Unfavorable Disease Outcome Research Articles

Interleukin-6 and interleukin-8 serum levels in prognosis of hormone-dependent breast cancer

BackgroundIncreasing amount of evidence points to the importance of immunity in breast cancer. The prognostic value of cytokines and their effect on tumorigenesis remains inconsistent. AimTo investigate the prognostic significance of IL6 and IL8 and their association with ER and HER2 in estrogen-dependent (ER+) breast cancer. Material and methodsThe study included 79 premenopausal women with early and locally advanced ER+ breast cancer. All patients received adjuvant hormonal therapy: tamoxifen alone (56/79) or combination with LHRH agonist goserelin (23/79). IL6 and IL8 serum protein levels were measured by ELISA. Cox proportional hazards regression analysis was implemented for prognostic evaluation of the data categorized based on metastasis outcome. ResultsIL6 associated with good (P = 0.001, HR = 0.05) and IL8 with poor disease outcome (P = 0.03, HR = 2.5) in the whole group of patients. Multivariate analyses highlighted IL6 as the independent prognostic factor (P = 0.001, HR = 0.0007). When patients were classified according to ER or HER2 status, IL6 did not have prognostic significance in ERlow and ERhigh subgroups, while IL8 retained prognostic significance only in the ERhigh subgroup (P = 0.04, HR = 2.8). IL6 was significant in both HER2− (P = 0.001, HR = 0.05) and HER2+ subgroups (P = 0.002, HR = 0.04), while IL8 retained its prognostic significance only in the HER2+ subgroup (P = 0.001, HR = 77.8). ConclusionsThis study contributes to the clarification of the prognostic performance of IL6 and IL8 by providing their first prognostic evaluation in the homogenized ER+ breast cancer patient group. IL6 was indicated as a marker of favorable, whereas IL8 was a marker of unfavorable disease outcome.

METABOLIC ASPECTS OF ACUTE stage ISCHEMIC STROKE

Aim. To study the influence of hyperglycemia on the course of ischemic stroke in its acute period. Materials and methods. 116 patients with primary ischemic stroke, associated with arterial hypertension, and with no diabetes mellitus in anamnesis were examined. Fasting blood glucose, glycolyzed hemoglobin, immunoreactive insulin and C-peptide levels were determined. Results. Raised levels of glycemia to 5.31 ± 0.68 mmol/l, C-peptide to 0.90 ± 0.31 nmol/l and decreased level of insulin to 9.38 ± 4.34 mcIU/ml were detected. C-peptide to insulin ratio values were reliably higher in patients with severe course of stroke (by 35.6 %, p < 0.05) and unfavorable outcome of disease (by 39.6 %, p < 0.05). Conclusions. Development of ischemic stroke is accompanied by high blood C-peptide levels against the background of normo-and-hypoinsulinemia, hyperglycemia. Manifestation of disorders is connected with severity and clinical outcome of this disease.

P143 Risk of impaired nutritional status is associated with an unfavourable disease outcome in IBD

P143 Risk of impaired nutritional status is associated with an unfavourable disease outcome in IBD

ГЕНЕТИЧНИЙ КОНТРОЛЬ ІМУННОЇ СИСТЕМИ У ХВОРИХ НА МЕНІНГІТ

Мета роботи – аналіз і узагальнення сучасних уявлень про вплив генетичних факторів на механізми порушень функцій центральної нервової системи у хворих на менінгіт.Збудники менінгіту (М) володіють різноманітними антигенними детермінантами, що викликають в організмі поліклональну імунну відповідь, в яку залучаються фактори природної та адаптивної (набутої) системи імунітету (АСІ). В останні роки, поряд з раніше вивченими причинно-наслідковими зв’язками різноманітних проявів реакцій АСІ на збудників М, набуло актуальності вивчення генетичних факторів, що визначають функціональний стан АСІ. Як показали дослідження, виникнення М як мультифакторного захворювання залежить від поєднання генотипу хворого й незалежно діючих індукторів зовнішнього середовища. Серед завдань першорядного значення, які вирішує АСІ у відповідь на проникнення патогена, відповідальне місце займає розпізнавання антигену специфічними лімфоцитами. Генетичні зміни в цій ділянці імунної відповіді можуть провокувати збільшення сприйнятливості до М, його тяжкий перебіг і несприятливий вислід захворювання. Ушкодження генного апарата, який експресує фактори клітинної ланки АСІ, асоціюється з інфекціями, що спричинюють мікобактерії, найпростіші, гриби, віруси й опортуністичні бактерії. Дефіцит антитіл переважно асоціюється з інфекціями, викликаними грампозитивними бактеріями. У специфічному розпізнаванні антигенів також беруть участь молекули головного комплексу гістосумісністі (MHC). Туберкульозний М характеризувався значним підйомом рівня антигену HLA-DR3 з істотним підвищенням частоти антигенів B14 й DR2. У пацієнтів із гнійними М більшою мірою виявляли антиген HLA-B12. У хворих із серозними М визначалося підвищення рівня антигену HLA-A19. Поряд із забезпеченням адаптаційної функції контролю сприйнятливості до інфекції, фактори АІС можуть бути відповідальними за ушкодження власних тканин організму. Висновки. Для правильної оцінки сприйнятливості організму до інфекції, тяжкості стану хворого й прогнозу результату М необхідне визначення співвідношення внесків спадкоємного й «зовнішнього» факторів у кожному конкретному випадку. Крайні позиції в цьому співвідношенні займають первинні імунодефіцити, при яких хвороба істотно залежить від конкретної мутації, й вторинні імунодефіцити, коли чітко виражена залежність від етіологічного фактора захворювання. Визначення цього співвідношення, можливо, буде корисним при розробці генетичних методів корекції в комплексі лікувальних заходів у хворих на менінгіт.

Regional brain morphometry in patients with traumatic brain injury based on acute- and chronic-phase magnetic resonance imaging.

Traumatic brain injury (TBI) is caused by a sudden external force and can be very heterogeneous in its manifestation. In this work, we analyse T1-weighted magnetic resonance (MR) brain images that were prospectively acquired from patients who sustained mild to severe TBI. We investigate the potential of a recently proposed automatic segmentation method to support the outcome prediction of TBI. Specifically, we extract meaningful cross-sectional and longitudinal measurements from acute- and chronic-phase MR images. We calculate regional volume and asymmetry features at the acute/subacute stage of the injury (median: 19 days after injury), to predict the disability outcome of 67 patients at the chronic disease stage (median: 229 days after injury). Our results indicate that small structural volumes in the acute stage (e.g. of the hippocampus, accumbens, amygdala) can be strong predictors for unfavourable disease outcome. Further, group differences in atrophy are investigated. We find that patients with unfavourable outcome show increased atrophy. Among patients with severe disability outcome we observed a significantly higher mean reduction of cerebral white matter (3.1%) as compared to patients with low disability outcome (0.7%).

Non-HLA gene polymorphisms in juvenile idiopathic arthritis: associations with disease outcome

Objective: To test the hypothesis that non-HLA single-nucleotide polymorphisms (SNPs) associated with the risk of juvenile idiopathic arthritis (JIA) are risk factors for an unfavourable disease outcome at long-term follow-up.Methods: The Nordic JIA cohort is a prospective multicentre study cohort of patients from the Nordic countries. In all, 193 patients met the inclusion criteria of having an 8 year follow-up assessment and available DNA sample. Seventeen SNPs met the inclusion criteria of having significant associations with JIA in at least two previous independent study cohorts. Clinical endpoints were disease remission, actively inflamed joints and joints with limitation of motion (LOM), articular or extra-articular damage, and history of uveitis.Results: Evidence of associations between genotypes and endpoints were found for STAT4, ADAD1-IL2-IL21, PTPN2, and VTCN1 (p = 0.003–0.05). STAT4_rs7574865 TT was associated with the presence of actively inflamed joints [odds ratio (OR) 20.6, 95% confidence interval (CI) 2.2–> 100, p = 0.003] and extra-articular damage (OR 7.9, 95% CI 1–56.6, p = 0.057). ADAD1_rs17388568 AA was associated with a lower risk of having joints with LOM (OR 0.1, 95% CI 0–0.55, p = 0.016). PTPN2_rs1893217 CC was associated with a lower risk of having joints with LOM (OR 0.2, 95% CI 0–0.99, p = 0.026), while VTCN1_rs2358820 GA was associated with uveitis (OR 3.5, 95% CI 1–12.1, p = 0.029).Conclusion: This exploratory study, using a prospectively followed JIA cohort, found significant associations between long-term outcome and SNPs, all previously associated with development of JIA and involved in immune regulation and signal transduction in immune cells.

Liver Transplantation in Polish Children With α1-Antitrypsin Deficiency: A Single-Center Experience

Backgroundα1-Antitrypsin deficiency (ATD) is the most common genetic cause of liver injury in young children. Asymptomatic hepatitis is observed in most patients. However, the course of liver disease due to ATD is unpredictable, and some children develop liver cirrhosis. Liver transplantation (Ltx) dramatically improves their outcome and in some cases is required in the first years of life. The aim of the study was to evaluate the course of the disease in children with ATD treated with Ltx in a single center. MethodsWe retrospectively reviewed the clinical features (ascites, esophageal varices, esophageal bleeding) and laboratory parameters of liver function in children with ATD who were treated with Ltx. ResultsTwenty-two Ltxs were performed in 20 children (13 boys, 7 girls). Median age at transplantation was 12 years (range 0.5 to 17.1). Four children were transplanted in the first 2 years of life and 16 patients were over 7 years old. The indications for Ltx in younger children were progressive cholestasis with coagulopathy and ascites. In older patients, the indications were as follows: liver failure presenting with variceal bleeding in 7 patients, ascites in 5 patients, hypersplenism in all but 1 patient. In the group of children transplanted over 7 years old, the frequency of cholestasis decreased intermittently in the second year of life: 4 patients (25%) compared to 15 patients (94%) and 10 patients (63%) in the neonatal and pretransplant period, respectively. In the group of children transplanted earlier, cholestasis and hepatitis were maintained until Ltx. Of transplanted patients, 50% were malnourished at the transplantation, and 50% were followed for more than 10 years. Five-year post-transplant survival was 100% (n = 14), and 10-year survival was 90%. Two patients died as adults with biliary post-transplant complications and problems with compliance. ConclusionsOur experience suggests that transient normalization of liver parameters in some patients with ATD do not exclude the liver disease progression to cirrhosis and unfavorable outcome of liver disease in childhood. In our group of patients, median age at transplantation was high compared to other centers. The long-term prognosis in children after transplantation is very good, but early post-transplant complications and probable problems with compliance in young adults may lead to graft failure.

ERBB2 Overexpression Establishes ERBB3-Dependent Hypersensitivity of Breast Cancer Cells to Withaferin A.

The catalytically deficient ERBB3 strongly synergizes with the receptor tyrosine kinase ERBB2, and elevated levels represent an overall risk factor for unfavorable disease outcomes in breast cancer. Although itself not a target of pan-ERBB kinase inhibitors, it contributes to resistance in ERBB2-targeted treatment regiments. The steroidal lactone Withaferin A (WA) has established broad anticancer properties through several modes of action and was shown to be effective against triple-negative breast cancers at elevated concentrations. We found that ERBB2 overexpression does render cells hypersensitive to WA. Although ERBB2 downregulation is one aspect of WA treatment at high concentrations, it is not causal for the elevated sensitivity at lower dosages. Instead, WA targets the ability of ERBB3 to amplify ERBB2 signaling. ERBB3 receptor levels, constitutive phosphorylation of both ERBB3 and ERBB2, as well as signaling through AKT are eliminated by WA treatment. By targeting ERBB2/ERBB3 as a functional unit, it is also effective in cases in which ERBB2-directed inhibitors, such as lapatinib, alone show reduced potency. Hence, WA or derivatives thereof may present a low toxicity addition to ERBB2-targeting therapeutics, especially in cases in which ERBB3 involvement is driving resistance or reduced overall sensitivity. Mol Cancer Ther; 15(11); 2750-7. ©2016 AACR.

Procjena citomorfologije, HPV statusa i HPV 16 genotipa u predikciji ishoda bolesti kod pacijentica s citološkim nalazom ASCUS i LSIL

Objective: To analyse characteristics and prognostic value of HPV status (human papilloma virus), HPV 16 genotype and cytomorphology in the patients with cervical cytology finding of borderline and mild abnormalities of squamous epithelium. Material and methods: Patients with initial cytology finding of atypical squamous cells of undetermined significance (ASCUS, N = 160) and low-grade squamous intraepithelial lesion (LSIL, N = 155) were included. Cytomorphological characteristics of koilocytosis, parakeratosis and macrocytosis were analysed. In all patients HPV DNA test was performed using high risk probe of hybrid capture 2 test. In positive samples additional HPV genotyping was doneusing INNO-LiPA HPV Genotyping v2 assay. Patients were followed by cytology, colposcopy and histology for average of 26 months. Three possible clinical outcomes: regression, stagnation or progression were recorded. Results: The most frequent HPV genotype was HPV 16 and it was found in 27.9% ASCUS (N = 29) and in 16.5% LSIL (N = 16) cases. It was found more frequently in women under 30 years of age (P < 0.001). Macrocytosis was more frequent finding in HR HPV negative cases in ASCUS and LSIL (P < 0.05). Koilocytosis and parakeratosis did not show relationship with HR HPV status. When analysed according to HPV genotype, in LSIL, koilocytosis was more frequent finding in HPV non-16 genotype compared to HPV 16 genotype (P=0.002). Parakeratosis is more frequently found in HPV non-16 genotype cases, but statistically significant difference is found only in LSIL (P = 0.005). Unfavourable disease outcome was recorded in 25.3% of ASCUS and 13.8% LSIL. Disease progression was associated with HR HPV positivity (P < 0.001) and HPV 16 genotype (P < 0.001). Presence of koilocytosis, parakeratosis and macrocytosis are not associated with the unfavourable disease outcome in ASCUS and LSIL. Conclusion: HPV 16 was the most frequent genotype in ASCUS and LSIL and it is more frequently associated with koilocytosis and parakeratosis absence. HR HPV DNA positivity and HPV 16 genotype were associated with the disease progression in ASCUS and LSIL. Cytomorphology features showed no association with the unfavourable disease outcome. These results could help in optimising follow up and management of patients with initial cytology diagnosis of ASCUS and LSIL and have possible impact on used guidelines for cervical abnormalities.

P53, cathepsin D, Bcl-2 are joint prognostic indicators of breast cancer metastatic spreading.

BackgroundTraditional prognostic indicators of breast cancer, i.e. lymph node diffusion, tumor size, grading and estrogen receptor expression, are inadequate predictors of metastatic relapse. Thus, additional prognostic parameters appear urgently needed. Individual oncogenic determinants have largely failed in this endeavour. Only a few individual tumor growth drivers, e.g. mutated p53, Her-2, E-cadherin, Trops, did reach some prognostic/predictive power in clinical settings. As multiple factors are required to drive solid tumor progression, clusters of such determinants were expected to become stronger indicators of tumor aggressiveness and malignant progression than individual parameters. To identify such prognostic clusters, we went on to coordinately analyse molecular and histopathological determinants of tumor progression of post-menopausal breast cancers in the framework of a multi-institutional case series/case-control study.MethodsA multi-institutional series of 217 breast cancer cases was analyzed. Twenty six cases (12 %) showed disease relapse during follow-up. Relapsed cases were matched with a set of control patients by tumor diameter, pathological stage, tumor histotype, age, hormone receptors and grading. Histopathological and molecular determinants of tumor development and aggressiveness were then analyzed in relapsed versus non-relapsed cases. Stepwise analyses and model structure fitness assessments were carried out to identify clusters of molecular alterations with differential impact on metastatic relapse.Resultsp53, Bcl-2 and cathepsin D were shown to be coordinately associated with unique levels of relative risk for disease relapse. As many Ras downstream targets, among them matrix metalloproteases, are synergistically upregulated by mutated p53, whole-exon sequence analyses were performed for TP53, Ki-RAS and Ha-RAS, and findings were correlated with clinical phenotypes. Notably, TP53 insertion/deletion mutations were only detected in relapsed cases. Correspondingly, Ha-RAS missense oncogenic mutations were only found in a subgroup of relapsing tumors.ConclusionsWe have identified clusters of specific molecular alterations that greatly improve prognostic assessment with respect to singularly-analysed indicators. The combined analysis of these multiple tumor-relapse risk factors promises to become a powerful approach to identify patients subgroups with unfavourable disease outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2713-3) contains supplementary material, which is available to authorized users.

Signal Sequence Receptor 2 is required for survival of human melanoma cells as part of an unfolded protein response to endoplasmic reticulum stress.

Current therapy approaches in melanoma targeting have met with the development of resistance and tumour recurrence with a more aggressive phenotype. In a quest for alternative therapy targets, we had previously identified Signal Sequence Receptor 2 (SSR2) as a gene with high expression in a subgroup of human primary melanomas. Now we show that SSR2 exerts a prosurvival functionality in human melanoma cells and that high expression levels of SSR2 are associated with an unfavourable disease outcome in primary melanoma patients. Consistent with SSR's role in translocation of proteins from the ribosome across the endoplasmic reticulum (ER) membrane, our data supports induction of SSR2 as a part of the ER stress response. This response included SSR2 upregulation upon development of therapy resistance to BRAF inhibitors, as well as the dependency of cell survival of BRAF inhibitor-resistant melanoma cells on SSR2. Complementary gain and loss of function data showed the Unfolded Protein Response (UPR) to ER stress as an inducer of SSR2 via transcriptional regulation through X-Box Binding Protein 1s (XBP1s) and support an ER stress-UPR-Transcription Factor XBP1s-SSR2 response axis in human melanocytic cells. Together with its dispensability for survival in normal human cells, these data propose SSR2 as a potential therapeutic target in (therapy-resistant) human melanoma.

FUNCTIONAL RE-MODELING INFLUENCE OF EPILEPS IN BRAIN TUMOR

Pathological electrical activity in proximity as well as distant cortical and subcortical zones induced by brain tumors alter the functioning of higher regulatory centers. These bioelectric changes in intricately connected brain functional zones lead to misbalances in compensatory mechanisms in turn influencing unfavorable disease outcome. Objective. This study is aimed at analyzing electroencephalographic (EEG) spectral peculiarities of as well as the peculiarities of cardiac rhythm variability in patients with epilepsy associated brain tumors. Materials and Methods. 72 patients participated in the survey aged from 22 to 83 years, divided into 2 groups: Brain tumor patients with epileptic seizures and brain tumor patients without seizures. The patients included in the study were those admitted to the neurosurgical department at Ryazan state regional hospital. Statistical, geometric and spectral parameters of heart rate variability as well as coherence and cross-correlational EEG analyses used to access the functional states of the patients. Results. The study revealed sympathetic predominance of the autonomic nervous system in patients with epilepsy associated brain tumors as opposed to parasympathetic predominance in non epilepsy associated brain tumors indicating significant stress to regulatory systems and depletion of subcortical reserves of the cardiovascular system, further more stretching the adaptation limits, ultimately leading to depression of autonomic regulatory mechanisms and predominance of central mechanisms of regulation and adaptation. Conclusion. Frequency-amplitude analysis of electroencephalogram and cardiointervalogram allow us to assess the degree of distress of different cortical and subcortical regulatory systems in patients with brain tumors, and is recommended as an additional method of investigation in these patients.

Aquaporin 5 expression is frequent in prostate cancer and shows a dichotomous correlation with tumor phenotype and PSA recurrence

Aquaporin 5 (AQP5) is an androgen-regulated member of a family of small hydrophobic integral transmembrane water channel proteins regulating cellular water homeostasis and growth signaling. To evaluate its clinical impact and relationship with key genomic alterations in prostate cancer, AQP5 expression was analyzed by immunohistochemistry on a tissue microarray containing 12427 prostate cancers. The analysis revealed weak to moderate immunostaining in normal prostate epithelium. In prostate cancers AQP5 staining levels were more variable and also included completely negative and highly overexpressing cases. Negative, weak, moderate, and strong AQP5 staining was found in 25.0%, 32.5%, 32.5%, and 10.0% of 10239 interpretable tumors. Comparison of AQP5 expression levels with tumor characteristics showed a dichotomous pattern with both high and low staining levels being linked to unfavorable tumor phenotype. AQP5 was negative in 28%, 23%, 24%, and 35% of tumors with Gleason score ≤3 + 3, 3 + 4, 4 + 3 and ≥4 + 4, while the rate of strongly positive cases continuously increased from 7.0% over 10.0% and 12.0% to 13.0% in cancers with Gleason score ≤3 + 3, 3 + 4, 4 + 3 and ≥4 + 4. AQP5 expression was also related to ERG positivity and phosphatase and tensin homolog (PTEN) deletion (P < .0001 each). Strong AQP5 positivity was seen in 15.5% of ERG-positive and 5.8% of ERG-negative cancers (P < .0001) as well as in 14.7% of cancers with PTEN deletion and 9.4% of cancers without PTEN deletion. Remarkably, both negativity and strong positivity of AQP5 were linked to unfavorable disease outcome. This was however only seen in subgroups defined by TMPRSS2-ERG fusion and/or PTEN deletion. In summary, AQP5 can be both overexpressed and lost in subgroups of prostate cancers. Both alterations are linked to unfavorable outcome in molecularly defined cancer subgroups. It is hypothesized that this dichotomous role of AQP5 is due to two highly different mechanisms as to how the protein can influence cancer cells, that is, hydraulic motility regulation and Ras/MAPK pathway activation.

221 Influence of nutritional status of children with cystic fibrosis on disease outcome

Objectives To establish the influence of nutritional status of children with CF, who are in critical condition, on disease outcome. Methods This is a retrospective study of children with CF admitted to the pediatric ICU of St. George University Hospital, Plovdiv, from January 2004 to June 2013. Children were admitted because of respiratory failure, heart failure or dehydration. We analyzed patients' weight, height, BMI, severity of the disease based on the Shwachman-Kulczycki score, colonization with P. aeruginosa, length of hospital stay and disease outcome. Results 23 children are included in the study – 12 boys and 11 girls. The mean age of the patients is 63.7 months (1–214 months). The main reason for admission to ICU was respiratory infection (78.3%). Two of the children had severe dehydration and one had arrhythmia. Five of the patients died in ICU (21.7%). There is a positive correlation between the nutrition deficit on one side, low Shwachman-Kulczycki score, longer hospital stay and unfavourable disease outcome on the other. Children without nutritional deficit had a significantly shorter hospital stay and higher Shwachman-Kulczycki score on admission. We did not establish a statistically significant correlation between the degree of nutritional deficit and colonization with P. aeruginosa . Conclusion Children with nutritional deficit and low Shwachman-Kulczycki score have a longer hospital stay and are at a higher risk of unfavorable disease outcome. If the nutritional deficit is diagnosed early and actively corrected, this could lead to shorter hospital stay and reduced disease severity while on ICU.

ENERGY METABOLISM STATUS IN ACUTE PERIOD OF ISCHEMIC STROKE

Aim. To study the peculiarities of carbohydrate metabolism in the acute period of ischemic stroke. Materials and methods. Sixty two patients with primary ischemic stroke associated with arterial hypertension and free of diabetes mellitus in anamnesis were examined. Fasting blood glucose, immunoreactive insulin and C-peptide levels were determined. Insulin resistance was assessed using calculation index HOMA and coefficient Caro. Results. Increase in glycemia levels to 5,31 ± 0,68 mmol/l, C-peptide to 0,90 ± 0,31 nmol/l and decline in insulin level to 9,38 ± 4,34 mcME/ml was demonstrated. C-peptide to insulin ratio values were reliably higher in patients with severe course of stroke (by 35,6 %, p < 0,05) and unfavorable outcome of disease (by 39,6 %, p < 0,05). Conclusions. Development of ischemic stroke is accompanied by high blood C-peptide levels against the background of hypoinsulinemia and minor hyperglycemia. Manifestation of disorders correlates with severity and clinical outcome of disease.

Chronic Kidney Disease--Chronic Liver Disease. An Immunologic Cross-talk.

The relationship between the kidney and other organs is notable. The best known is the relation with the cardiovascular system. Relationships with other organs are less studied, although their involvement sometimes dominates the clinical picture and the outcome of disease. The paper analyzes the kidney-liver relationship, namely chronic kidney disease and chronic liver disease from an immune viewpoint. The immune system operates as a unitary whole. There is an interdependence between the immune system of the liver, considered a lymphoid organ, and the kidney, whose participation in immune processes is well-known. The most important chronic liver diseases are viral hepatitis B and C. Infection with these viruses can lead to renal involvement, producing mainly glomerular disease. At the same time, secondary glomerulonephritis can cause an unfavorable outcome of the primary disease. The relationship between chronic liver disease and chronic kidney disease during chronic B and C hepatitis occurs via circulating immune complexes or complexes formed in situ. Cell-mediated immunity is also involved. The antiviral treatment of B and C hepatitis is also aimed at secondary glomerular disease. The participation of immune mechanisms raises the question of administering immunomodulating medication, a type of medication that influences viral replication--this is why it is associated with antiviral medication. Other two chronic liver diseases, namely liver cirrhosis, in which the main mechanism is a toxic one, and non-alcoholic steatohepatitis can produce via immune mechanisms glomerular involvement. In its turn, chronic kidney disease in advanced stages causes lipid metabolism disturbances with hypertriglyceridemia, which can influence fatty loading of the liver in the above-mentioned liver diseases. One can speak about a cross-talk between the liver and the kidney, in which immune mechanisms play an important role.

An intuitive risk factors search algorithm: usage of the Bayesian network technique in personalized medicine

The article focuses on the application of the Bayesian networks (BN) technique to problems of personalized medicine. The simple (intuitive) algorithm of BN optimization with respect to the number of nodes using naive network topology is developed. This algorithm allows to increase the BN prediction quality and to identify the most important variables of the network. The parallel program implementing the algorithm has demonstrated good scalability with an increase in the computational cores number, and it can be applied to the large patients database containing thousands of variables. This program is applied for the prediction for the unfavorable outcome of coronary artery disease (CAD) for patients who survived the acute coronary syndrome (ACS). As a result, the quality of the predictions of the investigated networks was significantly improved and the most important risk factors were detected. The significance of the tumor necrosis factor-alpha gene polymorphism for the prediction of the unfavorable outcome of CAD for patients survived after ACS was revealed for the first time.

SAT0138 Cumulative Burden of Rheumatoid Arthritis Disease Severity Impacts Cardiovascular Disease Risk

BackgroundRheumatoid arthritis (RA) disease severity is linked to unfavorable cardiovascular disease (CVD) outcomes. Cumulative measures of RA disease burden on CVD have not been well-studied and could be used to...

Platelet mitochondrial membrane depolarization reflects disease severity in patients with sepsis and correlates with clinical outcome

IntroductionSepsis is still a leading cause of morbidity and mortality, even in modern times, and thrombocytopenia has been closely associated with unfavorable disease outcome. Decreases in mitochondrial membrane potential (depolarization) were found in different tissues during sepsis. Previous work suggests that mitochondrial dysfunction of platelets correlates with clinical disease activity in sepsis. However, platelet mitochondrial membrane potential (Mmp) has not been investigated in a clinical follow-up design and not with regard to disease outcome.MethodsIn this study, platelet mitochondrial membrane depolarization was assessed by means of a fluorescent Mmp-Index with flow cytometry in 26 patients with sepsis compared with control patients. Platelet Mmp-Index on admission was correlated with the clinical disease scores Acute Physiology and Chronic Health Evaluation Score II (APACHE II), Sequential Organ Failure Score (SOFA), and Simplified Acute Physiology Score II (SAPS II). Finally, platelet Mmp-Index on admission and follow-up were compared in the group of sepsis survivors and nonsurvivors. Expression of the prosurvival protein Bcl-xL in platelets was quantified by immunoblotting.ResultsPlatelet mitochondrial membrane depolarization correlated significantly with the simultaneously assessed clinical disease severity by APACHE II (r = -0.867; P < 0.0001), SOFA (r = -0.857; P <0.0001), and SAPS II score (r = -0.839; P < 0.0001). Patients with severe sepsis showed a significant reduction in platelet Mmp-Index compared with sepsis without organ failure (0.18 (0.12 to 0.25) versus 0.79 (0.49 to 0.85), P < 0.0006) or with the control group (0.18 (0.12 to 0.25) versus 0.89 (0.68 to 1.00), P < 0.0001). Platelet Mmp-Index remained persistently low in sepsis nonsurvivors (0.269 (0.230 to 0.305)), whereas we observed recovery of platelet Mmp-Index in the survivor group (0.9 (0.713 to 1.017)). Furthermore, the level of prosurvival protein Bcl-xL decreased in platelets during severe sepsis.ConclusionIn this study, we demonstrated that mitochondrial membrane depolarization in platelets correlates with clinical disease severity in patients with sepsis during the disease course and may be a valuable adjunct parameter to aid in the assessment of disease severity, risk stratification, and clinical outcome.

EPA-1668 - Differential diagnostic classification of schizophrenia and depression using mri-based pattern recognition

Background The clinical differentiation of schizophrenic and mood disorders is frequently challenged by co-occurring affective and psychotic symptoms. Thus, it has long been discussed whether these disease groups are subserved by common or distinct neurobiological surrogates. Aims The detection of diagnostic biomarkers for schizophrenic and mood disorders could facilitate clinical decision making in ambiguous cases. Objective To evaluated whether multivariate pattern classification of structural MRI enables the differential diagnostic classification of 158 patients with schizophrenia (SZ) and 104 patients with major depression (MD). Methods T1-weighted patient scans were processed using voxel-based morphometry. Diagnostic features were extracted from the age- and sex-adjusted GM maps using PCA and linear SVMs. Repeated nested cross-validation was emplyoed to assess the generalizability of diagnostic performance. Results Cross-validated classification accuracy was 76% based on a discriminative pattern involving perisylvian, limbic, medial prefrontal and precuneal GM volume reductions in SZ vs. MD. GM volume reductions in MD vs. SZ were detected in the premotor, sensorimotor, parietal, cerebellar and brainstem structures. The 'SZ-likehood' of MD was correlated with the age of disease onset, leading to a significantly higher misclassification rate among MD patients with an age of onset between 15 and 30 yrs. Conclusions The findings suggest that SZ and MD can be identified at the single subject level using neuroanatomical pattern recognition. The decreased diagnostic separability of MD patients with an early disease onset may challenge the traditional nosological boundaries and may relate to higher levels of chronicity and unfavorable disease outcomes in this patient population.