of the AUC0-t for 3-O-methyldopa (3-OMD)/L-dopa significantly decreased by about 56, 68 and 76% (P < 0.05), respectively. In addition, a single dose of 5/1.25 mg/kg L-dopa/carbidopa was co-administrated with 150 mg/kg green tea essence via an intragastric route with an oral-gastric tube. Comparing the related pharmacokinetic parameters of L-dopa, the clearance and metabolic ratio of L-dopa decreased by 20 and 19% (P < 0.05), respectively. In conclusion, catechin and green tea essence can significantly affect the metabolism of L-dopa by the catechol-O-methyltransferase (COMT) metabolic pathway. Catechin can enhance L-dopa bioavailability, and both catechin and green tea essence decreased 3-OMD formation. Therefore, catechin and green tea essence may increase L-dopa efficacy for Parkinson's disease treatment.
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Catequina , Interacciones de Hierba-Droga , Levodopa , Té/química , Animales , Disponibilidad Biológica , Carbidopa/sangre , Carbidopa/química , Carbidopa/farmacocinética , Catequina/metabolismo , Catequina/farmacocinética , Catecol O-Metiltransferasa , Cromatografía Liquida , Levodopa/sangre , Levodopa/química , Levodopa/farmacocinética , Masculino , Conejos , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem , Tirosina/análogos & derivados , Tirosina/sangre , Tirosina/química , Tirosina/farmacocinéticaRESUMEN
BACKGROUND/AIM: Low branched-chain amino acid (BCAA) to tyrosine ratio (BTR) is known as an indicator of amino acid imbalance. We elucidated usefulness of newly developed albumin-bilirubin (ALBI) score as alternative methods of BTR in patients with naïve hepatocellular carcinoma (HCC) retrospectively. MATERIALS/METHODS: In 842 patients with HCC and without BCAA supplementation (71 years, male 614, Child-Pugh A:B:C = 689:116:37), relationships among BTR and clinical features were evaluated. Of those, 438 patients, with Milan criteria HCC, treated curatively were divided into the high-BTR (>4.4) (n = 293) and low-BTR (≤4.4) (n = 145) groups. The prognostic value of BTR was evaluated using inverse probability weighting (IPW) with propensity score. RESULTS: The low-BTR group showed worse prognosis than the other (3-, 5-, 10-year overall survival rates: 88.9% vs. 86.3%/70.5% vs. 78.1%/38.1% vs. 52.3%, respectively; p < 0.001). Multivariate Cox-hazard analysis adjusted for IPW showed elderly (≥65 years) HR 2.314, p = 0.001), female gender (HR 0.422, p < 0.001), ECOG PS ≥2 (HR 3.032, p = 0.002), low platelet count (HR 1.757, p = 0.010), and low BTR (≤4.4) (HR 1.852, p = 0.005) to be significant prognostic factors. Both serum albumin level (r = 0.370, p < 0.001) and ALBI score (r = -0.389, p < 0.001) showed a significant relationship with BTR. Child-Pugh class B, modified ALBI grade (mALBI) 2a, and mALBI 2b predictive values for BTR were 3.589, 4.509, and 4.155 (AUC range: 0.735-0.770), respectively, while the predictive value of ALBI score for low-BTR (≤4.4) was -2.588 (AUC 0.790). CONCLUSION: ALBI score -2.588 was a predictor for low-BTR (≤4.4), which was prognostic factors for early HCC patients, and at least patients with mALBI 2b might have an amino acid imbalance.