Comprehensive Metabolic Signature of Renal Dysplasia in Children. A Multiplatform Metabolomics Concept

Renal dysplasia is a severe congenital abnormality of the kidney parenchyma, which is an important cause of end-stage renal failure in childhood and early adulthood. The diagnosis of renal dysplasia relies on prenatal or postnatal ultrasounds as children show no specific clinical symptoms before chronic kidney disease develops. Prompt diagnosis is important in terms of early introduction of nephroprotection therapy and improved long-term prognosis. Metabolomics was applied to study children with renal dysplasia to provide insight into the changes in biochemical pathways underlying its pathology and in search of early indicators for facilitated diagnosis. The studied cohort consisted of 72 children, 39 with dysplastic kidneys and 33 healthy controls. All subjects underwent comprehensive urine metabolic profiling with the use of gas chromatography and liquid chromatography coupled to mass spectrometry, with two complementary separation modes of the latter. Univariate and multivariate statistical calculations identified a total of nineteen metabolites, differentiating the compared cohorts, independent of their estimated glomerular filtration rate. Seven acylcarnitines, xanthine, and glutamine were downregulated in the urine of renal dysplasia patients. Conversely, renal dysplasia was associated with higher urinary levels of dimethylguanosine, threonic acid or glyceric acid. This is the first metabolomic study of subjects with renal dysplasia. The authors define a characteristic urine metabolic signature in children with dysplastic kidneys, irrespective of renal function, linking the condition with altered fatty acid oxidation, amino acid and purine metabolisms.

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Untargeted Plasma Metabolomics Unravels a Metabolic Signature for Tissue Sensitivity to Glucocorticoids in Healthy Subjects: Its Implications in Dietary Planning for a Healthy Lifestyle

Nutrients ◽

10.3390/nu13062120 ◽

2021 ◽

Vol 13 (6) ◽

pp. 2120

Author(s):

Nicolas C. Nicolaides ◽

Maria-Konstantina Ioannidi ◽

Eleni Koniari ◽

Ifigeneia Papageorgiou ◽

Anastasia Bartzeliotou ◽

...

Keyword(s):

Healthy Subjects ◽

Healthy Lifestyle ◽

Serum Cortisol ◽

Polyol Pathway ◽

Gas Chromatography Mass Spectrometry ◽

Multivariate Statistical ◽

Glucocorticoid Sensitivity ◽

Metabolic Signature ◽

Resistant Group ◽

One Carbon Metabolism

In clinical practice, differences in glucocorticoid sensitivity among healthy subjects may influence the outcome and any adverse effects of glucocorticoid therapy. Thus, a fast and accurate methodology that could enable the classification of individuals based on their tissue glucocorticoid sensitivity would be of value. We investigated the usefulness of untargeted plasma metabolomics in identifying a panel of metabolites to distinguish glucocorticoid-resistant from glucocorticoid-sensitive healthy subjects who do not carry mutations in the human glucocorticoid receptor (NR3C1) gene. Applying a published methodology designed for the study of glucocorticoid sensitivity in healthy adults, 101 healthy subjects were ranked according to their tissue glucocorticoid sensitivity based on 8:00 a.m. serum cortisol concentrations following a very low-dose dexamethasone suppression test. Ten percent of the cohort, i.e., 11 participants, on each side of the ranking, with no NR3C1 mutations or polymorphisms, were selected, respectively, as the most glucocorticoid-sensitive and most glucocorticoid-resistant of the cohort to be analyzed and compared with untargeted blood plasma metabolomics using gas chromatography–mass spectrometry (GC–MS). The acquired metabolic profiles were evaluated using multivariate statistical analysis methods. Nineteen metabolites were identified with significantly lower abundance in the most sensitive compared to the most resistant group of the cohort, including fatty acids, sugar alcohols, and serine/threonine metabolism intermediates. These results, combined with a higher glucose, sorbitol, and lactate abundance, suggest a higher Cori cycle, polyol pathway, and inter-tissue one-carbon metabolism rate and a lower fat mobilization rate at the fasting state in the most sensitive compared to the most resistant group. In fact, this was the first study correlating tissue glucocorticoid sensitivity with serine/threonine metabolism. Overall, the observed metabolic signature in this cohort implies a worse cardiometabolic profile in the most glucocorticoid-sensitive compared to the most glucocorticoid-resistant healthy subjects. These findings offer a metabolic signature that distinguishes most glucocorticoid-sensitive from most glucocorticoid-resistant healthy subjects to be further validated in larger cohorts. Moreover, they support the correlation of tissue glucocorticoid sensitivity with insulin resistance and metabolic syndrome-associated pathways, further emphasizing the need for nutritionists and doctors to consider the tissue glucocorticoid sensitivity in dietary and exercise planning, particularly when these subjects are to be treated with glucocorticoids.

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FGF23, a novel muscle biomarker detected in the early stages of ALS

Scientific Reports ◽

10.1038/s41598-021-91496-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ying Si ◽

Mohamed Kazamel ◽

Michael Benatar ◽

Joanne Wuu ◽

Yuri Kwon ◽

...

Keyword(s):

Biomarker Discovery ◽

Clinical Symptoms ◽

Early Stage ◽

Fold Increase ◽

Progressive Increase ◽

Molecular Signature ◽

Muscle Membrane ◽

Sequencing Project ◽

Progressive Muscle Weakness ◽

End Stage

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness. Skeletal muscle is a prime source for biomarker discovery since it is one of the earliest sites to manifest disease pathology. From a prior RNA sequencing project, we identified FGF23 as a potential muscle biomarker in ALS. Here, we validate this finding with a large collection of ALS muscle samples and found a 13-fold increase over normal controls. FGF23 was also increased in the SOD1G93A mouse, beginning at a very early stage and well before the onset of clinical symptoms. FGF23 levels progressively increased through end-stage in the mouse. Immunohistochemistry of ALS muscle showed prominent FGF23 immunoreactivity in the endomysial connective tissue and along the muscle membrane and was significantly higher around grouped atrophic fibers compared to non-atrophic fibers. ELISA of plasma samples from the SOD1G93A mouse showed an increase in FGF23 at end-stage whereas no increase was detected in a large cohort of ALS patients. In conclusion, FGF23 is a novel muscle biomarker in ALS and joins a molecular signature that emerges in very early preclinical stages. The early appearance of FGF23 and its progressive increase with disease progression offers a new direction for exploring the molecular basis and response to the underlying pathology of ALS.

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A novel variant in the COL4A3 gene: etiology of Alport syndrome type 2 in a 38-year-old male with suspected hereditary kidney disease

Advances in Laboratory Medicine / Avances en Medicina de Laboratorio ◽

10.1515/almed-2021-0058 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Paula Sienes Bailo ◽

José Luis Bancalero Flores ◽

Raquel Lahoz Alonso ◽

María Santamaría González ◽

Alex Gutiérrez Dalmau ◽

...

Keyword(s):

Kidney Disease ◽

Alport Syndrome ◽

Clinical Symptoms ◽

Molecular Testing ◽

Syndrome Type ◽

Variant Of Uncertain Significance ◽

Type Iv ◽

Novel Variant ◽

End Stage

ABSTRACT Objectives Patients with Alport syndrome develop progressive kidney function deterioration, sensorineural hearing loss, and ocular abnormalities. This condition is caused by mutations in COL4A5 (X-linked inheritance), COL4A3 and COL4A4 (autosomal dominant or recessive inheritance), and encoding type IV collagen α3, α4, and α5, respectively. If left untreated, clinical symptoms progress from microscopic hematuria to proteinuria, progressive kidney failure, and end-stage kidney disease. At present, kidney transplantation is the only effective approach. Next-generation sequencing is the method of choice for the diagnosis of this condition. Case presentation We report the case of a young man with chronic kidney disease who eventually underwent transplantation. Molecular testing made it possible to determine the etiology of his clinical symptoms and autosomal recessive Alport syndrome type 2. The patient was found to be a compound heterozygote for two missense variants (trans configuration) in the COL4A3 gene: A likely pathogenic variant c.4981C>T (p.Arg1661Cys) in exon 52 inherited from the mother (described elsewhere), and another variant of uncertain significance, c.943G>A (p.Gly315Ser), in exon 17 inherited from the father that has not been previously reported in the literature or found in relevant databases. Conclusions Following genetic confirmation, genetic counseling was provided to the patient and his direct relatives.

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Diet, nutrients and metabolism: cogs in the wheel driving Alzheimer's disease pathology?

British Journal Of Nutrition ◽

10.1017/s0007114515000926 ◽

2015 ◽

Vol 113 (10) ◽

pp. 1499-1517 ◽

Cited By ~ 19

Author(s):

Rhona Creegan ◽

Wendy Hunt ◽

Alexandra McManus ◽

Stephanie R. Rainey-Smith

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Symptoms ◽

Aged Care ◽

Ageing Population ◽

People With Dementia ◽

Stage Disease ◽

Custodial Care ◽

Global Statistics ◽

End Stage

Alzheimer's disease (AD), the most common form of dementia, is a chronic, progressive neurodegenerative disease that manifests clinically as a slow global decline in cognitive function, including deterioration of memory, reasoning, abstraction, language and emotional stability, culminating in a patient with end-stage disease, totally dependent on custodial care. With a global ageing population, it is predicted that there will be a marked increase in the number of people diagnosed with AD in the coming decades, making this a significant challenge to socio-economic policy and aged care. Global estimates put a direct cost for treating and caring for people with dementia at $US604 billion, an estimate that is expected to increase markedly. According to recent global statistics, there are 35·6 million dementia sufferers, the number of which is predicted to double every 20 years, unless strategies are implemented to reduce this burden. Currently, there is no cure for AD; while current therapies may temporarily ameliorate symptoms, death usually occurs approximately 8 years after diagnosis. A greater understanding of AD pathophysiology is paramount, and attention is now being directed to the discovery of biomarkers that may not only facilitate pre-symptomatic diagnosis, but also provide an insight into aberrant biochemical pathways that may reveal potential therapeutic targets, including nutritional ones. AD pathogenesis develops over many years before clinical symptoms appear, providing the opportunity to develop therapy that could slow or stop disease progression well before any clinical manifestation develops.

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Developmental changes in cortisol secretion in normal and at-risk youth

Development and Psychopathology ◽

10.1017/s0954579401003169 ◽

2001 ◽

Vol 13 (3) ◽

pp. 721-732 ◽

Cited By ~ 126

Author(s):

ELAINE F. WALKER ◽

DEBORAH J. WALDER ◽

FELICIA REYNOLDS

Keyword(s):

Hpa Axis ◽

Clinical Symptoms ◽

Psychiatric Symptoms ◽

Early Adulthood ◽

At Risk Youth ◽

Cortisol Secretion ◽

Cross Sectional ◽

Axis Ii ◽

Schizotypal Personality ◽

Cortisol Levels

Adolescence is associated with an increase in the rate of certain psychiatric symptoms, and it is typically the developmental period when prodromal features of the major psychiatric disorders emerge. This is especially true of schizophrenia, with the majority of patients showing a marked postpubertal rise in schizotypal signs that predates the onset of clinical symptoms in early adulthood. Cross-sectional studies of youth have revealed a positive correlation between age and saliva cortisol level, suggesting a normative maturational increase in activity of the hypothalamic–pituitary–adrenal (HPA) axis. It has been hypothesized that this increase may trigger the expression of symptoms in vulnerable individuals. The present longitudinal study measured cortisol secretion and its relation with symptom development in samples of youth with schizotypal personality disorder (SPD), other personality disorders, or no Axis II disorder. The findings indicate moderate stability in cortisol levels across a 2-year period, with a longitudinal increase in cortisol levels over time. Cortisol levels at the first and second assessments were correlated with the severity of SPD symptoms at follow-up. The results are consistent with the notion that the HPA axis undergoes a postpubertal maturational process that moderates the expression of psychiatric symptoms.

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Brain-behaviour modes of covariation in healthy and clinically depressed young people

10.1101/487421 ◽

2018 ◽

Author(s):

Agoston Mihalik ◽

Fabio S. Ferreira ◽

Maria J. Rosa ◽

Michael Moutoussis ◽

Gabriel Ziegler ◽

...

Keyword(s):

Brain Connectivity ◽

Demographic Data ◽

Strong Association ◽

Early Adulthood ◽

Well Being ◽

Self Report ◽

Multivariate Statistical ◽

Functional Brain ◽

Clinically Depressed ◽

Critical Developmental Period

AbstractUnderstanding how variations in dimensions of psychometrics, IQ and demographics relate to changes in brain connectivity during the critical developmental period of adolescence and early adulthood is a major challenge. This has particular relevance for mental health disorders where a failure to understand these links might hinder the development of better diagnostic approaches and therapeutics. Here, we investigated this question in 306 adolescents and young adults (14-24y, 25 clinically depressed) using a multivariate statistical framework, based on canonical correlation analysis (CCA). By linking individual functional brain connectivity profiles to self-report questionnaires, IQ and demographic data we identified two distinct modes of covariation. The first mode mapped onto an externalization/internalization axis and showed a strong association with sex. The second mode mapped onto a well-being/distress axis independent of sex. Interestingly, both modes showed an association with age. Crucially, the changes in functional brain connectivity associated with changes in these phenotypes showed marked developmental effects. The findings point to a role for the default mode, frontoparietal and limbic networks in psychopathology and depression.

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Brain-Dead and Coma Patients Exhibit Different Serum Metabolic Profiles: A Novel Diagnostic Approach in Neurocritical Care

10.21203/rs.3.rs-451161/v1 ◽

2021 ◽

Author(s):

Tomasz Dawiskiba ◽

Wojciech Wojtowicz ◽

Badr Qasem ◽

Marceli Łukaszewski ◽

Karolina Anna Mielko ◽

...

Keyword(s):

Brain Death ◽

Neurocritical Care ◽

Clinical Symptoms ◽

Proton Nuclear Magnetic Resonance ◽

Sample Collection ◽

Serum Samples ◽

Multivariate Statistical ◽

Brain Death Diagnosis ◽

Brain Dead ◽

Metabolomic Approach

Abstract There is a clear difference between severe brain damage and brain death. However, in clinical practice, the differentiation of these states can be challenging. Currently, there are no laboratory tools that facilitate brain death diagnosis. The aim of our study was to evaluate the utility of serum metabolomic analysis in differentiating coma patients (CP) from individuals with brain death (BD). Serum samples were collected from 23 adult individuals with established diagnosis of brain death and 24 patients in coma with Glasgow Coma Scale 3 or 4, with no other clinical symptoms of brain death for at least 7 days after sample collection. Serum metabolomic profiles were investigated using proton nuclear magnetic resonance (NMR) spectroscopy. The results obtained were examined by univariate and multivariate data analysis (PCA, PLS-DA, and OPLS-DA). Metabolic profiling allowed us to quantify 43 resonance signals, of which 34 were identified. Multivariate statistical modeling revealed a highly significant separation between coma patients and brain-dead individuals, as well as strong predictive potential. The findings not only highlight the potential of the metabolomic approach for distinguishing patients in coma from those in the state of brain death but also may provide an understanding of the pathogenic mechanisms underlying these conditions.

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Colonic necrosis of vague aetiology presenting scarce clinical and radiological symptoms: a case report

Pomeranian Journal of Life Sciences ◽

10.21164/pomjlifesci.721 ◽

2020 ◽

Vol 66 (3) ◽

Author(s):

Andrzej Żyluk ◽

Wojciech Jagielski

Keyword(s):

Clinical Symptoms ◽

Traumatic Shock ◽

End Stage Renal Failure ◽

Abdominal Disease ◽

Colonic Necrosis ◽

Angio Ct ◽

Post Traumatic ◽

Terminal Ileostomy ◽

End Stage ◽

Biochemical Abnormalities

Spontaneous colonic necrosis is very uncommon in a patient without predisposed disorders such as end-stage renal failure in dialysed patients, serious cardiac failure, sepsis, post-traumatic shock, and vascular surgery within an abdominal aorta. This paper presents the case of an elderly patient in whom necrosis of almost the whole colon had occurred within 2 days. At presentation the patient had no clinical symptoms or signs suggesting serious abdominal disease. There was also a lack of biochemical abnormalities and changes in angio-CT. Due to deterioration of the patient’s general condition, he underwent surgery which revealed necrosis of almost the whole colon. The necrotic colon was resected, followed by a terminal ileostomy. Despite the operation, the patient died 2 days after.

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Sex Differences in Biomarkers Associated With Insulin Resistance in Obese Adolescents: Metabolomic Profiling and Principal Components Analysis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2014-2080 ◽

2014 ◽

Vol 99 (12) ◽

pp. 4730-4739 ◽

Cited By ~ 53

Author(s):

Dorothee Newbern ◽

Pinar Gumus Balikcioglu ◽

Metin Balikcioglu ◽

James Bain ◽

Michael Muehlbauer ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Uric Acid ◽

Fatty Acid ◽

Acid Oxidation ◽

Z Score ◽

Obese Adolescents ◽

Metabolic Signature ◽

Components Analysis

Objective Obesity and insulin resistance (IR) predispose to type 2 diabetes mellitus. Yet only half of obese adolescents have IR and far fewer progress to type 2 diabetes mellitus. We hypothesized that amino acid and fatty acid metabolites may serve as biomarkers or determinants of IR in obese teens. Research Design and Methods Fasting blood samples were analyzed by tandem mass spectrometry in 82 obese adolescents. A principal components analysis and multiple linear regression models were used to correlate metabolic components with surrogate measures of IR: homeostasis model assessment index of insulin resistance (HOMA-IR), adiponectin, and triglyceride (TG) to high-density lipoprotein (HDL) ratio. Results Branched-chain amino acid (BCAA) levels and products of BCAA catabolism were higher (P < .01) in males than females with comparable body mass index (BMI) z-score. In multivariate analyses, HOMA-IR in males correlated positively with BMI z-score and a metabolic signature containing BCAA, uric acid, and long-chain acylcarnitines and negatively with byproducts of complete fatty acid oxidation (R2 = 0.659, P < .0001). In contrast, only BMI z-score correlated with HOMA-IR in females. Adiponectin correlated inversely with BCAA and uric acid (R2 = 0.268, P = .0212) in males but not females. TG to HDL ratio correlated with BMI z-score and the BCAA signature in females but not males. Conclusions BCAA levels and byproducts of BCAA catabolism are higher in obese teenage boys than girls of comparable BMI z-score. A metabolic signature comprising BCAA and uric acid correlates positively with HOMA-IR in males and TG to HDL ratio in females and inversely with adiponectin in males but not females. Likewise, byproducts of fatty acid oxidation associate inversely with HOMA-IR in males but not females. Our findings underscore the roles of sex differences in metabolic function and outcomes in pediatric obesity.

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