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Background: The global incidence of hypertension, a condition of elevated blood pressure, is rising alarmingly. According to the World Health Organization's Qatar Hypertension Profile for 2023, around 33% of adults are affected by hypertension. This is a significant public health concern that can lead to serious health complications if left untreated. Metabolic dysfunction is a primary cause of hypertension. By studying key biomarkers, we can discover new treatments to improve the lives of those with high blood pressure. Aims: This study aims to use explainable artificial intelligence (XAI) to interpret novel metabolite biosignatures linked to hypertension in Qatari Population. Methods: The study utilized liquid chromatography-mass spectrometry (LC/MS) method to profile metabolites from biosamples of Qatari nationals diagnosed with stage 1 hypertension (n = 224) and controls (n = 554). Metabolon platform was used for the annotation of raw metabolite data generated during the process. A comprehensive series of analytical procedures, including data trimming, imputation, undersampling, feature selection, and biomarker discovery through explainable AI (XAI) models, were meticulously executed to ensure the accuracy and reliability of the results. Results: Elevated Vanillylmandelic acid (VMA) levels are markedly associated with stage 1 hypertension compared to controls. Glycerophosphorylcholine (GPC), N-Stearoylsphingosine (d18:1/18:0)*, and glycine are critical metabolites for accurate hypertension prediction. The light gradient boosting model yielded superior results, underscoring the potential of our research in enhancing hypertension diagnosis and treatment. The model's classification metrics: accuracy (78.13%), precision (78.13%), recall (78.13%), F1-score (78.13%), and AUROC (83.88%) affirm its efficacy. SHapley Additive exPlanations (SHAP) further elucidate the metabolite markers, providing a deeper understanding of the disease's pathology. Conclusion: This study identified novel metabolite biomarkers for precise hypertension diagnosis using XAI, enhancing early detection and intervention in the Qatari population. [ABSTRACT FROM AUTHOR]

The incidence of congenital neuroblastoma has increased in the recent years. The purpose of this study was to describe the clinical and biochemical characteristics of cases of congenital neuroblastoma diagnosed in our center.

The incidence of congenital neuroblastoma has increased in the recent years. The purpose of this study was to describe the clinical and biochemical characteristics of cases of congenital neuroblastoma diagnosed in our center. We report three cases of congenital neuroblastoma diagnosed in our hospital. In two, diagnosis was made prenatally, whereas the other case was detected in the immediate neonatal period. In the three cases, neuroblastoma was located in the abdominal region and exhibited elevated concentrations of catecholamines or their metabolites in single voided urine samples. Two tumors were classified as stage M, and one as stage L2. The N-MYC oncogen was not amplified in any of the cases studied. Histopathological analysis was favorable in the three cases. The tumor was resected in two patients. The three received chemotherapy. The measurement of catecholamines and their metabolites is essential in the diagnosis of neuroblastoma. When 24 h urine cannot be collected, single voided urine can be used to calculate the index based on creatinine concentrations. [ABSTRACT FROM AUTHOR]

Objective: To validate urinary Vanillylmandelic acid (VMA) for screening adrenal medullary disorders, taking plasma-free Metanephrine as the gold standard. Study Design: Cross-sectional validation study. Place and Duration of Study: Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, Rawalpindi, in collaboration with Armed Forces Institute of Urology, Rawalpindi from Pakistan, Jan 2020 to Mar 2021. Methodology: One hundred and thirty (130) symptomatic hypertensive patients with adrenal masses on ultrasound were selected Urine and blood samples were collected under specified conditions after taking necessary precautions and subsequently analyzed. Taking plasma Metanephrine as a reference, sensitivity, specificity and predictive values were calculated at predefined cut-off values. Results: In a young population with a mean age of 28.55±5.54 years, headache, palpitations and sweating were the predominant symptoms having a frequency of 130(100%), 116(89.2%) and 111(85.4%), respectively. Twenty-four hours urinary Vanillylmandelic acid had lower sensitivity (66.3%) than a random urinary VMA/cr ratio (72.1%) but similar specificity (97.7%). On the other hand, plasma-free Normetanephrine had 100% sensitivity but lower specificity (93.2%). ROC curve was plotted, and AUC for 24 hours urinary VMA, urinary VMA/cr ratio and plasma-free Normetanephrine were 0.820, 0.849 and 0.966, respectively. Conclusion: Plasma-free Metanephrine could be used for screening pheochromocytoma and other adrenal medullary disorders like paraganglionoma. In addition, VMA/cr ratio can be used for biochemical confirmation of the disease owing to the high specificity found in our study. [ABSTRACT FROM AUTHOR]

On-site monitoring of vanillylmandelic acid (VMA), homovanillic acid (HVA), and dopamine (DA) as key diagnostic biomarkers for a wide range of neurological disorders holds utmost significance in clinical settings. Numerous colorimetric sensors with mechanistic approaches based on aggregation or silver metallization have been introduced for this purpose. However, these mechanisms have drawbacks, such as sensitivity to environmental factors and probe toxicity. Therefore, there is a great demand for a robust yet non-toxic colorimetric sensor that employs a novel route to monitor these biomarkers effectively. Here, we present a single-component multi-colorimetric probe based on the controllable etching suppression of gold nanorods (AuNRs) upon exposure to the mild etchant N-bromosuccinimide (NBS), designed to accurately detect and discriminate VMA, HVA, DA, and their corresponding mixtures, i.e., VMA:HVA, VMA:DA, HVA:DA, and VMA:HVA:DA. To enhance the sensitivity and automation capabilities of the designed multi-colorimetric sensor, two machine learning techniques were employed: linear discriminant analysis (LDA) for the qualitative classification and partial least-squares regression (PLSR) for the quantitative analysis of pure biomarkers and their mixtures. The outcomes revealed a high correlation between measured and predicted values, covering a linear range of 0.8–25, 1.2–25, and 2.7–100 μmol L−1, with remarkably low detection limits of 0.260, 0.397, and 0.913 μmol L−1 for VMA, HVA, and DA, respectively. Lastly, the performance of the probe was validated by successfully detecting the neuroblastoma biomarker VMA:HVA in human urine. Our designed multi-colorimetric probe introduces a rapid, cost-effective, user-friendly, non-toxic, and non-invasive approach to detecting and discriminating not only the pure biomarkers but also their corresponding binary and ternary mixtures. The distinctive response profiles produced by the probe in the presence of different mixture ratios can indicate various disease states in patients, which is highly crucial in clinical diagnostics. [Display omitted] • The multi-colorimetric probe is based on the controllable etching suppression of gold nanorods (AuNRs). • A probe has been developed for multiplex analysis of neuroblastoma biomarkers. • The etching of AuNRs results in a blue shift in the longitudinal localized surface plasmon resonance (LLSPR) peak. • Sharp color variations from pink to brownish-orange of the probe facilitate the visual tracking of biomarkers. • Machine learning techniques were employed to enhance the reliability of distinguishing biomarkers and their mixtures. [ABSTRACT FROM AUTHOR]

Objective: To validate urinary Vanillylmandelic acid (VMA) for screening adrenal medullary disorders, taking plasma-free Metanephrine as the gold standard. Study Design: Cross-sectional validation study. Place and Duration of Study: Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology,Rawalpindi, in collaboration with Armed Forces Institute of Urology, Rawalpindi from Pakistan, Jan 2020 to Mar 2021. Methodology: One hundred and thirty (130) symptomatic hypertensive patients with adrenal masses on ultrasound were selected Urine and blood samples were collected under specified conditions after taking necessary precautions and subsequently analyzed. Taking plasma Metanephrine as a reference, sensitivity, specificity and predictive values were calculated at predefined cut-off values. Results: In a young population with a mean age of 28.55±5.54 years, headache, palpitations and sweating were the predominant symptoms having a frequency of 130(100%), 116(89.2%) and 111(85.4%), respectively. Twenty-four hours urinary Vanillylmandelic acid had lower sensitivity (66.3%) than a random urinary VMA/cr ratio (72.1%) but similar specificity(97.7%). On the other hand, plasma-free Normetanephrine had 100% sensitivity but lower specificity (93.2%). ROC curve was plotted, and AUC for 24 hours urinary VMA, urinary VMA/cr ratio and plasma-free Normetanephrine were 0.820, 0.849 and0.966, respectively. Conclusion: Plasma-free Metanephrine could be used for screening pheochromocytoma and other adrenal medullary disorders like paraganglionoma. In addition, VMA/cr ratio can be used for biochemical confirmation of the disease owing to the high specificity found in our study.

Background: Bilateral tumors in double organs like bilateral adrenal neuroblastoma are highly rare. Few cases have been reported in the literature. Case reports: A full-term male infant, 11 months old, had an abdominal mass diagnosed by triphasic abdominal CT as bilateral adrenal neuroblastoma. The case was stage 1, and the management was bilateral adrenalectomy. Discussion: When the neuroblastoma mass measures less than 5 cm in diameter, the infant can likely be safely supervised without cytoreduction surgery or histological confirmation of the tumor, but if the tumour progressively increases in size or the size is greater than 5 cm, then surgery is essential. Conclusion: Surgery is the best option when an infant has bilateral large localized adrenal neuroblastoma.

This is a case of a 3 year old male with a free floating neuroblastic tumor in the abdomen that was unattached to any organs. A focused comprehensive literature search was conducted, which yielded no results for a case with this presentation.This case involves a 3 year old male who presented to the emergency department after 3 days of vomiting (projectile, non-bloody, non bilious) after every meal. The patient complained of generalized abdominal pain that resolves after vomiting, and a mass was palpated in the left lower quadrant (LLQ), consistent with ultrasound findings that showed a 7 cm discrete mass medial to the spleen and superior to the left kidney.Surgical resection of ganglioneuroblastoma is typically curative and has low complication rates. During clinical follow up for this patient, patient had no subsequent symptoms suspicious of recurrence. Thus, we hypothesize that because his tumor was free-floating, this could possibly be a contributing factor for him to continue to stay disease free in the future. This is the first reported case of a free floating abdominal ganglioneuroblastoma. This unique feature can present special considerations surgically and have an impact on symptom presentation and prognosis.

Neuroblastoma (NB), an embryonic tumor of the autonomous nervous system, poses a significant threat to the health and lives of children. Accurate measurement of vanillylmandelic acid (VMA) and homovanillic acid (HVA) in human urine is crucial for screening and diagnosis of NB. Although various laboratories have developed liquid chromatography tandem mass spectrometry (LC-MS/MS) method to detect VMA and HVA, the comparability between the results obtained from different laboratories and methods was poor. The absence of reference method for VMA and HVA hinders the standardization of their measurements. Therefore, a candidate reference measurement procedure (cRMP) based on isotope dilution LC-MS/MS (ID-LC-MS/MS) for the detection of VMA and HVA in human urine was established. Urine samples were spiked with VMA-d3 and HVA-d5 as internal standards and extracted using a protein precipitation method. The cRMP exhibited desirable precision with the total imprecision below 5 %. The accuracy of this cRMP was demonstrated by the high analytical recovery (98.64 % - 102.22 % and 98.41 % - 100.97 % for VMA and HVA, respectively), and comparability between different reference systems. The limit of detection for HVA and VMA were 15.625 ng/mL and 3.906 ng/mL, respectively; the quantification limits were 62.5 ng/mL and 7.813 ng/mL, respectively, which can meet the clinical detection requirements. The linear range was from 78.125 ng/mL to 20 μg/mL. Specificity evaluations showed no corresponding interference from structurally similar analogs. In conclusion, we have established a cRMP based on ID-LC-MS/MS for the measurement of VMA and HVA in urine samples, demonstrating well-defined method performance including accuracy, precision, and specificity. This newly established cRMP is suitable for routine assay standardization and evaluation of clinical samples. Furthermore, this method has the potential to significantly enhance the diagnostic accuracy for neuroblastoma. • The cRMP has been developed for the measurement of urine HVA and VMA. • A multiple-site method comparison with clinical samples is presented. • The newly established cRMP displayed desirable method performance. [ABSTRACT FROM AUTHOR]

Rationale: Melanotic neuroectodermal tumour of infancy (MNTI) is universally described as a rare, benign, pigmented lesion which most frequently involves the maxilla. Its origin is well established to be in the neural crest cells. Due to the high recurrence rate and aggressive behaviour mimicking malignancy, it poses a great challenge in their diagnosis, treatment planning, and prognosis. Patient Concern: Two-year-old female with no known comorbidities was brought in with the chief complaint of a growing swelling in the upper lip region. Diagnosis and Treatment: She was taken up for resection of the tumour under general anaesthesia. The specimen was subjected to histological and immunological examination confirming the diagnosis of MNTI. Outcome: The postoperative period was uneventful. After regular follow-up, the patient showed satisfactory healing with no signs of recurrence. Take-Away Lessons: Based on our experience, we feel that the diagnosis of MNTI is mainly clinical. Early conservative surgical excision and regular follow-up provide an excellent result with good prognosis. [ABSTRACT FROM AUTHOR]

Abstract Vanillylmandelic acid (VMA) is one of the most important catecholamine metabolites, and it is usually used to aid in diagnosis of pheochromocytoma and paraganglioma. A new digital control microextraction by packed sorbent (MEPS) procedure coupled to liquid chromatography-mass spectrometry (LC-MS/MS) method has been developed to determine VMA in human urine. We evaluated important parameters influencing MEPS efficiency, including stationary phase, extracting cycles, and sample dilution. In optimized MEPS conditions, Only 10 μL of sample volume and 3 min preparation time for one sample were needed. Chromatographic separation was achieved with a hydrophilic interaction liquid chromatography (HILIC) column using gradient elution. VMA was detected using multiple reaction monitoring (MRM) with an electrospray source operating in negative ion mode. The method was validated for linearity, limit of quantification, accuracy, imprecision, matrix effect, and interference. Linearity was 0.5–100 μg/mL for VMA. Intra-assay, inter-assay, and total imprecision were less than 9.6%. Interferences precluding quantitation of VMA in dilute-and-shoot approach were reduced significantly using a MEPS approach. Method comparison of LC-MS/MS and homogeneous enzyme immunoassay was performed, and the reference interval was established. The developed MEPS-LC-MS/MS method certainly contributes to method robustness and makes it suitable for measurement of urinary VMA in routine clinical biochemistry laboratories.

Ayurveda uses seeds of Celastrus paniculatus to treat various stress related disorders. In the present investigation, the hydroalcoholic seed extract of C. paniculatus was evaluated for anti-stress activity by forced swim stress model. Vanillylmandelic acid and ascorbic acid were selected as non-invasive biomarkers to assess the anti-stress activity. Nootropic activity in rats was evaluated by conditioned avoidance response using Cook's pole climbing apparatus, the antioxidant potential was determined based on the ability of the extract to scavenge hydroxyl radicals. Pretreatment with the extract significantly (p < 0.05) inhibited the stress induced urinary biochemical levels. The cognition was observed to be dose dependent. The extract also produced significant dose dependent inhibition of hydroxyl radicals. The present study provides scientific support for the anti-stress, antioxidant and nootropic activities of hydroalcoholic seed extract of C. paniculatus and substantiates the traditional claims for the usage of C. paniculatus willd. in stress induced disorders. [ABSTRACT FROM AUTHOR]

• We studied preanalytical stability of 9 currently measured biogenic amines in urine. • Stabilization by sodium citrate and HCl were compared with native urine. • Biogenic amines except epinephrine are stable in citrate urines four weeks at 22 °C. • HCl does not prevent 5-HIAA and catecholamine degradation. • Sodium citrate is non-hazardous to handle for patients. Urinary 5-hydroxyindoleacetic acid (5-HIAA), vanillylmandelic (VMA), homovanillic acid (HVA), catecholamines and metanephrines are produced in excess by catecholamine-producing tumors. These biogenic amines are unstable at low or high pH and require hydrochloric acid (HCl) to prevent their degradation. However, HCl addition may result in very low pH causing degradation or deconjugation of several metabolites. This study evaluated the buffering properties of sodium citrate to stabilize all biogenic amines. The metabolite concentrations were measured by LC-MS/MS or by a coulometric assay in 22 urine samples collected native and with HCl or sodium citrate. We studied the effect of pH, time (48 h, four weeks) and storage temperature at 22 °C, 4 °C, and −20 °C. We found that catecholamines degradation was prevented by HCl and citrate and that 5-HIAA was degraded in 5 out of 22 samples collected with HCl. All biogenic amines were efficiently stabilized by citrate for four weeks at 22 °C, except epinephrine (48 h at 4 °C, or four weeks at −20 °C). Sodium citrate did not cause quantification or analytical artefacts concerns. In conclusion, sodium citrate is a non-hazardous alternative to HCl for patients to send unfrozen urine samples to the laboratory which may safely store the sample for four weeks. [ABSTRACT FROM AUTHOR]

Objective  The aim of the study is to determine the surgical candidacy and nuances of skull base paraganglioma surgery in the era of radiotherapy. Materials and Methods  This was a retrospective observational study conducted in patients who presented with skull base paragangliomas between January 2017 and December 2019. Primary data, including indication for surgery, the approach used, the extent of resection, complications, and postoperative lower cranial nerve status were studied. Results  A total of 21 cases of skull base paragangliomas were analyzed, including seven cases of tympanic paraganglioma, 10 cases of jugular foramen paraganglioma, three cases of multiple paragangliomas, and one case of vagal paraganglioma. Indications for surgery were young age, bleeding from ear, neck mass with upper aerodigestive pressure symptoms, lower cranial nerve paralysis, and patients with intracranial pressure symptoms. Total excision was done in 11 patients, near-total excision in five patients, subtotal in three patients, and surgery was not done in two patients. Facial nerve paralysis was the most common complication observed, followed by bleeding and flap necrosis. Radiotherapy was considered as adjuvant treatment wherever indicated. Conclusion  A thorough knowledge and understanding of the pathophysiology of the skull base paragangliomas and its management strategies can help to achieve excellent results in terms of tumor clearance and reduction in complications. A multidisciplinary team approach and meticulous skull base surgical techniques have a significant role to play in the management of paragangliomas, especially in developing countries where availability of radiosurgery is still a challenge. [ABSTRACT FROM AUTHOR]

Vanillylmandelic acid (VMA) is one of the most important catecholamine metabolites, and it is usually used to aid in diagnosis of pheochromocytoma and paraganglioma. A new digital control microextraction by packed sorbent (MEPS) procedure coupled to liquid chromatography-mass spectrometry (LC-MS/MS) method has been developed to determine VMA in human urine. We evaluated important parameters influencing MEPS efficiency, including stationary phase, extracting cycles, and sample dilution. In optimized MEPS conditions, Only 10 μL of sample volume and 3 min preparation time for one sample were needed. Chromatographic separation was achieved with a hydrophilic interaction liquid chromatography (HILIC) column using gradient elution. VMA was detected using multiple reaction monitoring (MRM) with an electrospray source operating in negative ion mode. The method was validated for linearity, limit of quantification, accuracy, imprecision, matrix effect, and interference. Linearity was 0.5–100 μg/mL for VMA. Intra-assay, inter-assay, and total imprecision were less than 9.6%. Interferences precluding quantitation of VMA in dilute-and-shoot approach were reduced significantly using a MEPS approach. Method comparison of LC-MS/MS and homogeneous enzyme immunoassay was performed, and the reference interval was established. The developed MEPS-LC-MS/MS method certainly contributes to method robustness and makes it suitable for measurement of urinary VMA in routine clinical biochemistry laboratories. [ABSTRACT FROM AUTHOR]

Abstract Background Exposure to polychlorinated biphenyls (PCBs) is associated with depressive symptomatology. A cause of depressive symptoms is a disturbance in the neurotransmitter system of dopamine (DA). Animal as well as human studies report that PCBs can influence the DA system. This study examined whether PCB-related depressive symptoms are affected by DA metabolites in humans with high PCB body burden. Methods This study is part of the German HELPcB surveillance program (Health Effects in high Level exposure to PCB) for occupationally exposed workers and their relatives. Data was collected from 178 participants on two measurement time points (t1 and t2) with a one-year time lag in between the two time points. PCBs were analyzed in plasma via human biomonitoring and a validated questionnaire was used to identify existence and severity of depressive symptoms. As a surrogate for DA, we measured its metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) in urine. Mediation analyses were performed to test whether the association between PCB exposure and severity of depressive symptoms is mediated by urinary concentration of DA metabolites HVA and VMA. The mediation was tested with the SPSS macro MEDIATE. Results We found a significant mediation over time for lower-chlorinated, higher-chlorinated and dioxin-like PCBs. The positive association between PCB exposure with severity of depressive symptoms was mediated by the main DA metabolite HVA. At t1 a higher exposure with PCBs was associated with lower concentration in urinary HVA. A reduced HVA concentration at t1 was correlated with increased depressive symptoms severity at t2. No meditations were found for VMA. Conclusions This work indicates that the association of PCB exposure and an increase of depressive symptoms after one year is mediated by the DA metabolite HVA as a surrogate for DA. These are first steps towards finding an explanation for an underlying neurochemical pathomechanism of PCB-related depressive symptomatology.

Homovanillic acid (HVA) and vanillylmandelic acid (VMA) are end-stage metabolites of catecholamine and are clinical biomarkers for the diagnosis of neuroblastoma. For the first time in Korea, we implemented and validated a liquid chromatography tandem mass spectrometry (LC–MS/MS) assay to measure urinary concentrations of HVA and VMA according to Clinical and Laboratory Standards Institute guidelines. Our LC–MS/MS assay with minimal sample preparation was validated for linearity, lower limit of detection (LOD), lower limit of quantification (LLOQ), precision, accuracy, extraction recovery, carryover, matrix effect, and method comparison. A total of 1209 measurements was performed to measure HVA and VMA in spot urine between October 2019 and September 2020. The relationship between the two urinary markers, HVA and VMA, was analyzed and exhibited high agreement (89.1% agreement, kappa’s k = 0.6) and a strong correlation (Pearson’s r = 0.73). To our knowledge, this is the first study to utilize LC–MS/MS for simultaneous quantitation of spot urinary HVA and VMA and analyze the clinical application of both markers on a large scale for neuroblastoma patients.

A new method for the simultaneous determination of two tumour biomarkers, homovanillic (HVA) and vanillylmandelic acid (VMA), using flow injection analysis (FIA) with amperometric detection (AD) at a commercially available boron doped diamond electrode (BDDE) was developed. It was found that this method is suitable for the determination of HVA (in the presence of VMA) and VMA (in the presence of HVA) in optimum medium of Britton-Robinson buffer (0.04 mol L−1, pH 3.0). Calibration dependences consist of two linear parts for both biomarkers, the first one being in the concentration range from 1 to 10 μmol L−1 and the second one from 10 to 100 μmol L−1 (with obtained LOD s 0.44 μmol L−1 for HVA and 0.34 μmol L−1 for VMA, respectively). To minimize any negative effects related to the passivation of the working electrode, suitable cleaning pulses (+2.4 V for 30 s) were imposed on the working electrode after each measurement. An attempt to use FIA with multiple pulse amperometric detection to determine both analytes in one run was not successful. Changing potentials in short intervals in multiple pulse detection probably results in mutual interaction of analytes and/or products of their electrochemical oxidation, thus preventing the application of this approach. Image 1 • FIA at boron doped diamond electrode was used for the first time for determination of tumour biomarkers HVA and VMA in mixture. • Electrode passivation was successfully eliminated by imposing suitable cleaning pulses on the working electrode. • The limit of detection for both studied analytes is in the submicromolar concentration range. [ABSTRACT FROM AUTHOR]

Vanillylmandelic acid, a catecholamine end-metabolite, has been shown to have several biological properties in previous studies, despite considered biologically inactive. We examined the potential effects of vanillylmandelic acid on the ischemic heart following myocardial infarction and reperfusion on a rat model. Thirty-four female Wistar rats were randomized into two groups, control and experimental. They were anesthetized and subjected to myocardial infarction through left anterior descending artery ligation. A previously studied dose of vanillylmandelic acid (10 mg/kg) was administered and the following parameters were studied during ischemia and reperfusion: a) mortality b) severity of ventricular tachyarrhythmias c) premature ventricular contractions and d) heart rate. Administration of vanillymandelic acid significantly reduced the severity of ventricular tachyarrhythmias and mortality rate during reperfusion, while it did not affect any other of the parameters studied. In conclusion, reperfusion injury was blunted through vanillylmandelic acid administration, which seems to be mediated by parasympathetic activation. [ABSTRACT FROM AUTHOR]

Several confounders must be considered in the evaluation of urinary catecholamine excretion. However, literature is contradictory about potential confounders. The aim of the present study was to assess correlations between catecholamine excretion and anthropometric or clinical parameters with special attention to urine volume. A total of 967 24-h urinary catecholamine measurements were performed in 593 patients for diagnostic purposes. The indication for urine examination was suspicion of secondary hypertension, phaeochromocytoma, or paraganglioma. From the patients examined, 57% were females and 43% were males. The patients' age ranged between 15 and 87 years with a median [Q1; Q3] of 51 [39; 62] years. Seventy-eight percent of the patients suffered from hypertension. Seventy percent of patients took one or more antihypertensive drugs. The most commonly used drugs were ACE inhibitors (43%), while α-blockers (15%) were the least used drugs. Urinary excretion was between 500 and 11 950 ml/24 h with a median of 2200 [1600; 2685] ml/24 h. The median body mass index (BMI) was 26.7 [24.0; 30.4] kg/m2. The excretion of all catecholamines was greater in men than in women (all p<0.0001). Epinephrine (p=0.0026), dopamine (p<0.0001), and metanephrine (p=0.0106) excretion decreased with age. BMI was associated with urinary excretion of dopamine (p<0.0001), norepinephrine (p=0.0026), normetanephrine (p<0.0001), and homovanillylmandelic acid (HVMA; p=0.0251). Urine volume correlated with urinary dopamine (p=0.0127), metanephrine (p<0.0001), normetanephrine (p=0.0070), and HVMA (p<0.0028) excretion. In addition to the established associations between urinary catecholamine excretion and age, gender, and BMI in the present study, urinary catecholamine excretion correlated also with urine volume. [ABSTRACT FROM AUTHOR]

Methylphenidate is a psychostimulant used for the treatment of (ADHD) attention deficit hyperactivity syndrome in children and adults. After chronic administration it is known to produce behavioral disorders including anxiety. Previous studies demonstrated that co-administration of buspirone can reduce behavioral and cognitive adverse effects produced by methylphenidate. The aim of the present study is to measure the levels vanillylmandelic acid (VMA) excretion in urine following prolong administration of methylphenidate, buspirone and their combination. Samples of urine for the estimation of the urinary VMA excretion were collected from treated and control male Wistar rats. We found significant (P<0.01) raised urinary VMA excretion in methylphenidate group however significant (P<0.01) reduction in VMA levels were seen after buspirone co-administration. Excretion of VMA in urine would allow the monitoring of sympatho-adrenomedullary system activity. This study could be helpful to increase the clinical use of methylphenidate in the treatment of different disoders. [ABSTRACT FROM AUTHOR]

Flow injection analysis with amperometric detection (FIA‐AD) at screen‐printed carbon electrodes (SPCEs) in optimum medium of Britton‐Robinson buffer (0.04 mol ⋅ L−1, pH 2.0) was used for the determination of three tumor biomarkers (homovanillic acid (HVA), vanillylmandelic acid (VMA), and 5‐hydroxyindole‐3‐acetic acid (5‐HIAA)). Dependences of the peak current on the concentration of biomarkers were linear in the whole tested concentration range from 0.05 to 100 μmol ⋅ L−1, with limits of detection (LODs) of 0.065 μmol ⋅ L−1 for HVA, 0.053 μmol ⋅ L−1 for VMA, and 0.033 μmol ⋅ L−1 for 5‐HIAA (calculated from peak heights), and 0.024 μmol ⋅ L−1 for HVA, 0.020 μmol ⋅ L−1 for VMA, and 0.012 μmol ⋅ L−1 for 5‐HIAA (calculated from peak areas), respectively. [ABSTRACT FROM AUTHOR]

In this research, a single-component multi-colorimetric sensor array was developed to simultaneously detect homovanillic acid (HVA) and vanillylmandelic acid (VMA) tumor markers based on their oxidation ability in exposure to silver ions. To this aim, gold nanorods (AuNRs) were used as optical signal transducers. The aspect ratio alterations of AuNRs in response to the concentration of the analytes were achieved by silver shell metallization on the surface of AuNRs. Under optimal conditions, absorbance spectra of the probe and associated vivid color variations were recorded, followed by analysis using a hybrid machine learning classification algorithm to discriminate between HVA, VMA, HVA: VMA along with presumptive interfering compounds (INF). Data was prepared for classification using linear discriminant analysis (LDA), by creating a new space through principal component analysis (PCA). The ideal number of PCs was determined via Leave-Many-Out cross-validation to maximize the classification performance of the model. Besides, partial least squares regression (PLSR), which maximizes covariance between different concentrations of biomarkers, was utilized for quantification. Results indicated that the proposed ML-based sensor array has the potential to diagnose childhood metabolic errors. This is supported by its capability of detecting HVA, VMA, and HVA:VMA concurrently with 100% sensitivity and specificity in human urine samples. Also, a high correlation between predicted and measured values verified the model's exceptional prediction performance with low detection limits of 0.22 μM and 0.29 μM for HVA and VMA, respectively. [Display omitted] • A single-component sensor array has been developed to detect tumor markers at the same time. • Colorimetric fingerprints were generated by AuNRs for identifying HVA and VMA. • A hybrid machine-learning approach was used for qualitative and quantitative evaluations. • The outcomes of prediction in urine sample show good potential for diagnosing metabolic issues of children. [ABSTRACT FROM AUTHOR]

In the present review, we set out a new high-tech method for determining the major metabolites of catecholamines and serotonin in urine. We then discuss the effects of these substances and the value of their main metabolites in normal and various pathological conditions, and show the efficiency of applying this technique in the laboratory diagnosis of several diseases.

Background: Urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) are biomarkers for the diagnosis and follow-up of neuroblastoma, whereas urinary 5-hydroxyindoleacetic acid (5-HIAA) is used to assess a carcinoid tumor. These analytes are conventionally analyzed in a single run by chromatography (LC) coupled with electrochemical detection (LC-ECD) using commercial kits. A rapid dilute-and-shoot LC tandem mass spectrometry (LC-MS/MS) assay was validated in order to replace the LC-ECD method and therefore improve analytical specificity and throughput. Methods: Sample preparation was carried out by dilution of the urine sample with a solution containing the deuterated internal standards. The separation was achieved on an ultra-high pressure LC system with MS detection using a triple quadrupole mass spectrometer. The method was validated according to the current EMA and FDA guidelines. Results: The full chromatographic run was achieved in 8 min. The method validation showed excellent linearity (r² > 0.999 for all three analytes), precision (CV <15%), negligible matrix effect (recoveries >90%), low carryover (<1%) and LLOQ of 0.25, 0.4 and 0.4 µM for VMA, HVA and 5-HIAA, respectively. Deming fits and Bland-Altman analyses showed no significant differences between the values obtained between the two assays. Conclusions: The LC-MS/MS method proposed in this study is fast and robust, and the simple sample preparation saves time and avoids the additional costs of dedicated kits used for the LC-ECD assays by switching to LC-MS/MS. Additionally, the near-perfect correlation observed herein between both assays allows the previously established reference ranges to be maintained. [ABSTRACT FROM AUTHOR]

The electrochemical behaviour of two main catecholamine metabolites serving as diagnostic tumour biomarkers, homovanillic acid (HVA) and vanillylmandelic acid (VMA), on anodically oxidized boron doped diamond (BDD) electrodes, non-modified glassy carbon electrodes (GCE), and GCE modified by polymers, namely by Nafion (Nafion/GCE) and by poly(neutral red) (PNR/GCE), was investigated. The voltammetric responses of both biomarkers are strongly dependent on pH of the aqueous buffer solution and electrode material used. BDD electrodes exhibit more positive oxidation potentials and lower current densities for oxidation of both analytes, depending also on the surface termination. Concentration dependences were measured in 0.1 mol L −1 phosphate buffer pH 3.0, as optimal supporting electrolyte for differential pulse voltammetric determination. Achieved detection limits were 0.6, 0.9, 0.8, and 1.2 μmol L −1 for HVA and 0.4, 1.5, 2.4, and 1.1 μmol L −1 for VMA at BDD electrodes, non-modified GCE, Nafion/GCE, and PNR/GCE, respectively. The limits of quantification for both organic compounds on all tested electrode materials are sufficiently low for their determination in urine. Verification of the possibility of simultaneous voltammetric determination of the studied biomarkers in the mixture was also carried out. [ABSTRACT FROM AUTHOR]

Vanillylmandelic acid (VMA), an important metabolite of catecholamines that is routinely screened as tumor marker, was investigated by the various spectroscopic techniques (IR, Raman, UV–Vis, antioxidant decolorization assay and NMR). Structures optimized by the employment of five common functionals (M05-2X, M06-2X, B3LYP, CAM-B3LYP, B3LYP-D3) were compared with the crystallographic data. The M05-2X functional reproduced the most reliable experimental bond lengths and angles (correlation coefficient >0.999). The importance of intramolecular hydrogen bonds for structural stability was discussed and quantified by the NBO analysis. The most prominent bands in vibrational spectrum were analyzed and compared to the experimental data. The positions of the carbon and hydrogen atoms in NMR spectra were well reproduced. The differences in UV–Vis spectrum were investigated by adding the explicit solvent and by performing NBO and QTAIM analyses. The discrepancy in the two spectra of about 50 nm could be explained by the solvent effect on carboxyl group. The most probable antioxidant activity mechanism was discussed for VMA and its carboxylate anion. The Molecular Docking study with the C - reactive protein additionally proved that variety of functional groups present in VMA and its anion allowed strong hydrogen and hydrophobic interactions. [ABSTRACT FROM AUTHOR]

Background & objectives: Vitiligo is an acquired skin disease characterized by depigmented areas of the skin. Increased release of catecholamines from autonomic nerve endings in microenvironment of melanocytes in affected skin might be involved in the aetiopathogenesis of vitiligo. Levels of catecholamines are considered as being related to onset or worsening of the disease. Therefore, in this study, the role of catecholamines was evaluated in mapping disease stability and outcome of vitiligo patients undergoing melanocyte transfer. Methods: In this study, circulatory and urinary levels of catecholamine (CA) and vanillylmandelic acid (VMA) were determined in 45 individuals (30 vitiligo patients and 15 healthy controls) using ELISA. Results: A significant increase for plasma and urinary catecholamines along with VMA was observed as compared to healthy controls. When the pre- and post-intervention levels were analyzed in responders and non-responders, respectively, only dopamine showed significant decline in urine, rest of the molecules in plasma as well as urine showed non-significant decline except VMA which showed insignificant increase. Interpretation & conclusions: Levels of plasma/urinary epinephrine, and plasma dopamine, could not be established as biomarkers for disease stability or successful outcome of autologous melanocyte transfer in generalized vitiligo patients. However, dopamine (urine) might be of help in determining the stability in patients with generalized vitiligo undergoing melanocyte transfer. Further studies need to be done on a large sample of patients to confirm our findings. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) accounts for 10% of pediatric malignancies. Urinary vanillylmandelic acid (VMA) and urinary homovanillic acid (HVA) are the most commonly measured in the diagnosis of NB. The aim of this study was to evaluate the performance of urinary VMA and HVA assay for the diagnosis of NB and to determine diagnostic cuts-off values. A retrospective chart review was performed. We analyzed the medical records of 70 patients admitted for suspicion of NB in an Oncology Unit of Pediatric Department from 2007 to 2012. We measured urine catecholamine metabolites using high-performance liquid chromatography with electrochemical detection in the department of Biochemistry Laboratory at Institut Pasteur of Tunis. The patients were divided into two groups: a NB group (n=25) with a histologically-proven NB and a control group (n=45). Receiver Operating Characteristic (ROC) curves were used to determine the best sensitivities and specificities. The median age of the population was 18.5 months [min=5, max=156]. The analysis of biological parameters showed that means and standard deviations of urinary VMA and HVA in NB group were significantly higher than those of the control group (p= 0.023 and p = 0.028 respectively). In infants under than 1 year, the sensitivity and specificity of urinary VMA were 83% and 77% respectively for a cut-off value of 21.5 µmol/mmol creatinine. In children over 1 year, the sensitivity and specificity of urinary VMA were 79% and 65% respectively for a cut-off value of 17.5 µmol/mmol creatinine. No significant correlations were found between the urinary levels of VMA and HVA and the site of the tumor as well as the tumor stage and the presence of metastasis. These data confirm the diagnostic utility of urinary VMA and HVA. The analysis of other catecholamine metabolites ensures the highest sensitivity to diagnose NB patients. [ABSTRACT FROM AUTHOR]

Melanotic neuroectodermal tumor of infancy is a rare benign but locally aggressive neoplasm of neural crest origin with a high recurrence rate. It usually affects infants of <1 year of age. Involvement of maxilla of an infant is the most common presentation although cases outside this setting have been reported. We report the case of a 6-month-old male child presenting with intraoral swelling. Radiologically, a tumor was detected in the right maxilla, and wide local excision was done. Histological examination revealed typical biphasic population of cells with deposits of melanin pigment. Immunohistochemistry study was done confirming the diagnosis. [ABSTRACT FROM AUTHOR]

Background and objectives: Autism Spectrum Disorder (ASD) is a complex neuro-developmental disorder and it has been suggested that symptoms of ASD are associated with neural networks that regulate the Autonomic Nervous System (ANS). However, the nature of autonomic atypicalities in ASDs remain largely unknown. Measures like Heart Rate Variability (HRV) and urinary Vanillylmandelic Acid (VMA) estimation are sensitive and non-invasive physiological and biochemical indicators of autonomic nervous activity. This study aimed to compare the physiological and biochemical autonomic indices in children with and without ASD. Materials and Methods: In this case-control study, 40 children with autism and 40 Typically Developing (TD) children were recruited. Measures of physiological autonomic index were assessed by the analysis of short term HRV, and the urinary levels of VMA estimation was used as a biochemical autonomic index. Results: Cardiac sympathetic activity assessed by Low Frequency (nu) of HRV was significantly higher in the ASD group in comparison with the TD group (p = 0.006). On the contrary, both the High Frequency (abs) and (nu) of HRV were found to be significantly lower in autistic children (p = 0.034 and p = 0.000) than controls. Autistic children also exhibited a significantly higher level (p = 0.049) of VMA concentration compared to TD children. Conclusion: The study concludes that children with ASD exhibit lower cardio-vagal activity as measured by HRV and increased sympathetic activity as assessed by urinary VMA compared to that of TD children. The core autistic symptoms exhibited by children with ASD could be due to the differences in baseline arousal or stress which might be associated with autonomic dysfunction. Further studies are needed to examine the association of this autonomic dysregulation with ASD symptoms and comorbidities.

Background:Suitable biomarkers that have prognostic values are one of the key points of interest in ischaemic stroke. Increased sympathetic nervous system activity in ischaemic stroke causes multiple local and systemic effects that can be detrimental to the outcome. The mechanism of action is increased secretion and activity of catecholamines, whose end metabolic products are vanillylmandelic acid and homovanilic acid. Aim of our study was to determine whether these compounds can be used as potential prognostic biomarkers in ischaemic stroke, as a unique insight into the activity of the sympathetic nervous system. Methods:Urine samples of 96 patients with ischaemic stroke and transitory ischaemic attacks were analysed. Values of vanillylmandelic and homovanillic acids in urine were tested using liquid chromatography on the first and third day post-stroke. Severity of stroke was determined using the NIHSS scale, while functional outcome was determined using the Modified Rankin Scale. Results:Values of vanillylmandelic and homovanillic acids positively correlated with functional outcome of ischaemic stroke. Favorable outcomes correlated with decreased values, on contrary to increased values, which were associated with unfavourable outcomes. Conclusion:Determining the values of these compounds in the urine is an easily available prognostic tool for the ischaemic stroke outcome, while also influencing potential therapeutic changes. [ABSTRACT FROM PUBLISHER]

Background: Exposure to polychlorinated biphenyls (PCBs) is associated with depressive symptomatology. A cause of depressive symptoms is a disturbance in the neurotransmitter system of dopamine (DA). Animal as well as human studies report that PCBs can influence the DA system. This study examined whether PCB-related depressive symptoms are affected by DA metabolites in humans with high PCB body burden.Methods: This study is part of the German HELPcB surveillance program (Health Effects in high Level exposure to PCB) for occupationally exposed workers and their relatives. Data was collected from 178 participants on two measurement time points (t1 and t2) with a one-year time lag in between the two time points. PCBs were analyzed in plasma via human biomonitoring and a validated questionnaire was used to identify existence and severity of depressive symptoms. As a surrogate for DA, we measured its metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) in urine. Mediation analyses were performed to test whether the association between PCB exposure and severity of depressive symptoms is mediated by urinary concentration of DA metabolites HVA and VMA. The mediation was tested with the SPSS macro MEDIATE.Results: We found a significant mediation over time for lower-chlorinated, higher-chlorinated and dioxin-like PCBs. The positive association between PCB exposure with severity of depressive symptoms was mediated by the main DA metabolite HVA. At t1 a higher exposure with PCBs was associated with lower concentration in urinary HVA. A reduced HVA concentration at t1 was correlated with increased depressive symptoms severity at t2. No meditations were found for VMA.Conclusions: This work indicates that the association of PCB exposure and an increase of depressive symptoms after one year is mediated by the DA metabolite HVA as a surrogate for DA. These are first steps towards finding an explanation for an underlying neurochemical pathomechanism of PCB-related depressive symptomatology. [ABSTRACT FROM AUTHOR]

Background Neuroblastomas are pediatric tumors characterized by overproduction of catecholamines. The catecholamine metabolites, vanillylmandelic acid (VMA) and homovanillic acid (HVA), are used in clinical evaluation of neuroblastoma. Tandem mass spectrometry (LC-MS/MS) is an effective analytical method for measurement of VMA and HVA in urine. Methods Dilute-and-shoot sample preparation was performed in a 96-well format using a liquid handler. Chromatographic separation was achieved using a reverse phase column; detection was accomplished by triple quadrupole mass spectrometry with electrospray ionization in positive mode. Data were acquired by multiple reaction monitoring. Two transitions, quantifier and qualifier, were monitored for each analyte and its stable isotope-labeled internal standard. Analytical specificity studies were performed. Results Injection-to-injection time was 4 min. The method was validated for linearity, limit of quantification, imprecision, accuracy, and interference. Linearity was 0.5–100 mg/l for both analytes. Within-run, between-day, and total imprecision were 1.0–4.1% for VMA and 0.8–3.8% for HVA. The method correlated well with our established HPLC method. Interferences precluding quantitation of VMA in 3% of specimens were reduced significantly (to 0.1% of specimens) using a modified LC gradient to reanalyze affected samples. Conclusions A simple, robust, economical, fast LC-MS/MS method was developed and validated for measurement of urinary VMA and HVA. [ABSTRACT FROM AUTHOR]

Two methods, using glassy carbon paste electrode for the simultaneous determination homovanillic acid and vanillylmandelic acid, of two catecholamine neurotransmitter metabolites that can serve as biomarkers of several oncological diseases, were developed, based on differential pulse voltammetry and HPLC with amperometric detection. Low selectivity of the voltammetric method was limiting for the determination in urine samples; inclusion of chromatographic separation enabled the application in complex matrix. Graphical abstract: [ABSTRACT FROM AUTHOR]

Three tumor biomarkers (homovanillic acid (HVA), vanillylmandelic acid (VMA), and 5-hydroxyindole-3-acetic acid (5-HIAA)) have been determined by differential pulse voltammetry (DPV) at screen-printed carbon electrodes (SPCEs). As an optimum medium for all three analytes, Britton-Robinson buffer (0.04 mol ⋅ L−1, pH 3.0) was used. Dependencies of the peak current on the concentration of a biomarker were linear in the concentration range from 0.2 to 100 μmol ⋅ L−1 for all the tested compounds, with the limits of quantification 0.8 μmol ⋅ L−1 for homovanillic acid, 0.2 μmol ⋅ L−1 for vanillylmandelic acid, and 0.4 μmol ⋅ L−1 for 5-hydroxyindole-3-acetic acid. Moreover, it was verified that the newly developed methods can be used for simultaneous determination of HVA and VMA in mixture. [ABSTRACT FROM AUTHOR]

Melanotic neuroectodermal tumor of infancy (MNTI) is a relatively uncommon osteolytic-pigmented neoplasm that primarily affects the jaws of infants. The early onset and its rapid disfiguring spread necessitate early diagnosis. A 4-month-old male child reported with the complaint of swelling in the right back tooth region of the upper jaw, which rapidly increased in size causing disfigurement of the face. Radiographic examination showed a diffuse osteolytic radiolucent lesion in the right maxilla and displacement and dysmorphic changes in the developing primary tooth buds. Wide surgical excision was performed under general anesthesia. Histopathological report revealed characteristic large pigmented epitheloid cells (melanocyte like cells). The biphasic tumor cell population arranged in a background of fibrous connective tissue stroma is suggestive of MNTI involving the cancellous bone. Early diagnosis and management of such aggressive tumors precludes significant morbidity of the patient.