Circulating ceramide levels and ratios in Emirati youth under 18 years: associations with cardiometabolic risk factors.

BACKGROUND: Circulating ceramide (Cer) drives various pathological processes associated with cardiovascular diseases, liver illness, and diabetes mellitus. Although recognized as predictors of cardiometabolic diseases (CMD) in research and clinical settings, their potential for predicting CMD risk in individuals under 18 remains unexplored. OBJECTIVES: This study was designed to utilize Liquid Chromatography-Mass Spectrometry (LC-MS/MS) methodology to determine the biological reference ranges for Cer in plasma samples of Emirati children and develop a risk assessment score (CERT-1) based on Cer concentrations. METHODS: Using LC-MS/MS, we developed a method to measure five Cer species in plasma samples of 582 Emirati participants aged 5-17. We used the circulating concentrations of these Cer to determine their reference intervals in this population. We employed traditional statistical analyses to develop a risk score (CERT-1) and assess the association between Cer levels and conventional biomarkers of CMD. RESULTS: We validated a high-throughput methodology using LC-MS/MS to quantify five Cer species in human plasma. Reference values for this population (n = 582) were quantified: CerC16:0 (0.12-0.29 µmol/L), CerC18:0 (0.019-0.067 µmol/L), CerC22:0 (0.102-0.525 µmol/L), CerC24:0 (0.65-1.54 µmol/L) and CerC24:1 (0.212-0.945 µmol/L). We devised a risk assessment score (CERT-1) based on plasma Cer content in the study participants, showing that 72.5% have low to moderate risk and 9.3% are at a higher risk of developing CMD. Our analyses also revealed a significant correlation (P < 0.05) between this score and the conventional risk factors linked to CMD, indicating its potential clinical implication. CONCLUSION: This study presents a clinical-scaled LC-MS/MS methodology for assessing clinically relevant Cer, setting reference ranges, and developing a risk score (CERT-1) for young Emirati individuals. Our findings can enhance primary risk prediction and inform the management and follow-up of CMD from an early age.

Unveiling the pathogenic mechanisms of NPR2 missense variants: insights into the genotype-associated severity in acromesomelic dysplasia and short stature.

Introduction: Natriuretic peptide receptor 2 (NPR2 or NPR-B) plays a central role in growth development and bone morphogenesis and therefore loss-of-function variations in NPR2 gene have been reported to cause Acromesomelic Dysplasia, Maroteaux type 1 and short stature. While several hypotheses have been proposed to underlie the pathogenic mechanisms responsible for these conditions, the exact mechanisms, and functional characteristics of many of those variants and their correlations with the clinical manifestations have not been fully established. Methods: In this study, we examined eight NPR2 genetic missense variants (p.Leu51Pro, p.Gly123Val, p.Leu314Arg, p.Arg318Gly, p.Arg388Gln, p.Arg495Cys, p.Arg557His, and p.Arg932Cys) Acromesomelic Dysplasia, Maroteaux type 1 and short stature located on diverse domains and broadly classified as variants of uncertain significance. The evaluated variants are either reported in patients with acromesomelic dysplasia in the homozygous state or short stature in the heterozygous state. Our investigation included the evaluation of their expression, subcellular trafficking and localization, N-glycosylation profiles, and cyclic guanosine monophosphate (cGMP) production activity. Results and Discussion: Our results indicate that variants p.Leu51Pro, p.Gly123Val, p.Leu314Arg, p.Arg388Gln have defective cellular trafficking, being sequestered within the endoplasmic reticulum (ER), and consequently impaired cGMP production ability. Conversely, variants p.Arg318Gly, p.Arg495Cys, and p.Arg557His seem to display a non-statistically significant behavior that is slightly comparable to WT-NPR2. On the other hand, p.Arg932Cys which is located within the guanylyl cyclase active site displayed normal cellular trafficking profile albeit with defective cGMP. Collectively, our data highlights the genotype-phenotype relationship that might be responsible for the milder symptoms observed in short stature compared to acromesomelic dysplasia. This study enhances our understanding of the functional consequences of several NPR2 variants, shedding light on their mechanisms and roles in related genetic disorders which might also help in their pathogenicity re-classification.

Introducing and Implementing Genetic Assessment in Cardio-Obstetrics Clinical Practice: Clinical and Genetic Workup of Patients with Cardiomyopathy.

Cardiovascular disease (CVD) during pregnancy varies significantly worldwide, influenced by factors such as access to healthcare, delayed diagnosis, causes, and risk factors. Our study sought to explore the spectrum of CVD present in pregnant women in the United Arab Emirates to better understand this population's unique needs and challenges. Central to our study is an emphasis on the importance of implementing a multidisciplinary approach that involves the collaboration of obstetricians, cardiologists, geneticists, and other healthcare professionals to ensure that patients receive comprehensive and coordinated care. This approach can also help identify high-risk patients and implement preventive measures to reduce the occurrence of adverse maternal outcomes. Furthermore, increasing awareness among women about the risk of CVD during pregnancy and obtaining detailed family histories can help in the early identification and management of these conditions. Genetic testing and family screening can also aid in identifying inherited CVD that can be passed down through families. To illustrate the significance of such an approach, we provide a comprehensive analysis of five women's cases from our retrospective study of 800 women. The findings from our study emphasize the importance of addressing maternal cardiac health in pregnancy and the need for targeted interventions and improvements in the existing healthcare system to reduce adverse maternal outcomes.

A dual-channel incoherent broadband cavity-enhanced absorption spectrometer for sensitive atmospheric NOx measurements.

We describe and characterize a dual-channel incoherent broadband cavity-enhanced absorption spectrometer (DC-IBBCEAS) for the sensitive measurements of NOx: the sum of nitrogen monoxide (NO) and nitrogen dioxide (NO2) in the atmosphere. The instrument employs two 1 m long optical cavities, with air being extracted from a common sampling line. The first channel (cavity-1) spans 340-380 nm and the second channel (cavity-2) spans the 405-460 nm spectral range, both measuring NO2 simultaneously. High absorption cross-sections of NO2 in both channels are effectively utilized for its sensitive quantification. NO is quantified by titrating it with ozone to NO2 in channel-2, where the difference of NO2 measured from that in channel-1 corresponds to the NO concentration in the sampled air. The instrument offers 1-ppb detection sensitivity for both NO and NO2 with a maximum possible uncertainty of ∼9%. The use of close yet different spectral regions in the two channels readily extended measurements to a broader range without compromising its sensitivity to NOx quantification. This would extend the DC-IBBCEAS applicability to simultaneously monitor interfering species with significant absorption cross-sections in the region in either channel, such as glyoxal (CHOCHO), methylglyoxal (CH3COCHO), and nitrous acid (HONO).