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1.
Nutrients ; 16(3)2024 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-38337670

RESUMEN

Micronutrient deficiencies can develop in critically ill patients, arising from factors such as decreased intake, increased losses, drug interactions, and hypermetabolism. These deficiencies may compromise important immune functions, with potential implications for patient outcomes. Alternatively, micronutrient blood levels may become low due to inflammation-driven redistribution rather than consumption. This explorative pilot study investigates blood micronutrient concentrations during the first three weeks of ICU stay in critically ill COVID-19 patients and evaluates the impact of additional micronutrient administration. Moreover, associations between inflammation, disease severity, and micronutrient status were explored. We measured weekly concentrations of vitamins A, B6, D, and E; iron; zinc; copper; selenium; and CRP as a marker of inflammation state and the SOFA score indicating disease severity in 20 critically ill COVID-19 patients during three weeks of ICU stay. Half of the patients received additional (intravenous) micronutrient administration. Data were analyzed with linear mixed models and Pearson's correlation coefficient. High deficiency rates of vitamins A, B6, and D; zinc; and selenium (50-100%) were found at ICU admission, along with low iron status. After three weeks, vitamins B6 and D deficiencies persisted, and iron status remained low. Plasma levels of vitamins A and E, zinc, and selenium improved. No significant differences in micronutrient levels were found between patient groups. Negative correlations were identified between the CRP level and levels of vitamins A and E, iron, transferrin, zinc, and selenium. SOFA scores negatively correlated with vitamin D and selenium levels. Our findings reveal high micronutrient deficiency rates at ICU admission. Additional micronutrient administration did not enhance levels or expedite their increase. Spontaneous increases in vitamins A and E, zinc, and selenium levels were associated with inflammation resolution, suggesting that observed low levels may be attributed, at least in part, to redistribution rather than true deficiencies.


Asunto(s)
COVID-19 , Selenio , Oligoelementos , Humanos , Micronutrientes , Enfermedad Crítica , Proyectos Piloto , Vitaminas , Vitamina A , Zinc , Hierro , Inflamación , Vitamina K
2.
Eur J Endocrinol ; 183(3): 265-273, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32580148

RESUMEN

OBJECTIVE: Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency at birth due to disorders of the thyroid gland (thyroidal CH, CH-T), or the hypothalamus or pituitary (central CH, CH-C). The Dutch Newborn Screening (NBS) strategy is primarily based on determination of thyroxine (T4) concentrations in dried blood spots followed, if necessary, by thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) measurement enabling detection of both CH-T and CH-C. A calculated T4/TBG ratio serves as an indirect measure for free T4. A T4/TBG ratio ≤ 17 in a second heel puncture is suggestive of CH-C. DESIGN AND METHODS: In the present study, we evaluated 11 years of Dutch CH NBS using a database of referred cases by assessing the contribution of each criterion in the unique stepwise T4-TSH-TBG NBS algorithm. RESULTS: Between 2007 and the end of 2017, 1 963 465 newborns were screened in the Netherlands. Use of the stepwise algorithm led to 3044 referrals and the identification of 612 CH cases, consisting of 496 CH-T, 86 CH-C, and 30 CH of unknown origin diagnoses. We detected 62.8% of CH-C cases by the T4/TBG ratio in the second heel puncture. The positive predictive value (PPV) of the stepwise T4-TSH-TBG NBS algorithm was 21.0%. CONCLUSION: This evaluation shows that the Dutch stepwise T4-TSH-TBG NBS algorithm with a calculated T4/TBG ratio is of great value for the detection of both CH-T and CH-C in the Netherlands, at the cost of a lower PPV compared to TSH-based NBS strategies.


Asunto(s)
Hipotiroidismo Congénito/diagnóstico , Tamizaje Neonatal/métodos , Algoritmos , Bases de Datos Factuales , Femenino , Humanos , Hipotálamo/patología , Recién Nacido , Masculino , Países Bajos , Hipófisis/patología , Pruebas de Función de la Tiroides , Glándula Tiroides/patología
3.
PLoS One ; 14(9): e0221591, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31527879

RESUMEN

BACKGROUND: Methotrexate (MTX) is an important anti-folate agent in pediatric acute lymphoblastic leukemia (ALL) treatment. Folinic acid rescue therapy (Leucovorin) is administered after MTX to reduce toxicity. Previous studies hypothesized that Leucovorin could 'rescue' both normal healthy cells and leukemic blasts from cell death. We assessed whether Leucovorin is able to restore red blood cell folate levels after MTX. METHODS: We prospectively determined erythrocyte folate levels (5-methyltetrahydrofolate (THF) and non-methyl THF) and serum folate levels in 67 children with ALL before start (T0) and after stop (T1) of HD-MTX and Leucovorin courses. RESULTS: Erythrocyte folate levels increased between T0 and T1 (mean ± SD: 416.7 ± 145.5 nmol/L and 641.2 ± 196.3 nmol/L respectively, p<0.001). This was due to an increase in 5-methyl THF levels (mean increase: 217.7 ± 209.5 nmol/L, p<0.001), whereas non-methyl THF levels did not change (median increase: 0.6 nmol/L [-9.9-11.1], p = 0.676). Serum folate levels increased between T0 and T1 (median increase: 29.2 nmol/L [32.9-74.0], p<0.001). Results were not significantly affected by age, sex, ALL immunophenotype and MTHFR c.677C>T genotype. CONCLUSION: Intracellular folate levels accumulate after HD-MTX and Leucovorin therapy in children with ALL, suggesting that Leucovorin restores the intracellular folate pool. Future studies are necessary to assess concomitant lower uptake of MTX.


Asunto(s)
Ácido Fólico/sangre , Leucovorina/administración & dosificación , Metotrexato/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Antídotos/administración & dosificación , Niño , Preescolar , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Femenino , Antagonistas del Ácido Fólico/administración & dosificación , Antagonistas del Ácido Fólico/efectos adversos , Homocisteína/sangre , Humanos , Lactante , Masculino , Redes y Vías Metabólicas , Metotrexato/efectos adversos , Estudios Prospectivos , Vitamina B 12/sangre
4.
PLoS One ; 13(7): e0199574, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29985926

RESUMEN

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) often suffer from toxicity of chemotherapeutic drugs such as Methotrexate (MTX). Previously, we reported that 20% of patients receiving high-dose MTX developed oral mucositis. MTX inhibits folate metabolism, which is essential for DNA methylation. We hypothesize that MTX inhibits DNA methylation, which results into adverse effects. We studied DNA methylation markers during high-dose methotrexate treatment in pediatric acute lymphoblastic leukemia (ALL) in relation to developing oral mucositis. MATERIALS & METHODS: S-Adenosyl-Methionine (SAM) and S-Adenosyl-Homocysteine (SAH) levels and LINE1 DNA methylation were measured prospectively before and after high-dose methotrexate (HD-MTX 4 x 5g/m2) therapy in 82 children with ALL. Methotrexate-induced oral mucositis was registered prospectively. Oral mucositis (grade ≥ 3 National Cancer Institute Criteria) was used as clinical endpoint. RESULTS: SAM levels decreased significantly during methotrexate therapy (-16.1 nmol/L (-144.0 -+46.0), p<0.001), while SAH levels and the SAM:SAH ratio did not change significantly. LINE1 DNA methylation (+1.4% (-1.1 -+6.5), p<0.001) increased during therapy. SAM and SAH levels were not correlated to LINE1 DNA methylation status. No association was found between DNA methylation markers and developing oral mucositis. CONCLUSIONS: This was the first study that assessed DNA methylation in relation to MTX-induced oral mucositis in children with ALL. Although global methylation markers did change during methotrexate therapy, methylation status was not associated with developing oral mucositis.


Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Metilación de ADN , Metotrexato/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estomatitis/etiología , Adolescente , Antimetabolitos Antineoplásicos/uso terapéutico , Niño , Preescolar , Femenino , Humanos , Inmunofenotipificación , Lactante , Elementos de Nucleótido Esparcido Largo , Masculino , Redes y Vías Metabólicas , Metotrexato/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , S-Adenosilmetionina/sangre , S-Adenosilmetionina/metabolismo
5.
J Nutr ; 139(12): 2315-21, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19812220

RESUMEN

B vitamin deficiencies lead to moderate hyperhomocysteinemia, which has been associated with health and disease. However, concomitant derangements in cellular methylation, reflected by altered plasma S-adenosylmethionine (SAM) or S-adenosylhomocysteine (SAH) concentrations, may be the primary cause. Therefore, we identified determinants of homocysteine, SAM, and SAH concentrations in 336 women, aged 20-48 y, as part of a large study focusing on risk factors for reproductive disorders. Blood was obtained to determine plasma SAM, SAH, and total homocysteine (tHcy), serum vitamin B-12 and folate, RBC folate concentrations, and the related single nucleotide polymorphisms 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C > T and 1298A > C, methionine synthase reductase (MTRR) 66A > G, and nicotinamide N-methyltransferase IVS1-151G > A. Questionnaires provided information on demographics, lifestyles, and nutrient intakes. Correlation coefficients were calculated and multivariable associations were assessed with a general linear model. Serum folate was positively correlated with SAM concentrations (r = 0.159; P = 0.004). Folate and vitamin B-12 were not correlated with SAH concentrations or the SAM:SAH ratio but were inversely correlated with tHcy concentrations (serum folate r = -0.324; RBC folate r = -0.294; vitamin B-12 r = -0.307; P < 0.01). From the multivariable analysis, BMI was the strongest determinant of SAM (standardized beta = 19.145; P < 0.001) and SAH concentrations (standardized beta = 3.241; P = 0.010). MTHFR 677TT (standardized beta = 0.195; P = 0.001), B vitamin supplement use (standardized beta = -0.156; P < 0.001) and dietary protein intake (standardized beta = -0.011; P < 0.001) were the strongest determinants of tHcy concentrations. Thus, the determinants of SAM and SAH differ from those of tHcy concentrations. Given that BMI was a strong determinant of SAM concentrations, it should be included in future studies on cellular methylation.


Asunto(s)
Biomarcadores/sangre , Índice de Masa Corporal , Fertilidad/fisiología , S-Adenosilmetionina/sangre , Adulto , Femenino , Ácido Fólico/sangre , Homocisteína/sangre , Humanos , Estilo de Vida , Metilación , Persona de Mediana Edad , Análisis Multivariante , Países Bajos , S-Adenosilhomocisteína/sangre , Encuestas y Cuestionarios , Vitamina B 12/sangre , Adulto Joven
6.
Obstet Gynecol ; 112(2 Pt 1): 277-83, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18669723

RESUMEN

OBJECTIVE: To investigate whether the association between the maternal methylation status as reflected by low S-adenosylmethionine and high S-adenosylhomocysteine, is detrimental for cardiogenesis and congenital heart disease (CHD) in the offspring. METHODS: As part of a case-control study in the western part of the Netherlands, we evaluated 231 mothers of children with CHD and 315 control mothers of nonmalformed children. The total case group was analyzed and stratified into isolated (n=180) and nonisolated CHDs (n=51). The latter subgroup was further subdivided into Nonsyndromic (n=20), Down Syndrome (n=19), and Other Syndromes (n=12). A multivariable general linear model was used to test for differences between the case groups and controls. All analyses were adjusted for current B vitamin supplement use. RESULTS: Plasma total homocysteine was significantly different between the total case group (median, range 10.3, 4.0-43.8, P=.026) and the nonisolated cases (11.1, 5.5-43.8, P=.006) compared with the controls (10.0, 5.3-42.0). The subgroup of Down Syndrome presented significantly higher total homocysteine and S-adenosylhomocysteine levels and a lower S-adenosylmethionine/S-adenosylhomocysteine ratio than controls. CONCLUSION: Maternal hyperhomocysteinemia, and not hypomethylation, is a risk factor for having a child with CHD. Maternal hypomethylation, however, seems to be associated with offspring having CHD and Down syndrome.


Asunto(s)
Cardiopatías Congénitas/epidemiología , Hiperhomocisteinemia/complicaciones , Complicaciones del Embarazo , Efectos Tardíos de la Exposición Prenatal , S-Adenosilhomocisteína/sangre , S-Adenosilmetionina/sangre , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Síndrome de Down/epidemiología , Síndrome de Down/etiología , Femenino , Corazón/embriología , Cardiopatías Congénitas/etiología , Humanos , Hiperhomocisteinemia/sangre , Lactante , Modelos Lineales , Metilación , Embarazo , Resultado del Embarazo/epidemiología , Factores de Riesgo
7.
Birth Defects Res A Clin Mol Teratol ; 82(6): 474-81, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18452180

RESUMEN

BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are associated with complex congenital malformations. Whether these polymorphisms are associated with CHDs is not clear. We studied both MTHFR polymorphisms, folate and vitamin B2 by maternal food intake and supplements, and CHD risk. METHODS: A case-control family study was conducted in a European population in the Netherlands including 230 case and 251 control children with both parents. Approximately 17 months after the index pregnancy, mothers filled out standardized questionnaires on periconception use of folic acid supplements and a validated food frequency questionnaire on current dietary folate and vitamin B2 intake. All subjects were genotyped for the MTHFR C677T and A1298C polymorphisms. Data were analyzed by logistic regression analysis and ORs and 95% CIs were calculated. For the interaction analysis the dominant model was used. RESULTS: The risk estimates for the MTHFR 677 CT genotypes were 1.4 (0.9-2.0) in mothers, 1.1 (0.8-1.6) in fathers, and 1.2 (0.8-1.7) in children, and for the MTHFR 677 TT genotypes 0.9 (0.6-1.2), 1.4 (1.0-1.9), and 1.0 (0.7-1.3), respectively. The MTHFR 1298 CC genotype in fathers and the MTHFR 1298 AC genotype in children significantly reduced CHD risk, 0.6 (0.5-0.9) and 0.6 (0.4-0.9), respectively. Of interest is the significant interaction (p = .008) towards a nearly twofold increased risk in mothers carrying the MTHFR 1298C allele and using a periconception folic acid supplement. CONCLUSIONS: The MTHFR C677T and A1298C polymorphisms are not strong risk factors for CHDs.


Asunto(s)
Ligasas de Carbono-Nitrógeno/genética , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/genética , Adulto , Estudios de Casos y Controles , Femenino , Ácido Fólico/administración & dosificación , Genotipo , Humanos , Lactante , Masculino , Países Bajos , Riboflavina/administración & dosificación , Factores de Riesgo
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