ABSTRACT
Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system, usually diagnosed during the reproductive period. Both MS and its commonly used animal model, experimental autoimmune encephalomyelitis (EAE), exhibit sex-specific features regarding disease progression and disturbances in the neuroendocrine and endocrine systems. This study investigates the hypothalamic-pituitary-adrenal (HPA) axis response of male and female Dark Agouti rats during EAE. At the onset of EAE, Crh expression in the hypothalamus of both sexes is decreased, while males show reduced plasma adrenocorticotropic hormone levels. Adrenal gland activity is increased during EAE in both males and females, as evidenced by enlarged adrenal glands and increased StAR gene and protein expression. However, only male rats show increased serum and adrenal corticosterone levels, and an increased volume of the adrenal cortex. Adrenal 3ß-HSD protein and progesterone levels are elevated in males only. Serum progesterone levels of male rats are also increased, although testicular progesterone levels are decreased during the disease, implying that the adrenal gland is the source of elevated serum progesterone levels in males. Our results demonstrate a sex difference in the response of the HPA axis at the adrenal level, with male rats showing a more pronounced induction during EAE.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Hypothalamo-Hypophyseal System , Pituitary-Adrenal System , Animals , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Male , Pituitary-Adrenal System/metabolism , Rats , Hypothalamo-Hypophyseal System/metabolism , Corticosterone/blood , Adrenocorticotropic Hormone/blood , Adrenal Glands/metabolism , Adrenal Glands/pathology , Sex Characteristics , Progesterone/bloodABSTRACT
Dysregulations in cholesterol homeostasis contribute to the pathogenesis of multiple sclerosis (MS) and its best described animal model, experimental autoimmune encephalomyelitis (EAE). Cholesterol is an important component of myelin, which is necessary for signal transmission between neurons. Demyelination leads to the formation of oxysterols, degradation products of cholesterol that are ligands for nuclear liver X receptors (LXRs). Genes regulated by LXRs are involved in cholesterol efflux, absorption, transport, and excretion, which we investigated in this study. In this study, we detected changes in gene expression of Srebf1, Ldlr, Soat1, Abca1, Lrp1, and Npc1, all of which are important in the regulation of cholesterol homeostasis, during the course of EAE in male and female rats. In particular, differential expression of Srebf1, Ldlr, and Soat1 was observed in the spinal cord of male and female rats during EAE. Moreover, these genes are altered during EAE. In contrast, the expression of Abca1 and Lrp1 was significantly affected only by sex. In male animals, the expression of Npc1 is conspicuously reduced in EAE pathology. Thus, our study confirms the involvement of enzymes of cholesterol metabolism in the pathophysiology of EAE, with sex and disease progression affecting the expression of these genes. These findings may improve the understanding of neurodegenerative diseases associated with impaired lipid metabolism in the brain, such as MS/EAE.
ABSTRACT
Inflammation, demyelination, and axonal damage to the central nervous system (CNS) are the hallmarks of multiple sclerosis (MS) and its representative animal model, experimental autoimmune encephalomyelitis (EAE). There is scientific evidence for the involvement of growth hormone (GH) in autoimmune regulation. Previous data on the relationship between the GH/insulin like growth factor-1 (IGF-1) axis and MS/EAE are inconclusive; therefore, the aim of our study was to investigate the changes in the GH axis during acute monophasic EAE. The results show that the gene expression of Ghrh and Sst in the hypothalamus does not change, except for Npy and Agrp, while at the pituitary level the Gh, Ghrhr and Ghr genes are upregulated. Interestingly, the cell volume of somatotropic cells in the pituitary gland remains unchanged at the peak of the disease. We found elevated serum GH levels in association with low IGF-1 concentration and downregulated Ghr and Igf1r expression in the liver, indicating a condition resembling GH resistance. This is likely due to inadequate nutrient intake at the peak of the disease when inflammation in the CNS is greatest. Considering that GH secretion is finely regulated by numerous central and peripheral signals, the involvement of the GH/IGF-1 axis in MS/EAE should be thoroughly investigated for possible future therapeutic strategies, especially with a view to improving EAE disease.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Growth Hormone , Insulin-Like Growth Factor I , Animals , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/genetics , Female , Rats , Growth Hormone/metabolism , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor I/genetics , Hypothalamus/metabolism , Hypothalamus/pathology , Pituitary Gland/metabolism , Pituitary Gland/pathology , Receptors, Somatotropin/metabolism , Receptors, Somatotropin/genetics , Receptors, Pituitary Hormone-Regulating Hormone/genetics , Receptors, Pituitary Hormone-Regulating Hormone/metabolism , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Multiple Sclerosis/genetics , Growth Hormone-Releasing Hormone/metabolism , Growth Hormone-Releasing Hormone/genetics , Liver/metabolism , Liver/pathology , Disease Models, AnimalABSTRACT
BACKGROUND AND OBJECTIVES: induced sputum is used to assess different inflammatory phenotypes in asthma, but is not used routinely. We aimed to determine the proportion of inflammatory asthma phenotypes based on induced sputum, to find biomarkers that can discriminate between phenotypes, and to evaluate biomarkers in patients with and without biological therapy in different inflammatory asthma phenotypes. MATERIALS AND METHODS: this cross-sectional study investigated clinical characteristics, asthma control tests, skin prick test, impulse oscillometry (IOS), spirometry, induced sputum, biomarkers (IgE, eosinophils, fractional exhaled nitric oxide (FeNO), serum periostin, IL-5, IL-6, IL-8, IL-17A, IL-33) in 80 asthmatics. A total of 17/80 patients were treated with biologics (10 with omalizumab, 7 with benralizumab). RESULTS: a total of 31% of patients had eosinophilic asthma (EA), 30% had mixed granulocytic asthma (MGA), 24% had paucigranulocytic asthma (PGA), and 15% had neutrophilic asthma (NA). The difference was found in blood eosinophils (p = 0.002), the highest observed in EA. The cut-off ≥ 240/µL eosinophils, with 64% sensitivity and 72.7% specificity, identified EA (AUC = 0.743, p = 0.001). A higher IL-8 level was associated with NA (p = 0.025). In 63 non-biologic asthma group, eosinophils were higher in EA than in NA, MGA, and PGA (p = 0.012, p = 0.028, and p = 0.049, respectively). A higher IL-17A was associated with EA without biologics (p = 0.004). A significantly higher IL-5 was found in EA treated with biologics, in comparison with EA without biologics (p = 0.043). The number of leucocytes and neutrophils was higher in MGA without biologics (p = 0.049, p = 0.019), while IL-5, IL-6, and IL-8 levels were higher in MGA treated with biologics (p = 0.012, p = 0.032, p = 0.038, respectively). CONCLUSIONS: EA and MGA were the most prevalent asthma phenotypes. Blood eosinophils can identify EA, both in patients with and without biologics. Apart from the clinical profile, a broad spectrum of biomarkers for assessing inflammatory phenotypes is necessary for an adequate therapy approach to patients with asthma.
ABSTRACT
Multiple sclerosis (MS) is an autoimmune disease affecting the CNS and occurring far more prevalently in women than in men. In both MS and its animal models, sex hormones play important immunomodulatory roles. We have previously shown that experimental autoimmune encephalomyelitis (EAE) affects the hypothalamic-pituitary-gonadal axis in rats of both sexes and induces an arrest in the estrous cycle in females. To investigate the gonadal status in female rats with EAE, we explored ovarian morphometric parameters, circulating and intraovarian sex steroid levels, and the expression of steroidogenic machinery components in the ovarian tissue. A prolonged state of diestrus was recorded during the peak of EAE, with maintenance of the corpora lutea, elevated intraovarian progesterone levels, and increased gene and protein expression of StAR, similar to the state of pseudopregnancy. The decrease in CYP17A1 protein expression was followed by a decrease in ovarian testosterone and estradiol levels. On the contrary, serum testosterone levels were slightly increased. With unchanged serum estradiol levels, these results point at extra-gonadal sites of sex steroid biosynthesis and catabolism as important regulators of their circulating levels. Our study suggests alterations in the function of the female reproductive system during central autoimmunity and highlights the bidirectional relationships between hormonal status and EAE.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Male , Rats , Female , Animals , Gonadal Steroid Hormones/metabolism , Ovary/metabolism , Testosterone/metabolism , Estradiol/metabolismABSTRACT
Drug hypersensitivity reactions (DHRs) are a type of adverse drug reactions with heterogeneous pathophysiological mechanisms and a broad spectrum of clinical manifestations. Since over-diagnosing is common in children, a complete allergy work-up is needed. A cross-sectional study was conducted at a tertiary care institution, covering the five-year period. Five hundred and four patients of both sexes, mean age 7.5 and with a medical history suggestive of DHR were evaluated. ENDA/EAACI guidelines were used for a diagnostic algorithm. Single drug hypersensitivity was registered in 375 patients and multiple drug hypersensitivity in 129. The main culprits in medical history were antibiotics (83%), non-steroidal anti-inflammatory drugs (NSAIDs) (8.4%) and analgoantipyretics (3.8%). Skin involvement was registered in 96.2%. DHRs were confirmed in 4.4% patients-six patients had positive skin tests and 13 had a positive drug provocation test. In the proven DHRs group, the main agents were antibiotics (72.7%), followed by NSAIDs (8.3%), and of all the skin manifestations, urticaria was most common (78.2%), followed by exanthema (10.5%) and angioedema (5.3%). Considering the above, anticipating DHRs and a proper referral of children to an allergologist is a key step in the assessment of drug hypersensitivity. A complete allergy work-up prevents unnecessary drug exclusion and allows most children to safely continue the use of first-line medications when needed.
ABSTRACT
Preschool children are particularly susceptible to recurrent upper and lower respiratory tract infections due to their immune immaturity and other contributing factors. Preventing and/or treating children suffering from recurrent respiratory tract infections (RRTIs) is challenging, and it is important to provide more clinical evidence about the safety and efficacy of natural immunomodulating preparations, including ß-glucans. The aim of the present study was to assess the incidence of respiratory tract infections (RTIs) in children with a history of RRTIs for a period of 6 months (3 months of pleuran supplementation and 3 months of follow-up) compared with the same period from October to March of the previous year prior to enrolment in the study. A total of 1,030 children with a mean age of 3.49 ± 1.91 years from seven countries were included in this study. The total number of RTIs observed during the study period was significantly lower compared to the same period of the previous year (7.07 ± 2.89 vs. 3.87 ± 3.19; p < 0.001). Analysis of each type of RTI revealed significant reductions in the mean number and duration of infections for all RTI subtypes compared to the previous year. This study also confirmed the beneficial safety profile of pleuran supplementation. In conclusion, pleuran supplementation represents an interesting and prospective supplement in preventing respiratory infections and reveals new strategies for supporting immune functions in the paediatric population.
ABSTRACT
Neuroinflammation and microglial activation, common components of most neurodegenerative diseases, can be imitated in vitro by challenging microglia cells with Lps. We here aimed to evaluate the effects of agmatine pretreatment on Lps-induced oxidative stress in a mouse microglial BV-2 cell line. Our findings show that agmatine suppresses nitrosative and oxidative burst in Lps-stimulated microglia by reducing iNOS and XO activity and decreasing O2- levels, arresting lipid peroxidation, increasing total glutathione content, and preserving GR and CAT activity. In accordance with these results, agmatine suppresses inflammatory NF-kB, and stimulates antioxidant Nrf2 pathway, resulting in decreased TNF, IL-1 beta, and IL-6 release, and reduced iNOS and COX-2 levels. Together with increased ARG1, CD206 and HO-1 levels, our results imply that, in inflammatory conditions, agmatine pushes microglia towards an anti-inflammatory phenotype. Interestingly, we also discovered that agmatine alone increases lipid peroxidation end product levels, induces Nrf2 activation, increases total glutathione content, and GPx activity. Thus, we hypothesize that some of the effects of agmatine, observed in activated microglia, may be mediated by induced oxidative stress and adaptive response, prior to Lps stimulation.
Subject(s)
Agmatine , NF-E2-Related Factor 2 , Agmatine/metabolism , Agmatine/pharmacology , Animals , Glutathione/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Lipopolysaccharides/pharmacology , Mice , Microglia/metabolism , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Oxidative StressABSTRACT
Therapeutic recommendations for pediatric acute respiratory distress syndrome (PARDS) include conventional (CMV) and rescue high-frequency oscillatory mode (HFOV) of mechanical ventilation (MV). The pediatric risk of mortality (PRISM) is a frequently used mortality score for critically ill patients. In search of methods to recognize those patients, we analyzed the PRISM III score as a potential predictor of the short-term outcome in MV subjects with PARDS. A retrospective five-year study of PARDS in children on MV was conducted in the Pediatric ICU. Seventy patients were divided into two groups (age group <1 year and age group 1−7 years). The PRISM III score was used to assess the 28-day outcome and possible development of complications. The most common causes of PARDS were pneumonia and sepsis. Male sex, malnourishment, sepsis, and shock were significant indicators of poor outcome. The PRISM III score values were significantly higher in those who died, as well as in subjects requiring HFOV. The score had a significant prognostic value for short-term mortality. There was no significant difference in outcome based on the comparison of two modes of ventilation. A significantly higher score was noted in subjects who developed sepsis and cardiovascular insufficiency. The PRISM III score is a fair outcome predictor during the 28-day follow-up in MV subjects with PARDS, regardless of the ventilation mode.
ABSTRACT
PURPOSE: The aim of this study was to assess the association between oxygenation index (OI) and outcome in children with acute respiratory distress syndrome (ARDS). PATIENTS AND METHODS: Patients (age, >30 days) in the pediatric intensive care unit from April 2011 to March 2016 with ARDS and who were mechanically ventilated were included. Patients were divided into two age groups: infants (<12month) and older children. Lowest PaO2/FiO2 and SpO2/FiO2 ratios and highest mean airway pressure (MAP) were recorded on the ï¬rst day of ARDS and after 72 h. OI was calculated on the first and third days of mechanical ventilation (MV) and its association with OI (first and third days) and short-term mortality evaluated at 28 days. RESULTS: MV was initiated a mean of 2.3 days after admission (median, 1.0 day; maximum 14 days). The average MV duration for all patients was 11.8 (median, 7.0) days. Mean (95% confidence interval (CI)) OI values on the first day of MV were 14.17 (11.94-16.41), 12.72 (10.68-14.75), and 13.24 (11.73-14.74) for infants, older children, and all participants, respectively. In survivors (n=39) mean OI was 11.66 (9.64-13.68) compared with 15.22 (13.03-17.40) in non-survivors (n=31). Logistic regression analysis revealed that OI on day 3 had highly significant prognostic value for mortality (odds ratio, 256.5, 95% CI 27.1-2424, p<0.001), with an AUC of 0.919 (cut-off value, 17; positive predictive value, 0.905; negative predictive value, 0.964; p=0.0001). In contrast, OI on day 1 did not have significant prognostic value (AUC, 0.634; p=0.056) for short-term mortality. Different modes of MV were not significantly associated with outcome (p>0.05). CONCLUSION: OI is a simple, highly accurate, and sensitive predictor of the survival (short-term mortality) of children mechanically ventilated for ARDS.
ABSTRACT
Background: High heterogeneity levels of cystic fibrosis transmembrane regulator (CFTR) are manifested in different populations. The aim of this study was to analyze comprehensively all mutations in the CFTR gene in Serbian patients with cystic fibrosis (CF) and to use the findings to propose a testing algorithm for the Serbian population. Materials and Methods: Cascade screening was employed to detect mutations in the CFTR gene of 90 patients suspected of having CF, using polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism or PCR-mediated site directed mutagenesis, Sanger sequencing, and/or next-generation sequencing. Results: This is the first report for the Serbian CF population where single nucleotide polymorphisms, small insertions and deletions, large genome rearrangements, and copy number variants were analyzed in detail. A high degree of heterogeneity within the CFTR was documented among our cohort of 90 patients. We identified 19 CF-causing mutations and 3 with varying consequences, including a previously unreported deletion of the entire exon 11. Conclusion: Considering the spectrum and frequency of mutations found, we recommend a multistep sequencing algorithm in combination with evaluation of large rearrangements for future analyses of the CFTR gene in the Serbian population.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis/diagnosis , Cohort Studies , Cystic Fibrosis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Exons/genetics , Female , Genetics, Population/methods , High-Throughput Nucleotide Sequencing/methods , Humans , Male , Mutation/genetics , Pathology, Molecular/methods , Polymerase Chain Reaction/methods , Polymorphism, Restriction Fragment Length/genetics , Serbia/epidemiologyABSTRACT
PURPOSE: The maintaining of asthma control is difficult due to high variability in response to therapy among patients. Since matrix metalloproteinase 9 (MMP9) is implicated in inflammation and remodeling of asthmatic airways, it could be associated with adequate response to asthma therapy. The aim of this study was to investigate whether variants in 3' end of the MMP9 gene are associated with clinical phenotype and responsiveness to treatment in children with asthma. METHODS: The study included 127 asthmatic children from Slovenia. Variants in the 3' end of the MMP9 gene were analyzed by direct DNA sequencing and the obtained results were correlated with clinical parameters. RESULTS: Two variants were detected, rs13925 and rs20544. For the variant rs20544, statistically significant difference in airway hyperresponsiveness (p = 0.011) and asthma control (p = 0.049) between genotypes was found. Patients with TT genotype had lower airway sensitivity, and after 12 months of treatment showed significant improvement in Asthma Control Test (ACT) scores compared to CC and CT genotype. For the variant rs13925, the association with lung function was observed. The carriers of A allele showed noticeable improvement of lung function after the first 6 months of treatment in comparison to the carriers of G allele (p = 0.046). CONCLUSION: The main finding of our study is the association of MMP9 genotypes rs20544 TT and rs13925 AA and AG with better asthma control, and indirectly better response to treatment. Based on these results, MMP9 deserves further research as a potential predictive biomarker for asthma.
Subject(s)
3' Untranslated Regions/genetics , Asthma/genetics , Matrix Metalloproteinase 9/genetics , Respiratory Hypersensitivity/genetics , Acetates/therapeutic use , Adolescent , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Asthma/physiopathology , Bronchodilator Agents/therapeutic use , Child , Cyclopropanes , Female , Fluticasone/therapeutic use , Forced Expiratory Volume , Genetic Variation , Humans , Male , Nitric Oxide , Prognosis , Quinolines/therapeutic use , Respiration , Sequence Analysis, DNA , Slovenia , Sulfides , Treatment Outcome , Vital CapacityABSTRACT
INTRODUCTION: The significance of oxidative stress in pathogenesis of childhood asthma was recognized, but its role in the clinical manifestations of disease is still unclear. MATERIALS AND METHODS: The study was conducted in 96 asthmatic children. The urinary biomarker of oxidative stress, 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG/creatinine) was determined by using HPLC-MS/MS. ELISA was performed to measure myeloperoxidase (MPO) and Cu,Zn- superoxide dismutase (Cu,Zn-SOD) in serum. RESULTS: Logistic regression analysis revealed that female gender, tobacco smoke exposure, and increased 8-oxodG/creatinine were associated with risk for intermittent asthma, while the positive allergy test and increased Cu,Zn-SOD were associated with eczema in asthmatic children. Higher MPO (p = 0.033), and percent of granulocytes (p = 0.030) were found in severe persistent asthma in comparison to intermittent or mild persistent asthma. CONCLUSION: The main findings that TSE-induced oxidative stress is a risk for intermittent asthma and eczema may be clinically significant for the disease prevention and therapeutic improvements.
Subject(s)
Asthma/etiology , Oxidative Stress , Tobacco Smoke Pollution/adverse effects , 8-Hydroxy-2'-Deoxyguanosine , Adolescent , Asthma/metabolism , Biomarkers/analysis , Child , Child, Preschool , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/urine , Eczema/etiology , Female , Humans , Male , Peroxidase/blood , Superoxide Dismutase-1/blood , Young AdultABSTRACT
Transforming growth factor beta 1 (TGFB1) is a multifunctional cytokine with a key role in asthma airway inflammation and remodeling. Since elevated levels of this cytokine in airways might be associated with response to asthma therapy, the aim of this study was to investigate whether the presence of the polymorphism C-509T in the promoter of the TGFB1 gene is associated with response to montelukast. A group of 102 asthmatic patients was genotyped for the presence of the C-509T polymorphism by DNA sequencing and subjected to induced sputum sampling. Cells from sputum samples and BEAS 2B cells were treated with montelukast and endogenous TGFB1 expression was measured by quantitative real-time polymerase chain reaction. The promoter activity was analyzed by luciferase assays in BEAS 2B cells transfected with constructs carrying variants -509C and -509T of the TGFB1 gene promoter. After treatment with montelukast, the decrease in TGFB1 gene expression was greater for the -509TT genotype (58.9%) than for the -509CC and -509CT genotypes (49.6% and 31.8%, respectively) (P = 0.071). In BEAS 2B cells, expression of endogenous TGFB1 was reduced by about 27% after montelukast treatment, while luciferase activity of both promoter variants was increased after montelukast treatment (-509C allele: 48.3%, P = 0.060; and -509T allele: 100.5%, P = 0.062). A more intensive response was registered in the promoter containing the -509T allele, which had 135% higher activity than the -509C variant (P = 0.035). This study showed that the presence of the -509T allele in the TGFB1 promoter might modulate effects of montelukast on TGFB1 gene expression, but future studies are necessary, taking into consideration other genetic and nongenetic factors. It is of potential importance for clinical management of asthma to clarify the influence of the C-509T polymorphism on the response to treatment with montelukast.
ABSTRACT
BACKGROUND: The aim of this study was to investigate polymorphisms in the promoter region of the neutrophil elastase (ELANE) gene as potential modulators of the therapeutic response in children with idiopathic bronchiectasis. METHODS: The study included 48 children between 5 and 17 years old who were diagnosed with idiopathic bronchiectasis based on high-resolution computed tomography of the thorax. In all patients therapy included administration of antibiotics, anti-inflammatory drugs, expectorants, and postural drainage. Response to therapy was evaluated by the change in FeNO levels before and after administration of therapy. The ELANE promoter region polymorphisms were analyzed by PCR-direct DNA sequencing. RESULTS: According to the predicted activity of ELANE genotypes, subjects were divided into two groups: low/intermediate activity (n = 18) and high activity (n = 30). Subjects in the group with high-activity genotype had higher initial FeNO levels and this difference was statistically significant (t = 2.906; p = 0.006). The difference between FeNO levels before and after therapy was also statistically significantly higher in children with high-activity genotype (t = 3.329; p = 0.002). Statistically significant correlation was observed between the change in FeNO levels and ELANE genotypes (r = 0.350; p = 0.015). CONCLUSION: Children with high-activity genotype had higher initial FeNO levels and showed better response to therapy than children with low/intermediate-activity genotypes.
Subject(s)
Bronchiectasis/genetics , Bronchiectasis/therapy , Leukocyte Elastase/genetics , Polymorphism, Genetic , Adolescent , Age Factors , Anti-Bacterial Agents/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Breath Tests , Bronchiectasis/diagnostic imaging , Bronchiectasis/enzymology , Bronchiectasis/physiopathology , Child , Child, Preschool , Drainage/methods , Expectorants/therapeutic use , Female , Genetic Predisposition to Disease , Humans , Lung/physiopathology , Male , Phenotype , Predictive Value of Tests , Promoter Regions, Genetic , Respiratory Function Tests , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
BACKGROUND: Mechanical ventilation is a frequently applied therapy in critically ill children and can be lifesaving in many cases. Clinical use of this technique has well documented benefits, but can be associated with different complications and adverse physiologic effects. OBJECTIVES: The aim of this study was to investigate the complications and clinical outcome of mechanical ventilation in Serbian pediatric patients. MATERIAL AND METHODS: The study encompassed 42 children with respiratory insufficiency that underwent mechanical ventilation during hospitalization over a period of 12 consecutive months. The influence of clinical and mechanical parameters on the occurrence of complications and clinical outcome were analyzed. RESULTS: The patients were ventilated for a total of 432 days and a total of 61 complications were observed in 42 patients (97 complications per 1000 ventilation days). The most common complications associated with mechanical ventilation in Serbian pediatric patients with respiratory insufficiency were cardiovascular insufficiency (52.4%) and multiple organ failure (35.7%). High values of applied PIP (> 26 cm H 2 O), PEEP (> 6 cm H 2 O) and Tv (> 6 mL/kg) were associated with the occurrence of complications and negative clinical outcome. CONCLUSIONS: Complications of mechanical ventilation in the pediatric population occur frequently, but lower volumes/pressures of ventilation contribute to a decrease in incidence. Further studies are needed to examine associated risk factors and strategies to reduce the occurrence of complications and improve clinical outcome.
Subject(s)
Respiration, Artificial/adverse effects , Adolescent , Child , Child, Preschool , Female , Humans , Infant , MaleABSTRACT
We present a case of a 19-year old male with uncommon initial clinical cystic fibrosis (CF) presentation and a rare CFTR genotype, homozygote for c.1393-1G>A mutation (legacy name 1525-1G>A).
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis/diagnosis , Cystic Fibrosis/genetics , Point Mutation , Severity of Illness Index , Genotype , Homozygote , Humans , Male , Phenotype , Young AdultABSTRACT
A 36-year-old woman was stung in the right wrist by a bee, suffered typical anaphylaxis, and was transferred to a local hospital. After a few hours, which corresponded to late-onset reaction, she developed shortness of breath and weakness and was transferred to the emergency department, where the diagnosis of anaphylaxis was confirmed. Serum complement levels, components C3 and C4, were undetectable. Flexible bronchoscopy excluded lung hemorrhage. She was on the ventilator for 4 days and was fully awake during that time. After the treatment, her improvement was rapid, and she fully recovered. Three weeks after she had been stung by a bee, skin prick tests to bee, wasp, and yellow jacket venom were done, and all tests came back negative as well as IgE and IgG4 antibodies to the same venoms. Coagulation factors and the complement, including C1q inhibitor, were normal. Occurrence of complement activation and consumption could point to the immune complexes as basis of pathophysiological mechanism. It remains unclear why such a reaction would involve only the right lung and why no detectable immune complexes were discovered. The clinical picture in the presented case resembled acute respiratory distress syndrome, but the exact nature of lung consolidation remains puzzling. The most likely explanation is a very rare case of airway obstruction. To our knowledge, this is the only reported case of anaphylaxis associated with undetectable serum complement levels. The potential role and diagnostic significance of hypocomplementemia in cases of anaphylaxis should be further investigated.
Subject(s)
Anaphylaxis/complications , Complement System Proteins/deficiency , Lung Diseases/etiology , Adult , Anaphylaxis/etiology , Bee Venoms/adverse effects , Complement C3/analysis , Complement C3/deficiency , Complement C4/analysis , Complement C4/deficiency , Complement System Proteins/analysis , Female , Humans , Insect Bites and Stings/complications , Lung/diagnostic imaging , Lung/pathology , Lung Diseases/diagnostic imaging , Lung Diseases/pathology , RadiographyABSTRACT
This study has investigated a potential role of common Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene variants in the etiology of noncystic fibrosis bronchiectasis in Serbian children. The study has encompassed 48 patients (19 male and 29 female, aged between 5 and 18 years, median age 10.6±3.3), diagnosed with idiopathic bronchiectasis based on high-resolution computed tomography of thorax and pathologic examination of lobectomy materials. The CFTR gene analysis was performed on genomic DNA extracted from peripheral blood samples of patients by polymerase chain reaction (PCR)-Mediated Site-Directed Mutagenesis method, Denaturing Gradient Gel Electrophoresis method, and DNA sequencing. Mutation c.1521_1523delCTT (F508del) was detected with an allelic frequency of 1.0%, and c.224G>A (R75Q) variant. Carriers of c.1210-12T[5] (IVS8-5T) allele were significantly more common than in the general population (10.4% vs. 5.0%, P=0.0302). The frequency of homozygotes for Met 470 allele was higher in patients than in the general population (33% vs. 20%), while heterozygotes for p.Met470Val were less frequent (31% vs. 50%), and this difference was statistically significant (P=0.0222). The results obtained in this study indicate involvement of 2 common CFTR variants, c.1210-12T[5] and c.1408A, in idiopathic bronchiectasis in children, but this observation should be further confirmed by more extensive analysis of the CFTR gene in a larger group of patients.
ABSTRACT
This paper reports a novel Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene variant, 1811+1G-->T, detected in a 5-year-old girl diagnosed with idiopathic disseminated bronchiectasis and negative sweat chloride test (17 mmol/L). The performed CFTR gene mutation analysis included detection of the F508del mutation, analysis of Tn polymorphism and screening of CFTR exons 3, 10 and 11. The CFTR gene screening has shown the altered band pattern in exon 11. The DNA sequencing of CFTR exon 11 revealed the presence of the novel sequence variation 1811+1G-->T in heterozygous state. This sequence variation was not found in any of 100 control alleles, analyzed by polymerase chain reaction - restriction fragment length polymorphism method. The novel sequence variation 1811+1G-->T is located at the splicing site at the boundary of exon 11 and intron 11 and might be either a sequence variation or a splicing site defect.