Behçet syndrome: The disturbed balance between anti- (CLEC12A, CLC) and proinflammatory (IFI27) gene expressions.

INTRODUCTION: Behçet syndrome (BS) is a chronic, multisystemic inflammatory condition with unanswered questions regarding its pathogenesis and rational therapeutics. A microarray-based comparative transcriptomic analysis was performed to elucidate the molecular mechanisms of BS and identify any potential therapeutic targets. METHODS: Twenty-nine BS patients (B) and 15 age and sex-matched control subjects (C) were recruited. Patients were grouped as mucocutaneous (M), ocular (O), and vascular (V) according to their clinical phenotypes. GeneChip Human Genome U133 Plus 2.0 arrays were used for expression profiling on peripheral blood samples of the patients and the control subjects. Following documentation of the differentially expressed gene (DEG) sets, the data were further evaluated with bioinformatics analysis, visualization, and enrichment tools. Validation of the microarray data was performed using quantitative reverse transcriptase polymerase chain reaction. RESULTS: When p ≤ 0.05 and fold change ≥2.0 were chosen, the following numbers of DEGs were obtained; B versus C: 28, M versus C: 20, O versus C: 8, V versus C: 555, M versus O: 6, M versus V: 324, O versus V: 142. Venn diagram analysis indicated only two genes, CLEC12A and IFI27, in the intersection of M versus C ∩ O versus C ∩ V versus C. Another noteworthy gene appeared as CLC in the DEG sets. Cluster analyses successfully clustered distinct clinical phenotypes of BS. While innate immunity-related processes were enriched in the M group, adaptive immunity-specific processes were significantly enriched in the O and V groups. CONCLUSIONS: Distinct clinical phenotypes of BS patients displayed distinct expression profiles. In Turkish BS patients, expression differences regarding the genes CLEC12A, IFI27, and CLC seemed to be operative in the disease pathogenesis. Based on these findings, future research should consider the immunogenetic heterogeneity of BS clinical phenotypes. Two anti-inflammatory genes, namely CLEC12A and CLC, may be valuable as therapeutic targets and may also help design an experimental model in BS.

Potential effects of metformin in DNA BER system based on oxidative status in type 2 diabetes.

Metformin is used to reduce hyperglycemia that induces energetic stress and leads to reduction in gluconeogenesis. Also, metformin inhibits complex I in oxidative phosphorylation, thereby decreasing cellular ATP levels. Activation of AMPK by the reduced ATP levels can induce inhibition of reactive oxygen species (ROS) production and activate p53-mediated DNA repair. DNA polymerase-ß and XRCC1 function to repair DNA damages in the BER (base excision repair) system. In type 2 diabetes patients, metformin can enhance AMPK activation therefore suppress oxidative stress. The changes on oxidative stress may alter p53's function and effect many cellular pathways such as; DNA repair. In our project we aim to understand the effects of metformin on p53 and DNA-BER system based on the oxidative status in type 2 diabetes patients. Oxidative and antioxidative capacity, catalase, SOD, GPx activities and, DNA pol beta, XRCC1 and p53 levels were measured in metformin using or non-using type 2 diabetes patients and controls. Metformin enhanced SOD and GPx activities in type 2 diabetes patients but the reflection of this increase to the total antioxidant capacity was not significant. Although the increase in DNA pol beta was not significant, XRCC1 and p53 levels were significantly upregulated with metformin treatment in type 2 diabetes patients. Our study reinforces the potential benefit of metformin in antioxidative capacity to protect cells from diabetic oxidative stress and in regulation of DNA BER system.

Behçet's: A Disease or a Syndrome? Answer from an Expression Profiling Study.

Behçet's disease (BD) is a chronic, relapsing, multisystemic inflammatory disorder with unanswered questions regarding its etiology/pathogenesis and classification. Distinct manifestation based subsets, pronounced geographical variations in expression, and discrepant immunological abnormalities raised the question whether Behçet's is "a disease or a syndrome". To answer the preceding question we aimed to display and compare the molecular mechanisms underlying distinct subsets of BD. For this purpose, the expression data of the gene expression profiling and association study on BD by Xavier et al (2013) was retrieved from GEO database and reanalysed by gene expression data analysis/visualization and bioinformatics enrichment tools. There were 15 BD patients (B) and 14 controls (C). Three subsets of BD patients were generated: MB (isolated mucocutaneous manifestations, n = 7), OB (ocular involvement, n = 4), and VB (large vein thrombosis, n = 4). Class comparison analyses yielded the following numbers of differentially expressed genes (DEGs); B vs C: 4, MB vs C: 5, OB vs C: 151, VB vs C: 274, MB vs OB: 215, MB vs VB: 760, OB vs VB: 984. Venn diagram analysis showed that there were no common DEGs in the intersection "MB vs C" ∩ "OB vs C" ∩ "VB vs C". Cluster analyses successfully clustered distinct expressions of BD. During gene ontology term enrichment analyses, categories with relevance to IL-8 production (MB vs C) and immune response to microorganisms (OB vs C) were differentially enriched. Distinct subsets of BD display distinct expression profiles and different disease associated pathways. Based on these clear discrepancies, the designation as "Behçet's syndrome" (BS) should be encouraged and future research should take into consideration the immunogenetic heterogeneity of BS subsets. Four gene groups, namely, negative regulators of inflammation (CD69, CLEC12A, CLEC12B, TNFAIP3), neutrophil granule proteins (LTF, OLFM4, AZU1, MMP8, DEFA4, CAMP), antigen processing and presentation proteins (CTSS, ERAP1), and regulators of immune response (LGALS2, BCL10, ITCH, CEACAM8, CD36, IL8, CCL4, EREG, NFKBIZ, CCR2, CD180, KLRC4, NFAT5) appear to be instrumental in BS immunopathogenesis.

Xanthelasma palpebrarum: a new side effect of nilotinib.

Chronic myeloid leucaemia (CML) is a chronic myeloproliferative disorder characterised by a reciprocal translocation between the chromosomes 9 and 22 resulting in constitutionally active tyrosine kinase signalling. BCR-ABL tyrosine kinase inhibitors (TKIs) are highly effective molecules in the treatment of CML. Unfortunately, these novel therapeutic agents are accompanied by various side effects, and haematological, cutaneous and metabolic abnormalities are among the most prevalent. Nilotinib, a second-generation TKI, has been shown to cause both--cutaneous lesions and lipid profile abnormalities. We present two CML cases developing xanthelasma palpebrarum while receiving nilotinib. Case 1 also acquired a lipid abnormality following the start of nilotinib therapy, while case 2 meanwhile stayed normolipidemic. In addition to a low cholesterol diet, atorvastatin was prescribed to case 1. Currently, both cases are normolipidemic and continuing their nilotinib therapy. Xanthelasma palpebrarum secondary to nilotinib therapy is new to the literature.

Hyponatremia in the outpatient setting: clinical characteristics, risk factors, and outcome.

PURPOSE: Hyponatremia is a common disorder and hyponatremia in the outpatient setting is not extensively studied. Our aim was to investigate the characteristics of hyponatremia in ambulatory patients. METHODS: Seventy-six adult outpatients with hyponatremia were enrolled in this prospective study. Demographic features, presenting symptoms and signs, associating morbidities, medications, laboratory findings, mortalities, and length of hospital stay, were recorded. RESULTS: Mean age was 74.7 ± 12.7 years, and 52 (68.4 %) were female whereas 24 (31.6 %) were male. Mean sodium concentration was 123.6 ± 6.6 mEq/L. Leading cause was thiazide diuretic use (n = 37, 48.7 %) and approximately half of the patients (n = 40, 52.6 %) had a multifactorial etiology. Severe hyponatremia (sodium < 125 mEq/L) was identified in 37 (48.7 %). Thiazide diuretic use, vomiting, and apathy were independent predictors of severe hyponatremia. Eight (10.5 %) patients had a mortal course. A relatively younger age, male gender, presenting sign of lethargy, associating morbidities of malignancy, chronic liver disease, and hypoalbuminemia were risk factors for mortality. CONCLUSIONS: Hyponatremia is prevalent among elderly, especially in women and with thiazide diuretics. Apart from the trend toward sodium depletion observed in healthy elderly which occurs due to changes in the tubular handling of sodium, a multifactorial etiology including thiazides seems to predict the occurrence and the severity of hyponatremia. Hyponatremia may be a significant cause of mortality in seniors. A relatively younger age, male gender, association of cirrhosis, malignancy, and hypoalbuminemia predict mortality. In elderly outpatients, identification of the risk factors for hyponatremia and close monitoring are imperative to reduce the related mortality and morbidity.

Increased risk of contrast-induced acute kidney injury in patients with pulmonary thromboembolism.

INTRODUCTION: Computed tomography pulmonary angiography (CTPA) is currently an effective, reliable and widely employed diagnostic test for pulmonary thromboembolism (PT). PT harbors intrinsic clinical and biochemical abnormalities which may be associated with an increased risk of contrast-induced acute kidney injury (CIAKI). OBJECTIVES: To assess the incidence and risk factors of CIAKI among patients with PT diagnosed with CTPA. METHODS: One hundred and twenty-two consecutive patients who had been diagnosed with PT using CTPA between February 2006 and December 2010 were evaluated retrospectively. In addition to the classical risk factors of CIAKI, arterial blood gases, CTPA and transthoracic echocardiography findings of the patients were also recorded. RESULTS: The incidence of CIAKI was 13.1%. There were statistically important differences with respect to age, the presence of congestive heart failure (CHF), the use of angiotensin converting enzyme inhibitor-angiotensin II receptor blocker drugs (ACEI-ARB), the arterial blood pH (ABpH) and the length of hospitalization between the two groups of patients who developed (n:16) and did not develop (n:106) CIAKI. In the logistic regression analysis, age and ABpH were preserved in the final equation. CONCLUSION: The incidence of CIAKI among PT patients is significantly higher than the expected average. Older age, the presence of CHF, the use of ACEI-ARB, and additionally, low ABpH are important risk factors of CIAKI in patients with PT. Hypoxemia and low bicarbonate levels intrinsic to PT may contribute to the increased risk of CIAKI in this patient population and their correction may carry a prophylactic potential.

Nonsecretory Multiple Myeloma and AL Amyloidosis Presenting with Nephrotic Range Proteinuria.

Nonsecretory multiple myeloma (NSMM) is the absence of a detectable monoclonal protein in serum and urine of a multiple myeloma (MM) patient and immunoglobulin light chain (AL) amyloidosis is a significantly rare complication. A case of NSMM with AL amyloidosis and nephrotic range proteinuria is presented. Sharing clinical, therapeutic, and prognostic characteristics with MM, real challenge may be during initial diagnosis of NSMM and assessment of treatment response. In elderly patients with unexplained renal dysfunction, MM should be in the differential diagnosis and the absence of a monoclonal protein should not rule out MM but should remind us of the possibility of NSMM.

The Rarest of the Rare: Crossed Fused Renal Ectopia of the Superior Ectopia Type.

Crossed fused renal ectopia is a rare congenital anomaly of the urinary system where one kidney crosses over to opposite side and the parenchyma of the two kidneys fuse. Herein, we present an atypical CFRE case whose renal anatomy does not exactly match any of the already defined CFRE types. Both of the kidneys are ectopic with the crossed ectopic right kidney lying superiorly and fused to the upper pole of the left kidney. Renal arteries were originating from the common iliac arteries. A focal 90% stenosis was observed on the right main renal artery. The patient is borderline hypertensive.

C-type lectin domain family 12, member A: A common denominator in Behçet's syndrome and acute gouty arthritis.

C-type lectin domain family 12, member A (CLEC12A) is a C-type lectin-like pattern recognition receptor capable of recognizing monosodium urate crystals. Monosodium urate crystals, the causative agents of gout are also among the danger-associated molecular patterns reflecting cellular injury/cell death. In response to monosodium urate crystals, CLEC12A effectively inhibits granulocyte and monocyte/macrophage functions and hence acts as a negative regulator of inflammation. Behçet's syndrome and gout are autoinflammatory disorders sharing certain pathological (neutrophilic inflammation), clinical (exaggerated response to monosodium urate crystals) and therapeutic (colchicine) features. We propose the hypothesis that decreased expression of CLEC12A is a common denominator in the hyperinflammatory responses observed in Behçet's syndrome and gout. Major lines of evidence supporting this hypothesis are: (1) Downregulation/deficiency of CLEC12A is associated with hyperinflammatory responses. (2) CLEC12A polymorphisms with functional and clinical implications have been documented in other inflammatory diseases. (3) Colchicine, a fundamental therapeutic agent used both in Behçet's syndrome and gout is shown to oppose the downregulation of CLEC12A. (4) Behçet's syndrome and gout are characterized by a hyperinflammatory response to monosodium urate crystals and other than gout, Behçet's syndrome is the only inflammatory condition exhibiting this exaggerated response. (5) Genomewide linkage and association studies of Behçet's syndrome collectively point to 12p12-13, the chromosomal region harboring CLEC12A. (6) Patients with severe forms of Behçet's syndrome underexpress CLEC12A with respect to patients with mild forms of the disease. If supported by well-designed, rigorous experiments, the forementioned hypothesis pertinent to CLEC12A will carry important implications for therapy, designing experimental models, and uncovering immunopathogenic mechanisms in Behçet's syndrome and gout.

A novel finding in thoracic outlet syndrome: tachycardia.

In this case report, we rendered a 22 year old woman with the diagnosis of neurogenic thoracic outlet syndrome. We have evaluated her symptoms of palpitation with Holter monitorization during Roos test before and after surgery where transaxillary first rib resection and scalenectomy were performed. Postoperatively she improved and the tachycardia resolved. We propose that stellate ganglion or postganglionic efferent sympathetic fibers forming the cardiac plexus are exposed to compression while Roos test is being performed. Due to this irritation, there can be an increase in the cardiac sympathetic activity.