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Introducción. El yodo desempeña un rol fundamental en el metabolismo, el crecimiento y el desarrollo humano. Durante el embarazo y la infancia, la demanda de este micronutriente aumenta considerablemente. La tirotropinemia neonatal (TSHn) aumentada, definida como TSHn ≥5 mUI/l, es un marcador que señala la deficiencia de yodo en una población cuando su prevalencia supera el 3 %. Objetivo. Determinar la prevalencia de TSHn ≥ 5 en La Pampa durante el período 2021-2022, analizar su correlación con diferentes variables y compararla con datos de una cohorte histórica. Población y métodos. Estudio transversal, de diseño descriptivo-analítico, sobre una población de neonatos nacidos en las cinco zonas sanitarias de la provincia de La Pampa durante los años 2021 y 2022. Resultados. De los 5778 neonatos evaluados, el 9,6 % presentó niveles de TSHn ≥5 mUI/l. El 70,4 % de estas mediciones fueron realizadas después del tercer día de vida. No se observaron diferencias significativas en la frecuencia de niveles elevados de TSHn según el año de nacimiento, peso al nacer o días hasta la extracción. Se registró una mayor prevalencia en el sexo masculino (10,6 % versus 8,5 %; p = 0,007) y entre los neonatos nacidos a término (9,8 % versus 6,6 %; p = 0,02). La prevalencia de hipertirotropinemia fue superior a la observada en una cohorte de 2001-2002. Conclusiones. La prevalencia de hipertirotropinemia neonatal en La Pampa durante los años 2021 y 2022 fue del 9,6 %, lo que indica un estado de deficiencia leve de yodo en la provincia, superior al reportado hace dos décadas.
Introduction. Iodine plays a key role in human metabolism, growth, and development. During pregnancy and childhood, the demand for this micronutrient increases notably. Increased neonatal thyroid stimulating hormone (nTSH) levels, defined as nTSH ≥ 5 mIUL, are a marker of iodine deficiency in a population if its prevalence is higher than 3%.Objective. To establish the prevalence of nTSH ≥ 5 in La Pampa in the 20212022 period, analyze its correlation with different variables, and compare it with data from a historical cohort.Population and methods. Cross-sectional, descriptive-analytical study in a population of newborn infants born in the 5 health regions of the province of La Pampa in 2021 and 2022. Results. Of the 5778 assessed newborn infants, 9.6% had nTSH levels ≥ 5 mIU/L. It was reported that 70.4% of these measurements were done after the third day of life. No significant differences were observed in the frequency of high nTSH levels by year of birth, birth weight, or days until samplecollection.A higher prevalence was observed among male infants (10.6% versus 8.5%; p = 0.007) and term infants (9.8% versus 6.6%; p = 0.02). The prevalence of high TSH levels was superior to that observed in the 20012002 cohort. Conclusions. The prevalence of high nTSH levels in La Pampa during 2021 and 2022 was 9.6%, suggesting the presence of mild iodine deficiency in the population of this province, higher that what had been reported 2 decades ago.
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Humanos , Masculino , Femenino , Recién Nacido , Tirotropina/sangre , Yodo/deficiencia , Biomarcadores/sangre , Prevalencia , Estudios TransversalesRESUMEN
The 5-lipoxygenase/leukotriene system has been implicated in both physiological and pathological states within the central nervous system. Understanding how this system interacts with the dopaminergic system could provide valuable insights into dopamine-related pathologies. This study focused on examining both motor and non-motor dopamine-related responses in 5-lipoxygenase/leukotriene-deficient mice. We used pharmacological agents such as amphetamine, apomorphine, and reserpine to challenge the dopaminergic system, evaluating their effects on prepulse inhibition reaction (PPI), general motor activity, and oral involuntary movements. Additionally, we analyzed striatal glial marker expression (GFAP and Iba-1) in reserpine-treated mice. The 5-lipoxygenase/leukotriene-deficient mice exhibited increased spontaneous locomotor activity, including both horizontal and vertical exploration, along with stereotyped behavior compared to wild-type mice. This hyperactivity was reduced by acute apomorphine treatment. Although basal PPI responses were unchanged, 5-lipoxygenase/leukotriene-deficient mice displayed a significant reduction in susceptibility to amphetamine-induced PPI disruption. Conversely, these mice were more vulnerable to reserpine-induced involuntary movements. There were no significant differences in the basal expression of striatal GFAP and Iba-1 positive cells between 5-lipoxygenase/leukotriene-deficient and wild-type mice. However, reserpine treatment significantly increased GFAP immunoreactivity in wild-type mice, an effect not observed in 5-lipoxygenase-deficient mice. Additionally, the percentage of activated microglia was significantly higher in reserpine-treated wild-type mice, an effect absents in 5-lipoxygenase/leukotriene-deficient mice. Our findings suggest that 5-lipoxygenase/leukotriene deficiency leads to a distinctive dopaminergic phenotype, indicating that leukotrienes may influence the modulation of dopamine-mediated responses.
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Anfetamina , Araquidonato 5-Lipooxigenasa , Dopamina , Animales , Masculino , Ratones , Anfetamina/farmacología , Apomorfina/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Araquidonato 5-Lipooxigenasa/deficiencia , Araquidonato 5-Lipooxigenasa/genética , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/deficiencia , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/metabolismo , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Inhibición Prepulso/efectos de los fármacos , Inhibición Prepulso/fisiología , Reserpina/farmacología , Conducta Estereotipada/efectos de los fármacosRESUMEN
Zinc plays a crucial role in cell structure and functionality. Neurodegenerative Duchenne muscular dystrophy (DMD) alters muscle membrane structure, leading to a loss of muscle mass and strength. The objective of this study was to evaluate the changes in phase angle (PA) and bioelectrical impedance vector analysis (BIVA) results in patients with DMD after oral zinc supplementation. This clinical trial included 33 boys aged 5.6 to 24.5 years diagnosed with DMD. They were divided into three groups according to age (G1, G2, and G3) and supplemented with oral zinc. The mean serum zinc concentration was 74 µg/dL, and 29% of patients had concentrations below the reference value. The baseline values (mean (standard deviation)) of the bioelectrical impedance parameters PA, resistance (R), and reactance (Xc) were 2.59° (0.84°), 924.36 (212.31) Ω, and 39.64 (8.41) Ω, respectively. An increase in R and a decrease in PA and lean mass proportional to age were observed, along with a negative correlation (r = -0.614; p < 0.001) between age and PA. The average cell mass in G1 was greater than that in G3 (p = 0.012). There were no significant differences in serum zinc levels or bioelectrical impedance parameters before and after zinc supplementation. We conclude that this population is at risk of zinc deficiency and the proposed dosage of zinc supplementation was not sufficient to alter serum zinc levels, PA and BIVA results.
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Suplementos Dietéticos , Impedancia Eléctrica , Distrofia Muscular de Duchenne , Zinc , Humanos , Distrofia Muscular de Duchenne/tratamiento farmacológico , Zinc/administración & dosificación , Zinc/sangre , Zinc/deficiencia , Masculino , Adolescente , Niño , Adulto Joven , Preescolar , Composición Corporal/efectos de los fármacos , Administración Oral , Músculo Esquelético/efectos de los fármacosRESUMEN
Systemic vasculitis is a group of rare diseases that share an essential characteristic: inflammation of blood vessel walls. This injury occurs during the disease course, but specific features vary for each entity. In this paper, we will address relevant aspects of the newest monogenic mutation vasculitis, such as deficiency of adenosine deaminase 2 (ADA2) and VEXAS syndrome (UBA1), and other relevant vasculitis, such as Cogan syndrome and Susac syndrome that may share some similarities with them.
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Adenosina Desaminasa , Enfermedades Raras , Humanos , Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Síndrome de Cogan/complicaciones , Síndrome de Susac/complicaciones , Síndrome de Susac/diagnóstico , Vasculitis Sistémica/diagnóstico , Agammaglobulinemia/complicaciones , Mutación , Vasculitis , Péptidos y Proteínas de Señalización IntercelularRESUMEN
Macrophages play a pivotal role in tissue homeostasis, pathogen defense, and inflammation resolution. M1 and M2 macrophage phenotypes represent two faces in a spectrum of responses to microenvironmental changes, crucial in both physiological and pathological conditions. Neuraminidase 1 (Neu1), a lysosomal and cell surface sialidase responsible for removing terminal sialic acid residues from glycoconjugates, modulates several macrophage functions, including phagocytosis and Toll-like receptor (TLR) signaling. Current evidence suggests that Neu1 expression influences M1/M2 macrophage phenotype alterations in the context of cardiovascular diseases, indicating a potential role for Neu1 in macrophage polarization. For this reason, we investigated the impact of Neu1 deficiency on macrophage polarization in vitro and in vivo. Using bone marrow-derived macrophages (BMDMs) and peritoneal macrophages from Neu1 knockout (Neu1-/- ) mice and wild-type (WT) littermate controls, we demonstrated that Neu1-deficient macrophages exhibit an aberrant M2-like phenotype, characterized by elevated macrophage mannose receptor 1 (MMR/CD206) expression and reduced responsiveness to M1 stimuli. This M2-like phenotype was also observed in vivo in peritoneal and splenic macrophages. However, lymph node (LN) macrophages from Neu1-/- mice exhibited phenotypic alterations with reduced CD206 expression. Further analysis revealed that peripheral LNs from Neu1-/- mice were highly fibrotic, with overexpression of transforming growth factor-beta 1 (TGF-ß1) and hyperactivated TGF-ß signaling in LN macrophages. Consistently, TGF-ß1 was found to alter M1/M2 macrophage polarization in vitro. Our findings showed that Neu1 deficiency prompts macrophages towards an M2 phenotype and that microenvironmental changes, particularly increased TGF-ß1 in fibrotic tissues such as peripheral LNs in Neu1-/- mice, further influence M1/M2 macrophage polarization, highlighting its sensitivity to the local microenvironment. Therapeutic interventions targeting Neu1 or TGF-ß signaling pathways may offer the potential to regulate macrophage behavior across different diseases.
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Microambiente Celular , Fibrosis , Ganglios Linfáticos , Macrófagos , Ratones Noqueados , Neuraminidasa , Animales , Ratones , Macrófagos/inmunología , Macrófagos/metabolismo , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Neuraminidasa/deficiencia , Neuraminidasa/genética , Neuraminidasa/metabolismo , Ratones Endogámicos C57BL , Activación de Macrófagos , Lectinas Tipo C/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/deficiencia , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Células Cultivadas , Transducción de Señal , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/deficiencia , Receptor de Manosa , Fenotipo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome with a wide spectrum of cognitive deficits, motor impairment, and psychiatric disturbances resulting from liver damage. The cytokine TNF has been considered the main cytokine in the development and progression of HE, with a pivotal role in the initiation and amplification of the inflammatory cascade. The aim of the present study was to evaluate the involvement of TNF type 1 receptor (TNFR1) in locomotor deficits and in the levels of TNF, IFN-γ, IL-6, IL-10, IL-12p70, CCL2, CX3CL1 and BDNF from the frontal cortex and hippocampus of TNFR1 knockout mice (TNFR1-/-) mice with HE induced by thioacetamide. Wild-type (WT) animals with HE developed locomotor deficit. The absence of TNFR1 absence of TNFR1 in HE animals attenuated the locomotor activity impairment in parallel with a balanced neuroinflammatory environment 24 h after the administration of thioacetamide. Taken together, the data suggests that the absence of TNFR1 promoted a protective response in the early phase of hepatic encephalopathy induced by thioacetamide in mice.
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Encefalopatía Hepática , Ratones Noqueados , Receptores Tipo I de Factores de Necrosis Tumoral , Tioacetamida , Animales , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/deficiencia , Tioacetamida/toxicidad , Encefalopatía Hepática/metabolismo , Ratones , Masculino , Citocinas/metabolismo , Ratones Endogámicos C57BLRESUMEN
INTRODUCTION: Iodine is an essential mineral for fetal growth and brain development. The aim of this research was to evaluate goiter, iodine deficiency and intrauterine growth restriction in pregnant women of minority ethnic groups in Colombia. METHODS: A cross-sectional study was performed in six non-metropolitan areas of Colombia. RESULTS: A total of 318 Indigenous and Afro-descendant pregnant women were invited to participate: 248 (83.2%) Indigenous and 50 (16.8%) Afro-descendants were studied. The mean age was 24 years (range 13-44 years). Of the women, 130 (43.5%) were from the department of Cauca, 72 (24.1%) were from Córdoba, 28 (9.4%) were from Guajira, 26 (8.8%) were from Sierra Nevada de Santa Marta, 22 (7.4%) were from Amazonas, 16 (5.4%) were from Meta and 4 (1.3%) were from the department of Cesar. A total of 244 (81.8%) were illiterate and 291 (97.7%) were of very low socioeconomic level. Goiter was observed in 69 (23.3%) pregnant women (38 (41.7%) from the department of Cauca, 10 (35.7%) from Guajira, 5 (31.2%) from Meta, 6 (27.2%) from Amazonas and 10 (13.8%) from Córdoba). Iodine deficiency (<100 µg/L) was observed in 42 (14.9%) pregnant women (16 (11.6%) mild (50-99 µg/L), 19 (13.8%) moderate (20-49 µg/L) and 7 (5.1%) severe (<20 µg/L)). Being literate was a protective factor for iodine deficiency (odds ratio (OR)=0.19, 95% confidence interval (CI) 0.04-0.84, p=0.016). Being illiterate and iodine deficient was only a risk factor for goiter (OR=6.72, 95%CI 3.9-9.5, p=0.038) in the department of Cauca. CONCLUSION: A high prevalence of goiter, iodine deficiency and intrauterine growth restriction was observed in minority ethnic groups of Colombia. The highest prevalence and risk was observed in the department of Cauca.
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Retardo del Crecimiento Fetal , Bocio , Yodo , Adolescente , Adulto , Femenino , Humanos , Embarazo , Adulto Joven , Colombia/epidemiología , Estudios Transversales , Retardo del Crecimiento Fetal/epidemiología , Retardo del Crecimiento Fetal/etnología , Bocio/epidemiología , Bocio/etnología , Yodo/deficiencia , Yodo/administración & dosificación , Minorías Étnicas y RacialesRESUMEN
This study explores the therapeutic benefits of tannic acid (TnA) in an experimental protocol of chronic hypermethioninemia in rats. Rats were categorized into four groups: Group I - control, Group II - TnA 30 mg/kg, Group III - methionine (Met) 0.2-0.4 g/kg + methionine sulfoxide (MS) 0.05-0.1 g/kg, Group IV - TnA/Met + MS. Saline was administered by subcutaneous pathway into groups I and II twice daily from postnatal day 6 (P6) to P28, whereas those in groups III and IV received Met + MS. From P28 to P35, groups II and IV received TnA orally. Animals from group III presented cognitive and memory impairment assessed through object recognition and Y-maze tests (p < 0.05). Elevated levels of reactive species, lipid peroxidation, and nitrites followed by a decline in sulfhydryl content, catalase activity, and superoxide dismutase activity were observed in animals treated with Met + MS (p < 0.05). However, TnA treatment reversed all these effects (p < 0.05). In group III, there was an increase in acetylcholinesterase activity and IL-6 levels, coupled with a reduction in Na+/K+-ATPase activity (p < 0.05). TnA was able to protect against these effects (p < 0.05). The gene expression of catalase, brain-derived neurotrophic factor, and nuclear factor erythroid 2-related factor 2 was decreased in the hippocampus and striatum from group III (p < 0.05). TnA reversed almost all of these alterations (p < 0.05). These findings suggest that TnA is a therapeutic target for patients with hypermethioninemia.
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Errores Innatos del Metabolismo de los Aminoácidos , Taninos , Animales , Taninos/farmacología , Ratas , Errores Innatos del Metabolismo de los Aminoácidos/tratamiento farmacológico , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Masculino , Ratas Wistar , Peroxidación de Lípido/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Glicina N-Metiltransferasa/deficiencia , PolifenolesRESUMEN
Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette-Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis1. Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette-Guérin disease and tuberculosis3. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents.
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Macrófagos , Tuberculosis Pulmonar , Factores de Necrosis Tumoral , Adulto , Femenino , Humanos , Masculino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Homocigoto , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/inmunología , Células Madre Pluripotentes Inducidas/citología , Inflamación/inmunología , Interferón gamma/inmunología , Mutación con Pérdida de Función , Pulmón/citología , Pulmón/efectos de los fármacos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Macrófagos Alveolares/citología , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/microbiología , Macrófagos Alveolares/patología , Mycobacterium tuberculosis/inmunología , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/deficiencia , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Estallido Respiratorio , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/genética , Inhibidores del Factor de Necrosis Tumoral/farmacología , Factores de Necrosis Tumoral/deficiencia , Factores de Necrosis Tumoral/genética , Adolescente , Adulto JovenRESUMEN
Lysosomal acid lipase deficiency (LALD) varies from a severe infantile-onset form (Wolman disease) to a late-onset form known as cholesteryl ester storage disease (CESD), both of which are autosomal recessive disorders caused by biallelic LIPA pathogenic variants. We evaluated seventy-three patients enlisted for liver transplant (LT) at Instituto da Criança (HCFMUSP-Brazil) who were subjected to LAL activity measurement and LIPA Sanger sequencing analysis, resulting in a positive LALD diagnosis for only one of these individuals. This LALD patient presented recurrent diarrhea, failure to thrive, hepatomegaly, and dyslipidemia at the age of 4 months and liver failure by the age of 13 years. The LALD diagnosis confirmation was conducted at 24 years old due to low levels of LAL enzyme activity. The causal homozygous variant LIPA(NM_000235.4):c.266T>C(p.Leu89Pro) was identified, but the patient had already undergone his first LT at 18 years with several rejection episodes. Despite beginning treatment with sebelipase alfa at 26 years old (total of five infusions), this patient died at 28 years from complications after his second liver transplant. LALD is an important differential diagnosis in cases presenting with hepatomegaly, elevated liver enzymes, and dyslipidemia. Detecting low/absent LAL activity and identifying the LIPA causal variant are essential for diagnosis and specific treatment, as well as for appropriate genetic counseling. Early diagnosis, along with sebelipase alfa therapy, may improve the prognosis of affected patients.
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Trasplante de Hígado , Esterol Esterasa , Enfermedad de Wolman , Humanos , Enfermedad de Wolman/genética , Enfermedad de Wolman/diagnóstico , Masculino , Esterol Esterasa/genética , Esterol Esterasa/deficiencia , Femenino , Adolescente , Lactante , Adulto , Preescolar , Niño , Adulto JovenRESUMEN
BACKGROUND: Giardiasis and zinc deficiency have been identified as serious health problems worldwide. Although Zn depletion is known to occur in giardiasis, no work has investigated whether changes occur in brain structures. METHODS: Three groups of gerbils were used: control (1), orogastrically inoculated on day 3 after birth with trophozoites of two isolates of Giardia intestinalis (HGINV/WB) group (2 and 3). Estimates were made at five ages covering: establishment of infection, Giardia population growth, natural parasite clearance and a post-infection age. QuantiChrome zinc assay kit, cresyl violet staining and TUNEL technique were used. RESULTS: A significant decrease (p<0.01) in tissue zinc was observed and persisted after infection. Cytoarchitectural changes were observed in 75% of gerbils in the HGINV or WB groups. Ectopic pyramidal neurons were found in the cornus ammonis (CA1-CA3). At 60 and 90 days of age loss of lamination was clearly visible in CA1. In the dentate gyrus (DG), thinning of the dorsal lamina and abnormal thickening of the ventral lamina were observed from 30 days of age. In the cerebellum, we found an increase (p<0.01) in the thickness of the external granular layer (EGL) at 14 days of age that persisted until day 21 (C 3 ± 0.3 µm; HGINV 37 ± 5 µm; WB 28 ± 3 µm); Purkinje cell population estimation showed a significant decrease; a large number of apoptotic somas were observed scattered in the molecular layer; in 60 and 90 days old gerbils we found granular cell heterotopia and Purkinje cell ectopia. The pattern of apoptosis was different in the cerebellum and hippocampus of parasitized gerbils. CONCLUSION: The morphological changes found suggest that neuronal migration is affected by zinc depletion caused by giardiasis in early postnatal life; for the first time, the link between giardiasis-zinc depletion and damaged brain structures is shown. This damage may explain the psychomotor/cognitive delay associated with giardiasis. These findings are alarming. Alterations in zinc metabolism and signalling are known to be involved in many brain disorders, including autism.
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Cerebelo , Gerbillinae , Giardia lamblia , Giardiasis , Hipocampo , Zinc , Animales , Gerbillinae/parasitología , Zinc/deficiencia , Zinc/metabolismo , Giardiasis/parasitología , Giardiasis/patología , Cerebelo/patología , Cerebelo/parasitología , Hipocampo/patología , Hipocampo/parasitología , Giardia lamblia/crecimiento & desarrollo , Masculino , Modelos Animales de EnfermedadRESUMEN
Lowe Syndrome (LS) is a rare X-linked disorder characterized by renal dysfunction, cataracts, and several central nervous system (CNS) anomalies. The mechanisms underlying the neurological dysfunction in LS remain unclear, albeit they share some phenotypic characteristics similar to the deficiency or dysfunction of the Reelin signaling, a relevant pathway with roles in CNS development and neuronal functions. In this study, we investigated the role of OCRL1, an inositol polyphosphate 5-phosphatase encoded by the OCRL gene, mutated in LS, focusing on its impact on endosomal trafficking and receptor recycling in human neuronal cells. Specifically, we tested the effects of OCRL1 deficiency in the trafficking and signaling of ApoER2/LRP8, a receptor for the ligand Reelin. We found that loss of OCRL1 impairs ApoER2 intracellular trafficking, leading to reduced receptor expression and decreased levels at the plasma membrane. Additionally, human neurons deficient in OCRL1 showed impairments in ApoER2/Reelin-induced responses. Our findings highlight the critical role of OCRL1 in regulating ApoER2 endosomal recycling and its impact on the ApoER2/Reelin signaling pathway, providing insights into potential mechanisms underlying the neurological manifestations of LS.
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Moléculas de Adhesión Celular Neuronal , Endosomas , Proteínas de la Matriz Extracelular , Proteínas Relacionadas con Receptor de LDL , Proteínas del Tejido Nervioso , Neuronas , Monoéster Fosfórico Hidrolasas , Transporte de Proteínas , Proteína Reelina , Serina Endopeptidasas , Humanos , Monoéster Fosfórico Hidrolasas/metabolismo , Monoéster Fosfórico Hidrolasas/genética , Monoéster Fosfórico Hidrolasas/deficiencia , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/deficiencia , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/genética , Serina Endopeptidasas/deficiencia , Moléculas de Adhesión Celular Neuronal/metabolismo , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión Celular Neuronal/deficiencia , Proteínas de la Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/deficiencia , Endosomas/metabolismo , Neuronas/metabolismo , Proteínas Relacionadas con Receptor de LDL/metabolismo , Proteínas Relacionadas con Receptor de LDL/genética , Transducción de Señal , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/metabolismoRESUMEN
The white matter is an important constituent of the central nervous system, containing axons, oligodendrocytes, and its progenitor cells, astrocytes, and microglial cells. Oligodendrocytes are central for myelin synthesis, the insulating envelope that protects axons and allows normal neural conduction. Both, oligodendrocytes and myelin, are highly vulnerable to toxic factors in many neurodevelopmental and neurodegenerative disorders associated with disturbances of myelination. Here we review the main alterations in oligodendrocytes and myelin observed in some organic acidurias/acidemias, which correspond to inherited neurometabolic disorders biochemically characterized by accumulation of potentially neurotoxic organic acids and their derivatives. The yet incompletely understood mechanisms underlying the high vulnerability of OLs and/or myelin in glutaric acidemia type I, the most prototypical cerebral organic aciduria, are particularly discussed.
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Errores Innatos del Metabolismo de los Aminoácidos , Encefalopatías Metabólicas , Glutaril-CoA Deshidrogenasa , Oligodendroglía , Sustancia Blanca , Oligodendroglía/metabolismo , Oligodendroglía/patología , Errores Innatos del Metabolismo de los Aminoácidos/patología , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Glutaril-CoA Deshidrogenasa/deficiencia , Glutaril-CoA Deshidrogenasa/metabolismo , Humanos , Animales , Sustancia Blanca/patología , Sustancia Blanca/metabolismo , Encefalopatías Metabólicas/patología , Encefalopatías Metabólicas/metabolismo , Vaina de Mielina/metabolismo , Vaina de Mielina/patologíaRESUMEN
Blood selenium (Se) concentrations differ substantially by population and could be influenced by genetic variants, increasing Se deficiency-related diseases. We conducted a genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with serum Se deficiency in 382 adults with admixed ancestry. Genotyping arrays were combined to yield 90,937 SNPs. R packages were applied to quality control and imputation. We also performed the ancestral proportion analysis. The Search Tool for the Retrieval of Interacting Genes was used to interrogate known protein-protein interaction networks (PPIs). Our ancestral proportion analysis estimated 71% of the genome was from Caucasians, 22% was from Africans, and 8% was from East Asians. We identified the SNP rs1561573 in the TraB domain containing 2B (TRABD2B), rs425664 in MAF bZIP transcription factor (MAF), rs10444656 in spermatogenesis-associated 13 (SPATA13), and rs6592284 in heat shock protein nuclear import factor (HIKESHI) genes. The PPI analysis showed functional associations of Se deficiency, thyroid hormone metabolism, NRF2-ARE and the Wnt pathway, and heat stress. Our findings show evidence of a genetic association between Se deficiency and metabolic pathways indirectly linked to Se regulation, reinforcing the complex relationship between Se intake and the endogenous factors affecting the Se requirements for optimal health.
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Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Selenio , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Brasil , Predisposición Genética a la Enfermedad , Genotipo , Mapas de Interacción de Proteínas/genética , Selenio/sangre , Selenio/deficiencia , Población Blanca/genética , Pueblo Africano , Pueblos del Este de AsiaRESUMEN
BACKGROUND: Gestational weight gain below or above the Institute of Medicine recommendations has been associated with adverse perinatal and neonatal outcomes. Very few studies have evaluated the association between serum and red blood cell folate concentrations and gestational weight gain in adolescents. Additionally, zinc deficiency during pregnancy has been associated with impaired immunity, prolonged labor, preterm and post-term birth, intrauterine growth restriction, low birth weight, and pregnancy-induced hypertension. OBJECTIVE: The purpose of our study is to evaluate the association between serum concentrations of zinc, serum folate, and red blood cell folate, with the increase in gestational weight and the weight and length of the newborn in a group of adolescent mothers from Mexico City. RESULTS: In our study, 406 adolescent-neonate dyads participated. The adolescents' median age was 15.8 years old. The predominant socioeconomic level was middle-low (57.8%), single (57%), 89.9% were engaged in home activities, and 41.3% completed secondary education. Excessive gestational weight gain was observed in 36.7% of cases, while insufficient gestational weight gain was noted in 38.4%. Small for gestational age infants were observed in 20.9% of the sample. Low serum folate (OR 2.1, 95% CI 1.3-3.3), decreased red blood cell folate (OR 1.6, 95% CI 1.0-2.6), and reduced serum zinc concentrations (OR 3.3, 95% CI 2.1-5.2) were associated with insufficient gestational weight gain. Decreased serum zinc levels (OR 1.2, 95% CI 1.2-3.4) were linked to an increased probability of delivering a baby who is small for their gestational age. CONCLUSIONS: Low serum folate, red blood cell folate, and serum zinc concentrations were associated with gestational weight gain and having a small gestational age baby. Both excessive and insufficient gestational weight gain, as well as having a small gestational age baby, are frequent among adolescent mothers.
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Peso al Nacer , Eritrocitos , Ácido Fólico , Ganancia de Peso Gestacional , Zinc , Humanos , Femenino , Zinc/sangre , Zinc/deficiencia , Adolescente , Embarazo , Ácido Fólico/sangre , Recién Nacido , México , Recién Nacido Pequeño para la Edad Gestacional/sangre , Embarazo en Adolescencia/sangreRESUMEN
Atherosclerosis (AS) has become the leading cause of cardiovascular disease worldwide. Our previous study had observed that Nippostrongylus brasiliensis (Nb) infection or its derived products could inhibit AS development by inducing an anti-inflammatory response. We performed a metabolic analysis to screen Nb-derived metabolites with anti-inflammation activity and evaluated the AS-prevention effect. We observed that the metabolite uridine had higher expression levels in mice infected with the Nb and ES (excretory-secretory) products and could be selected as a key metabolite. ES and uridine interventions could reduce the pro-inflammatory responses and increase the anti-inflammatory responses in vitro and in vivo. The apolipoprotein E gene knockout (ApoE-/-) mice were fed with a high-fat diet for the AS modeling. Following the in vivo intervention, ES products or uridine significantly reduced serum and liver lipid levels, alleviated the formation of atherosclerosis, and reduced the pro-inflammatory responses in serum or plaques, while the anti-inflammatory responses showed opposite trends. After blocking with 5-HD (5-hydroxydecanoate sodium) in vitro, the mRNA levels of M2 markers were significantly reduced. When blocked with 5-HD in vivo, the degree of atherosclerosis was worsened, the pro-inflammatory responses were increased compared to the uridine group, while the anti-inflammatory responses decreased accordingly. Uridine, a key metabolite from Nippostrongylus brasiliensis, showed anti-inflammatory and anti-atherosclerotic effects in vitro and in vivo, which depend on the activation of the mitochondrial ATP-sensitive potassium channel.
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Antiinflamatorios , Aterosclerosis , Nippostrongylus , Uridina , Animales , Masculino , Ratones , Antiinflamatorios/farmacología , Apolipoproteínas E/genética , Apolipoproteínas E/deficiencia , Aterosclerosis/metabolismo , Aterosclerosis/genética , Modelos Animales de Enfermedad , Canales KATP/metabolismo , Canales KATP/genética , Ratones Noqueados , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Uridina/farmacologíaRESUMEN
Herein, we present a thorough examination of the impact of maternal nutrition on fetal and infant neurodevelopment, focusing on specific nutrients and their critical roles in perinatal and pediatric health. Through a comprehensive narrative review of the literature, this study highlights the importance of a balanced maternal diet rich in nutrients like eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), folic acid, iron, and iodine in shaping children's neurological functions. Key findings underscore the influence of maternal nutrition during pregnancy and the peri-gestational period on children's cognitive, motor, speech, and socio-emotional development. Deficiencies in essential nutrients, such as DHA, are linked to adverse long-lasting outcomes such as premature birth and intrauterine growth restriction, where a suitable intake of iron and folic acid is vital to prevent neural tube defects and promote healthy brain development. We highlight areas requiring further investigation, particularly regarding iodine's impact and the risks associated with alcohol consumption during pregnancy. In conclusion, this research sheds light on our current understanding of maternal nutrition and child neurodevelopment, offering valuable insights for health professionals and researchers.
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Desarrollo Infantil , Desarrollo Fetal , Fenómenos Fisiologicos Nutricionales Maternos , Humanos , Embarazo , Femenino , Desarrollo Fetal/efectos de los fármacos , Desarrollo Fetal/fisiología , Desarrollo Infantil/efectos de los fármacos , Desarrollo Infantil/fisiología , Yodo/deficiencia , Yodo/administración & dosificación , Dieta/métodos , Lactante , Recién Nacido , Encéfalo/crecimiento & desarrollo , Encéfalo/efectos de los fármacos , Ácido Fólico/administración & dosificación , Estado Nutricional , Ácidos Docosahexaenoicos/administración & dosificaciónRESUMEN
The moral imperative of public health systems is to maximize the health and welfare of the population to the extent possible. Constraints often include a lack of resources, political will, popular acceptance, or an acceptable safety margin. Major agencies have established iron, iodine, and vitamin A as the principal elements for micronutrients, with folate and zinc on the second plane. As the armamentarium of interventions to favor micronutrient nutrition, for example, preventive health measures, dietary improvement, forms of fortification, and nutrient supplements, is offered in public health policy. The utility of their merger with other nutrients, emergent nutrients, has been considered. The Latin America and Caribbean Region has unique characteristics. The scientific and epidemiology considerations for action in the Region's health concern on 4 emergent nutrient deficiencies of public health-vitamins D and E, essential fatty acids, and choline-are reviewed.
Plain language titleMicronutrient Deficiencies of Interest in Latin America and the CaribbeanPlain language summaryThe diets consumed in the diverse corners and societies in the nations of Latin America and the Caribbean area do not fully supply the vitamins and minerals needed by people of all ages and conditions. Some public health actions are being taken, but only against a limited selection of such nutrients as iron, vitamin A, iodine, and folic acid. The composition of diets and environmental conditions across the region suggests that 4 additional nutrients might be candidates for public health efforts. These include vitamin D, vitamin E, certain large fatty acid molecules, and choline.
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Micronutrientes , Humanos , Región del Caribe/epidemiología , Suplementos Dietéticos , Ácidos Grasos Esenciales/deficiencia , América Latina/epidemiología , Micronutrientes/deficiencia , Política Nutricional , Salud PúblicaRESUMEN
Infantile colic is excessive crying for no apparent reason in an otherwise healthy infant. Although its physiopathology is not completely understood, therapies usually target gastrointestinal symptoms. This systematic review of randomized controlled trials (RCTs) analyzes the efficacy of lactase supplementation in infantile colic. PubMed, Embase, and Cochrane were searched for RCTs evaluating lactase supplementation in infants up to 6 months old with infantile colic. Out of six RCTs including 394 patients, three reported a significantly shorter crying time in the lactase group than in the placebo group, while the other three found no significant difference between groups. Of the two studies that performed the hydrogen breath test, only one reported a significant reduction in exhaled hydrogen levels. The pharmacological approach to infantile colic remains debatable, and new studies with standardized diagnostic criteria and outcomes are required to guide lactase supplementation in clinical practice.