Respiratory Sinus Arrhythmia Mechanisms in Young Obese Subjects.

Autonomic nervous system (ANS) activity and imbalance between its sympathetic and parasympathetic components are important factors contributing to the initiation and progression of many cardiovascular disorders related to obesity. The results on respiratory sinus arrhythmia (RSA) magnitude changes as a parasympathetic index were not straightforward in previous studies on young obese subjects. Considering the potentially unbalanced ANS regulation with impaired parasympathetic control in obese patients, the aim of this study was to compare the relative contribution of baroreflex and non-baroreflex (central) mechanisms to the origin of RSA in obese vs. control subjects. To this end, we applied a recently proposed information-theoretic methodology - partial information decomposition (PID) - to the time series of heart rate variability (HRV, computed from RR intervals in the ECG), systolic blood pressure (SBP) variability, and respiration (RESP) pattern measured in 29 obese and 29 age- and gender-matched non-obese adolescents and young adults monitored in the resting supine position and during postural and cognitive stress evoked by head-up tilt and mental arithmetic. PID was used to quantify the so-called unique information transferred from RESP to HRV and from SBP to HRV, reflecting, respectively, non-baroreflex and RESP-unrelated baroreflex HRV mechanisms, and the redundant information transferred from (RESP, SBP) to HRV, reflecting RESP-related baroreflex RSA mechanisms. Our results suggest that obesity is associated: (i) with blunted involvement of non-baroreflex RSA mechanisms, documented by the lower unique information transferred from RESP to HRV at rest; and (ii) with a reduced response to postural stress (but not to mental stress), documented by the lack of changes in the unique information transferred from RESP and SBP to HRV in obese subjects moving from supine to upright, and by a decreased redundant information transfer in obese compared to controls in the upright position. These findings were observed in the presence of an unchanged RSA magnitude measured as the high frequency (HF) power of HRV, thus suggesting that the changes in ANS imbalance related to obesity in adolescents and young adults are subtle and can be revealed by dissecting RSA mechanisms into its components during various challenges.

Arterial Stiffness and Endothelial Function in Young Obese Patients - Vascular Resistance Matters.

AIM: Motivated by the paradoxical and differing results of the early atherosclerosis related indices - Cardio-Ankle Vascular Index (CAVI) reflecting arterial stiffness and Reactive Hyperemia Index (RHI) evaluating endothelium dependent flow-induced vasodilation - in obesity, we aimed to assess CAVI and RHI in obese adolescents and young adults in the context of differences in systemic vascular resistance (SVR). METHODS: We examined 29 obese (14f, 15.4 [12.3-18.5] y; BMI: 33.2±4.4 kg.m-2) and 29 non-obese gender and age matched adolescents and young adults (BMI: 21.02±2.3 kg.m-2). CAVI and RHI were measured using VaSera VS-1500 (Fukuda Denshi, Japan) and Endo-PAT 2000 (Itamar Medical, Israel), respectively. Hemodynamic measures were recorded using volume-clamp plethysmography (Finometer Pro, FMS, Netherlands) and impedance cardiography (CardioScreen 2000, Medis GmbH, Germany). SVR and sympathetic activity related indices - Velocity Index (VI) and Heather Index (HI), and LFSAP (spectral power in low frequency band of systolic blood pressure oscillations) were determined. RESULTS: In obese group, CAVI (4.59±0.88 vs. 5.18±0.63, p=0.002) and its refined version CAVI0 (6.46±1.39 vs.7.33±0.99, p=0.002) were significantly lower. No significant difference in RHI was found. SVR and sympathetic activity indices were all significantly lower in the obese group than in the non-obese group. RHI correlated positively with SVR (r=0.390, p=0.044) in obese subjects. CONCLUSION: Our results indicate that both indices used for the detection of early atherosclerotic changes are influenced by vascular tone. Vascular resistance could influence CAVI and RHI results impairing their interpretation.

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.

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.

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.

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.

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 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.

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.

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.

Severe quadriparesis caused by wasp sting.

Besides the typical symptoms of allergic reaction after wasp sting, unusual and unexpected reactions may also develop. In this report, a case of severe peripheral quadriparesis and sphincteric disorder (urinary incontinence) in a 10-year-old boy occurring within 24 hours after wasp sting is presented. Corticosteroids had very good therapeutic effect, and improvement in clinical status was observed within 72 hours. The exact pathogenic mechanism of peripheral nervous system damage is not very well known. Several studies have suggested that besides the neurotoxic effect of wasp venom, delayed immunological response to wasp antigens followed by an allergy-triggered autoimmune reaction is possible. Wasp venom may activate an allergic reaction or effects by toxic impacts; however, typical clinical symptoms of allergic reaction are not necessarily present.

Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers.

CONTEXT: Mutations in the KCNJ11 and ABCC8 genes encoding the pancreatic beta-cell K(ATP) channel have recently been shown to be the most common cause of permanent neonatal diabetes mellitus (PNDM). Information regarding the frequency of PNDM has been based mainly on nonpopulation or short-term collections only. Thus, the aim of this study was to identify the incidence of PNDM in Slovakia and to switch patients to sulfonylurea (SU) where applicable. DESIGN: We searched for PNDM patients in the Slovak Children Diabetes Registry. In insulin-treated patients who matched the clinical criteria for PNDM, the KCNJ11 or ABCC8 genes were sequenced, and mutation carriers were invited for replacement of insulin with SU. RESULTS: Eight patients with diabetes onset before the sixth month of life without remission were identified since 1981, which corresponds to the PNDM incidence in Slovakia of one case in 215,417 live births. In four patients, three different KCNJ11 mutations were found (R201H, H46Y, and L164P). Three patients with the KCNJ11 mutations (R201H and H46Y) were switched from insulin to SU, decreasing their glycosylated hemoglobin from 9.3-11.0% on insulin to 5.7-6.6% on SU treatment. One patient has a novel V86A mutation in the ABCC8 gene and was also substituted with SU. CONCLUSIONS: PNDM frequency in Slovakia is much higher (one in 215,417 live births) than previously suggested from international estimates (about one in 800,000). We identified one ABCC8 and four KCNJ11 mutation carriers, of whom four were successfully transferred to SU, dramatically improving their diabetes control and quality of life.