Elastography as a non-invasive method of screening non-alcoholic fatty liver disease in the adult phenotype of paediatric obstructive sleep apnoea.

PURPOSE: The high prevalence of non-alcoholic fatty liver disease (NAFLD) in obese children with obstructive sleep apnoea (OSA) calls for early non-invasive screening. The aim of this study was to use ultrasonographic liver echogenicity and elasticity to evaluate the early stages of liver injury in obese children with OSA. METHODS: Fifty-five obese children with OSA aged 12 to 15 years were included. The control group (n = 56) consisted of healthy, non-obese children. All children underwent ultrasound examination to assess liver echogenicity using the hepatorenal index (HRI) and real-time elastography to determine the liver fibrosis index (LFI). Polysomnographic parameters, sonographic values, and clinical-biochemical assessment were statistically analysed according to OSA and its severity. Subgroup 1 was obese children with OSA and AHI < 5 and subgroup 2 was obese children with OSA and AHI ≥ 5. RESULTS: Higher average values of HRI and LFI were recorded in the group of obese paediatric patients with OSA (mean age ± SD, 14.1 ± 2.2 year; 53% male; BMI z-score, 2.6 ± 0.35) compared to the control group (1.37 ± 0.19 vs. 1.12 ± 0.07, p < 0.001 and 1.82 ± 0.31 vs. 1.02 ± 0.27, p < 0.001). A significantly higher LFI was recorded in subgroup 2 compared to subgroup 1 (2.0 ± 0.3 vs. 1.6 ± 0.2, p < 0.001) while laboratory parameters and HRI (1.4 ± 0.2 vs. 1.4 ± 0.2, p = 0.630) did not change significantly. A strong positive correlation was found between the severity of OSA and the LFI (r = 0.454; p < 0.01). CONCLUSIONS: These findings suggest that ultrasound elastography is a useful non-invasive screening test for OSA-related steatohepatitis in obese adolescents, but other clinical studies are needed to confirm this result.

Mild Hyperglycaemia in Hospitalised Children with Moderate COVID-19 Infection.

Background and Objectives: COVID-19 infection may influence many physiological processes, including glucose metabolism. Acute hyperglycaemia has been related to a worse prognosis in patients with severe COVID-19 infection. The aim of our study was to find out if moderate COVID-19 infection is associated with hyperglycaemia. Materials and Methods: A total of 235 children were enrolled in the study between October 2021 and October 2022, 112 with confirmed COVID-19 infection and 123 with other RNA viral infection. In all patients, types of symptoms, glycaemia at the time of admission, and basic anthropometric and biochemical parameters were recorded. Results: Average glycaemia was significantly higher in COVID-19 patients compared to other viral infections (5.7 ± 1.12 vs. 5.31 ± 1.4 mmol/L, p = 0.011). This difference was more obvious in subgroups with gastrointestinal manifestations (5.6 ± 1.11 vs. 4.81 ± 1.38 mmol/L, p = 0.0006) and with fever (5.76±1.22 vs. 5.11±1.37 mmol/L, p = 0.002), while no significant difference was found in subgroups with mainly respiratory symptoms. The risk of hyperglycaemia (>5.6 mmol/L) was higher in COVID-19 patients compared to other viral infections (OR = 1.86, 95%CI = 1.10-3.14, p = 0.02). The risk of hyperglycaemia was significantly higher in COVID-19 compared to other viral infections in the subgroups of patients with fever (OR = 3.59, 95% CI 1.755-7.345, p = 0.0005) and with gastrointestinal manifestations (OR = 2.48, 95% CI 1.058-5.791, p = 0.036). Conclusion: According to our results, mild hyperglycaemia was significantly more common in children with moderate COVID-19 infection compared to other RNA virus respiratory and gastrointestinal infections, especially when accompanied by fever or gastrointestinal symptoms.

An association between fibrinogen gene polymorphisms and diabetic peripheral neuropathy in young patients with type 1 diabetes.

In complex etiopathogenesis of diabetic peripheral neuropathy (DPN), hemostatic dysfunction and subclinical inflammation play a possible role. Fibrinogen is involved in both the hemostatic and inflammatory pathways, so we hypothesize that fibrinogen gene polymorphisms might be associated with DPN. A total of 127 young patients with type 1 diabetes (T1D) (average age, 18.5 ± 4.65 years; average diabetes duration, 14.5 ± 2.26 years) and 90 healthy controls were enrolled into the study. Basic biochemical and coagulation parameters were measured and gene polymorphisms of fibrinogen alpha (rs6050) and beta (rs1800790) were established. DPN was diagnosed in 38 diabetic patients by neurological examination. AA genotype and A allele of rs1800790 polymorphism of fibrinogen beta were associated with increased risk of DPN (odds ratio [OR] 4.537, 95% confidence interval [95CI] 1.14-19.94, p = 0.019 and OR 1.958, 95CI 1.038-3.675, p = 0.029, respectively). No association was found between DPN and rs6050 gene polymorphisms. Plasma fibrinogen concentration significantly correlated with HbA1c (Spearman's correlation coefficient [r] = 0.54) and HDL cholesterol (r = - 0.67). A allele and AA genotype of rs1800790 seem to be associated with DPN in young patients with T1D. Further studies are appropriate to elucidate the role of fibrinogen gene polymorphisms in the complex etiology of DPN.

Changes of Motile Ciliary Phenotype in Patients with Primary Ciliopathies.

Primary ciliopathies are a group of disorders associated with abnormal formation and function of primary cilia. Many cilia-associated proteins found in primary cilia are also present in motile cilia. Such proteins are important for the ciliary base, such as the transition zone or basal bodies, and the intraflagellar transport. Their exact role in the respiratory motile cilia is unsettled. In this prospective clinical single-center study, we investigated the hypothesis that these proteins regulate the function of motile cilia. We addressed the issue by defining the motile cilia beat frequency in the respiratory tract of patients with primary ciliopathies accompanied by chronic kidney disease and comparing it in those without kidney involvement. Ciliary beat frequency in the nasal mucosa samples was evaluated by the ciliary analysis software LabVIEW. Both children and their parents with primary ciliopathies and kidney involvement had significantly lower median airway ciliary beat frequencies than those without kidney involvement who have normal ciliary motility. Further, the ciliary beat frequency is inversely associated with the serum creatinine level. These findings strongly suggest that kidney involvement in patients with primary ciliopathy may underlie the development of motile cilia dysfunction in the respiratory tract, potentially increasing respiratory morbidity.

The association between gene polymorphisms of glutathione S-transferase T1/M1 and type 1 diabetes in Slovak children and adolescents.

BACKGROUND: Considering a dramatic increase in the incidence of type 1 diabetes (T1D) worldwide, current research focuses on complex etiology of T1D where immune system, environmental and genetic factors play a significant role. Glutathione S-transferase family of enzymes protects tissue from oxidative damage which is discussed in the context of T1D. The aim of the study was to investigate an association of glutathione S-transferase mu 1 (GST M1) and glutathione S-transferase theta 1 (GST T1) polymorphisms with type 1 diabetes. METHODS: 163 children, 116 with type 1 diabetes and 47 healthy controls, at the age 6-19 years were enrolled to the study. Basic anthropometric, biochemical parameters and GST T1 diabetes and M1 polymorphisms were established in each subject. RESULTS: Subjects with T1D had significantly lower concentration of uric acid compared to the healthy subjects (212.85 +/- 57.10 micromol/l vs. 269.57 +/- 72.53; p < 0.001). GST T1 null genotype was more frequent in patients with diabetes compared to the healthy controls (36.2% vs. 21.3%) and represented 2.1-fold increased risk of T1D of borderline statistical significance (OR = 2.1; 95% Cl = 0.949-4.648; p = 0.06). GST T1 null/M1 wild genotype combination was more frequent in patients with diabetes (25.9% vs. 10.6%) and represented 2.9-fold increased risk for T1D development (OR = 2.93; 95% CI = 1.061-8.095; p = 0.032). CONCLUSION: The study indicates that GST T1 null genotype and GST T1 null/M1 wild combination could be considered a risk factor for type 1 diabetes development in Slovak children and adolescents.

Dysfunctional mucociliary clearance in asthma and airway remodeling - New insights into an old topic.

Bronchial asthma is a heterogeneous respiratory condition characterized by chronic airway inflammation, airway hyperresponsiveness and airway structural changes (known as remodeling). The clinical symptoms can be evoked by (non)specific triggers, and their intensity varies over time. In the past, treatment was mainly focusing on symptoms' alleviation; in contrast modern treatment strategies target the underlying inflammation, even during asymptomatic periods. Components of airway remodeling include epithelial cell shedding and dysfunction, goblet cell hyperplasia, subepithelial matrix protein deposition, fibrosis, neoangiogenesis, airway smooth muscle cell hypertrophy and hyperplasia. Among the other important, and frequently forgotten aspects of airway remodeling, also loss of epithelial barrier integrity, immune defects in anti-infectious defence and mucociliary clearance (MCC) dysfunction should be pointed out. Mucociliary clearance represents one of the most important defence airway mechanisms. Several studies in asthmatics demonstrated various dysfunctions in MCC - e.g., ciliated cells displaying intracellular disorientation, abnormal cilia and cytoplasmic blebs. Moreover, excessive mucus production and persistent cough are one of the well-recognized features of severe asthma and are also associated with defects in MCC. Damaged airway epithelium and impaired function of the ciliary cells leads to MCC dysfunction resulting in higher susceptibility to infection and inflammation. Therefore, new strategies aimed on restoring the remodeling changes and MCC dysfunction could present a new therapeutic approach for the management of asthma and other chronic respiratory diseases.

Polysomnographic profile in children diagnosed with celiac disease before starting on a gluten free diet.

STUDY AIMS: The study assessed the presence of sleep abnormalities in children who had recently been diagnosed with celiac disease (CD) and not started a gluten free diet (GFD). The children's polysomnographic profiles were also characterized and further compared with healthy children of the same age. METHODS: This prospective cross-sectional study involved 46 pediatric subjects (aged 1-19 years) who had recently been diagnosed with CD and not started a GFD. The control group consisted of 32 healthy children (aged 2-17 years). All children underwent anthropometric measurement, laboratory testing and standard overnight observation with in-laboratory video-PSG. The study and control group were divided into subgroups according to the subjects' median ages (8.1 years): celiac children aged less than 8.1 years (n = 23) and more than 8.1 years (n = 23), healthy children less aged than 8.1 years (n = 16) and more than 8.1 years (n = 16). RESULTS: No significant differences in the basic demographic and anthropometric parameters between the celiac and control group were observed. Significantly prolonged sleep latency (SOL) was evident in the celiac subjects (21.89 ± 20.77 min. vs. 10.99 ± 7.94 min, p = 0.02), with a probability of prolonged SOL of 4.23-fold greater (OR = 4.23; 95 % CI 1.1-16.22) than the healthy controls, especially in the subgroup of older celiac patients. No significant differences in the sleep period time (SPT), total sleep time (TST), wake during sleep (WASO), sleep efficiency (SE) and sleep stage distribution and cyclization were found. The respiratory rates during sleep indicated a significantly greater incidence of the central apnea-hypopnea index (CAHI) (0.54 ± 0.78 vs. 0.18 ± 0.24, p = 0.03) with a 3.16-fold greater probability of pathological CAHI (OR = 3.16; 95 % CI 1.02-9.77) than the control group. An increased incidence of CSA in the subgroup of younger celiac patients compared to younger healthy controls was especially evident. CONCLUSIONS: The findings of our study suggest a difference in sleep architecture and an increased incidence of CSA in children with untreated CD, but additional research is required to verify the results.

Hypovitaminosis D in children with type 1 diabetes mellitus and its influence on biochemical and densitometric parameters.

The aim of the study was to establish the frequency of hypovitaminosis D in children with type 1 diabetes mellitus (T1D), its influence on biochemical and densitometric parameters and the relation to diabetic nephropathy. 58 children with T1D at the age 9-19 years were enrolled to the study. Vitamin D concentration less than 30 ng/ml was considered as insufficient. 37 children (63.79%) had vitamin D level under 30 ng/ml, from these 19 subjects (32.7%) had vitamin D level under 20 ng/ml and 2 subjects (3.44%) under 10 ng/ml. Children with vitamin D deficiency had significantly lower magnesium concentration and lower Z score of lumbar spine (-1.34 +/- 1.24 vs. -.030 +/- 1.21, p = 0.01) compared to diabetics with sufficient vitamin D concentration. No significant difference was found in parameters calcium, phosphorus or glycosylated hemoglobin. Patients with diabetic nephropathy (n = 18) showed no significant difference in vitamin D, glycosylated hemoglobin or Z score of lumbar spine compared to the patients without nephropathy (n = 40). Subjects with nephropathy had significantly longer diabetes duration, significantly higher cholesterol and triacylglycerol concentration. In our cohort of patients nearly two thirds of children had insufficient vitamin D concentration what supports the need to monitor and eventually supplement vitamin D in T1D subjects.

Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe.

Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Design and methods: A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN. Results: Pdex treatment is currently provided by 36% of the surveyed centres. The treatment is initiated by different specialties, that is paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23% stated to initiate therapy at 4-5 weeks postconception (wpc), 31% at 6 wpc and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 µg/kg/day is used. Dose distribution among the centres varies from once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72% of the responding centres. Cases treated per country and year vary between 0.5 and 8.25. Registries for long-term follow-up are only available at 46% of the centres that are using Pdex treatment. National registries are only available in Sweden and France. Conclusions: This study reveals a high international variability and discrepancy in the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence-based guidelines on prenatal diagnostics, treatment and follow-up of pregnancies at risk for CAH.

Immune Parameters and COVID-19 Infection - Associations With Clinical Severity and Disease Prognosis.

Severe acute respiratory syndrome caused by a novel 2019 coronavirus (SARS-CoV2) represents one of the most studied infectious diseases of today. The number of scientific reports and publications increases exponentially day by day. While the majority of infected subjects are asymptomatic or show mild symptoms, there is an important proportion of patients who requires hospitalization and, sometimes, intensive care. Immune response to novel coronavirus is complex, involves both innate and adaptive immunity, and is biphasic. Significant differences were observed when comparing severe and non-severe patients. Analysis of the reported results from clinical trials clearly show an involvement of specific cellular immunity (predominantly leucopenia, decreased counts of CD3+, CD4+, and CD8+ T lymphocytes, changes of T cell compartment) and the so-called cytokine storm, which is associated with worsening of symptoms and the promotion of lung damage. An interesting finding regarding eosinopenia that can have both diagnostic and prognostic value is reported by some authors. Examination of selected immune parameters could help to identify severe patients with the risk of unfavorable course of the disease, predict the prognosis and recognize improvement in the clinical status. Moreover, detailed analysis of the immune changes could help to select novel prospective therapeutic strategies.

Short-term metabolic control and sleep in children and adolescents with type 1 diabetes mellitus.

AIMS: The aim of this study was to examine sleep in T1D children and in healthy controls by polysomnographic (PSG) examination and to determine the influence of short-term metabolic compensation on sleep quality and sleep disordered breathing (SDB). METHODS: The prospective cross-sectional study included 44 T1D subjects and 60 healthy controls, aged 10-19 years. Subjects underwent anthropometric measurements, laboratory testing and standard overnight in-laboratory video polysomnography with continuous glucose monitoring (CGM). RESULTS: No significant differences were found in total sleep time, sleep efficiency, percentage of sleep stages and respiratory parameters between T1D and healthy group. T1D children with more optimal short-term metabolic control (AvgSG < 10 mmol/l, n = 18) had a significantly lower apnea-hypopnea index (AHI) (0.3(0-0.5) vs. 0.6 (0.2-0.9) events/h, p < 0.05)and respiratory arousal index (0(0-0,1) vs. 0.2(0-0.3)), p < 0.01) compared to children with suboptimal short-term control(n = 26), no significant differences were found in parameters of sleep architecture. Obstructive sleep apnea (OSA) was diagnosed in only one T1D patient, nine T1D children had mild central apnea. CONCLUSIONS: There may be an association between short-term metabolic compensation and SDB in T1D children without chronic complications, obesity or overweight and hypoglycemia. Further research is needed to confirm this result.

Association of Polymorphisms in CYBA, SOD1, and CAT Genes with Type 1 Diabetes and Diabetic Peripheral Neuropathy in Children and Adolescents.

AIMS: The aim of our study was to investigate possible associations between three SNPs: rs4673 in the CYBA gene; rs1041740 in the SOD1 gene; and rs1001179 in the CAT gene, and type 1 diabetes (T1D) or diabetic peripheral neuropathy (DPN) in T1D patients. MATERIALS AND METHODS: Allelic variants of the selected SNPs were determined by allelic discrimination assays in 114 T1D patients enrolled in the study group and in 90 healthy individuals from a control group. Associations between each of the three SNPs were tested in subgroups of T1D patients divided according to the presence of DPN. RESULTS: The TT genotype of rs4673 in the CYBA gene was associated with DPN in T1D patients (OR 4.997, 95% CI 1.403-19.083, p = 0.016). Weak significance was observed for a protective effect of the TT genotype of rs1041740 in the SOD1 gene relative to T1D development (OR 0.318, 95% CI 0.092-0.959, p = 0.056). There was no significant association between the CAT gene SNP rs1001179 and T1D or DPN. CONCLUSION: We showed a strong association of the CYBA polymorphism rs4673 with DPN in Slovak children and adolescents with T1D. Further studies are necessary to assess the relationship between rs1041740 and T1D or DPN.

Pulmonary function tests in type 1 diabetes adolescents with diabetic cardiovascular autonomic neuropathy.

Chronic diabetic complications may afflict all organ tissues including cardiovascular and respiratory system. The aim of the study was to establish if the presence of cardiovascular autonomic neuropathy (CAN) was associated with impaired pulmonary function tests in adolescents with type 1 diabetes (T1D). 46 adolescents with T1D and 25 healthy subjects at the age 15-19years were enrolled to the study. Basic anthropometric data, diabetes onset and duration, plasma glucose and A1c were established. Pulmonary function tests were measured by spirometry and the presence of CAN was examined by heart rate variability. Adolescents with T1D had significantly lower pulmonary function test parameters - FVC (p<0.01), FEV1 (p<0.01), MMEF (p<0.05) and PEFR (p<0.05) compared to the control subjects. In diabetic group, patients with CAN (CAN+, n=19) had significantly lower FVC (p<0.05), FEV1 (p<0.05) and PEFR (p<0.05) compared to patients without CAN (CAN-, n=27). All spirometric parameters were significantly lower in CAN+ subjects compared to healthy controls; however, no significant difference was found in these parameters between CAN- subjects and healthy controls. Spirometric parameters (FVC, FEV1) significantly positively correlated with diabetes onset and body mass index; and negatively correlated with diabetes duration and resting heart rate. Our results indicate that CAN may be associated with reduced pulmonary functions in adolescents with T1D.

Two novel RFX6 variants in siblings with Mitchell-Riley syndrome with later diabetes onset and heterotopic gastric mucosa.

Mitchell-Riley syndrome, an autosomal recessive disorder caused by mutations in the RFX6 gene, is defined as a combination of neonatal diabetes mellitus and serious congenital gastrointestinal defects. We describe Mitchell-Riley syndrome in two sisters with two novel compound heterozygous variants in the RFX6 gene: c.1154G > A, p.(Arg385Gln), and c.1316_1319delTCTA, p.(Ile439Thrfs*13). Both sisters present milder forms of the syndrome, likely due to possible residual activity of the p.Arg385Gln variant, which is localized in a dimerization domain of the RFX6 transcription factor. We propose that the prognosis is dependent on patient RFX6 genotype and possible residual activity of RFX6 transcription factor. Both sisters had atypical later onset of diabetes, at 2 years and 10 months and 2 years and 7 months, respectively. This supports the need of extending the definition of diabetes in Mitchell-Riley syndrome from neonatal to childhood onset and regular glyceamia check in patients with gastrointestinal tract malformations typical for Mitchell-Riley syndrome. The clinical course in both sisters improved significantly after surgical removal of parts of the small intestine with heterotopic gastric mucosa. We suggest that gastric mucosa heterotopy is an important actionable part of Mitchell-Riley syndrome and could have been responsible for the malabsorption, failure to thrive and severe anemia present in previously reported patients with Mitchell-Riley syndrome.

Exhaled carbon monoxide in adolescents with diabetic cardiovascular autonomic neuropathy.

The aim of the study was to determine if cardiovascular autonomic neuropathy (CAN) is associated with changed concentration of exhaled carbon monoxide (eCO) in adolescents with type 1 diabetes (T1D). A total of 46 T1D patients and 25 healthy controls (15-19 years) were enrolled. The parameters eCO and carboxyhemoglobin (HbCO) were established using a MICRO-4 Smokerlyser. CAN was examined by standard cardiovascular tests. Adolescents with T1D did not significantly differ in eCO compared to healthy subjects. eCO and HbCO were significantly lower in CAN-positive subjects (n=19) (1.36 ± 1.65 ppm vs. 3.09 ± 2.31, p=0.01 and 0.58 ± 0.49% vs. 1.04 ± 0.44, p<0.01, respectively) compared to CAN-negative subjects (n=27), whereas no significant difference was found in other measured parameters. By multivariate logistic regression, eCO and HbCO were associated with higher risk of CAN (OR=1.824, p<0.05 and OR=10.989, p<0.01). Our results indicate that eCO is decreased in CAN-positive diabetic subjects. Further studies are necessary to investigate the possible role of eCO as a marker for CAN.

The association between glutathione S-transferase T1 and M1 gene polymorphisms and cardiovascular autonomic neuropathy in Slovak adolescents with type 1 diabetes mellitus.

Glutathione S-transferase (GST), as antioxidant enzyme, protects tissue from oxidative damage typical for many pathologic conditions as type 1 diabetes (T1D) and its chronic complications. The aim of the study was to compare the prevalence of GST T1/M1 gene polymorphisms between diabetic adolescents with (CAN+) and without (CAN-) cardiovascular autonomic neuropathy. Forty-six subjects with T1D at the age 15-19 years were enrolled. CAN was diagnosed in 19 patients (41.3%) based on standard cardiovascular tests. GST M1 null genotype was more prevalent in CAN+subjects but this was not statistically significant (OR=1.889, 0.61-6.55, p>0.05). GST T1 wild genotype nearly 5-fold increased the risk of CAN (OR=4.952, 1.13-21.739, p<0.05). Regarding genotype combination, GST T1/M1 wild/null genotype was significantly more frequent in CAN+compared to the CAN- subjects (OR=3.96, 1.024-15.302, p<0.05). No significant difference was found in any biochemical parameters between CAN+and CAN- subgroups. Multivariable logistic regression showed that none of the biochemical parameters estimated was considered a risk factor for CAN, however GST T1 wild and GST T1/M1 wild/null represented a risk factor for CAN development (OR=2.227, 1.079-4.587, p<0.05 and OR=1.990, 1.026-3.859, p<0.05, respectively). GST T1 wild allele and GST T1/M1 wild/null genotype can be considered as risk factors for CAN in Slovak adolescents with T1D.

Chronic complications of diabetes mellitus related to the respiratory system.

The quality of life in patients with diabetes mellitus is mainly determined by chronic diabetic complications which may affect all organ tissues including respiratory system. Microangiopathy of pulmonary capillaries, autonomic neuropathy, myopathy of respiratory muscles or changes in collagen belong to supposed pathophysiological pathways. This paper brings brief review about reported functional consequences in subjects with diabetes - decreased vital lung capacity and pulmonary volumes, decreased diffuse lung capacity for carbon monoxide, lower basal bronchial tone, lower cough reflex sensitivity, increased incidence of sleep obstructive apnea, increase in respiratory infections, disorders in respiratory muscles or phrenical nerve. Examination of pulmonary functions may serve for early detection of chronic complications in patients with diabetes.