Genetic Diversity in Bronchial Asthma Susceptibility: Exploring the Role of Vitamin D Receptor Gene Polymorphisms in Varied Geographic Contexts.

Bronchial asthma (BA) exhibits varying prevalence across global populations, prompting a comprehensive investigation into genetic and environmental determinants. Vitamin D is a potent immunomodulator capable of suppressing inflammatory signals in several cell types involved in the asthmatic response; it exerts effects on the immune system by binding to the nuclear vitamin D receptor (VDR). VDR gene genetic variations are affecting serum vitamin D levels with a possible role in the BA risk. The current study aimed to examine the complex interaction of various factors (genetic background, serum vitamin D levels, and geographic location) to identify differences in the influence of these factors on the susceptibility to asthma between populations at different latitudes. Focusing on Eastern European cohorts from Latvia and Lithuania and comparing them with published data on East Asian populations, we explore the impact of VDR gene polymorphisms on BA susceptibility. Genotyping four key VDR SNPs and assessing their association with 25-hydroxyvitamin D levels, our study unveils significant associations of the studied loci with the risk of asthma-both risk-reducing and increasing effects, differently distributed between Baltic and East Asian populations. The functional effects of in silico VDR gene genetic variations are also identified and discussed.

Prenatal ultrasound screening and congenital anomalies at birth by region: Pattern and distribution in Latvia.

Objective: The objective was to compare the ultrasound scan frequency and rate of congenital malformations between urban and rural areas. Study design: We conducted a population-based retrospective study using linked data from administrative data sources and register data. All singleton live births in 2018 that could be linked (n = 18,759) were included in the data analysis. Place of residence was categorized into three groups: Riga (capital city), other big cities and rural areas (including regional cities). Adjusted ORs were calculated. The multiple regression model was adjusted for maternal age, living area and prenatal screenings. Results: Overall, 3% (n = 536) of the live-born infants were reported to have congenital malformations at birth. The proportion of congenital anomalies was, on average, 2% higher (p < 0.001) in Riga (4%, n = 334) than in the rural regions (2%, n = 93) and other cities (1%, n = 109). Women whose infants had congenital anomalies at birth had higher and statistically significant odds of having abnormal findings on ultrasound (US) screening (OR=2.3; 95% CI 1.5-3.4; p < 0.001) and undergoing invasive diagnostic tests during pregnancy (OR=2.2; 95% CI 1.4-3.5; p < 0.001). The median number of ultrasound scans during pregnancy was 3 (IQR 2) in Riga and 4 (IQR 2) in the other cities and rural regions. The top 3 types of congenital anomalies at birth were deformations of the musculoskeletal system and congenital malformations of the circulatory system and genital organs. Conclusions: The findings of this study showed a statistically significant association between the rate of foetal anomalies and the frequency of prenatal examinations. A higher average number of US examinations per pregnancy was observed in the rural regions. Regional variations exist in the rates of specific congenital anomalies. Further studies are recommended in this field for better understanding. Surveillance systems that are able to analyse the efficiency of US examinations need to be developed for the early prenatal detection of congenital anomalies.

Breath Volatile Organic Compounds in Surveillance of Gastric Cancer Patients following Radical Surgical Management.

As of today, there is a lack of a perfect non-invasive test for the surveillance of patients for potential relapse following curative treatment. Breath volatile organic compounds (VOCs) have been demonstrated to be an accurate diagnostic tool for gastric cancer (GC) detection; here, we aimed to prove the yield of the markers in surveillance, i.e., following curative surgical management. Patients were sampled in regular intervals before and within 3 years following curative surgery for GC; gas chromatography-mass spectrometry (GC-MS) and nanosensor technologies were used for the VOC assessment. GC-MS measurements revealed a single VOC (14b-Pregnane) that significantly decreased at 12 months, and three VOCs (Isochiapin B, Dotriacontane, Threitol, 2-O-octyl-) that decreased at 18 months following surgery. The nanomaterial-based sensors S9 and S14 revealed changes in the breath VOC content 9 months after surgery. Our study results confirm the cancer origin of the particular VOCs, as well as suggest the value of breath VOC testing for cancer patient surveillance, either during the treatment phase or thereafter, for potential relapse.

Low Prevalence of Celiac Disease among Patients with Functional Gastrointestinal Disorders in Latvia.

BACKGROUND AND AIMS: Studies suggest that the prevalence of celiac disease (CD) is increased in individuals with functional gastrointestinal disorders (FGIDs), in particular, irritable bowel syndrome (IBS); however, the evidence is conflicting. We aimed to analyze the prevalence of CD in patients with FGIDs in Latvia. METHODS: This retrospective study included patients with FGIDs, referred for a gastroenterologist consultation in a secondary gastroenterology practice unit. Patients were divided into three groups - patients only with IBS (IBS group), patients only with functional dyspepsia (FD) (FD group), patients with mixed symptoms IBS and FD (Mixed group). Patient levels of tissue transglutaminase IgA (tTG-IgA) and/or antiendomysial IgA group antibodies (EMA-IgA) were evaluated. Four duodenal biopsies were obtained and reported according to Marsh classification. Patients diagnosed or being referred for confirmation of CD were excluded from the study. RESULTS: Overall, 1,833 FGIDs patients were enrolled. Celiac serology was available for 1,570 patients, duodenal histology for 582 patients, both histology and serology for 319 patients. In total, celiac seropositivity was present in 1.78% (28/1570) (3.18% in IBS group, 0.90% in FD group and 1.11% of cases in the mixed group). Fifteen patients had histopathological changes (2.58%; 15/582). Three IBS patients (2.36%) were both serology and biopsy positive. None of the FD patients had CD. CONCLUSION: Prevalence of biopsy-proven CD in patients from Latvia with FGIDs was low. Routine screening for CD could be considered only among patients with IBS.

Maternal Risk Factors for Stillbirth: A Registry-Based Study.

Background and Objectives: The number of stillbirths has reduced more slowly than has maternal mortality or mortality in children younger than 5 years, which were explicitly targeted in the Millennium Development Goals. Placental pathologies and infection associated with preterm birth are linked to a substantial proportion of stillbirths. Appropriate preconception care and quality antenatal care that is accessible to all women has the potential to reduce stillbirth rates. The aim of the present study was to assess potential risk factors associated with stillbirth within maternal medical diseases and obstetric complications. Materials and Methods: Retrospective cohort study (2001-2014) was used to analyse data from the Medical Birth Register on stillbirth and live births as controls. Adjusted Odds ratios (aOR) with 95% confidence intervals (CI) were estimated. Multiple regression model adjusted for maternal age, parity and gestational age. Results: The stillbirth rate was 6.2 per 1000 live and stillbirths. The presence of maternal medical diseases greatly increased the risk of stillbirth including diabetes mellitus (aOR = 2.5; p < 0.001), chronic hypertension 3.1 (aOR = 3.1; p < 0.001) and oligohydromnios/polyhydromnios (aOR = 2.4; p < 0.001). Pregnancy complications such as intrauterine growth restriction (aOR = 2.2; p < 0.001) was important risk factor for stillbirth. Abruption was associated with a 2.8 odds of stillbirth. Conclusions: Risk factors most significantly associated with stillbirth include maternal history of chronic hypertension and abruptio placenta which is a common cause of death in stillbirth. Early identification of potential risk factors and appropriate perinatal management are important issues in the prevention of adverse fetal outcomes and preventive strategies need to focus on improving antenatal detection of fetal growth restriction.

Etanercept treatment for extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, or psoriatic arthritis: 6-year efficacy and safety data from an open-label trial.

BACKGROUND: To describe the 6-year safety and efficacy of etanercept (ETN) in children with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA) METHODS: Patients who completed the 2-year, open-label, phase III CLinical Study In Pediatric Patients of Etanercept for Treatment of ERA, PsA, and Extended Oligoarthritis (CLIPPER) were allowed to enroll in its 8-year long-term extension (CLIPPER2). Children received ETN at a once-weekly dose of 0.8 mg/kg, up to a maximum dose of 50 mg/week. Efficacy assessments included the JIA core set of outcomes, the JIA American College of Rheumatology response criteria (JIA-ACR), and the Juvenile Arthritis Disease Activity Score (JADAS). Efficacy data are reported as responder analyses using a hybrid method for missing data imputation and as observed cases. Safety assessments included treatment-emergent adverse events (TEAEs). RESULTS: Out of 127 patients originally enrolled in CLIPPER, 109 (86%) entered CLIPPER2. After 6 years of trial participation (2 years in CLIPPER and 4 years in CLIPPER2), 41 (32%) patients were still taking ETN, 13 (11%) entered the treatment withdrawal phase after achieving low/inactive disease (of whom 7 had to restart ETN), 36 (28%) discontinued treatment for other reasons but are still being observed, and 37 (29%) discontinued treatment permanently. According to the hybrid imputation analysis, proportions of patients achieving JIA ACR90, JIA ACR100, and JADAS inactive disease after the initial 2 years of treatment were 58%, 48%, and 32%, respectively. After the additional 4 years, those proportions in patients who remained in the trial were 46%, 35%, and 24%. Most frequently reported TEAEs [n (%), events per 100 patient-years] were headache [28 (22%), 5.3], arthralgia [24 (19%), 4.6], and pyrexia [20 (16%), 3.8]. Number and frequency of TEAEs, excluding infections and injection site reactions, decreased over the 6-year period from 193 and 173.8, respectively, during year 1 to 37 and 61.3 during year 6. A single case of malignancy (Hodgkin's lymphoma) and no cases of active tuberculosis, demyelinating disorders, or deaths were reported. CONCLUSIONS: Open-label etanercept treatment for up to 6 years was safe, well tolerated, and effective in patients with eoJIA, ERA, and PsA. TRIAL REGISTRATION: ClinicalTrials.gov: CLIPPER, NCT00962741 , registered 20 August, 2009, CLIPPER2, NCT01421069 , registered 22 August, 2011.

Phenotypic variability and disparities in treatment and outcomes of childhood arthritis throughout the world: an observational cohort study.

BACKGROUND: To our knowledge, the characteristics and burden of childhood arthritis have never been studied on a worldwide basis. We aimed to investigate, with a cross-sectional study, the prevalence of disease categories, treatment methods, and disease status in patients from across different geographical areas and from countries with diverse wealth status. METHODS: In this multinational, cross-sectional, observational cohort study, we asked international paediatric rheumatologists from specialised centres to enrol children with a diagnosis of juvenile idiopathic arthritis, according to International League of Associations for Rheumatology criteria, who were seen consecutively for a period of 6 months. Each patient underwent retrospective and cross-sectional assessments, including measures of disease activity and damage and questionnaires on the wellbeing and quality of life of the children. We qualitatively compared the collected data across eight geographical areas, and we explored an association between disease activity and damage and a country's gross domestic product (GDP) with a multiple logistic regression analysis. FINDINGS: Between April 4, 2011, and Nov 21, 2016, 9081 patients were enrolled at 130 centres in 49 countries, grouped into eight geographical areas. Systemic arthritis (125 [33·0%] of 379 patients) and enthesitis-related arthritis (113 [29·8%] of 379) were more common in southeast Asia, whereas oligoarthritis was more prevalent in southern Europe (1360 [56·7%] of 2400) and rheumatoid factor-negative polyarthritis was more frequent in North America (165 [31·5%] of 523) than in the other areas. Prevalence of uveitis was highest in northern Europe (161 [19·1%] of 845 patients) and southern Europe (450 [18·8%] of 2400) and lowest in Latin America (54 [6·4%] of 849), Africa and Middle East (71 [5·9%] of 1209), and southeast Asia (19 [5·0%] of 379). Median age at disease onset was lower in southern Europe (3·5 years, IQR 1·9-7·3) than in other regions. Biological, disease-modifying antirheumatic drugs were prescribed more frequently in northern Europe and North America than in other geographical settings. Patients living in countries with lower GDP had greater disease activity and damage than those living in wealthier countries. Damage was associated with referral delay. INTERPRETATION: Our study documents a variability in prevalence of disease phenotypes and disparities in therapeutic choices and outcomes across geographical areas and wealth status of countries. The greater disease burden in lower-resource settings highlights the need for public health efforts aimed at improving equity in access to effective treatments and care for juvenile idiopathic arthritis. FUNDING: IRCCS Istituto Giannina Gaslini.

The European network for care of children with paediatric rheumatic diseases: care across borders.

OBJECTIVES: To provide an overview of the paediatric rheumatology (PR) services in Europe, describe current delivery of care and training, set standards for care, identify unmet needs and inform future specialist service provision. METHODS: An online survey was developed and presented to national coordinating centres of the Paediatric Rheumatology International Trials Organisation (PRINTO) (country survey) and to individual PR centres (centre and disease surveys) as a part of the European Union (EU) Single Hub and Access point for paediatric Rheumatology in Europe project. The survey contained components covering the organization of PR care, composition of teams, education, health care and research facilities and assessment of needs. RESULTS: Response rates were 29/35 (83%) for country surveys and 164/288 (57%) for centre surveys. Across the EU, approximately one paediatric rheumatologist is available per million population. In all EU member states there is good access to specialist care and medications, although biologic drug availability is worse in Eastern European countries. PR education is widely available for physicians but is insufficient for allied health professionals. The ability to participate in clinical trials is generally high. Important gaps were identified, including lack of standardized clinical guidelines/recommendations and insufficient adolescent transition management planning. CONCLUSION: This study provides a comprehensive description of current specialist PR service provision across Europe and did not reveal any major differences between EU member states. Rarity, chronicity and complexity of diseases are major challenges to PR care. Future work should facilitate the development, dissemination and implementation of standards of care, treatment and service recommendations to further improve patient-centred health care across Europe.

Maternal and Neonatal Characteristics for Late Foetal Death in Latvia between 2001 and 2014: Population-Based Study.

INTRODUCTION: Stillbirth is one of the most common adverse pregnancy outcomes worldwide. Late foetal death (LFD) rates are mostly used for international comparisons because of the large variations in stillbirth rates between countries. OBJECTIVE: To examine trends in LFD (including antepartum and intrapartum) by multiple births, birth weight, and maternal age in two time periods. METHODS: A retrospective cohort study was used to analyse data from the Medical Birth Register (2001-2014), divided into 2 periods of 7 years each. In total, data on 1,340 singletons were analysed. This study calculated LFD rates and rate ratios (RR). RESULTS: The overall LFD rate showed a slight statistically significant reduction (p < 0.001) of 18% between 2001-2007 and 2008-2014. There was a slight increase in the mortality rate from multiple pregnancies (RR 1.1/1000; 95% CI 0.6-1.9). There were no major differences in the LFD rate by maternal age during the time periods. CONCLUSIONS: LFD decreased (RR 0.8/1000 births), as well as intrapartum LFD (RR 0.6/1000 births). Older maternal age influenced pregnancy outcomes, and higher LFD rates were observed in the age group ≥35 years. Substantial intrapartum stillbirths rates indicate problems with quality of intrapartum care and emergency obstetric care. Further research is needed to evaluate the strategies necessary to substantially reduce the number of stillbirths in the country.

The Latvian version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Latvian language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 100 JIA patients (2% systemic, 56% oligoarticular, 17% RF negative polyarthritis, 25% other categories) and 204 healthy children, were enrolled at the paediatric rheumatology centre. The JAMAR components discriminated healthy subjects from JIA patients, except for the paediatric rheumatology quality of life (HRQoL), psychosocial health (PsH) subscales, the HRQoL total score and for the school-related problems variable. All JAMAR components revealed good psychometric performances. In conclusion, the Latvian version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Helicobacter pylori Infection and Risk Factors in Relation to Allergy in Children.

PURPOSE: To analyze presence of Helicobacter pylori infection and environmental risk factors among children with and without allergy. METHODS: Parents of children at primary health care centres/kindergartens and allergologist consultation were asked to answer a questionnaire and to bring a faecal sample. H. pylori infection was detected by monoclonal stool antigen test. Prevalence of H. pylori infection and risk factors were compared between individuals with and without allergy using χ2 test, ANOVA test and parameters and logistic regression. RESULTS: Among 220 children (mean age, 4.7 years; ±standard deviation 2.3 years) H. pylori positivity was non-significantly lower among patients with allergy (n=122) compared to individuals without allergy (n=98): 13.9% (17/122) vs. 22.4% (22/98); p=0.106. In logistic regression analysis presence of allergy was significantly associated with family history of allergy (odds ratio [OR], 8.038; 95% confidence interval [CI], 4.067-15.886; p<0.0001), delivery by Caesarean section (OR, 2.980; 95% CI, 1.300-6.831; p=0.009), exclusive breast feeding for five months (OR, 2.601; 95% CI, 1.316-5.142; p=0.006), antibacterial treatment during the previous year (OR, 2.381; 95% CI, 1.186-4.782; p=0.015). CONCLUSION: Prevalence of H. pylori infection did not differ significantly between children with and without allergy. Significant association of allergy with delivery by Caesarean section and antibacterial therapy possibly suggests the role of gastrointestinal flora in the development of allergy, while association with family history of allergy indicates the importance of genetic factors in the arise of allergy.

Prevalence of Helicobacter pylori infection among preschool children in Latvia: no significant decrease in prevalence during a ten year period.

AIMS: Published data show a trend of decreasing prevalence of Helicobacter pylori in Eastern European countries due to socioeconomic changes. The aim of this study was to determine the prevalence of H. pylori infection among children in Latvia and to compare these results with previous studies in the same population. The risk factors associated with infection were also analysed. METHODS: Preschool children in kindergartens and primary health care centres were investigated using a stool antigen test. Their parents were asked to fill out a questionnaire about possible risk factors. Statistical analysis included Pearson's χ(2) test and linear regression analysis. RESULTS: The prevalence of H. pylori infection determined by the monoclonal stool antigen test in children aged 1-6 years (median 5 years) was 15.5% (15/101) (95% confidence interval 8.67-23.48%). In the regression analysis, H. pylori positivity was significantly negatively associated with the consumption of imported fruit at least once per week (p=0.02). CONCLUSIONS THE PREVALENCE OF H PYLORI IN THE STUDIED POPULATION HAS NOT DECREASED SIGNIFICANTLY DURING THE LAST DECADE AND IS STILL ASSOCIATED WITH SOCIOECONOMIC FACTORS THE ROLE OF SOME DIETARY FACTORS EG THE CONSUMPTION OF FRUIT IN THE SPREAD OF INFECTION SHOULD BE STUDIED FURTHER.

Territorial differences in infant mortality in Latvia in the first decade of the third millennium.

OBJECTIVE: Infant and child mortality are some of the most substantial indicators of country welfare. Infant mortality (IM) in Latvia is constantly the highest among 25 Member States of the European Union. Since the regaining of independence in 1991, IM has decreased by almost 50%, however, it is still high enough to cause concern that the country will not be able to meet the UN Millennium Development Goals to decrease IM in Latvia by 2015. The Medical Faculty at the University of Latvia has conducted several studies identifying correlations between IM and GDP, total expenditure on health, unemployment and GINI coefficient. It is necessary to identify all IM causes and relationships which have not been studied, including the effect of social factors causing inequality between inhabitants of urban and rural areas: - The aim of the study was to determine the IM rate and the main death causes and their differences between rural and urban areas in Latvia (2000-2010). MATERIALS: This is a register-based study. The data of 1994 deceased infants was analyzed over the time period from 2000-2010. The studied population was divided into two groups - urban and rural areas by mothers' area of residence. Descriptive and analytical methods were used for analysis - frequency distribution, correlation and regression analysis. RESULTS: IM by maternal residence as well as IM indicators in the most common diagnostic subgroups have been higher in rural areas in the entire studied period (2000-2010). The decrease proportion of IM was more rapid in rural regions with a period average of 6.2% in comparison to urban regions - 2.6%. Annual decrease of IM from perinatal period conditions was 50% lower in rural than urban areas; annual decrease of IM from congenital malformations, deformations and chromosomal abnormalities was 20% lower in urban than rural areas; annual decrease in other diagnostic groups was 40% lower in urban than rural areas. During the study period, differences in infant mortality based on maternal socio- demographic factors, maternal health as well as pregnancy and obstetric history have been found, but the results of statistical analysis cannot be used to define these relationships as statistically significant in either areas. CONCLUSIONS: infant mortality in Latvia due to various conditions prevailing during perinatal period, external causes and sudden infant death syndrome can be substantially decreased - by improving the theoretical and technical capacity of obstetric departments in rural areas as well as educating society on preventable causes of death.

Dissecting the heterogeneity of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.

OBJECTIVE: To seek insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey. METHODS: International pediatric rheumatologists and hemato-oncologists entered their patient data, collected retrospectively, in a Web-based database. The demographic, clinical, laboratory, histopathologic, therapeutic, and outcome data were analyzed in relation to (1) geographic location of caring hospital, (2) subspecialty of attending physician, (3) demonstration of hemophagocytosis, and (4) severity of clinical course. RESULTS: A total of 362 patients were included by 95 investigators from 33 countries. Demographic, clinical, laboratory, and histopathologic features were comparable among patients seen in diverse geographic areas or by different pediatric specialists. Patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. Patients with demonstration of hemophagocytosis had shorter duration of sJIA at MAS onset, higher prevalence of hepatosplenomegaly, lower levels of platelets and fibrinogen, and were more frequently administered cyclosporine, intravenous immunoglobulin (IVIG), and etoposide. Patients with severe course were older, had longer duration of sJIA at MAS onset, had more full-blown clinical picture, and were more commonly given cyclosporine, IVIG, and etoposide. CONCLUSION: The clinical spectrum of MAS is comparable across patients seen in different geographic settings or by diverse pediatric subspecialists. There was a disparity in the therapeutic choices among physicians that underscores the need to establish uniform therapeutic protocols.

Pepsinogen testing for evaluation of the success of Helicobacter pylori eradication at 4 weeks after completion of therapy.

BACKGROUND AND OBJECTIVE: Pepsinogen levels in plasma are increased by inflammation in the gastric mucosa, including inflammation resulting from Helicobacter pylori infection. A decrease in pepsinogen II level has been suggested as a reliable marker to confirm the successful eradication of infection. The aim of our study was to evaluate the potential role of pepsinogens I and II, gastrin-17 and H. pylori antibodies in confirming successful eradication. MATERIAL AND METHODS: Altogether 42 patients (25 women, 17 men), mean age 45 years (range 23-74), were enrolled. Pepsinogens I and II, gastrin-17 and H. pylori IgG antibodies were measured in plasma samples using an ELISA test (Biohit, Oyj., Finland) before the eradication and 4 weeks after completing the treatment. The success of eradication was determined by a urea breath test. RESULTS: Eradication was successful in 31 patients (74%) and unsuccessful in 11 patients (26%). Pepsinogen II decreased significantly in both the successful (P=0.029) and unsuccessful (P=0.042) eradication groups. Pepsinogen I decreased significantly in the successful (P=0.025) but not the unsuccessful (P=0.29) eradication group. The pepsinogen I/II ratio increased in the successful eradication group (P=0.0018) but not in the group in which treatment failed (P=0.12). There were no differences in gastrin-17 or H. pylori antibody values. CONCLUSIONS: A decrease in pepsinogen II levels cannot be used as a reliable marker for the successful eradication of H. pylori 4 weeks after the completion of treatment. The increase in pepsinogen I/II ratio reflects differences in pepsinogen production following the eradication irrespective of improvement in atrophy.

Juvenile idiopathic arthritis subtype- and sex-specific associations with genetic variants in the PSMA6/PSMC6/PSMA3 gene cluster.

BACKGROUND: The ubiquitin proteasome system plays an exceptional biological role in the antigen processing and immune response and it could potentially be involved in pathogenesis of many immunity-related diseases, including juvenile idiopathic arthritis (JIA). METHODS: The PSMB5 (rs11543947), PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827), and PSMA3 (rs2348071) proteasomal genes were genotyped on JIA subtype- and sex-specific association; plasma proteasome levels was measured in patients having risk and protective four-locus genotypes and eventual functional significance of allele substitutions was evaluated in silico. RESULTS: Loci rs11543947 and rs1048990 were identified as disease neutral and other loci as disease susceptible (p < 0.05). The rs2277460, rs2295826, and rs2295827 loci had the strongest association with oligoarthritis [odds ratio (OR) = 2.024, 95% confidence interval (CI) 1.101-3.722; OR = 2.371, 95% CI 1.390-4.044; OR = 2.183, 95% CI 1.272-2.737, respectively), but the rs2348071 locus was associated with polyarthritis in females (OR = 3.438, 95% CI 1.626-7.265). A strong (p < 0.001) association was detected between the rs2277460/rs2295826/rs2295827/rs2348071 four-locus genotypes and the healthy phenotype when all loci were homozygous on common alleles (OR 0.439, 95% CI 0.283-0.681) and with the disease phenotype when the rs2348071 and the rs2295826 and/or rs2295827 loci were represented by risk genotypes simultaneously (OR 4.674, 95% CI 2.096-10.425). Rarely observed in controls, the double rs2277460/rs2348071 heterozygotes were rather frequent in affected males and more strongly associated with polyarthritis (p < 0.05). Haplotypes carrying the rare rs2295826/rs2295827 and rs2277460 alleles showed a strong (p < 0.001) association with oligo- and polyarthritis, respectively. The plasma proteasome level was found to be significantly higher in females having four-locus risk genotypes compared with protective genotypes (p < 0.001). Sequence affinity to transcription factors and similarity to splicing signals, microRNAs and/or hairpin precursors potentially depend on allele substitutions in disease susceptible loci. CONCLUSION: We demonstrate for the first time evidence of a sex-specific association of PSMA6/PSMC6/PSMA3 genetic variants with subtypes of JIA and plasma proteasome concentrations. Theoretical models of the functional significance of allele substitutions are discussed.

Efficacy and safety of open-label etanercept on extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis and psoriatic arthritis: part 1 (week 12) of the CLIPPER study.

OBJECTIVE: To investigate the efficacy and safety of etanercept (ETN) in paediatric subjects with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). METHODS: CLIPPER is an ongoing, Phase 3b, open-label, multicentre study; the 12-week (Part 1) data are reported here. Subjects with eoJIA (2-17 years), ERA (12-17 years), or PsA (12-17 years) received ETN 0.8 mg/kg once weekly (maximum 50 mg). Primary endpoint was the percentage of subjects achieving JIA American College of Rheumatology (ACR) 30 criteria at week 12; secondary outcomes included JIA ACR 50/70/90 and inactive disease. RESULTS: 122/127 (96.1%) subjects completed the study (mean age 11.7 years). JIA ACR 30 (95% CI) was achieved by 88.6% (81.6% to 93.6%) of subjects overall; 89.7% (78.8% to 96.1%) with eoJIA, 83.3% (67.2% to 93.6%) with ERA and 93.1% (77.2% to 99.2%) with PsA. For eoJIA, ERA, or PsA categories, the ORs of ETN vs the historical placebo data were 26.2, 15.1 and 40.7, respectively. Overall JIA ACR 50, 70, 90 and inactive disease were achieved by 81.1, 61.5, 29.8 and 12.1%, respectively. Treatment-emergent adverse events (AEs), infections, and serious AEs, were reported in 45 (35.4%), 58 (45.7%), and 4 (3.1%), subjects, respectively. Serious AEs were one case each of abdominal pain, bronchopneumonia, gastroenteritis and pyelocystitis. One subject reported herpes zoster and another varicella. No differences in safety were observed across the JIA categories. CONCLUSIONS: ETN treatment for 12 weeks was effective and well tolerated in paediatric subjects with eoJIA, ERA and PsA, with no unexpected safety findings.

Association of obesity with proteasomal gene polymorphisms in children.

The aim of this study was to ascertain possible associations between childhood obesity, its anthropometric and clinical parameters, and three loci of proteasomal genes rs2277460 (PSMA6 c.-110C>A), rs1048990 (PSMA6 c.-8C>G), and rs2348071 (PSMA3 c. 543+138G>A) implicated in obesity-related diseases. Obese subjects included 94 otherwise healthy children in Latvia. Loci were genotyped and then analyzed using polymerase chain reactions, with results compared to those of 191 nonobese controls. PSMA3 SNP frequency differences between obese children and controls, while not reaching significance, suggested a trend. These differences, however, proved highly significant (P < 0.002) in the subset of children reporting a family history of obesity. Among obese children denying such history, PSMA6 c.-8C>G SNP differences, while being nonsignificant, likewise suggested a trend in comparison to the nonobese controls. No PSMA6 c.-110C>A SNP differences were detected in the obese group or its subsets. Finally, PSMA3 SNP differences were significantly associated (P < 0.05) with circulating low-density lipoprotein cholesterol (LDL) levels. Our results clearly implicate the PSMA3 gene locus as an obesity risk factor in those Latvian children with a family history of obesity. While being speculative, the clinical results are suggestive of altered circulatory LDL levels playing a possible role in the etiology of obesity in the young.

Prevalence of Helicobacter pylori infection and atrophic gastritis in Latvia.

OBJECTIVES: Helicobacter pylori infection and atrophic gastritis are related to an increased risk for gastric cancer. There is a decrease in global H. pylori prevalence. We analyzed the prevalence of H. pylori infection in Latvia by the plasma IgG test and the presence of atrophy by means of pepsinogen testing. METHODS: This subanalysis was carried out on a randomly selected cross-sectional sample of a general population of adults to access cardiovascular risk factors. Plasma samples were screened for H. pylori IgG (cutoff value 24 U/ml), and pepsinogens (Pg) I and II. Pg cutoff values of PgI/PgII ≤ 3 and PgI ≤ 70 ng/ml were used to assess the prevalence of atrophy of any grade and PgI/PgII ≤ 2 and PgI ≤ 30 ng/ml for advanced atrophy. RESULTS: Altogether, 3564 serum samples were available for the study (2346 women, 1218 men; median age 54 years). Of the tested individuals, 79.21% were H. pylori positive, with no difference between sexes. The prevalence increased with age (P<0.001). Atrophy of any grade was identified in 1444 individuals (40.52%) and advanced atrophy in 475 individuals (13.33%). Linear association with age was present in both response types (P<0.001). The prevalence of atrophy of any grade was higher in women (41.73%) than in men (38.18%; P=0.04); this difference was lost for advanced atrophy (women 13.98%, men 12.07%; P=0.1). CONCLUSION: The prevalence of H. pylori infection or atrophy remains high in Latvia. Determining the right cutoff value is critically important for pepsinogen-based atrophy detection in Europe in order to objectively stratify gastric cancer risk.

Mortality of children under five and prevalence of newborn congenital anomalies in relation to macroeconomic and socioeconomic factors in Latvia.

BACKGROUND: Mortality of infants and children younger than 5 years is a globally recognized and broad national welfare indicator. Scientific literature has data on the correlation of mortality indicators with macroeconomic indicators. It is important to study the associations between prevalence and mortality indicators and socioeconomic factors, since deaths from congenital anomalies account for approximately 25%-30% of all deaths in infancy. The aim of the study was to analyze the overall trend in mortality of infants and young children aged 0 to 4 years in relation to macroeconomic factors in Latvia and prevalence of congenital anomalies in newborns in relation to socioeconomic factors. MATERIAL AND METHODS: The Newborns' Register and Causes of Death Register were used as data sources; data on specific socioeconomic factors were retrieved from the Central Statistics Office. RESULTS: The results of the study show a strong correlation between mortality in children younger than 5 years and gross domestic product, as well as health budget in LVL per capita and the national unemployment level. The average decrease in infant mortality from congenital anomalies in Latvia was found to be 6.8 cases per 100,000 live births. CONCLUSIONS: There is a strong correlation between child mortality and socioeconomic situation in the country. There is a need to analyze the data on child mortality in a transnational context on a regular basis and studying the correlations between child mortality indicators and socioeconomic indicators and health care management parameters.