Analysis of HLA-G 5'URR regulatory polymorphisms in Slovak women with pre-eclampsia.

OBJECTIVES: The objective of this study was to identify the impact of the selected HLA-G gene polymorphisms in the 5'URR region on the risk to develop pre-eclampsia. BACKGROUND: Pre-eclampsia (PE) is a serious multisystem disorder that affects women during pregnancy. Despite many research studies, the pathology of PE is not fully understood. Human leukocyte antigen G (HLA-G) belongs to the molecules that induce immune tolerance at the fetal-maternal interface. HLA-G expression was found to be impaired in the women suffering from PE suggesting its involvement in the development of PE. METHODS: 116 women with pre-eclampsia and 130 women with normotensive pregnancy were included in the study. The 16 gene polymorphisms in the HLA-G 5'URR region (promoter) affecting HLA-G expression were typed by direct sequencing. RESULTS: The -201AA genotypes in recessive model were significantly more frequent in women with pre-eclampsia than in the controls (p = 0.047). Furthermore, the analysis of HLA-G 5'URR variants with clinical findings of PE showed a significant association of the -533delA-/+ genotype with a higher mean level of diastolic blood pressure (p = 0.02). CONCLUSION: Our results suggest a genetic association of selected HLA-G 5'URR variants with a risk of developing pre-eclampsia and possible contribution of HLA-G to disease pathology (Tab. 4, Ref. 51).

Autoinflammatory process in the pathogenesis of generalized pustular psoriasis and perspectives of its targeted therapy.

The dysregulated inflammatory process not only plays an important role in the development of chronic plaque psoriasis but also is a major pathogenetic mechanism behind the generalized pustular psoriasis (GPP) and other rare pustular forms of the disease. The key players in this process are the cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF), IL-12/23, IL-17A and especially IL-36. Their excessive activity or production in some GPP patients is due to mutations in genes that encode molecules involved in inhibiting the action of IL-36 (IL-36Ra) or in intracellular inflammatory signaling (CARD14, AP1S3). Knowledge about the pathological role of inflammatory cytokines in the development of pustular forms of psoriasis has also found application in their biological therapy with monoclonal antibodies that neutralize the action of IL-12/23, IL-17A, TNF or IL-1β. Other promising agents are monoclonal antibodies against the interleukin 36 receptor, which have already successfully gone through the first phases of clinical trials and are currently being tested for their long-term efficacy, safety and tolerability.

Soluble HLA-G, its diagnostic and prognostic value and potential target molecule for future therapy in cancer.

Human leukocyte antigen G (HLA-G) is a non-classical MHC class I molecule that regulates many immune functions. The physiologic HLA-G expression is restricted to foetal tissues such as: amniotic cells, erythroid precursors, and cytotrophoblasts, and, in adults, to immune-privileged organs. The ectopic expression in tumours could point out to a strategy used by malignant cells to escape the immune surveillance. There are two forms of HLA-G, membrane-bound and soluble. The structure of the soluble and membrane bound isoforms differs at the C-terminus. The extracellular domain and the intracytoplasmic tail are replaced in the secreted isoforms by a short hydrophilic tail. These differences could serve as a marker to distinguish shed or proteolytically cleaved HLA-G isoforms from secreted HLA-G isoforms. HLA-G induces tolerance by inhibiting different cells and this function is mediated by binding of both soluble and membrane-bound HLA-G to the inhibitory receptors. There exists a consistent evidence in literature that HLA-G represents an important factor in determining prognosis in various types of cancer. In this review, we will focus on soluble form of HLA-G (sHLA-G) in cancers and its association with the prognosis of cancer patients, because this immune check-point molecule appears as a promising relevant target for cancer immunotherapy (Fig. 2, Ref. 115). Keywords: cancer, diagnosis, HLA-G, soluble HLA-G, tumour.

Triggering receptor expressed on myeloid cells 1 and 2 in patients with chronic maxillary sinusitis.

PURPOSE: Chronic sinusitis can result from variable types of immune-mediated process, whose pathogenesis is not fully understood. Triggering receptors expressed on myeloid cells 1 and 2 (TREM-1, TREM-2) are involved in myeloid cell activation enabling these cells to fine-tune the inflammatory response, which may have an impact on subsequent adaptive immunity and may be the key factor in pathogenesis. The aim of the study was to analyse soluble TREM-1 and TREM-2 molecules in maxillary sinus lavage fluid and compare the defined subgroups selected from patients with chronic sinusitis with/without nasal polyps and allergy (asthma and allergic rhinitis). METHODS: The levels of soluble TREM-1 and TREM-2 were measured by Elisa test in a cohort of patients with chronic maxillary sinusitis (n=45). We compared subgroups of patients with nasal polyps (n=33) and allergy (n=25: inclusive of asthma (n=11) and allergic rhinitis (n=14)) with the control group of patients without nasal polyps (n=13), and without allergy (n=21). RESULTS: The study did not prove the difference between subgroups with and without nasal polyps. The levels of soluble TREM-1 did not differ significantly between patients with allergy (asthma and allergic rhinitis) and the control group without allergy (p=0.4804). The levels of soluble TREM-2 were significantly higher in patients with allergy (p=0.0028), asthma (p=0.0103) and allergic rhinitis (p=0.0137) as compared with the control group. CONCLUSION: Our results suggest the role of TREM-2­mediated activation of myeloid cells in chronic sinusitis accompanied by allergy, asthma, and allergic rhinitis (Tab. 6, Ref. 25).

Low serum vitamin D levels are associated with a low percentage of TREM-2+ monocytes in low-grade gliomas and poorer overall survival in patients with high-grade gliomas.

INTRODUCTION: Anti-inflammatory effect of vitamin D (VD) could be beneficial in improving the survival of glioma patients. The aim of our study was to analyse the serum levels of vitamin D in glioma patients and to find an association with the prognosis of glioma patients and other investigated parameters. MATERIAL AND METHODS: The study included 63 patients with gliomas. Percentage of CD14+ monocytes, TREM-1+ and TREM-2+ monocytes were determined by flow cytometry, serum levels of 25(OH)D were evaluated by electrochemiluminescent binding test. RESULTS: Six patients out of 63 had normal levels of VD. A significant difference in the overall survival (OS) in the patients with severe VD deficiency, VD deficiency and insufficiency in grade IV was found. In grade II and III, the levels of vitamin D positively correlated with the percentage of TREM-2+ monocytes, and in grade II also a negative correlation of VD with TREM-1/TREM-2 ratio was observed. CONCLUSION: Levels of VD could influence the prognosis of patients with high-grade gliomas. Serum level of 25(OH)D in low-grade gliomas positively correlated with the percentage of anti-inflammatory acting TREM-2+ monocytes and negatively with TREM-1/TREM-2 ratio. This could be protective against the progression to high-grade glioma, because TREM-2 is associated with protective functions such as: tissue repair, control of local inflammation, or phagocytosis (Tab. 4, Fig. 4, Ref. 79).

TREM-1 and TREM-2 Expression on Blood Monocytes Could Help Predict Survival in High-Grade Glioma Patients.

OBJECTIVE: In recent years, the role of the modern inflammatory markers TREM-1 (triggering receptors expressed on myeloid cells) and HMGB1 (high mobility group box 1 protein) in tumorigenesis has begun to be studied. Their role in gliomas is not clear. The aim of our study was to find the role of inflammation in gliomas. Patients and Methods. In 63 adult patients with gliomas and 31 healthy controls, the expressions of TREM-1 and TREM-2 on CD14+ blood cells (method: flow cytometry) and the levels of soluble sTREM-1, HMGB1, IL-6, and IL-10 (Elisa tests) were analyzed. RESULTS: Cox proportional hazard analysis showed that a TREM-1/TREM-2 ratio was associated with reduced overall survival (HR = 1.001, P = 0.023). Patients with a TREM-1/TREM-2 ratio above 125 survived significantly shorter than patients with a TREM-1/TREM-2 ratio below 125. The percentage of CD14+ TREM-1+ cells was strongly associated with a plasma IL-6/IL-10 ratio (positively) and with IL-10 (negatively). Conversely, we found a higher percentage of CD14+ TREM-2+ monocytes in better surviving patients; these cells could downregulate the exaggerated inflammation and potentiate the phagocytosis in the tumor. The serum levels of HMGB1 negatively correlated with the percentage of CD14+ TREM-1+ cells and with the TREM-1/TREM-2 ratio. The positive correlation between the serum levels of a late proinflammatory cytokine HMGB1 with the percentage of TREM2+ CD14+ monocytes can be explained as an effort for suppression of systemic inflammation by anti-inflammatory acting CD14+ TREM-2+ cells. CONCLUSION: We showed that the TREM-1/TREM-2 ratio (expression on the surface of blood monocytes) could help predict prognosis in patients with gliomas, especially in high-grade gliomas, and that systemic inflammation has an impact on the patient's overall survival. This is the first study that showed that TREM expression on monocytes in peripheral blood could help predict prognosis in patients with gliomas.

TREM-1 and TREM-2 Expression on CD14+ Cells in Bronchoalveolar Lavage Fluid in Pulmonary Sarcoidosis and Hypersensitivity Pneumonitis in the Context of T Cell Immune Response.

BACKGROUND: Sarcoidosis and hypersensitivity pneumonitis (HP) are immunologically mediated processes caused by hypersensitivity reaction accompanied by similar features including lymphocytic alveolitis and granuloma formation. Recent studies describe the role of TREM receptors in T cell activation, differentiation, and granuloma formation. Alveolar macrophages activation via TREM receptors may be the key factor mediating subsequent immune response. The aim of the study was to analyse TREM-1 and TREM-2 expression to identify further molecular mechanisms participating in the immunopathogenesis of sarcoidosis and HP. METHODS: Flow cytometry was performed to analyse TREM-1 and TREM-2 expression on CD14+ cells in bronchoalveolar lavage fluid from patients having sarcoidosis or HP and a control group. RESULTS: The study proved increased TREM-1 expression on alveolar macrophages in pulmonary sarcoidosis and diminished TREM-1 expression in HP-Sarcoidosis: median: 76.7; HP: median: 29.9; control: median: 53.3, (sarcoidosis versus HP: p < 0.001; sarcoidosis versus control: p < 0.05). TREM-2 expression was increased in both, sarcoidosis and HP-sarcoidosis: median: 34.79; HP: median: 36.00; control: median: 12.98, (sarcoidosis versus control: p < 0.05; HP versus control: p < 0.05). Correlation analysis showed negative correlation between TREM-1 and total number of CD8+ cytotoxic T cells. In sarcoidosis TREM-1 expression decreased with changes of HRCT image, decrease in CD4/CD8 ratio and decrease in DLCO. CONCLUSIONS: Differences in TREM receptor expression in sarcoidosis (increase in TREM-1 and TREM-2) and HP (increase in TREM-2) and correlation analysis suggests that activation via TREM may participate in typical immunological characteristics of sarcoidosis and HP.

Decreased plasma levels of 25(OH)D in multiple sclerosis patients. Correlation with disease severity expressed by EDSS, MSSS, progression index and Herbert´s scale severity grade.

OBJECTIVES: Multiple sclerosis is a chronic inflammatory and autoimmune demyelinating disease of the brain and spinal cord. Vitamin D has anti-inflammatory and anti-Th1, Th17 activities, activates the function of regulatory T cells, shifts the immune response towards Th2, so it might be favorable for downregulation of the disease pathogenesis, and if inflammation and Th1 and Th17 immunity are hyperactivated. The aim of our study was to highlight the role of vitamin D in multiple sclerosis pathogenesis. METHODS: We investigated 178 patients with multiple sclerosis. Plasma levels of 25(OH)D and HMGB1 were investigated. RESULTS: Despite a regular use of VD by patients, the plasma levels of 25(0H)D were significantly decreased in 57% of them, 14.1% had VD deficiency (level of 25(OH)D < 20 ng/mL) and more than 6 % of patients had VD severe deficiency with the plasma level of 25(OH)D < 12 ng/mL. The level of 25(OH)D negatively correlated with the severity of the disease (EDSS, index of progression, duration of the disease) and negative association was found also with Herbert´s six severity grades. HMGB1 levels were higher in patients (p < 0.0001). CONCLUSION: Our result showed that vitamin D deficiency plays a role in multiple sclerosis pathogenesis. We believe that administration of vitamin D to patients at a sufficient dose providing a physiological level of vitamin D could have a positive effect on the course of the disease. However, regular monitoring of vitamin D levels is required, which should be at least within 30-75 ng/mL, and even more, but below the toxicity limit (Tab. 6, Ref. 66).

Analyses of tumor cells by mathematical models.

In this contribution we present graph theoretical approach to image processing focus on biological data. We use the graph cut algorithms and extend them for obtaining segmentation of biological data. We deal with tumor brain cells and rats brain to show the existence and presence of inflammatory molecules. We introduce a completely new method for filtering of data (Tab. 3, Schema 4, Fig. 7, Ref. 13). Keywords: graph cuts, segmentation, tumore analyses of cells, computer morphometry.

Artificial intelligence in service of medicine.

The race to make the dream of artificial intelligence a reality comes parallel with the increasing struggle of health care systems to cope with information overload and translational pressure. It is clear that a shift in the way data is generated requires a shift in the way they are processed. This is where AI comes with great promises to solve the problem of volume versus applicability of information in science. In medicine, AI is showing exponential progress in the fields of predictive analysis and image recognition. These promises however, come with an intricate package of ethico-social, scientific and economic implications, towards which a reductionist approach leads to distorted and dramatic predictions. All this, in a time when the growing pressure on healthcare systems towards defensive medicine begs the question of the true need for AI for good medical practice.This article examines the concept and achievements of AI and attempts to offer a complex view on the realistic expectations from it in medicine, in the context of current practice (Ref. 38). Keywords: algorithms, artificial intelligence, image recognition, neural networks, predictive analysis.

Vitamin D deficiency - a potential risk factor for sepsis development, correlation with inflammatory markers, SOFA score and higher early mortality risk in sepsis.

OBJECTIVES: Sepsis is a life-threatening organ dysfunction generated due to the dysregulation of the immune response to infection. The aim of this study was to highlight the role of vitamin D in sepsis and non-infectious SIRS (systemic inflammatory response syndrome) and to find correlation of vitamin D levels with inflammatory markers, severity of the disease, and association with the 7th and 28th survival rate of patients. METHODS: We investigated 32 patients (21 men, 11 women) admitted to an intensive care unit with both SIRS and sepsis. Blood was taken within 24 hours after admission. Plasma levels of 25(OH)D, sTREM-1, CRP, presepsin and procalcitonin were investigated. RESULTS: Patients with sepsis had lower levels of 25(OH)D (n = 25) than SIRS patients (n = 7; p = 0.0032). Significantly lower levels of 25(OH)D were found also in patients, who did not survive the 7th  (p = 0.0076) and 28th day  (p = 0.0338) of hospital care compared to 7th, resp. 28th day survivors. We revealed a negative correlation between the levels of 25(OH)D and inflammatory markers CRP (p = 0.0003), presepsin (p = 0.0032) and sTREM-1 (p = 0.0065) in all SIRS/sepsis patients and clinical condition (SOFA score; p = 0.0385). CONCLUSION: Our results showed that vitamin D deficiency predisposed to the development of sepsis, negatively correlated with CRP, presepsin, sTREM-1 and SOFA score and their levels associates with both 7th and 28th days survival of patients (Tab. 5, Ref. 64).

Analysis of HLA-G gene polymorphisms in Slovak women with pre-eclampsia.

OBJECTIVES: To identify possible association between the selected HLA-G gene polymorphisms and risk of pre-eclampsia. BACKGROUND: Pre-eclampsia is a serious multisystem disorder that affects women during pregnancy. Despite many research studies, the pathology of pre-eclampsia is not fully understood. Human leukocyte antigen G (HLA-G) belongs to the molecules that induce fetal acceptance by the maternal immune system. HLA-G expression was found to be impaired in the women suffering from pre-eclampsia suggesting its involvement in the development of pre-eclampsia. METHODS: 123 women with pre-eclampsia and 102 women with normotensive pregnancy were included in the study. HLA-G gene polymorphisms affecting its expression was determined, namely the HLA-G 14 bp insertion/deletion polymorphism in the 3'UTR and HLA-G 1597ΔC polymorphism tagging the HLA-G*01:05N null allele. Genotyping was performed by PCR and PCR-RFLP. RESULTS: No statistically significant differences in either allele or genotype frequencies between pre-eclampsia cases and control group have been observed (p > 0.05). CONCLUSION: Genetic predisposition of HLA-G to pre-eclampsia in Slovak women was examined for the first time. No association between analysed HLA-G gene polymorphisms and susceptibility to pre-eclampsia was observed. Further investigations are needed to determine the role of immunosuppressive molecule HLA-G in pre-eclampsia development (Tab. 5, Fig. 2, Ref. 37).

VLA4 Gene Polymorphism and Susceptibility to Multiple Sclerosis in Slovaks.

Multiple sclerosis (MS) is an inflammatory autoimmune disease occurring in genetically sensitive individuals. As migration of immune cells into the CNS is facilitated by the Very Late Antigen 4 (VLA-4) integrin molecule, the VLA4 gene may be considered as a plausible candidate genetic risk factor for susceptibility to MS. Therefore, the objective of our study was to investigate the association between two genetic polymorphisms located in the VLA4 gene and the risk of multiple sclerosis. One hundred seventeen MS patients and 165 control subjects from Slovakia were genotyped for VLA4 gene SNP polymorphisms at positions 269 (C/A) and 3061 (A/G). The same study cohorts were also genotyped for the rs3135388 polymorphism tagging the HLA-DRB1*15:01 allele, which is a known genetic factor associated with susceptibility to develop MS in many populations. Our findings show for the first time that the rs3135388 polymorphism is a strong risk factor for MS in the Slovak population. Investigation of the VLA4 gene polymorphisms revealed a significantly higher frequency of the 3061AG genotype in MS patients compared to the controls (P ≤ 0.05). We suggest that the 3061AG polymorphic variant is an independent genetic risk factor for MS development in our population as it was significantly associated with this disease. The association was also confirmed after applying multivariate logistic-regression analysis adjusted for gender, age and HLA-DRB1*15:01 positivity as possible influencing factors.

Increased antifungal antibodies in bronchoalveolar lavage fluid and serum in pulmonary sarcoidosis.

The recent studies suggest a role of fungi in development of sarcoidosis. Moreover, the immune response in sarcoidosis and fungal infection shows a striking similarity. We formulated a hypothesis of the possible increase in antifungal antibodies in bronchoalveolar lavage fluid (BALF) and serum in pulmonary sarcoidosis. BALF and serum levels of IgG-, IgM- and IgA-specific antibodies against the cell wall ß-D-glucan and mannan of Candida albicans and Saccharomyces cerevisiae were tested in 47 patients (29 pulmonary sarcoidosis patients and 18 patients with other interstitial lung diseases (ILD - control group)) and 170 healthy controls. Our results proved: (1) an increase in IgG-, IgM- and IgA-specific antifungal antibodies in BALF in pulmonary sarcoidosis compared with the control group (C. albicans: IgG: P = 0.0329, IgM: P = 0.0076, IgA: P = 0.0156; S. cerevisiae: IgG: P = 0.0062, IgM: P = 0.0367, IgA: P = 0.0095) and (2) elevated levels of serum antifungal antibodies in pulmonary sarcoidosis compared with healthy controls (C. albicans: IgG: P = 0.0329, IgM: P = 0.0076, IgA: P = 0.0156; S. cerevisiae: IgG: P > 0.05, IgM: P < 0.05, IgA: P < 0.001). The study showed increased serum and BALF levels of antifungal antibodies in pulmonary sarcoidosis. The hypothesis that fungal infection is one of the possible aetiologic agents of sarcoidosis is interesting and deserves further attention.

Diagnostic value of TREM-1 and TREM-2 expression in bronchoalveolar lavage fluid in sarcoidosis and other lung diseases.

BACKGROUND: Triggering receptors expressed on myelocytes (TREM) belong to new molecules with a great role in innate immune system and inflammation. While TREM-1 is known for its pro-inflammatory activity, the TREM-2 has anti-inflammatory activity and has a great impact on granuloma formation, typical sign of sarcoidosis and other granulomatous diseases. METHODS: In our study, we compared the TREM-1 and TREM-2 receptor expressions on the myeloid cell surfaces in bronchoalveolar lavage fluid in patients with pulmonary sarcoidosis (PS), other interstitial lung diseases (ILD), asthma bronchiale (AB), pneumonia, lung cancers, and Quantiferon TB positive patients. RESULTS: We found increased number of all TREM variables (total number, percentage, and mean fluorescence intensity /MFI/) of TREM-1 and TREM-2 positive cells in PS and AB patients compared to the control group of patients with other ILD. In patients with pneumonia, only expression of TREM-1 receptor was increased. In ILD, AB and group of pneumonia patients, the increase of TREM-1 and TREM-2 expression was associated with an increased number of eosinophils. CONCLUSION: TREM-1 and TREM-2 tests are good diagnostic tests for sarcoidosis. Their sensitivity and specificity are comparable with the currently common using test, that of CD4/CD8 ratio. The combination of both tests (CD4/CD8 ratio test together with TREM-1 and TREM-2 tests) resulted in an increased sensitivity and specificity (Tab. 7, Fig. 1, Ref. 28).

Increased plasma levels of the high mobility group box 1 protein (HMGB1) are associated with a higher score of gastrointestinal dysfunction in individuals with autism.

Autism is a disorder of neural development characterized by impairments in communication, social interaction, restricted interests and repetitive behavior. The etiology of autism is poorly understood, the evidence indicates that inflammation may play a key role. In autism a high prevalence of gastrointestinal disturbances is reported, that are linked to a low-grade chronic inflammation of the intestinal mucosa. High mobility group box 1 protein (HMGB1) is an intranuclear protein that can be passively released from necrotic cells or actively secreted under inflammatory conditions as alarmin or late proinflammatory cytokine. The objective of this study was to measure plasma levels of HMGB1 in individuals with autism and to analyze their association with gastrointestinal symptoms. The study involved 31 subjects with low-functioning autistic disorder aged 2-22 years and 16 healthy controls. Plasma HMGB1 levels were significantly higher in individuals with autism than in controls (13.8+/-11.7 ng/ml vs. 7.90+/-4.0 ng/ml, p<0.02). In subjects with plasma HMGB1 levels higher than 11 ng/ml severe forms of GI disorders were more prevalent (83.3 %) than in subjects with lower levels (38.9 %, p<0.04). Results of the study support the involvement of the systemic low-grade inflammation in the pathomechanisms of autism and its possible association with GI symptoms.

sTREM-1 in bronchoalveolar lavage fluid in patients with pulmonary sarcoidosis, effect of smoking and inflammation.

Soluble TREM-1 (sTREM-1; Triggering receptor expressed on myelocytes) is a new inflammatory marker indicating the intensity of myeloid cells activation and the presence of infection caused by extracellular bacteria and mould.The aim of our work was to detect and compare the levels of sTREM-1 in bronchoalveolar lavage fluid (BALF) in patients with pulmonary sarcoidosis (PS) and other ILD of non-infectious origin. The sTREM-1 levels were assessed by ELISA in 46 patients suffering from ILD, out of them 22 with PS. The levels of BALF sTREM-1 in PS patients were higher than in control group of ILD patients of non-infectious origin, however, the difference was not statistically significant. Since all PS patients except one were non-smokers we compared non-smokers PS with non-smokers ILD patients and found four times higher levels of BALF sTREM-1 in PS patients (P = 0.001). We also recorded the effect of smoking, ILD smokers had higher sTREM-1 levels than non-smokers (P = 0.0019). Higher concentrations of sTREM-1 were detected in BALF of patients with lymphadenopathy and with elevated inflammatory markers in BALF. Our results show that BALF sTREM-1 could be a good inflammatory marker and could help in diagnosis and PS monitoring. Detection of sTREM-1 in BALF indirectly points to myeloid cells activation in the lungs and helps to complete the information about the number of myeloid cells commonly determined in BALF with additional information concerning the intensity of their activation. This is the first study that analyses BALF sTREM-1 levels in patients with PS (Tab. 8, Ref. 28). Text in PDF www.elis.sk.

HMGB1 and its physiological and pathological roles.

HMGB1 has been formerly known for its intracellular function - as the intranuclear non-histone DNA binding protein, which contributes to stabilization of nucleosomes, mediation of DNA bending and is regarded to have an essential position in DNA repair. Lately, its participation in innate and specific immune responses has been revealed. Passively released from necrotic cells or actively produced by various cell types it acts as an alarmin and is responsible for production of pro-inflammaory cytokines. HMGB1 is able to interact with RAGE and TLRs, receptors that belong into family of pattern recognition receptors and are involved in activation of pathways leading to production of pro-inflammatory cytokines. Its key role has been revealed in mediation of sepsis and as it is released later than other pro-inflammatory cytokines it became known as a "late mediator of sepsis". HMGB1 also contributes to the development of atherosclerosis and autoimmune diseases, e.g. its association with immunopathogenesis of SLE and RA has been suggested. Beside its negative function, HMGB1 protein seems to be able to attract stem cells to the area of inflammation and thus promotes regeneration processes. This paradoxical function of HMGB1 protein has also been revealed in growth and spread of many types of tumours. HMGB1 represents a potential target in therapy of various disorders related to inflammation (Fig. 2, Ref. 137).

Genetic variations of interleukin-8, CXCR1 and CXCR2 genes and risk of acute pyelonephritis in children.

Acute pyelonephritis (APN) is the most severe form of urinary tract infection, the etiopathogenesis of which is still not well understood. Previous studies demonstrated that chemotaxis of neutrophils into the tissue and across the infected epithelial layer is a key step in rapid bacterial clearance. Variations within genes encoding the major chemokine interleukin-8 and its receptors CXCR1 and CXCR2 are therefore attractive candidates for participation in genetic predisposition to APN. The aim of our study was to evaluate the association of single nucleotide polymorphisms (SNPs) -251 T/A, +781 C/T, +1633 C/T and +2767 A/T in the IL-8 gene, +2608 G/C in the CXCR1 gene and +1208 C/T in the CXCR2 gene with susceptibility to APN in the Slovak population. PCR-SSP and PCR-RFLP were used to genotype SNPs in 147 children with APN (62 with recurrent and 85 with episodic form) and 215 healthy individuals. Statistical analysis revealed significantly increased frequency of CXCR1 +2608 C allele (P = 0.0238, OR = 2.452, 95% CI = 1.147-5.243) and GC genotype (P = 0.0201, OR = 2.627, 95% CI = 1.188-5.810) and lower frequency of CXCR2 +1208 T allele (P = 0.0408, OR = 0.645, 95% CI = 0.429-0.972) and TT+TC genotypes (P = 0.0497, OR = 0.5273, 95% CI = 0.288-0.964) in patients with recurrent APN compared with healthy controls. Furthermore, the A allele of IL-8 -251 T/A SNP was also significantly overrepresented in patients with recurrent APN when compared with those with only single episode of APN (P = 0.0439, OR = 1.627, 95% CI = 1.019-2.599). Our results indicate that the minor CXCR1 +2608 C allele is associated with significantly increased susceptibility to APN in childhood, while the CXCR2 +1208 T allele confers protection from recurrent APN. Moreover, allele A of the IL-8 -251 T/A may also increase the risk of developing recurrent attacks after the first-time APN.

HSP60, oxidative stress parameters and cardiometabolic risk markers in hypertensive and normotensive Slovak females.

BACKGROUND: The aim of our study was to analyse the relationships between hypertension, HSP60, oxidative stress, lipid profile and cardiometabolic risk in 126 females with arterial hypertension (AHW) and 39 normotensive females (AH-). RESULTS: Females with AH+ were significantly older and more frequently suffered from ischemic heart disease, angina pectoris, prior MI, abdominal obesity, obesity, metabolic syndrome and diabetes mellitus. On the other hand, normotensive females smoked significantly more often. Plasma levels of HSP60 were similar in both AH+ and AH- groups. However, hypertensive females exhibited almost two times lower values of oxidative glutation and lower levels of carbonyl protein, but significantly higher levels of homocysteine. In normotensive females, the total glutathione was the only parameter predicting females with the plasma level of HSP60 = 60 ng/ml. The independent predictors in hypertensive females were angina pectoris, triglycerides and the mean arterial pressure (MAP). MAP had also a borderline significance in normotensive females suggesting an association between HSP60 and blood pressure. MAP formed a J shaped curve with HSP60. CONCLUSION: Results suggest the association of blood pressure and heart shock protein 60 Kda in form of the J curve (Tab. 11, Fig. 3, Ref. 29).