Canakinumab as monotherapy for treatment of familial Mediterranean fever - first report in Central and Eastern Europe region.

Autoinflammatory disorders (AID) are characterized by spontaneous attacks of acute inflammation with a broad spectrum of clinical symptoms. Ongoing inflammation and reoccurrence of acute flares can lead to the development of amyloidosis. One group of AID is represented by monogenic periodic fever syndromes while familial Mediterranean fever (FMF) is the most common form of AID from this group. Its prevalence in Central and Eastern Europe was reported to be very low. We report a case of FMF patient with a very severe clinical course of FMF and intolerance to colchicine, which is a gold standard for FMF treatment. The clinical effect of the application of anakinra was insufficient and accompanied with side effects and low tolerability. Switching to canakinumab (human monoclonal antibody against IL-1ß) at dose of 150 mg every 4 weeks induced a rapid remission of the disease activity and inflammatory markers. However, due to relapse of acute flares after three weeks from application, the escalation of dose to 300 mg every 4 weeks induced a complete remission of symptoms and significantly improved the quality of life. This is the first report of successful canakinumab administration in FMF patient in Central and Eastern Europe, a region with very low incidence of FMF (Tab. 1, Ref. 16).

Studies on the regulation of transient lower esophageal sphincter relaxations (TLESRs) by acid in the esophagus and stomach.

Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism of gastroesophageal reflux, but the regulation of TLESR by stimuli in the esophagus is incompletely understood. We have recently reported that acid infusion in the esophagus substantially (by 75%) increased the number of meal-induced TLESR in healthy subjects. We concluded that the TLESR reflex triggered by gastric distention with meal was enhanced by the stimulation of esophageal nerves by acid. However, the possibilities that the acid infused into the esophagus acts after passing though lower esophageal sphincter in stomach to enhance TLESR, or that the acid directly initiates TLESR from the esophagus were not addressed. Here, we evaluated the effect of acid infusion into the proximal stomach on meal-induced TLESR (study 1) and the ability of acid infusion into the esophagus to initiate TLESR without prior meal (study 2). We analyzed TLESRs by using high-resolution manometry in healthy subjects in paired randomized studies. In study 1, we found that acid infusion into the proximal stomach did not affect TLESRs induced by standard meal. The number of meal-induced TLESRs following the acid infusion into the proximal stomach was similar to the number of meal-induced TLESRs following the control infusion. In study 2, we found that acid infusion into the esophagus without prior meal did not initiate TLESRs. We conclude that the increase in the meal-induced TLESRs by acid in the esophagus demonstrated in our previous study is not attributable to the action of acid in the stomach or to direct initiation of TLESR from the esophagus by acid. Our studies are consistent with the concept that the stimuli in the esophagus can influence TLESRs. The enhancement of TLESR by acid in the esophagus may contribute to pathogenesis of gastroesophageal reflux in some patients.

Airway Defense Control Mediated via Voltage-Gated Sodium Channels.

Expression of voltage-gated sodium channels (Nav) takes place in the airways and the role of Nav1.7 and Nav1.8 in the control of airway's defense reflexes has been confirmed. The activation of Nav channels is crucial for cough initiation and airway smooth muscle reactivity, but it is unknown whether these channels regulate ciliary beating. This study evaluated the involvement of Nav1.7 and Nav1.8 channels in the airway defense mechanisms using their pharmacological blockers in healthy guinea pigs and in the experimental allergic asthma model. Asthma was modeled by ovalbumin sensitization over a period of 21 days. Blockade of Nav1.7 channels significantly decreased airway smooth muscle reactivity in vivo, the number of cough efforts, and the cilia beat frequency in healthy animals. In the allergic asthma model, blockade of Nav1.8 efficiently relieved symptoms of asthma, without adversely affecting cilia beat frequency. The study demonstrates that Nav1.8 channel antagonism has a potential to alleviate cough and bronchial hyperreactivity in asthma.

The Role of Ion Channels to Regulate Airway Ciliary Beat Frequency During Allergic Inflammation.

Overproduction of mucus is a hallmark of asthma. The aim of this study was to identify potentially effective therapies for removing excess mucus. The role of voltage-gated (Kir 6.1, KCa 1.1) and store-operated ion channels (SOC, CRAC) in respiratory cilia, relating to the tracheal ciliary beat frequency (CBF), was compared under the physiological and allergic airway conditions. Ex vivo experiments were designed to test the local effects of Kir 6.1, KCa 1.1 and CRAC ion channel modulators in a concentration-dependent manner on the CBF. Cilia, obtained with the brushing method, were monitored by a high-speed video camera and analyzed with ciliary analysis software. In natural conditions, a Kir 6.1 opener accelerated CBF, while CRAC blocker slowed it in a concentration-dependent manner. In allergic inflammation, the effect of Kir 6.1 opener was insignificant, with a tendency to decrease CBF. A cilio-inhibitory effect of a CRAC blocker, while gently reduced by allergic inflammation, remained significant. A KCa 1.1 opener turned out to significantly enhance the CBF under the allergic OVA-sensitized conditions. We conclude that optimally attuned concentration of KCa 1.1 openers or special types of bimodal SOC channel blockers, potentially given by inhalation, might benefit asthma.

[Factors modifying cord blood IgE levels - a pilot study]. / Faktory modifikujúce koncentráciu IgE v pupocníkovej krvi - pilotná stúdia.

AIM: The complex influence of internal and external environmental factors on the individual and his/her immune system and the lack of suitable markers to assess and reduce the risk of the development of allergies during the lifetime can explain the continuous increase in the number of people affected by some form of allergy. According to the results of some studies, cord blood IgE level could be a useful early marker for assessing the risk of atopic diseases, but the studies showed controversial results. In addition, several authors discuss the origin of these antibodies (synthesis in utero, peripartum contamination from maternal blood or placental transfer). The aim of our pilot study was to investigate the possible influence of modifying factors on cord blood IgE level. MATERIAL AND METHODS: Our group of patients consisted of 184 retrospectively selected neonates (98 boys, 53.3% and 86 girls, 46.7%) from whom cord blood was collected and cord blood IgE level was measured 25 years ago (PRIST method). The impact of selected modifying factors (sex, type of delivery or month of birth) on cord blood IgE level was assessed retrospectively. RESULTS: Higher cord blood IgE levels were found in boys than in girls, in neonates born by Caesarean section than in those born by natural delivery, and in those born in the winter months than in other seasons of the year. Our findings are in agreement with those of other authors. CONCLUSION: Based on our results and those of others, we assume that the selected factors affect the cord blood IgE levels to varying degrees. These facts should be taken into consideration while interpreting the cord blood IgE levels.

Towards optimizing the protocol for untargeted profiling of urine volatiles via gas chromatography-ion mobility spectrometry. A pilot study.

The analysis of volatile organic compounds (VOCs) present in various biological samples holds immense potential for non-invasive disease diagnostics and metabolic profiling. One of the biological fluids that are suitable for use in clinical practice is urine. Given the limited quantity of VOCs in the urine headspace, it's imperative to enhance their extraction into the gaseous phase and prevent any degradation of VOCs during the thawing process. The study aimed to test several key parameters (incubation time, temperature, and thawing) that can influence urine volatilome and monitor selected VOCs for their stability. The analysis in this study was performed using a BreathSpec® (G.A.S., Dortmund, Germany) device consisting of a gas chromatograph (GC) coupled with an ion mobility spectrometer (IMS). Testing three different temperatures and incubation times yielded a low number of VOCs (9 out of 34) that exhibited statistically significant differences. However, examining three thawing conditions revealed no VOCs with statistically significant changes. Thus, we conclude that urine composition remains relatively stable despite exposure to various thermal stresses.

THE PREVALENCE OF MYOPIA IN SCHOOL-AGE CHILDREN IN SLOVAKIA AND THE COVID-19 PANDEMIC.

AIMS: The aim of the authors' study was to determine the prevalence of myopia and premyopia in children and adolescents attending primary school in a village in the north of Slovakia in the period before and after the peak of the Covid-19 pandemic. MATERIAL AND METHODS: Changes in the spherical equivalent and axial length of the eyes were measured in 2019 and 2022 in a group of 47 children and adolescents within the age range of 7-12 years at the time of first measurement. In all the individuals, refraction was measured using an automatic keratorefractometer without the use of cycloplegic eye drops, and axial length was measured with an optical biometer. Refraction was also measured using an automatic keratorefractometer after using cycloplegic eye drops. RESULTS: We recorded a significant change in the mean spherical equivalent (1.02 ±1.16 D vs. 0.72 ±1.29) and the axial length of the eyes (23.05 ±0.72mm vs. 23.30 ±0.74mm) when comparing the measurements from 2019 to 2022. The probands manifested a myopic refractive shift of -0.30 D throughout the entire cohort (-0.24 D in boys and -0.38 D in girls), and the mean axial length increased by 0.2 mm in the entire cohort (by 0.3 mm in boys and 0.2 mm in girls). The percentage of myopic and premyopic eyes increased (4.3% vs. 8.5% a 31.9% vs. 48.9%). CONCLUSION: We noted a decrease in the spherical equivalent and increase in the axial length of the eyes after the Covid-19 pandemic compared to the period before the pandemic in Slovak school-aged children. During this period, the prevalence of myopia and premyopia increased.

COVID-19 and the differences in physiological background between children and adults and their clinical consequences.

The SARS-CoV-2 pandemic has indeed been one of the most significant problems facing the world in the last decade. It has affected (directly or indirectly) the entire population and all age groups. Children have accounted for 1.7 % to 2 % of the diagnosed cases of COVID-19. COVID-19 in children is usually associated with a mild course of the disease and a better survival rate than in adults. In this review, we investigate the different mechanisms which underlie this observation. Generally, we can say that the innate immune response of children is strong because they have a trained immunity, allowing the early control of infection at the site of entry. Suppressed adaptive immunity and a dysfunctional innate immune response is seen in adult patients with severe infections but not in children. This may relate to immunosenescence in the elderly. Another proposed factor is the different receptors for SARS-CoV-2 and their differences in expression between these age groups. In infants and toddlers, effective immune response to viral particles can be modulated by the pre-existing non-specific effect of live attenuated vaccines on innate immunity and vitamin D prophylaxis. However, all the proposed mechanisms require verification in larger cohorts of patients. Our knowledge about SARS-CoV-2 is still developing.

Cough reflex sensitivity in adolescents with diabetic autonomic neuropathy.

OBJECTIVE: Diabetic autonomic neuropathy (DAN) is one of the chronic complications of diabetes mellitus which can involve one or more organ systems. DAN without apparent symptoms is more often in childhood and adolescence. While heart rate variability (HRV) and Ewing's battery of cardiovascular tests are regarded as a gold standard for the diagnosis of DAN, the examination of cough reflex sensitivity (CRS) is another possibility. The aim of this study was to compare HRV and CRS in children with diabetes mellitus. MATERIAL AND METHODS: Sixty one patients (37 girls, 24 boys) aged 15-19 suffering from diabetes mellitus type 1 completed the study. Based on HRV, patients were divided into 2 groups - with DAN (n=25) and without DAN (n=32), 4 patients were excluded because of ambiguous results. CRS was studied in each patient by inhalation of gradually increasing concentration of capsaicin. RESULTS: Subjects with DAN required a significantly higher concentration of capsaicin needed to evoke 2 coughs (median 625 micromol/l, IQR 68.4-625.0 micromol/l vs. median 29.3 micromol/l, IQR 9.8-156.3 micromol/l, P<0.001) and 5 coughs (median 2500.0 micromol/l, IQR 1250.0-2500.0 micromol/l vs. median 312.5 micromol/l, IQR 117.2-625.0 micromol/l, P<0.001) compared with those without DAN. Moreover, a strong negative correlation between HRV and CRS was established. CONCLUSION: Diabetes mellitus lowers the cough response. Cough reflex sensitivity appears to be another sensitive method for the evaluation of DAN in diabetes.

Factors attributable to the level of exhaled nitric oxide in asthmatic children.

BACKGROUND: Asthma is a heterogeneous disease with variable symptoms especially in children. Exhaled nitric oxide (FeNO) has proved to be a marker of inflammation in the airways and has become a substantial part of clinical management of asthmatic children due to its potential to predict possible exacerbation and adjust the dose of inhalant corticosteroids. OBJECTIVES: We analyzed potential factors that contribute to the variability of nitric oxide in various clinical and laboratory conditions. MATERIAL AND METHODS: Study population consisted of 222 asthmatic children and 27 healthy control subjects. All children underwent a panel of tests: fractioned exhaled nitric oxide, exhaled carbon monoxide, asthma control test scoring, blood sampling, skin prick tests, and basic spirometry. RESULTS: FeNO and other investigated parameters widely changed according to clinical or laboratory characteristics of the tested children. Asthmatics showed increased levels of FeNO, exhaled carbon monoxide, total serum IgE, and higher eosinophilia. Boys had higher FeNO levels than girls. We found a significant positive correlation between FeNO levels and the percentage of blood eosinophils, %predicted of forced vital capacity, total serum IgE levels, and increasing age. CONCLUSIONS: Various phenotypes of children's asthma are characterized by specific pattern of the results of clinical and laboratory tests. FeNO correlates with total serum IgE, blood eosinophilia, age, and some spirometric parameters with different strength. Therefore, the coexistence of atopy, concomitant allergic rhinitis/rhinoconjunctivitis, and some other parameters should be considered in critical evaluation of FeNO in the management of asthmatic children.

Cardiac autonomic control in adolescents with primary hypertension.

BACKGROUND: Impairment in cardiovascular autonomic regulation participates in the onset and maintenance of primary hypertension. OBJECTIVE: The aim of the present study was to evaluate cardiac autonomic control using long-term heart rate variability (HRV) analysis in adolescents with primary hypertension. SUBJECTS AND METHODS: Twenty two adolescent patients with primary hypertension (5 girls/17 boys) aged 14-19 years and 22 healthy subjects matched for age and gender were enrolled. Two periods from 24-hour ECG recording were evaluated by HRV analysis: awake state and sleep. HRV analysis included spectral power in low frequency band (LF), in high frequency band (HF), and LF/HF ratio. - RESULTS: In awake state, adolescents with primary hypertension had lower HF and higher LF and LF/HF ratio. During sleep, HF was lower and LF/HF ratio was higher in patients with primary hypertension. CONCLUSIONS: A combination of sympathetic predominance and reduced vagal activity might represent a potential link between psychosocial factors and primary hypertension, associated with increased cardiovascular morbidity.

Age-dependent changes of airway obstruction parameters.

The study was aimed at the assessment of the physiological range of phi and Tme/Te indices in children of up to 24 months of age, as based on noncalibrated respiratory inductive plethysmography performed in the supine position. We also examined the dependence of these indices on children's age and sex. The study was carried out in 127 healthy children. The results of the study indicate a significant decrease of phi in children aged 7-24 months in comparison with children of up to 6 months of age (P<0.001). Similarly, values of Tme/Te were found significantly higher in the group of older children (P<0.05). We did not find any appreciable sex differences in both measured parameters. The results of this study suggest that the Tme/Te index might be more stable, less age-dependent parameter of the Respitrace measurement than the phase angle j, but further research and analysis to achieve a correct verdict are warranted.

Cough reflex sensitivity in children with suspected and confirmed gastroesophageal reflux disease.

Experimental and clinical studies performed in adults revealed that gastresophageal reflux disease (GORD) is associated with an appreciable increase in cough reflex sensitivity (CRS). The association between respiratory diseases and GORD is also present in children, but there is little evidence that GORD without aspiration of refluxate (proximal reflux) is a frequent cause of cough in children. The aim of this study was to find out whether CRS in children with GORD will be changed compared with healthy children, and if so, to determine the role of proximal vs. distal reflux in these changes. CRS and 24-h esophageal pH monitoring were performed in 20 children of whom 13 had confirmed GORD and 7 were suspected to have GORD. The control group consisted of 27 healthy children. For assessing the CRS, each subject inhaled 12 capsaicin aerosol concentrations (0.61-1250 micromol/l) at 1 min intervals. CRS was defined as the lowest capsaicin concentration that evoked minimally 2 coughs (C2). CRS in the group of children with suspected GORD [C2: 17.0 micromol/l (6.4-45.6 micromol/l)] and with confirmed GORD [C2: 13.4 micromol/l (3.6-50.9 micromol/l)] were significantly elevated (P<0.05) compared with healthy children [C2: 72.1 micromol/l (25.5-203.9 micromol/l)]. According to the parameters of 24-h pH monitoring, a significantly higher exposure to acid was present in the distal compared with proximal oesophagus. CRS changes correlated negatively with the distal, but not proximal, esophageal acid exposure. In conclusion, CRS changes in children suffering from GORD are similar to those described in adult patients with GORD. It is plausible that the main role in increased CRS in children with GORD play episodes of distal acid refluxes.

The influence of autonomic neuropathy on cough reflex sensitivity in children with diabetes mellitus type 1.

Diabetic autonomic neuropathy (DAN) is manifested by dysfunction of one or more organ systems. Its subclinical form (sDAN) can be recognized with the use of noninvasive cardiovascular reflex tests. As the cough reflex is mediated via autonomic nervous system, there is a reason to suppose that it can also be changed due to presence of sDAN. The aim of the present study was to assess cough reflex sensitivity (CRS) in diabetic children with and without sDAN. A CRS test was performed in 35 children suffering from diabetes mellitus type 1 and the results were compared with those from age-matched 27 healthy children. Cough was induced by inhalation of capsaicin aerosol in doubling concentrations (0.61-1250 micromol/l) for 400 ms each. CRS was defined as the lowest capsaicin concentration that evoked 2 or more coughs (C2 parameter) and 5 or more coughs (C5 parameter). We found that CRS in the whole group of diabetic children was not significantly different from that in healthy children [diabetic children--C2: 75.1 micromol/l (95% CI: 42.0-134.2 micromol/l)] vs. healthy children--C2: 72.4 micromol/l (95% CI: 75.7-644.8 micromol/l)]. However, a significant decrease (P=0.005) in CRS was found in diabetic children with sDAN [n=12; C2: 221.0 micromol/l (95% CI: 75.7-644.8 micromol/l)] compared with diabetic children without sDAN [(n=23; C2: 42.7 micromol/l (95% CI: 23.1-79.0 micromol/l)]. We conclude that testing cough reflex sensitivity might be a way to establish the presence of diabetic neuropathy.

Hemolytic uremic syndrome caused by verotoxin-producing Escherichia coli O26. Case report.

Verotoxin-producing Escherichia coli (VTEC) are nowadays among the most important emerging group of food-borne pathogens (VTEC strains cause gastroenteritis that can be complicated by the hemorrhagic colitis or hemolytic uremic syndrome, HUS). Escherichia coli 026 producing verotoxin 2 was isolated and its identity confirmed by examination of phenotype and genotype; the strain was first described in Slovakia in association with the development of HUS in a 4-year-old girl.

Acid sensitivity of the spinal dorsal root ganglia C-fiber nociceptors innervating the guinea pig esophagus.

BACKGROUND: Gastroesophageal reflux can cause high acidity in the esophagus and trigger heartburn and pain. However, because of the esophageal mucosal barrier, the acidity at the nerve terminals of pain-mediating C-fibers in esophageal mucosa is predicted to be substantially lower. We hypothesized that the esophageal dorsal root ganglia (DRG) C-fibers are activated by mild acid (compared to acidic reflux), and express receptors and ion channels highly sensitive to acid. METHODS: Extracellular single unit recordings of activity originating in esophageal DRG C-fiber nerve terminals were performed in the innervated esophagus preparation ex vivo. Acid was delivered in a manner that bypassed the esophageal mucosal barrier. The expression of mRNA for selected receptors in esophagus-specific DRG neurons was evaluated using single cell RT-PCR. KEY RESULTS: Mild acid (pH = 6.5-5.5) activated esophageal DRG C-fibers in a pH-dependent manner. The response to mild acid at pH = 6 was not affected by the TRPV1 selective antagonist iodo-resiniferatoxin. The majority (70-95%) of esophageal DRG C-fiber neurons (TRPV1-positive) expressed mRNA for acid sensing ion channels (ASIC1a, ASIC1b, ASIC2b, and/or ASIC3), two-pore-domain (K2P) potassium channel TASK1, and the proton-sensing G-protein coupled receptor OGR1. Other evaluated targets (PKD2L1, TRPV4, TASK3, TALK1, G2A, GPR4, and TDAG8) were expressed rarely. CONCLUSIONS & INFERENCES: Guinea pig esophageal DRG C-fibers are activated by mild acid via a TRPV1-independent mechanism, and express mRNA for several receptors and ion channels highly sensitive to acid. The high acid sensitivity of esophageal C-fibers may contribute to heartburn and pain in conditions of reduced mucosal barrier function.

Effect of prostaglandin F2 alpha on the contractile tissues of the respiratory system of the cat in experimental airway inflammation.

The in vitro reactivity of the smooth musculature of the trachea and lungs to PGF2 alpha, was studied in control cats and cats with experimental airway inflammation induced by turpentine oil. No changes were found in the reactivity of the tracheal smooth muscle, but the reactivity of the pulmonary tissue was significantly raised compared with the controls. The results indicate that PGF2 alpha may play a role in the pathogenesis of bronchial hyperreactivity after airway inflammation.