RESUMEN
Mitochondrial diseases are a group of inherited diseases with highly varied and complex clinical presentations. Here, we report four individuals, including two siblings, affected by a progressive mitochondrial encephalopathy with biallelic variants in the cardiolipin biosynthesis gene CRLS1. Three affected individuals had a similar infantile presentation comprising progressive encephalopathy, bull's eye maculopathy, auditory neuropathy, diabetes insipidus, autonomic instability, cardiac defects and early death. The fourth affected individual presented with chronic encephalopathy with neurodevelopmental regression, congenital nystagmus with decreased vision, sensorineural hearing loss, failure to thrive and acquired microcephaly. Using patient-derived fibroblasts, we characterized cardiolipin synthase 1 (CRLS1) dysfunction that impaired mitochondrial morphology and biogenesis, providing functional evidence that the CRLS1 variants cause mitochondrial disease. Lipid profiling in fibroblasts from two patients further confirmed the functional defect demonstrating reduced cardiolipin levels, altered acyl-chain composition and significantly increased levels of phosphatidylglycerol, the substrate of CRLS1. Proteomic profiling of patient cells and mouse Crls1 knockout cell lines identified both endoplasmic reticular and mitochondrial stress responses, and key features that distinguish between varying degrees of cardiolipin insufficiency. These findings support that deleterious variants in CRLS1 cause an autosomal recessive mitochondrial disease, presenting as a severe encephalopathy with multi-systemic involvement. Furthermore, we identify key signatures in cardiolipin and proteome profiles across various degrees of cardiolipin loss, facilitating the use of omics technologies to guide future diagnosis of mitochondrial diseases.
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Encefalopatías , Enfermedades Mitocondriales , Animales , Ratones , Encefalopatías/genética , Encefalopatías/metabolismo , Cardiolipinas/genética , Cardiolipinas/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , ProteómicaRESUMEN
PURPOSE: Genome sequencing (GS)-specific diagnostic rates in prospective tightly ascertained exome sequencing (ES)-negative intellectual disability (ID) cohorts have not been reported extensively. METHODS: ES, GS, epigenetic signatures, and long-read sequencing diagnoses were assessed in 74 trios with at least moderate ID. RESULTS: The ES diagnostic yield was 42 of 74 (57%). GS diagnoses were made in 9 of 32 (28%) ES-unresolved families. Repeated ES with a contemporary pipeline on the GS-diagnosed families identified 8 of 9 single-nucleotide variations/copy-number variations undetected in older ES, confirming a GS-unique diagnostic rate of 1 in 32 (3%). Episignatures contributed diagnostic information in 9% with GS corroboration in 1 of 32 (3%) and diagnostic clues in 2 of 32 (6%). A genetic etiology for ID was detected in 51 of 74 (69%) families. Twelve candidate disease genes were identified. Contemporary ES followed by GS cost US$4976 (95% CI: $3704; $6969) per diagnosis and first-line GS at a cost of $7062 (95% CI: $6210; $8475) per diagnosis. CONCLUSION: Performing GS only in ID trios would be cost equivalent to ES if GS were available at $2435, about a 60% reduction from current prices. This study demonstrates that first-line GS achieves higher diagnostic rate than contemporary ES but at a higher cost.
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Secuenciación del Exoma , Exoma , Discapacidad Intelectual , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Masculino , Femenino , Exoma/genética , Secuenciación del Exoma/economía , Estudios de Cohortes , Pruebas Genéticas/economía , Pruebas Genéticas/métodos , Secuenciación Completa del Genoma/economía , Niño , Genoma Humano/genética , Variaciones en el Número de Copia de ADN/genética , Polimorfismo de Nucleótido Simple/genética , PreescolarRESUMEN
BACKGROUND: Trio exome sequencing can be used to investigate congenital abnormalities identified on pregnancy ultrasound, but its use in an Australian context has not been assessed. AIMS: Assess clinical outcomes and changes in management after expedited genomic testing in the prenatal period to guide the development of a model for widespread implementation. MATERIALS AND METHODS: Forty-three prospective referrals for whole exome sequencing, including 40 trios (parents and pregnancy), two singletons and one duo were assessed in a tertiary hospital setting with access to a state-wide pathology laboratory. Diagnostic yield, turn-around time (TAT), gestational age at reporting, pregnancy outcome, change in management and future pregnancy status were assessed for each family. RESULTS: A clinically significant genomic diagnosis was made in 15/43 pregnancies (35%), with an average TAT of 12 days. Gestational age at time of report ranged from 16 + 5 to 31 + 6 weeks (median 21 + 3 weeks). Molecular diagnoses included neuromuscular and skeletal disorders, RASopathies and a range of other rare Mendelian disorders. The majority of families actively used the results in pregnancy decision making as well as in management of future pregnancies. CONCLUSIONS: Rapid second trimester prenatal genomic testing can be successfully delivered to investigate structural abnormalities in pregnancy, providing crucial guidance for current and future pregnancy management. The time-sensitive nature of this testing requires close laboratory and clinical collaboration to ensure appropriate referral and result communication. We found the establishment of a prenatal coordinator role and dedicated reporting team to be important facilitators. We propose this as a model for genomic testing in other prenatal services.
RESUMEN
Parent feeding styles, behaviors, beliefs, and practices are associated with developing children's eating behaviors. However, many children spend considerable time in childcare; thus, are exposed to child-feeding practices of other adults, e.g., early care and education (ECE) staff. Limited research exists on how and whether current classroom feeding practices of ECE staff associate with their own childhood experiences. The About Feeding Children survey, conducted in 2005, examined self-reported feeding practices and beliefs and personal characteristics of ECE staff in Western United States. An exploratory factor analysis of questions related to childhood experiences (N = 1189), revealed two Mealtime Factors: Remembered Adult Control and Remembered Child Autonomy Support. Structural equation modeling was conducted to examine the hypothesis that these remembered experiences would be associated with current feeding practices (Structural Mealtime Strategies, Verbal Mealtime Strategies, and Beliefs about Mealtimes). For each outcome, models had good to moderate fit. Across models, Remembered Autonomy Support was associated with less control, bribing, autonomy undermining, and concern-based control beliefs and greater support at meals and autonomy promoting beliefs in teachers' classroom feeding practices. More research is called for to consider whether reflection on remembered childhood experiences might be beneficial to consider during ECE staff training related to feeding young children.
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Cuidado del Niño , Conducta Alimentaria , Adulto , Niño , Humanos , Estados Unidos , Preescolar , Escolaridad , Encuestas y Cuestionarios , ComidasRESUMEN
BACKGROUND: Beta-ureidopropionase deficiency, caused by variants in UPB1, has been reported in association with various neurodevelopmental phenotypes including intellectual disability, seizures and autism. AIM: We aimed to reassess the relationship between variants in UPB1 and a clinical phenotype. METHODS: Literature review, calculation of carrier frequencies from population databases, long-term follow-up of a previously published case and reporting of additional cases. RESULTS: Fifty-three published cases were identified, and two additional cases are reported here. Of these, 14 were asymptomatic and four had transient neurological features; clinical features in the remainder were variable and included non-neurological presentations. Several of the variants previously reported as pathogenic are present in population databases at frequencies higher than expected for a rare condition. In particular, the variant most frequently reported as pathogenic, p.Arg326Gln, is very common among East Asians, with a carrier frequency of 1 in 19 and 1 in 907 being homozygous for the variant in gnomAD v2.1.1. CONCLUSION: Pending the availability of further evidence, UPB1 should be considered a 'gene of uncertain clinical significance'. Caution should be used in ascribing clinical significance to biochemical features of beta-ureidopropionase deficiency and/or UPB1 variants in patients with neurodevelopmental phenotypes. UPB1 is not currently suitable for inclusion in gene panels for reproductive genetic carrier screening. SYNOPSIS: The relationship between beta-ureidopropionase deficiency due to UPB1 variants and clinical phenotypes is uncertain.
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Trastornos del Movimiento , Errores Innatos del Metabolismo de la Purina-Pirimidina , Humanos , Encefalopatías/diagnóstico , Encefalopatías/genética , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/genética , Fenotipo , Errores Innatos del Metabolismo de la Purina-Pirimidina/diagnóstico , Errores Innatos del Metabolismo de la Purina-Pirimidina/genética , Amidohidrolasas/genéticaRESUMEN
Several studies have demonstrated a high incidence of autistic spectrum features in individuals with Smith-Lemli-Opitz syndrome (SLOS). However, do these findings imply a converse relationship that has diagnostic utility? Is SLOS testing implicated when autism spectrum disorder (ASD) is the only clinical indication? AIM: To determine if there is any correlation with a clinical indication of ASD and a biochemical diagnosis of SLOS, based on historical test request and assay data. METHODS: Six years (2008-2013) of clinical test requests for 7-dehydrocholesterol (7-DHC) level were classified and summarised according to indication and final test result. RESULTS: From the audit period, 988 valid test results from post-natal samples were identified. In plasma/serum, mean 7-DHC level was 264.7 µmol/L (normal range < 2.0) for confirmed SLOS cases. No tests performed due to an isolated clinical indication of ASD or where no clinical information was supplied were associated with 7-DHC levels diagnostic for SLOS. CONCLUSIONS: Historical test data analysis supports the recommendation that autism/ASD as a single clinical feature is not an appropriate indication for SLOS (7-DHC) biochemical testing.
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Trastorno del Espectro Autista , Trastorno Autístico , Síndrome de Smith-Lemli-Opitz , Trastorno del Espectro Autista/diagnóstico , Trastorno Autístico/diagnóstico , Humanos , Valores de Referencia , Síndrome de Smith-Lemli-Opitz/diagnósticoRESUMEN
The cause of neurodegeneration in MPS mouse models is the focus of much debate and what the underlying cause of disease pathology in MPS mice is. The timing of development of pathology and when this can be reversed or impacted is the key to developing suitable therapies in MPS. This study is the first of its kind to correlate the biochemical changes with the functional outcome as assessed using non-invasive behaviour testing across multiple mucopolysaccharidosis (MPS) mouse models. In the MPS brain, the primary lysosomal enzyme dysfunction leads to accumulation of primary glycosaminoglycans (GAGs) with gangliosides (GM2 and GM3) being the major secondary storage products. With a focus on the neuropathology, a time course experiment was conducted in MPS I, MPS IIIA, MPS VII (severe and attenuated models) in order to understand the relative timing and level of GAG and ganglioside accumulation and how this correlates to behaviour deficits. Time course analysis from 1 to 6 months of age was conducted on brain samples to assess primary GAG (uronic acid), ß-hexosaminidase enzyme activity and levels of GM2 and GM3 gangliosides. This was compared to a battery of non-invasive behaviour tests including open field, inverted grid, rotarod and water cross maze were assessed to determine effects on motor function, activity and learning ability. The results show that the GAG and ganglioside accumulation begins prior to the onset of detectable changes in learning ability and behaviour. Interestingly, the highest levels of GAG and ganglioside accumulation was observed in the MPS IIIA mouse despite having 3% residual enzyme activity. Deficits in motor function were clearly observed in the severe Gusmps/mps, which were significantly delayed in the attenuated Gustm(L175F)Sly model despite their minimal increase in detectable enzyme activity. This suggests that genotype and residual enzyme activity are not indicative of severity of disease pathology in MPS disease and there exists a window when there are considerable storage products without detectable functional deficits which may allow an alteration to occur with therapy.
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Encéfalo/metabolismo , Glucuronidasa/genética , Mucopolisacaridosis III/metabolismo , Mucopolisacaridosis I/metabolismo , Mucopolisacaridosis VII/metabolismo , Animales , Encéfalo/patología , Modelos Animales de Enfermedad , Gangliósido G(M2)/genética , Gangliósido G(M2)/metabolismo , Gangliósido G(M3)/genética , Gangliósido G(M3)/metabolismo , Glicosaminoglicanos/genética , Glicosaminoglicanos/metabolismo , Heparitina Sulfato/metabolismo , Humanos , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Mucopolisacaridosis I/genética , Mucopolisacaridosis I/patología , Mucopolisacaridosis III/genética , Mucopolisacaridosis III/patología , Mucopolisacaridosis VII/genética , Mucopolisacaridosis VII/patologíaRESUMEN
Gaucher disease (GD) is an inherited metabolic disorder characterised by impaired catabolism of the glycosphingolipid, glucosylceramide. The deacetylated derivative, glucosylsphingosine (GluSph, lyso-Gb1) has materialised as a biomarker for GD. Further appraisal of the clinical utility of GluSph is required in terms of its prognostic power to inform disease course and pre-symptomatic testing. In this study, we show that plasma GluSph concentrations are significantly higher in GD patients with neuronopathic disease compared with non-neuronopathic disease, even in the neonatal period. A neonate diagnosed at 1 day of age (homozygous for N370S) due to an affected older sibling, returned GluSph of 70 nmol/L compared with 1070-2620 nmol/L for four neuronopathic patients diagnosed <20 days of age. Given this result shows promise for newborn screening, we developed a rapid, simple, and robust assay for GluSph in dried filter paper blood spots (DBS) and were able to detect 23 GD patients from 220 unaffected individuals. Neuronopathic GD patients also had significantly higher DBS concentrations of GluSph than their non-neuronopathic counterparts. We went on to measure GluSph in tissue extracts prepared from chorionic villus sampling and confirmed concentrations were undetectable in unaffected tissue but elevated in GD tissue demonstrating utility in the prenatal setting. Additionally, GluSph is a pharmacodynamic biomarker, revealing a precipitous drop following initiation of enzyme replacement therapy. In conclusion, GluSph is a reliable and specific biomarker for GD and shows promise for prenatal diagnosis and DBS screening programmes.
Asunto(s)
Pruebas con Sangre Seca/métodos , Enfermedad de Gaucher/sangre , Psicosina/análogos & derivados , Adolescente , Adulto , Biomarcadores/sangre , Niño , Preescolar , Cromatografía Liquida , Femenino , Enfermedad de Gaucher/diagnóstico , Humanos , Lactante , Recién Nacido , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Embarazo , Diagnóstico Prenatal , Psicosina/sangre , Espectrometría de Masas en Tándem , Adulto Joven , beta-Glucosidasa/metabolismoRESUMEN
PURPOSE: Expanding treatments for the mucopolysaccharidoses-a family of genetic disorders-place unprecedented demands for accurate, timely diagnosis because best outcomes are seen with early initiation of appropriate therapies. Here we sought to improve the diagnostic odyssey by measuring specific glycosaminoglycan fragments with terminal residues complicit with the genetic defect resulting in precise diagnosis rather than the usual first-line, ambiguous total glycosaminoglycan determinations that return poor diagnostic yield. METHODS: A derivatizing reagent was added to urine aliquots (0.5 µmol creatinine) before separation of the glycosaminoglycan fragments by liquid chromatography and quantification with electrospray ionization-tandem mass spectrometry using multiple reaction monitoring for 10 targeted fragments plus the internal standard. RESULTS: All 93 mucopolysaccharidosis patients were correctly identified as 1 of 10 subtypes from a total of 723 de-identified subjects-blinded to diagnosis-based on the presence of specific "signature" glycosaminoglycan fragments. Employing reference intervals calculated from 630 unaffected urines, with 99% confidence intervals, provided a laboratory test with 100% specificity and sensitivity. CONCLUSION: This novel urine assay allows diagnosis of 10 mucopolysaccharidosis subtypes in a single test. The precise quantification of unique glycosaminoglycan fragments also enables longitudinal biochemical monitoring following therapeutic interventions.
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Glicosaminoglicanos/análisis , Mucopolisacaridosis/diagnóstico , Estudios de Cohortes , Glicosaminoglicanos/genética , Glicosaminoglicanos/orina , Humanos , Lactante , Recién Nacido , Tamizaje Masivo , Mucopolisacaridosis/orina , Valores de Referencia , Estudios Retrospectivos , Sensibilidad y Especificidad , Espectrometría de Masa por Ionización de Electrospray/métodosRESUMEN
A young woman with a history of previously undiagnosed episodic neurological deterioration since early childhood associated with viral illnesses developed fulminant encephalitis. Standard investigations gave no diagnosis. Next-generation sequencing identified a heterozygous mutation c.1754C>T (p.Thr585Met) in the RANBP2 gene, giving the diagnosis of recurrent acute necrotising encephalopathy type 1. This condition is probably underdiagnosed, especially in adults, and should be considered in patients with recurrent encephalopathy.
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Enfermedad de Leigh/diagnóstico por imagen , Enfermedad de Leigh/genética , Chaperonas Moleculares/genética , Mutación/genética , Proteínas de Complejo Poro Nuclear/genética , Femenino , Humanos , Enfermedad de Leigh/metabolismo , Adulto JovenRESUMEN
Short stature is a characteristic feature of most of the mucopolysaccharidoses, a group of inherited lysosomal storage disorders caused by a single enzyme deficiency. MPS patients present with progressive skeletal defects from an early age, including short stature due to impaired cartilage-to-bone conversion (endochondral ossification). The aim of this study was to determine which murine MPS model best reproduces the bone length reduction phenotype of human MPS and use this model to determine the earliest developmental stage when disrupted endochondral ossification first appears. Gusmps/mps mice representing severe MPS VII displayed the greatest reduction in bone elongation and were chosen for histopathological analysis. Tibial development was assessed from E12.5 to 6â¯months of age. Chondrocytes in the region of the future primary ossification center became hypertrophic at a similar age to normal in the MPS VII mouse fetus, but a delay in bone deposition was observed with an approximate 1â¯day delay in the formation of the primary ossification centre. Likewise, chondrocytes in the region of the future secondary ossification center also became hypertrophic at the same age as normal in the MPS VII early postnatal mouse. Bone deposition in the secondary ossification centre was delayed by two days in the MPS VII proximal tibia (observed at postnatal day 14 (P14) compared to P12 in normal). The thickness of the tibial growth plate was larger in MPS VII mice from P9 onwards. Abnormal endochondral ossification starts in utero in MPS VII and worsens with age. It is characterized by a normal timeframe for chondrocyte hypertrophy but a delay in the subsequent deposition of bone in both the primary and secondary ossification centres, accompanied by an increase in growth plate thickness. This suggests that the signals for vascular invasion and bone deposition, some of which are derived from hypertrophic chondrocytes, are altered in MPS VII.
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Enfermedades Óseas/etiología , Enfermedades Óseas/patología , Modelos Animales de Enfermedad , Mucopolisacaridosis VII/complicaciones , Osteogénesis , Tibia/patología , Animales , Animales Recién Nacidos , Diferenciación Celular , Femenino , Masculino , Ratones , EmbarazoRESUMEN
BACKGROUND: Children spend a substantial amount of time in early care and education (ECE) settings and may eat a majority of their diet in this setting. While there are several instruments focused on measuring factors of the ECE environment that may influence diet and weight outcomes, there are few comprehensive, valid, and reliable measures for collecting self-report of ECE providers' feeding practices. The purpose of this study was to establish the factor structure and internal reliability of a survey developed to measure practices and beliefs of ECE providers relative to feeding children. METHODS: Licensed ECE centers from CA, CO, ID and NV were included in this cross-sectional survey study. The sample was stratified by states and census regions to yield equal numbers of centers from each category. The total sample distribution included 1600 randomly selected centers and up to 8000 staff members (who represented teachers, aides, assistants, or cooks); 1178 surveys were completed. We conducted an exploratory, unrestricted factor analysis as well as parallel analyses to inform the number of factors to be extracted. RESULTS: Factors within Structural Mealtime Strategies included Adult Control of Foods Consumed (Kuder-Richardson [KR] = 0.67), Bribing with Sweet Foods (KR = 0.70), and Supportive Adult Roles at Mealtime (KR = 0.55). Factors in Verbal Mealtime Strategies included Supporting Children's Eating Self-regulation (KR =0.61), Pressure to Eat (KR = 0.58), and Social Comparisons (KR = 0.59). Beliefs about Mealtime factors were Autonomy Promoting (α = 0.64), Coercive Beliefs (α = 0.77), and Concern-Based Control (α = 0.60). CONCLUSIONS: The AFC Strategies and Beliefs Survey provides a promising self-report instrument with a strong factor structure consistent with the extant literature to measure practices and beliefs related to feeding and mealtimes in the ECE setting. Feeding young children in group settings differs in many ways from feeding in a family setting; hence it is important that measures such as the AFC Strategies and Beliefs Survey capture unique aspects of the ECE feeding environment.
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Intervención Educativa Precoz , Conocimientos, Actitudes y Práctica en Salud , Comidas , Maestros/estadística & datos numéricos , Encuestas y Cuestionarios/estadística & datos numéricos , Adulto , Peso Corporal , Preescolar , Estudios Transversales , Dieta , Conducta Alimentaria , Femenino , Humanos , Lactante , Masculino , Reproducibilidad de los Resultados , Autoinforme , Estados UnidosRESUMEN
Fabry disease (FD) results from impaired globotriaosylceramide (Gb3) catabolism, due to a deficiency of the lysosomal hydrolase, α-galactosidase A (α-GalA). As a direct consequence, the deacetylated derivative, globotriaosylsphingosine (lyso-Gb3), is produced and contemporary evidence exemplifies its use as a biomarker. Here we developed a simple method to enable quantification of lyso-Gb3 in just 0.01mL of plasma and explored its concentration in a cohort of 73 Australian FD patients, as well as in individuals with other sphingolipidoses. In 2000 patients without FD, but with related metabolic conditions, lyso-Gb3 returned concentrations of <5pmol/mL. In the FD cohort, 53/60 patients with classical mutations returned lyso-Gb3 concentrations≥5pmol/mL whereas only 4/13 patients with "late-onset" mutations had lyso-Gb3≥5pmol/mL. Five females with normal α-GalA activity and genetically confirmed FD returned lyso-Gb3≥5pmol/mL. The prevalence of clinically significant disease including cardiomyopathy, nephropathy and cerebrovascular disease was congruent with higher lyso-Gb3 concentrations. Repeat testing was available for 51 patients-26 undergoing enzyme replacement therapy-and concentrations of lyso-Gb3 remained unaltered throughout 6-18 months independent of sex, mutation or treatment status. Our data suggest that the optimum use of lyso-Gb3 resides in laboratory confirmation of classical FD and for monitoring at least the initial response to therapeutic intervention. There is no evidence that lyso-Gb3 can inform on clinical events.
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Biomarcadores/sangre , Enfermedad de Fabry/sangre , Enfermedad de Fabry/diagnóstico , Glucolípidos/sangre , Esfingolípidos/sangre , Adulto , Australia , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Espectrometría de Masas en Tándem , alfa-Galactosidasa/genéticaRESUMEN
UNLABELLED: Mucopolysaccharidosis IIIA is a heritable neurodegenerative disorder resulting from the dysfunction of the lysosomal hydrolase sulphamidase. This leads to the primary accumulation of the complex carbohydrate heparan sulphate in a wide range of tissues and the secondary neuronal storage of gangliosides GM2 and GM3 in the brain. GM2 storage is associated with CNS deterioration in the GM2 gangliosidosis group of lysosomal storage disorders and may also contribute to MPS CNS disease. N-butyldeoxynojirimycin, an inhibitor of ceramide glucosyltransferase activity and therefore of ganglioside synthesis, was administered to MPS IIIA mice both prior to maximal GM2 and GM3 accumulation (early treatment) and after the maximum level of ganglioside had accumulated in the brain (late treatment) to determine if behaviour was altered by ganglioside level. Ceramide glucosyltransferase activity was decreased in both treatment groups; however, brain ganglioside levels were only decreased in the late treatment group. Learning in the water cross maze was improved in both groups and the innate fear response was also restored in both groups. A reduction in the expression of inflammatory gene Ccl3 was observed in the early treatment group, while IL1ß expression was reduced in both treatment groups. Thus, it appears that NB-DNJ elicits a transient decrease in brain ganglioside levels, some modulation of inflammatory cytokines and a functional improvement in behaviour that can be elicited both before and after overt neurological changes manifest. SYNOPSIS: NB-DNJ improves learning and restores the innate fear response in MPS IIIA mice by decreasing ceramide glucosyltransferase activity and transiently reducing ganglioside storage and/or modulating inflammatory signals.
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1-Desoxinojirimicina/análogos & derivados , Inhibidores de Glicósido Hidrolasas/uso terapéutico , Mucopolisacaridosis III/tratamiento farmacológico , 1-Desoxinojirimicina/farmacología , 1-Desoxinojirimicina/uso terapéutico , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Quimiocina CCL3/metabolismo , Modelos Animales de Enfermedad , Miedo/efectos de los fármacos , Gangliósidos/metabolismo , Glucosiltransferasas/antagonistas & inhibidores , Glucosiltransferasas/metabolismo , Inhibidores de Glicósido Hidrolasas/farmacología , Interleucina-1beta/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Mucopolisacaridosis III/metabolismo , Mucopolisacaridosis III/psicologíaRESUMEN
Fifty percent of inborn errors of metabolism are present in later childhood and adulthood, with crises commonly precipitated by minor viral illnesses or increased protein ingestion. Many physicians only consider IEM after more common conditions (such as sepsis) have been considered. In view of the large number of inborn errors, it might appear that their diagnosis requires precise knowledge of a large number of biochemical pathways and their interrelationship. As a matter of fact, an adequate diagnostic approach can be based on the proper use of only a few screening tests. A detailed history of antecedent events, together with these simple screening tests, can be diagnostic, leading to life-saving, targeted treatments for many disorders. Unrecognised, IEM can lead to significant mortality and morbidity. Advice is available 24/7 through the metabolic service based at the major paediatric hospital in each state and Starship Children's Health in New Zealand.
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Toma de Decisiones Clínicas/métodos , Servicio de Urgencia en Hospital , Errores Innatos del Metabolismo/diagnóstico , Medicina de Urgencia Pediátrica/métodos , Niño , Técnicas de Apoyo para la Decisión , Urgencias Médicas , Humanos , Errores Innatos del Metabolismo/terapia , Nueva ZelandaRESUMEN
Antenatal screening for fetal anomalies has provided women and their partners with information to make reproductive choices based on the risk of serious chromosomal or structural defects since the 1990s. Alternative tests include first-trimester screening (combined ultrasound and maternal serum markers), second-trimester maternal serum markers and noninvasive cell-free DNA testing. The recent recommendations by the Royal Australian and New Zealand College of Obstetrics and Gynaecology and the Human Genetics Society of Australasia against second-trimester triple testing are based on unsound performance criteria, raise several contestable issues around access and equity and challenge the principles of governments providing affordable options.
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Síndrome de Down/diagnóstico , Segundo Trimestre del Embarazo , Diagnóstico Prenatal/métodos , Australia , Femenino , Humanos , Nueva Zelanda , Guías de Práctica Clínica como Asunto , Embarazo , Diagnóstico Prenatal/normasRESUMEN
INTRODUCTION: In this study, we aimed to evaluate whether fasting plasma citrulline concentration predicts subsequent glucose absorption in critically ill patients. METHODS: In a prospective observational study involving 15 healthy and 20 critically ill subjects, fasting plasma citrulline concentrations were assayed in blood samples immediately prior to the administration of a liquid test meal (1 kcal/ml; containing 3 g of 3-O-methylglucose (3-OMG)) that was infused directly into the small intestine. Serum 3-OMG concentrations were measured over the following 4 hours, with the area under the 3-OMG concentration curve (AUC) calculated as an index of glucose absorption. RESULTS: The groups were well matched in terms of age, sex and body mass index (BMI) (healthy subjects versus patients, mean (range) values: age, 47 (18 to 88) versus 49 (21 to 77) years; sex ratio, 60% versus 80% male; BMI, 25.2 (18.8 to 30.0) versus 25.5 (19.4 to 32.2) kg/m(2)). Compared to the healthy subjects, patients who were critically ill had reduced fasting citrulline concentration (26.5 (13.9 to 43.0) versus 15.2 (5.7 to 28.6) µmol/L; P < 0.01) and glucose absorption (3-OMG AUC, 79.7 (28.6 to 117.8) versus 61.0 (4.5 to 97.1) mmol/L/240 min; P = 0.05). There was no relationship between fasting citrulline concentration and subsequent glucose absorption (r = 0.28; P = 0.12). CONCLUSIONS: Whereas both plasma citrulline concentrations and glucose absorption were reduced in critical illness, fasting plasma citrulline concentrations were not predictive of subsequent glucose absorption. These data suggest that fasting citrulline concentration does not appear to be a marker of small intestinal absorptive function in patients who are critically ill.
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Citrulina/sangre , Enfermedad Crítica , Ayuno/sangre , Absorción Intestinal , Intestino Delgado/fisiopatología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Nutrición Enteral , Femenino , Glucosa/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
Prostaglandin (PG)D2 has been shown to be an active agent in the resolution of experimentally induced inflammation. This study was undertaken to determine the presence of PGD2 in chronic joint effusions and to explore the potential contributions of dendritic cells (DC) and monocytes to the intra-articular synthesis of PGD2. Synovial fluid (SF) was obtained from patients with inflammatory arthritis and knee effusions. PGD2 and PGE2 were detected in SF by ultrahigh-performance tandem mass spectrometry. Cellular fractions in SF were separated by density-gradient centrifugation and flow cytometry. The expression of hematopoietic prostaglandin D-synthase (hPGDS) and PGE-synthase (PGES) mRNA was determined by RT-PCR. Both PGD2 and PGE2 were detected in blood and SF, with PGD2 being more abundant than PGE2 in SF. mRNA for hPGDS was more abundant in SF mDCs than SF monocytes (P < 0.01) or PB monocytes (P < 0.001). SF mDC expressed significantly more hPGDS than PGES. Expressions of PGD2 and hPGDS were inversely associated with serum C-reactive protein (P < 0.01) and erythrocyte sedimentation rate (P < 0.01). The findings suggest that synovial DCs may be an important source of hPGDS and that systemic disease activity may be influenced by actions of PGD2 in RA and other arthropathies.