Protective effect of pregabalin on renal and renal endothelial damage in sepsis induced by lipopolysaccharide.

OBJECTIVE: We investigated the protective effects of pregabalin (PRG) on kidney and renal endothelial damage in sepsis induced by Lipopolysaccharide (LPS). MATERIALS AND METHODS: Rats were randomly divided into three groups as control, LPS and LPS+PRG. Saline solution was administered 30 mg/kg orally and 5 mg/kg intraperitoneally (i.p.) to the control group. LPS was applied as 5 mg/kg, i.p. to the LPS group. In the LPS+PRG group, PRG at 30 mg/kg orally and one hour before LPS administration, one hour later 5 mg/kg i.p. LPS was applied. Rats were sacrificed 6 hours after LPS administration. RESULTS: White Blood Cell (WBC), granulocyte, Blood Urea Nitrogen (BUN), creatinine, uric asid, Total Oxidant Status (TOS) and Oxidative Stress Index (OSI) significantly increased (p<0.05); platelets (PLT), activated partial thromboplastin time (aPTT) and Total Antioxidant Status (TAS) significantly decreased in the LPS group compared to the control group (p<0.05). In the LPS+PRG group WBC, granulocyte, BUN, creatinine, uric asid, TOS and OSI significantly decreased (p<0.05); PLT, aPTT and TAS significantly increased compared to the LPS group(p<0.05). Histopathological examinations showed that kidney and renal endothelial damage in the LPS group decreased in the LPS+PRG group. Immunohistochemically IL1-ß, IL-6, IL-10, TNF-α expressions in kidney tissue and Toll-Like Receptors-4 (TLR-4) and NF-κB expressions in the renal endothelial tissue significantly increased in the LPS group compared to the control group and significantly decreased in the LPS+PRG group compared to the LPS group (p<0.001). CONCLUSIONS: Sepsis causes kidney and renal endothelial damage and PRG reduces this damage. Therefore PRG can be used in prophylactic treatment in sepsis, supported by more studies.

In this study, kidney and renal endothelial damage in sepsis was investigated. The effect of pregabalin on kidney and renal endothelial damage in sepsis was evaluated.

A Comprehensive Look at Maxillofacial Traumas: On the Basis of Orbital Involvement.

INTRODUCTION: Orbital wall fractures that may develop in maxillofacial traumas (MFTs) may cause ophthalmic complications (OCs). The aim of this study is to determine the frequency of orbital fractures (OFs) accompanying MFTs and findings suspicious for orbital traumatic involvement. MATERIALS AND METHODS: Computed tomography (CT) images of 887 patients who presented to the emergency department within a 1-year period with a history of MFT were retrospectively scanned. During the examination, patients with orbital wall fractures, craniofacial bone fractures, and posttraumatic soft tissue changes were recorded. RESULTS: OF was observed in 47 (5.3%) of the patients admitted for MFT. In cases with OFs, accompanying nasal (25.5%), ethmoid (2.1%), frontal (19.1%), maxillary (38%), and zygomatic bone fracture (10.6%), sphenoid (4.3%), and soft tissue damage (55.3%) were observed. It was observed that the pathologies mentioned at these levels were significantly higher than in patients without orbital involvement (p < 0.05). In our study, mild (48.9%) and moderate-severe (2.12-4.25%) OCs accompanying OFs were observed after MFT. CONCLUSIONS: The frequency of MFT varies depending on various factors, and such studies are needed to take preventive measures. Knowing the risk and frequency of orbital damage accompanying MFTs may help reduce complications by allowing rapid and accurate diagnosis.

Chronic otitis media and middle ear variants: Is there relation?

BACKGROUND: Chronic otitis media (COM) is an inflammatory disease that lasts for a long time. It is common in developing countries. Hearing loss can result from COM. The relationship between variations in middle ear anatomy and COM was investigated in our study. AIM: To compare the prevalence of middle ear anatomic variations between the cases with COM and healthy individuals. METHODS: This retrospective study included 500 patients with COM and 500 healthy controls. The presence of those variants was determined: Koerner's septum, facial canal dehiscence, high jugular bulb, jugular bulb dehiscence, jugular bulb diverticulum, sigmoid sinus anterior location and deep tympanic recesses. RESULTS: A total of 1000 temporal bones were examined. The incidences of these variants were respectively (15.4%-18.6%), (38.6%-41.2%), (18.2%-4.6%), (2.6%-1.2%), (1.2%-0%), (8.6%-0%), (0%-0%). It was observed that only high jugular bulb (P < 0.001) and anteriorly located sigmoid sinus frequencies (P = 0.002) in the case group were statistically significantly higher than the control groups. CONCLUSION: COM is a multifactorial disease and variants of middle ear have always been important in terms of potential risk for complication during surgery but rarely associated with COM as an etiology or as a consequence of the disease. We didn't find a positive correlation between COM and Koerner's septum and facial canal defect. We ended up with a significant conclusion with the variants of dural venous sinuses -high jugular bulb, dehiscence of jugular bulb, diverticulum of jugular bulb and anteriorly located sigmoid sinus- that have been studied less and frequently associated with inner ear illnesses.

Protective effect of melatonin on learning and memory impairment and hippocampal dysfunction in rats induced by high-fructose corn syrup.

Objectives: We investigated the harmful effects of high fructose corn syrup (HFCS) on learning and memory in the hippocampus and the ameliorative effects of melatonin (Mel). Materials and Methods: Thirty-six adult male Sprague Dawley rats were divided into three groups: Group I, control; Group II, HFCS; and Group III, HFCS+Mel. HFCS form F55 was prepared as a 20% fructose syrup solution. Rats in HFCS and HFCS+Mel groups were given drinking water for 10 weeks. Rats in the HFCS+Mel group have been given 10 mg/kg/day melatonin orally for the 6 weeks, in addition to HFCS 55. The Morris water maze (MWM) test was applied to all animals for 5 days to determine their learning and memory levels. After decapitation, one-half of the hippocampus samples were collected for western blot analysis, and another half of the tissues were collected for histopathological and immunohistochemical analyses. Results: In the HFCS group, there was a significant difference between the time to find the platform in the MWM test and time spent in the quadrant between days 1 and 5 (P=0.037 and P=0.001, respectively). In addition, a decreased level of MT1A receptor, TNF-α, iNOS, osteopontin (OPN), and interleukin-6 (IL-6) expressions were significantly increased in the HFCS group. Melatonin treatment reversed MT1A receptor levels and TNF-α, iNOS, OPN, and IL-6 expressions. During the histopathological examination, increased neuronal degenerations were observed in the HFCS group. Melatonin ameliorated these changes. Conclusion: Consumption of HFCS caused deterioration of learning and memory in adult rats. We suggest that melatonin is effective against learning and memory disorders.

Omalizumab and cancer risk: Current evidence in allergic asthma, chronic urticaria, and chronic rhinosinusitis with nasal polyps.

Omalizumab is a biological drug targeting circulating IgE, approved for use in allergic asthma, chronic spontaneous urticaria, and recently for chronic rhinosinusitis with nasal polyps, with good efficacy in all these settings. Some concerns about omalizumab safety have been raised as its use has been recently linked to potential increased cancer risk. Nevertheless, literature evidence does not support this statement, and clinical studies and evidence from real-world registries and surveillance analysis have consistently reported drug safety.

Investigation of long-term bisphenol A exposure on rainbow trout (Oncorhynchus mykiss): Hematological parameters, biochemical indicator, antioxidant activity, and histopathological examination.

As an industrial synthetic chemical, bisphenol A (BPA) has the potential to have physiologically and histologically adverse effects on aquatic organisms. BPA causes the reproductive disrupting of all vertebrates due to its degradation on endocrine system. Therefore, the effect of BPA on fish with high economic value is an important issue. This study focused weekly on long-term BPA exposure on rainbow trout (Oncorhynchus mykiss). Hematological, biochemical, antioxidant activity and histopathological examinations were performed on O. mykiss exposed to 1000 µg/L BPA concentration. Mortality was observed in the BPA group during the first three weeks. As a result of hematological studies, leukocyte count and hemoglobin in the BPA group were significantly higher in the first three weeks compared to the control group. Plasma cortisol level as a biochemical indicator showed a similar trend to leukocyte and hemoglobin. There was no significant difference between BPA and control groups in terms of superoxide dismutase and catalase. However, glutathione peroxidase activity in the BPA group was significantly lower than in the control group for four weeks. At the end of the study, many alterations were observed histologically in the gill tissues. While more intense hyperplasia and epithelial lifting were observed in the tissues in the BPA group compared to the control group, vacuolization, necrosis and hypertrophy were observed infrequently. In conclusion, this study argues that BPA causes negative effects on O. mykiss in terms of fish welfare and future study should be focused on its environmental adaptation with color preference patterns.

Astaxanthin ameliorates damage to the cerebral cortex, hippocampus and cerebellar cortex caused by methotrexate.

We investigated the ameliorating effects of astaxanthin (AXA) on methotrexate (MTX) induced damage to the cerebral cortex, hippocampus, cerebellar cortex and blood. We used 24 female Wistar albino rats divided into three groups of eight as follows: sham/control group, single dose of saline intraperitoneally (i.p.) and 7 days orally; MTX group, single dose of 20 mg/kg MTX (i.p.); MTX + AXA group, single dose of 20 mg/kg MTX i.p.+ 100 mg/kg AXA orally for 7 days. For all groups we measured total oxidant status (TOS) and total antioxidant status (TAS) in the cerebral cortex, hippocampus and blood. Histological sections of cerebral cortex, hippocampus and cerebellar cortex were inspected microscopically. Caspase-3 (cas-3), granulocyte colony-stimulating factor (GCSF), growth related oncogene (GRO), inducible nitric oxide synthase (iNOS) and myelin basic protein (MBP) were estimated immunohistochemically in the cerebral cortex, hippocampus and cerebellar cortex. In the MTX group, TAS was decreased significantly in the cerebral cortex, hippocampus and blood, while TOS was significantly increased. AXA significantly ameliorated oxidative stress parameters in the cerebral cortex and hippocampus. Histopathological examination revealed degeneration, edema and hyperemia in the cerebral cortex, hippocampus and cerebellar cortex in the MTX group. AXA treatment ameliorated histopathological changes. MTX decreased MBP expression in cerebral cortex. Although MBP expression was decreased in the cerebral cortex, hippocampus and cerebellar cortex stimulated with MTX, the expressions of cas-3, GCSF, GRO and iNOS were significantly increased. AXA ameliorated the expression of cas-3, GCSF, GRO, iNOS and MBP. AXA exhibits anti-inflammatory, antioxidant and anti-apoptotic effects on MTX induced toxicity in the cerebral cortex, hippocampus and cerebellar cortex by increasing MBP expression, regulating inflammatory cytokine release and reducing oxidative stress.

Does vitamin D deficiency in asthma affect clinical and functional parameters? A Turkish multicenter study.

Background: In recent years, interest in the effects of vitamin D on human health and the immune system has increased. Objective: This study aimed to investigate the relationship of vitamin D with asthma severity, attacks, and clinical and functional parameters in adult patients with asthma who were living in different geographic regions in Turkey. Methods: A total of 384 patients with stable asthma and 87 control subjects were included. A physical examination and a pulmonary function test were performed, and routine blood analyses and vitamin D levels were evaluated. Asthma Control Test was applied. The number of exacerbations in the previous year, asthma therapy, and medication adherence were recorded. Results: In our study, vitamin D levels were below the target values in both patients with asthma (median [minimum-maximum] 16.0 ng/mL [3.5-48 ng/ml]) and control subjects (median [minimum-maximum] 20.0 ng/mL [5.8-58.79 ng/mL]). However, it was lower in the patients with asthma than in the control subjects (p = 0.001). There was a negative relationship between the levels of vitamin D and the severity of asthma (Kendall τ = -0.146; p < 0.001). Furthermore, the patients with severe asthma were received The Global Initiative for Asthma (GINA) step 5 treatment showed significantly lower vitamin D compared with the patients who received GINA step 4 treatment (p = 0.037). Vitamin D levels correlated with forced vital capacity (FVC), forced expiratory volume in the first second of expiration (FEV1), and peak expiratory flow (r, 0.221-0.236; p ≤ 0.001). In addition, a positive relationship was found between Asthma Control Test and vitamin D (r = 0.229; p = 0.001). However, body mass index (BMI), asthma exacerbation, and hospitalization were inversely related to vitamin D (r, 0.198-0.233; p = 0.001). Multivariable regression analysis revealed that FVC (p = 0.002), FEV1 (p = 0.033), and BMI (p = 0.037) were independent determinants associated with vitamin D. Conclusion: This study suggested a high prevalence of vitamin D deficiency in adults with asthma living in different geographic areas in Turkey. Vitamin D deficiency is associated with asthma severity, poor control, and lower lung function.

Country-based report: the safety of omalizumab treatment in pregnant patients with asthma

Background/aim: We aimed to report outcomes of pregnant patients with asthma under omalizumab treatment and their infants in our country. Materials and methods: Patients with asthma who received omalizumab for at least 6 months and at least one dose during their pregnancy were retrospectively evaluated using a questionnaire regarding their disease and therapy and the health of their infants. Results: Twenty pregnant patients and their 23 infant's data were analyzed. The mean delivery age was 31.8 ± 7.4 years. They received omalizumab for 28.9 ± 21.8 months. Eight (36.4%) patients showed exacerbation of the disease during pregnancy. Forced expiratory volume in 1 s (FEV1) and asthma control test (ACT) scores at the starting time of omalizumab administration, first month of the pregnancy, and after delivery were 71 ± 18%, 83.4 ± 10.5%, and 80.5 ± 13% (FEV1), and 11.9 ± 4.9, 20.2 ± 2.6, and 20.4 ± 2.2 (ACT), respectively. One patient gave birth to twin infants, two patients to two infants each in different years, and 17 to one infant each. Three (13%) infants had low birth weight and five (21.7%) were born prematurely. No congenital anomalies were detected. Seven (30.4%) infants presented atopic diseases during their life. Conclusion: Omalizumab treatment during pregnancy seems to be safe for both patients and their infants.

The impact of moderate-intensity swimming exercise on learning and memory in aged rats: The role of Sirtuin-1.

OBJECTIVES: The purpose of this study was to evaluate the effect of moderate-intensity swimming exercise on learning and memory by the Morris water maze test. Changes in the expressions of cyclic AMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) proteins alternative pathway which were activated by sirtuin-1 (SIRT-1) were investigated. MATERIALS AND METHODS: The study included thirty-two male Sprague-Dawley rats (350-500 g, 11-12 and 15-16 months old). The rats were randomly divided into four groups with 8 rats in each group. The groups were designed as follows: Control-1 (11-12 months), Exercise-1 (11-12 months), Control-2 (15-16 months), Exercise-2 (15-16 months). Moderate-intensity exercise was assigned for 30 min/day, 5 days/week, for the whole training period of 8 weeks. RESULTS: There were statistically significant differences between the groups on the third day (P=0.005) when swim speeds increased in the exercise groups. There was a statistically significant difference between Exercise 1 and Exercise 2 groups, the entries in the platform zone decreased in Exercise 2 group (P=0.026). While there were no histopathological findings observed in any group, increased SIRT-1, BNDF, and CREB expressions were seen in exercise groups compared with control groups. CONCLUSION: In aged rats exercising at moderate intensity, increased expression of CREB and BDNF, and SIRT-1 could improve hippocampal-dependent memory.

Future perspective: biologic agents in patients with severe COVID-19.

The SARS-CoV-2 is a ß-CoV, which is enveloped by non-segmented positive-stranded RNA virüs. When ß-CoV infects the respiratory tract, it can cause mild and/or severe acute respiratory syndrome (SARS) with consequent release of cytokines/mediators, including interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8 (CXCL8), IL-10, IP10, IL-12, IL-13, IL-17, IL-33, IL-25, IL-37, IL-38, GCSF, GM-CSF, HGF, IP-10, MCP-1, MIP-1α (also known as CCL3), IFN-γ, IFN-α, TRAIL, MCSF, and TNF-α. Our hypothesis of writing this article can be summarized as; if the monoclonal antibody (mAb) administered by us does not inhibit the immune response for the ß-CoV and inhibits uncontrolled-adaptive/hyperimmune responses (also called cytokine storm) on endothelium level, then it may cause severe coronavirus disease 2019 (COVID-19). Anakinra is a human IL-1 receptor antagonist. By inhibiting IL-1α/IL-1ß competitively from binding to the IL-1 type-I receptor, anakinra, neutralizes the activity that pertains to these key mediators of autoinflammatory and/or immune processes. Tocilizumab is a blocker of IL-6R that can effectively block IL-6 signal transduction pathway. Omalizumab that binds to the CH3 domain is near to the binding site for the high-affinity IgE Fc receptors type-I of human IgE. Myocardial, lung and hepatorenal injury in patients with COVID-19 could be due to cytokine storm, hypoxic injury, or/and direct endothelial/vascular injury. We propose combination of mAbs with remdesivir and/or favipiravir in severe COVID-19 cases, such as septic shock, acute respiratory deficiency syndrome, and/or multiple organ failure. Finally, we highlight the therapeutic mAbs that target patients with severe COVID-19.

A case of asthma with Behcet's disease: successful treatment with omalizumab and its effects on recurrent aphthous lesions.

CONTEXT: Monoclonal antibody therapies have revolutionized the treatment of autoinflammatory-immune/genetic disease including spondylarthritis, asthma and rheumatoid arthritis. Behcet's disease (BD) is a multi-systemic vasculitis, which is generally recurrent aphthous lesions (RAL) as well as ocular and skin lesions. Today, the immunohistopathogenesis of BD is mostly unknown. METHOD: Omalizumab (Anti-IgE humanized monoclonal antibody) therapy is given for severe persistent allergic asthma, and unintentionally it had effect on RAL. Our patient has received omalizumab treatment for 3 years. The steroid treatment was completely discontinued a month later and the systemic-steroid dependent diabetes mellitus was healed. The IL-1 ß, IL-6, IL-8, IL-33, IL-25, IL-10, IL-23, and IL-17A levels were measured using an Enzyme-Linked Immunosorbent Assay (ELISA) kit. RESULTS: After a long-term omalizumab treatment administered, the levels of WBC, d-dimer, IL-33, IL-6, IL-25 and IL-1 ß decreased. The patient's hsCRP decreased from 3 to 0.1 and Eosinophil Cationic Protein (ECP) levels decreased from 78 to 21. A significant improvement was noticed in the RAL, the asthma symptoms (cough, shortness of breath), the number of emergency admissions, and the average length of stay of the patient within the days following the initiation of the omalizumab treatment. CONCLUSIONS: Here, for the first time, we introduce omalizumab treatment of a patient diagnosed with BD and the examination of the treatment for the clinical manifestations and the cytokines/coagulant protein levels. A significant improvement is observed in the patient's RAL following the initiation of omalizumab. There is strong evidence that the serum proinflammatory cytokines/coagulant factors could also play an important role in the relationship between RAL and IgE-dependent vascular autoinflammation.

Human(ized) monoclonal antibodies in atopic patients - state of the art.

Asthma is an important chronic disease affecting a lot of people worldwide. Treatment options for asthma like biological agents are being developed more frequently nowadays. Despite a lot of treatment options, some patients still remain symptomatic. As more and more practitioners choose treatment with biologic agents as a convenient way of therapy, biologic agents and other valuable methods must be discovered in order to cope with a growing number of treatment agents. This manuscript emphasizes on new generation monoclonal human(ized) antibodies in asthmatics and off-label use . The first developed biologic agent is the anti-immunoglobulin E monoclonal antibody called omalizumab. Currently it is an approved treatment option for asthma.

Tissue HE4 Expression Discriminates the Ovarian Serous Carcinoma but Not the Uterine Serous Carcinoma Patients. A New Adjunct to the Origin of the Tumor Site.

Both uterine serous carcinoma (USC) and ovarian serous carcinoma (OSC) are presented at advanced stage at the first admittion and dissseminated disease makes the anatomical site of the tumor origin imposible. CA125 and p53 are reliable markers that are useful for differentiating both uterine serous and ovarian serous carcinoma from their most common subtypes (endometrioid type carcinoma of ovary and uterus) but so far there is no histopathologic marker that differentiates USC from OSC. On the other hand, Trastuzumab (Herceptin) increases progression-free survival among USC patients, but not OSC patients and makes the histopathologically assigning the origin of the tumor important. So, the aim of this study was to evaluate the immunohistopathological discriminative value of the human epididymis secretory protein 4 (HE4) between OSC and USC patients. Patients with a diagnosis of OSC and UTC were enrolled. HE4 expression was evaluated by immunohistochemistry. The results were compared between groups. Of the tumor tissues studied, HE4 immunostaining was seen in the majority of ovarian serous carcinoma cases (89.65%), while endomatrial serous carcinoma cases were devoid of HE4 immunostaining. HE4 immunostaining was seen in 39.1% uterin serous carcinoma cases and this difference was statistically significant (p = 0.001). Our study demonstrated for the first time the potential of HE4 expression to predict the anatomical site of tumor origin. HE4 is a novel tumor marker that differentiates USC from OSC.

Anti-IgE Significantly Changes Circulating Interleukin-25, Vitamin-D and Interleukin-33 Levels in Patients with Allergic Asthma.

BACKGROUND: Multi-center, randomized-controlled trials and observational studies have demonstrated that, in severe asthmatic patients receiving omalizumab treatment, the frequency of exacerbations, the number of urgent adverse events, and the need for oral steroids tend to decrease. MATERIALS AND METHODS: This study included a total of 32 patients. The patients were divided into two groups as Group IA (pre-omalizumab) and Group IB (post-omalizumab). Serum IL-25 and IL-33 levels were measured and the number of emergency admissions, length of hospitalization (day), Asthma Control Test (ACT) scores, eosinophil cationic protein (ECP), and fractional exhaled nitric oxide (FeNO) value were analyzed. RESULTS: ACT and FeNO values increased after omalizumab treatment, while IL-33, IL-25 levels decreased after the completion of omalizumab treatment. Furthermore, there was a weak, positive, and significant relationship between the changes in the ECP levels and IL-33 levels (r=0.38, p=0.03). CONCLUSION: To the best of our knowledge, this is the first study to compare circulating IL-25 and IL-33 levels with specific IgE synthesis in the literature. Multivariate correlation analysis showed that the changes in serum IL-33 levels were significantly correlated with the changes in the mite sIgE levels and length of hospital stay (Fmodel=11.2, p=0.01, r2=0.45). On the other hand, there was no significant relationship between the other variables and changes in the IL-25 levels.

Long-Term Omalizumab Treatment: A Multicenter, Real-Life, 5-Year Trial.

BACKGROUND: Omalizumab has demonstrated therapeutic benefits both in controlled clinical trials and real-life studies. However, research concerning the long-term effects and tolerability of omalizumab is needed. The main objective of this study was to evaluate the effectiveness and tolerability of treatment with omalizumab for up to 5 years. METHODS: A multicenter, retrospective, chart-based study was carried out to compare documented exacerbations, hospitalizations, systemic steroid requirement, FEV1, and asthma control test (ACT) results during 1 year prior to omalizumab treatment versus at 1, 3, and 5 years of treatment. Adverse events and reasons for discontinuation were also recorded at each time point. RESULTS: Four hundred and sixty-five patients were enrolled in the study. Outcome variables had improved after the 1st year and were sustained after the 3rd and 5th years of treatment with omalizumab. Omalizumab treatment reduced the asthma exacerbation rate by 71.3% (p < 0.001) at 1 year, 64.3% (p < 0.001) at 3 years, and 54.8% (p = 0.002) at 5 years. The hospitalization rate also decreased; by the 5th year of the treatment no patients were hospitalized. ACT results had also improved significantly: 12 (p < 0.001) at 1 year, 12 (p < 0.001) at 3 years, and 12 (p = 0.002) at 5 years. Overall, 12.7% of patients reported adverse events (most of these were mild-to-moderate) and the overall dropout rate was 9.0%. CONCLUSION: Omalizumab had a significant effect on asthma outcomes and this effect was maintained over 5 years. The drug was found to be generally safe and treatment compliance was good.

The oligodendrocyte lineage transcription factor 2 (OLIG2) is epigenetically regulated in acute myeloid leukemia.

DNA methylation differences between normal tissue and cancerous tissue resulting in differential expression of genes are a hallmark of acute myeloid leukemia (AML) and can provide malignant cells with a growth advantage via silencing of specific genes, for example, transcription factors. Oligodendrocyte lineage transcription factor 2 (OLIG2) was reported to be differentially methylated and associated with prognosis in AML and, as reported for acute lymphoblastic leukemia and malignant glioma, may play a role in malignant transformation. We report that DNA methylation of OLIG2 is associated with decreased expression of mRNA in AML cell lines and patients. Moreover, in cell lines, decreased mRNA expression also translated into decreased OLIG2 protein expression. Treatment of non-expressing cell lines PL-21 and U-937 with the demethylating agent decitabine resulted in robust re-expression of OLIG2 on mRNA and protein levels. Furthermore, stable overexpression of OLIG2 in non-expressing cell lines Kasumi-1 and U-937, using a lentiviral vector system, led to moderate growth inhibition after 4 days and resulted in signs of differentiation in U-937 cells. Interestingly, although CD34 + cells from healthy donors and 10 of 12 AML patients exhibited no protein expression, OLIG2 was expressed in two patients, both bearing the translocation t(15;17), corresponding to OLIG2 expression in NB-4 cells, also harboring t(15;17). In conclusion, we provide first evidence that OLIG2 is epigenetically regulated via DNA methylation and expressed in a subset of AML patients. OLIG2 may exert antiproliferative activity in leukemia cell lines, and its potential leukemia-suppressing role in AML warrants further investigation.

High serum soluble CD200 levels in patients with autosomal dominant polycystic kidney disease.

CD200 is a novel immune-effective molecule, existing in a cell membrane-bound form, as well as in a soluble form in serum, which performs to modulate inflammatory and acquired immune responses. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of large renal cysts and progressive loss of renal function. As defects in cell cycle arrest and apoptosis of renal tubular epithelial cells occur in ADPKD, we asked whether serum soluble CD200 might underlie and effect on ADPKD. Serum soluble CD200 levels were measured in 44 patients with ADPKD and 24 healthy volunteers. Concentrations of soluble CD200 in the serum samples were quantified using an ELISA kit. The mean serum soluble CD200 levels were higher in patients with ADPKD than in the control group (71.4±29.2 and 21.4±5.6 pg/mL, p<0.001). Positive correlation was detected between serum soluble CD200 levels and glomerular filtration rate (r=0.772, p<0.001), and serum albumin level (r=0.466, p=0.001). Negative correlation was detected between serum soluble CD200 levels and serum creatinine levels (r=-0.761, p<0.001), and C reactive protein levels (r=-0.364, p=0.015). In the ADPKD patients group, serum soluble CD200 levels were lower in patients with stage 5 chronic kidney disease (CKD) than in patients with stages 1-2 (p<0.001), 3 (p=0.005) and 4 CKD (p=0.006). Serum soluble CD200 levels were similar in patients with stages 1-2, 3, and 4 CKD (p>0.05). Our results show that patients with ADPKD have activated soluble CD200 levels which were related to renal function and inflammation.

Evaluating the impact of genetic and epigenetic aberrations on survival and response in acute myeloid leukemia patients receiving epigenetic therapy.

Treatment with hypomethylating agents such as decitabine, which results in overall response rates of up to 50%, has become standard of care in older patients with acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy. However, there still exists a lack of prognostic and predictive molecular biomarkers that enable selection of patients who are likely to benefit from epigenetic therapy. Here, we investigated distinct genetic (FLT3-ITD, NPM1, DNMT3A) and epigenetic (estrogen receptor alpha (ERα), C/EBPα, and OLIG2) aberrations in 87 AML patients from the recently published phase II decitabine trial (AML00331) to identify potential biomarkers for patients receiving hypomethylating therapy. While FLT3-ITD and NPM1 mutational status were not associated with survival or response to therapy, patients harboring DNMT3A R882 mutations showed a non-significant association towards shorter overall survival (hazard ratio (HR) 2.15, 95% confidence interval (CI) 0.91-5.12, p = 0.08). Promoter DNA methylation analyses using pyrosequencing also revealed a non-significant association towards shorter overall survival of patients with higher levels of methylation of ERα (HR 1.50, CI 0.97-2.32, p = 0.07) and OLIG2 CpG4 (HR 1.52, CI 0.96-2.41, p = 0.08), while DNA methylation of C/EBPα showed no association with outcome. Importantly, in multivariate analyses adjusted for clinical baseline parameters, the impact of ERα and OLIG2 CpG4 methylation was conserved (HR 1.76, CI 1.01-3.06, p = 0.05 and HR 1.67, CI 0.91-3.08, p = 0.10, respectively). In contrast, none of the investigated genetic and epigenetic markers was associated with response to treatment. Additional to the previously reported adverse prognostic clinical parameters such as patients' age, reduced performance status, and elevated lactate dehydrogenase levels, DNMT3A R882 mutation status, as well as ERα and OLIG2 CpG4 DNA methylation status, may prove to be molecular markers in older AML patients prior to hypomethylating therapy.

The IL4-VNTR P1 Allele, IL4-VNTR P2P2 Genotype, and IL4-VNTR_IL6-174CG P2P1-GG Genotype Are Associated with an Increased Risk of Brucellosis.

In this study, associations between IL-4, IL-6, and macrophage migration inhibitory factor (MIF) polymorphisms and susceptibility to brucellosis were investigated. Consecutive adult patients with no known treatment against brucellosis and who did not have any other autoimmune and/or chronic disorders, were included in this study (n = 120, Group I). Age and sex-matched controls who had no other autoimmune and/or chronic disorders were also included (n = 120, healthy volunteers, Group II). The IL4_P2P2 genotype, IL4_P1 allele, and IL4_variable number of tandem repeats (VNTR)_IL6-174CG compound genotype were found to be more frequent in the patient group than in control subjects. There were significant differences between the patients and controls with respect to the frequencies of the IL4_P2P2 genotype (77.5% versus 87.5%; p = 0.001; OR, 0.36; 95% confidence interval [CI], 0.21-0.62) and the IL4_P1 allele (12.1% versus 6.7%; p = 0.030; OR, 0.92; CI, 1.02-3.64). The IL4-VNTR_IL6-174CG compound genotype was also present at a significantly higher frequency in the patient group than in control subjects (11.7% versus 4.2%; p = 0.027, OR, 3.04; CI, 1.06-8.68). No statistically significant differences in the frequencies of the IL-6-174, MIF-173, IL-4_P1P1, and IL4_P2P1 genotypes were observed between patients and control subjects. The IL4_VNTR P1 allele, P2P2 genotypes, and IL4-VNTR_IL6-174CG P2P1-GG genotypes are common in southern Turkey, and carriers of these polymorphisms are susceptible to brucellosis.