Semeniuk J

Respiratory response to proton pump inhibitor treatment in children with obstructive sleep apnea syndrome and gastroesophageal reflux disease

OBJECTIVE Evaluation of the respiratory response to proton pump inhibitors (PPI) in children with obstructive sleep apnea syndrome (OSAS) and gastroesophageal reflux disease (GERD). METHODS Of 131 children diagnosed with OSAS (Apnea Hypopnea Index, AHI >1/h), 37 children (6.9 years; 28.24%) with GERD symptoms (>3 times/week) were included. Overnight polysomnography with 24h pH-metry was performed before and after 4-8 weeks of PPI treatment (omeprazole once a day, 1mg/kg). RESULTS Of 37 children, 21 were diagnosed with acid GERD where pre- and post-treatment reflux indexes were 14.09±1.47 vs. 7.73±1.36; (p<0.001). The number of obstructive apneas and hypopneas decreased after PPI treatment, resulting in an AHI reduction from 13.08±3.11/h to 8.22±2.52/h; (p<0.01). Respiratory response to PPI ranged from complete resolution of OSA (three children with mild OSA; AHI<5/h; 10.31years; 14.29%) to lack of significant AHI change (six children with severe OSA; AHI>10/h; 3.62 years; 28.57%). Post-treatment AHI was predicted by pre-treatment reflux index (adjusted R(2)=0.487; p<0.001). CONCLUSIONS Reduction of obstructive respiratory events following short-term PPI treatment in children with both GERD and OSAS may suggest a causal relationship between apnea and reflux in some children. Questionnaire screening for GERD in children with OSAS may be of benefit.

The natural history of cow's milk allergy in north-eastern Poland

PURPOSE The rate of cows milk allergy diminishes with age. There is not enough information concerning geographical trends in persistent cows milk allergy in children. The objective of the study was to evaluate the prevalence of persistent cows milk allergy in children previously diagnosed with IgE-mediated cows milk allergy (CMA). MATERIAL/METHODS Diagnosis of cows milk allergy was established by a medical history of symptoms associated with exposure to cows milk, positive skin prick tests with cows milk, the presence of milk-specific IgE, and by a positive double- or single-blind placebo-controlled food challenge with milk confirmed by a positive open-controlled milk challenge. A second oral challenge was performed after at least one year of a milk-free diet and children with a positive oral milk rechallenge were diagnosed as having a persistent CMA. RESULTS Two hundred ninety-one children, 2-14 years of age (mean 5.30±3.16 years, 95% CI, 5.02-5.62 years) completed the study. Persistent CMA was diagnosed in 79 patients (27.1%). Two hundred twelve children (72.9%) outgrew their allergy to cows milk at a mean age of 5 years after an average time of 16.4±0.8 months on an elimination diet. Eighty percent of children below 3 years of age became milk tolerant. Milk-specific IgE (p=0.018) and history of paternal bronchial asthma and/or rhinitis (p=0.020) were associated with persistence of cows milk allergy in regression analysis. CONCLUSIONS An age above 3 years, as well as features of atopy, individual and familial, may be associated with a risk of delayed tolerance to milk in children.

The evaluation of angiogenesis and matrix metalloproteinase-2 secretion in bone marrow of multiple myeloma patients before and after the treatment

PURPOSE Angiogenesis appears to be a prominent feature of many hematological disorders, particularly in multiple myeloma (MM). Progression in MM also involves secretion of the metaloproteinases (MMPs). In this study, the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and its receptor, in bone marrow trephine biopsy (TB) of thirty six MM patients before and after the treatment or during progression was examined. The MMP-2 secretion was assessed from the same patients. MATERIAL/METHODS Immunohistochemical staining of bone marrow specimens for angiogenic factors and microvessel density (MVD) and bone marrow aspirates for Western blot analysis of MMP-2 expression was performed. RESULTS In active, untreated MM patients, we found statistically significant differences in the expression of angiogenic factors according to the patients after the anti-angiogenic treatment. We found statistical differences of the expression of angiogenic factors between the group of patients with a response after the treatment and the patients who had progression during the treatment. The data showed statistically significant decreased MVD after the treatment. The results showed statistically significant differences between initial secretion of MMP-2 in active, untreated MM patients and patients with a response after the treatment and patients with progression during the treatment. CONCLUSIONS We showed that not only decreased expression of angiogenic cytokines is present after the anti-angiogenic treatment but also activity of MMP-2 in MM patients who responded to the treatment. Combination therapy with the inhibition of the activity of MMPs could represent an interesting therapeutical approach in MM.

Manometric study of lower esophageal sphincter in children with primary acid gastroesophageal reflux and acid gastroesophageal reflux secondary to food allergy

PURPOSE The comparison of values of selected lower esophageal sphincter (LES) manometric parameters measured in children suspected of gastroesophageal reflux disease (GERD) (preliminary study) and in children with primary acid GER and acid GER secondary to cows milk allergy and/or other food (CMA/FA) in relation to the duration of the disease (prospective study). MATERIAL AND METHODS A 24-hour esophageal pH monitoring was performed on 264 children of both sexes suspected of GERD (mean age x=20.78+/-17.23 months). Pathological acid gastroesophageal reflux (GER) was diagnosed and divided into primary and secondary reflux in 138 children (52.3%). 76 patients (28.8%) (x=25.2+/-27.28 months) with primary GER made up Group 1. Group 2 consisted of 62 patients (23.5%) (x=21.53+/-17.79 months) with GER secondary to CMA/FA. 32 patients (12.1%) (x=23.7+/-12.63 months) with CMA/FA symptoms made up Group 3 (reference group). Prospective assessment of LES manometric parameters, i.e. resting LES pressure and LES length, was performed on 138 children with GER. Manometric parameters, resting LES pressure and LES length, measured at the preliminary study (0) and control studies (after 1, 2 and 8 years), were prospectively assessed in 138 children. The assessment resulted from clinical observation and/or conservative treatment. RESULTS The mean value of resting LES pressure (mm Hg) before treatment was x=11.75+/-3.98 in Group 1, x=11.05+/-3.31 in Group 2, and x=14.17+/-3.86 in Group 3 (reference group). After 2 years of clinical observation, the mean value of resting LES pressure accounted for x=13.71+/-3.88 in Group 1, x=13.01+/-2.94 in Group 2, and x=17.92+/-3.36 in Group 3. The mean LES length (cm) before treatment accounted for x=1.68+/-0.72 in Group 1, x=1.78+/-0.70 in Group 2, and x=2.0+/-0.86 in Group 3. After 2 years of clinical observation, the mean LES length was x=2.80+/-0.40 in Group 1, x=2.76+/-0.40 in Group 2, and x=2.97+/-0.48 in Group 3. 12 children with persistent GERD (Group 1) and 8 children with persistent GERD and food allergy (Group 2) underwent manometric evaluation of LES after 8 years. No statistical differentiation of the mean values of resting LES pressure and LES length were shown in examined children of Groups 1 and 2 during prospective studies. CONCLUSIONS Manometric studies of LES assessing only resting LES pressure and its length in the examined children with acid GER do not clearly differentiate GER into primary and secondary refluxes to food allergy.

Bone marrow megakaryocytes, soluble P-selectin and thrombopoietic cytokines in multiple myeloma patients

Abstract The expression of adhesion molecules and other cell-surface molecules is substantial in the communication between plasma cells and bone marrow microenvironment, and may lead to increased proliferation of myeloma cells. Many of the cytokines involved in multiple myeloma (MM) pathogenesis, e.g. thrombopoietin (TPO) and interleukin-6 (IL-6), play a pivotal role in different developmental stages of megakaryocytopoiesis and thrombopoiesis. The principal aim of our study was to explore the relationship between thrombopoietic cytokines, megakaryocytes (MKs) and soluble P-selectin (sP-selectin) levels in MM patients before and after anti-angiogenic treatment. Forty-four patients (20 female and 24 male) with a newly diagnosed MM were examined in three groups, following a division based on the International Staging System, ISS. Plasma levels of TPO, IL-6 and soluble P-selectin (human sP-selectin) were measured by means of ELISA. Bone marrow specimens were studied to determine the number of MKs and the so-called “naked nuclei” (NN), as well as the expression of platelet-derived growth factor (PDGF). The comparison revealed a significantly higher concentration of cytokines and sP-selectin in newly diagnosed MM patients compared to healthy volunteers: for TPO, p = 0.01, IL-6, p = 0.0005 and sP-selectin, p = 0.00008, respectively. Marked differences were observed in the concentration of sP-selectin, expression of PDGF and MKs counts between patients with MM stage I and MM stage III. Statistically meaningful correspondences were also found between MKs versus TPO, NN versus TPO, as well as MKs versus MPV, p = 0.009, p = 0.004 and p = 0.0005, respectively. Furthermore, the analysis exhibited some statistically meaningful divergences between initial concentrations of sP-selectin in subgroups with different response after chemotherapy. The initial concentration of sP-selectin in the group of MM patients with complete or partial remission stood at 31.86 ± 6.13 ng/ml. In the remaining patients (stable disease), the concentration of sP-selectin amounted to 35.15 ± 7.23 ng/ml (p = 0.048). We found a correlation between sP-selectin and IL-6 (ρ = 0.57, p = 0.0004), TPO and IL-6 (ρ = 0.46, p = 0.001) as well as sP-selectin and TPO (ρ = 0.36, p = 0.043), and sP-selectin and PDGF (ρ = 0.36, p = 0.03). Our study has eventually demonstrated that sP-selectin, as a marker of platelet activation, could be a useful marker of maximum response to therapy. Its strong association with another marker like PDGF-AB could further lead to the development of new combinational therapeutic strategies of anti-angiogenic therapy in MM patients.

Histological evaluation of esophageal mucosa in children with acid gastroesophageal reflux

AIM histological evaluation of esophageal mucosa in children, with regard to the duration of primary acid gastroesophageal reflux (GER) and acid GER secondary to cows milk allergy and/or other food allergy (CMA/FA) (prospective study). MATERIAL AND METHODS 264 children of both sexes suspected of GER were enrolled in the study. The age of examined children was 1.5-102 months, mean age 20.78+/-17.23 months. Pathological acid GER was confirmed with pH-monitoring in 138 children (52.3%). Taking into consideration complex differential diagnosis, including oral food challenge test with potentially noxious nutrient (open or blind study), children were assigned into study groups 1 and 2 (primary and secondary GER). Group 1: 76 patients (28.8%) aged 4-102 months (x=25.2+/-27.28 months) with primary GER. Group 2: 62 patients (23.5%) aged 4-74 months (x=21.53+/-17.79 months) with GER secondary to CMA/FA. Children with GERD underwent preliminary and control (after 1 year and 2 years of GERD diagnosis) endoscopic examination of the upper gastroinestinal tract. RESULTS Intensity of esophagitis was assessed initially in 25 children from group 1 (32.9%), in 29 children from group 2 (46.8%), and in 9 children from group 3 - reference group (28.1%). Histological evaluation revealed infiltration of inflammatory cells, mainly neutrophils and intraepithelial lymphocytes, and also eosinophils in 10 children (13.2%) with primary GER. Infiltration of eosinophils and lymphocytes was found in 5 children (8.1%) with secondary GER. In 8 children (25.0%) with food allergy there were only lymphocytes. Infiltration of neutrophils and lymphocytes and basal zone hyperplasia or infiltration of eosinophils and lymphocytes with elongation of lamina propria papillae was found in 10 children (13.1%) with primary GER and in 20 children (32.2%) with secondary GER. Differentiation of particular types of inflammatory cells in mucosal infiltration characterized histological picture in the following way: neutrophils in 21 children (27.6%) with primary GER, eosinophils in 22 children (35.5%) with secondary GER, lymphocytes in 15 children (19.7%) in children with primary GER and in 15 children (24.2%) with secondary GER. Histological examination of esophageal mucosa after 1 and 2 years of clinical observation and periodical conservative treatment in children with primary and secondary GER revealed significant alleviation of inflammatory abnormalities (with regard to the type of abnormalities and the number of particular types of inflammatory cells). CONCLUSIONS The value of histological findings obtained in own studies comprises the role of food allergy in pathogenesis of GER and is related to GERs contribution, both direct (primary reflux) and indirect (secondary reflux), to triggering off morphological results and clinical outcomes of esophagitis.

The levels of sMUC-1 in patients with multiple myeloma

Mucins have been shown to be aberrantly overexpressed in various diseases including cystic fibrosis, asthma, and cancer. Recent studies have uncovered the roles of these mucins in the pathogenesis of cancer. The presence of MUC-1 has also been detected on the cell surface of multiple myeloma (MM) cells in peripheral blood and showed direct correlation with tumor mass. In this study, we evaluated the levels of soluble MUC-1 (sMUC-1) in 50 new MM patients and correlated this with the levels of sMUC-1 after treatment. High levels of sMUC-1 were found in 20/50 (40%) MM patients, and in 2/50 (4%) healthy individuals (p = 0.001). According to the ISS, we found significant differences of mean sMUC-1 levels between the first stage of the disease (0.63 ± ± 0.26) and the third (0.93 ± 0.24; p = 0.03), but not with the second stage (0.80 ± 0.22; p = 0.08). Our study confirmed the correlation between elevated sMUC-1 and high elevated lactate dehydrogenase (p = 0.03) and the level of IgG in groups of patients with MM IgG at every stage of disease (p = 0.001). We showed for the first time that levels of sMUC-1 after treatment, in a group of patients with initially elevated levels of MUC-1, were statistically lower than in a group of patients with initially lower levels of sMUC-1 (21% vs. 42,6%; p = 0.05). At 37 months median of follow-up, we found a statistically significant difference between patients with normal versus elevated sMUC-1 in terms of progression-free survival (median 12 months vs. 8.1 months; p = 0.03).

Serum gastrin concentrations in children with primary gastroesophageal reflux and gastroesophageal reflux secondary to cow's milk allergy

PURPOSE The assessment of the serum gastrin concentrations and the role of enterohormone in children with primary acid gastroesophageal reflux (GER) and GER secondary to cows milk allergy (CMA). MATERIALS/METHODS 138 children were diagnosed with pathological acid GER on the basis of pH-metric examination. 76 (28.8%) patients had primary GER and 62 (23.5%) patients had GER secondary to CMA.Serum gastrin concentration (fasting and postprandial) was assessed before treatment and 1 and 2 years after initiation of the therapy. RESULTS The children with primary GER had the fasting gastrin concentration 69.46 ± 11.87 μU/ml before treatment, 77.86 ± 26.35 μU/ml after 1 year and 83.78 ± 25.21 μU/ml after 2 years of treatment. The children with GER secondary to CMA had gastrin concentrations 89.61 ± 26.75, 73.17 ± 19.49 and 73.90 ± 20.31 μU/ml respectively. The mean postprandial gastrin concentration after treatment was higher than before treatment in children with both primary and secondary GER. The primary GER group had postprandial gastrin concentration 96.07 ± 33.51 μU/ml before treatment and 116.06 ± 33.95 μU/ml and 118.48 ± 33.96 μU/ml after 1st and 2nd year of therapy respectively. The secondary GER group had postprandial gastrin concentration 85.33 ± 14.12 μU/ml before treatment and 106.55 ± 24.51 μU/ml and 110.36 ± 24.67 μU/ml after 1st and 2nd year of therapy respectively. CONCLUSIONS The mean fasting serum gastrin concentrations in patients with primary and secondary GER were similar and mean postprandial concentrations were higher than fasting concentrations in both study groups.

Sleep-wake schedules in preschool children who snore.

PURPOSE The aim of the study was to compare sleep-wake schedules between snoring and nonsnoring preschool age children. MATERIAL AND METHODS Daytime and nighttime sleep duration, daytime and nighttime symptoms were assessed in 34 children at preschool age who snore (5.38+/-1.21 years) and in 66 age- and sex-matched nonsnorers (5.67+/-1.12 years). The snoring group consisted of children with obstructive sleep apnea (OSA) scores <+3.5 and >-1, the nonsnoring group with OSA score <-1. RESULTS Children who snore differ from the nonsnorers in daytime sleep duration (51.62+/-28.9 minutes vs. 10.70+/-20.2 minutes; p<0.001), but not in nighttime sleep (10.97+/-0.52 hours vs. 9.83+/-1.34 hours; p>0.05). The percentage of children with daytime napping was higher in the snoring group than in the nonsnorers (47.1% vs. 9.1%; p<0.00004), and parents-reported behavioral problems were more frequent in children who snore (41.2% vs. 19.7%; p<0.02). Multivariate odds ratios, including variables for nighttime (sleep apnea) and daytime symptoms (daytime napping and oral breathing), showed that regular sleep during the day was the most predictive of snoring (OR=6.1; 95%CI 1.76-21.04; p<0.005). CONCLUSION In preschool age children, when the daytime nap begins to disappear, snoring may have an effect on daytime schedule through an increased need for daytime sleep.

Serum interleukin – 4 and tumor necrosis factor alpha concentrations in children with primary acid gastroesophageal reflux and acid gastroesophageal reflux secondary to cow's milk allergy

AIM The possible role of serum interleukin 4 (IL-4) and tumor necrosis factor alpha (TNF- α) in pathogenesis of the reflux symptoms in children with primary acid gastroesophageal reflux (GER) and acid GER secondary to cows milk allergy (CMA). MATERIAL AND METHODS Out of 264 children, 76 (28.8%) patients with primary GER and 62 (23.5%) patients with GER secondary to CMA (pH - monitoring) serum IL-4 and TNF- α concentrations were assessed before treatment, 1 and 2 years after the initiation of the periodically administered pharmacotherapy. RESULTS Children with primary GER had mean IL-4 concentrations 0.17 ± 0.06 pg/ml before treatment, 0.08 ± 0.07 pg/ ml after 1-year and 0.07 ± 0.06 pg/ml after 2-years of treatment. The mean IL-4 concentrations were 1.07 ± 0.24, 0.5 ± 0.22 and 0.44 ± 0.19 pg/ml respectively in children with GER secondary to CMA. The mean serum TNF- α concentrations was 3.62 ± 1.30 pg/ml before treatment , 2.16 ± 1,35 pg/ ml after 1 year and 1.65 ± 1.16 pg/ml after 2 years of treatment in children with primary GER. In group with GER secondary to CMA mean serum TNF- α concentrations were 4.95 ± 1.88, 2.53 ± 0.80 and 2.02 ± 0.78 pg/ml respectively. Statistical analysis of the concentration of both cytokines showed their differentiation between them and in the study groups. CONCLUSIONS The highest mean serum IL-4 and TNF-α concentrations were observed in children with GER secondary to CMA and in children in control group (with cows milk allergy and/or other food allergy diagnosed - CMA/FA) before the treatment administration.