Ali Kemal Oğuz

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.

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. Behçets 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 Behçets 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 Behçets syndrome and gout is shown to oppose the downregulation of CLEC12A. (4) Behçets syndrome and gout are characterized by a hyperinflammatory response to monosodium urate crystals and other than gout, Behçets syndrome is the only inflammatory condition exhibiting this exaggerated response. (5) Genomewide linkage and association studies of Behçets syndrome collectively point to 12p12-13, the chromosomal region harboring CLEC12A. (6) Patients with severe forms of Behçets 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 Behçets syndrome and gout.

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.

Rare abdominal findings in Behçet's disease.

To the editor, A 30-year-old woman was examined for her complaints of abdominal pain. She had a history of Behçet’s disease (BD) for 7 years. She is Turkish and a Caucasian. No HLA typing was performed. Ultrasonography results revealed splenomegaly and diffuse widening in distal portions of abdominal aorta. An abdominal computed tomography (CT) image demonstrated multiple splenic lesions (Fig. 1a), irregularities and scarring in the renal parenchyma bilaterally (Fig. 1b), and an infrarenal aneurysm in the abdominal aorta (Fig. 1c). She refused a secondary immunosuppressive agent (azathioprine and cyclophosphamide) to be added to her treatment protocol and also refused splenectomy. She has been closely followed-up with a maintenance steroid and colchicine therapy and is still in remission. She currently has a depressive mood mostly related to medial advice against a pregnancy; otherwise, she is living a normal life (she is a biologist and very busy working as a consultant for a famous microscope company). Splenic involvement is very seldom in BD [1] and is usually a slight splenomegaly [2]. In our patient, irregular multiple lesions, which are quite rare in BD, were detected in the spleen. The pattern of renal involvement was the other atypical finding in our patient. Renal involvement in Behcet’s disease is more frequent than has previously been recognized (0–55%) [3]. As a vasculitic syndrome affecting all types and sizes of blood vessels and also complicated by vascular thrombosis in one third of cases, the renal lesions in Behcet’s disease display a wide spectrum. It characteristically involves secondary amyloidosis (with nephrotic syndrome and renal failure), glomerulonephritis (with several different types of glomerular lesions), renal vascular disease (renal artery thrombosis and aneurysms, and renal vein thrombosis), and interstitial nephritis [3]. In our patient with normal urinalysis, bilateral irregular scars were detected in renal parenchyma—something not routinely observed in BD. The infrarenal multilobular abdominal aortic aneurysm was the last but perhaps the most potentially devastating lesion. A. K. Oğuz Department of Internal Medicine, Ufuk University Medical School, Ankara, Turkey

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.

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

Abstract 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.

Spinach attack: a funny turn in gouty arthritis

Dietary modification is a prime ingredient of successful management of gout. Simple dietary guidelines indisputably yield encouraging clinical outcome and are also quite satisfactory for patients. Meat is, by far, most famous for provoking arthritis attacks in gout; however, there is a roster of foods with high purine content that should also be consumed cautiously. Here we describe a patient who experienced an arthritis attack shortly after eating spinach, a less discomforting episode but, to the best of our knowledge, not yet mentioned in the literature. A 63-year-old man was seen with complaints of pain, swelling, erythema, and a warm sensation in the big toe of his left foot. Since we had been following him with the diagnosis of gout for the previous 2 years, we considered this episode to be an attack of gouty arthritis. He had been using colchicine once daily for 1 year and not experienced any attacks except when failing to comply with his diet. On detailed questioning, he stated that the arthritis had emerged at 12:00 P.M., and he denied eating anything else after dinner at 9:00 P.M., which comprised spinach. He allegedly had also eaten spinach the day before. The arthritis vanished in 24 h with indomethacin, colchicine, rest, and increased fluid intake. On the control visit, the patient described the current attack as shorter and less uncomfortable than former ones that had ensued due to meat. The main story about the effect of diet in gouty arthritis—to which we have already alluded—is in the patient’s degree of purine intake. It should be remembered that not only food with large amounts of purines but also large amounts of food containing small concentrations of purines provide a reasonable purine load. The purine content of a food depends on its nucleoprotein content and turnover. Food containing many nuclei, such as liver, are rich in purines, as are rapidly growing foods such as asparagus. Additionally, all types of meat including organs and seafood, meat extracts and gravies, yeast and yeast extracts, beer and other alcoholic beverages, beans, peas, lentils, oatmeal, spinach, cauliflower, and mushrooms are also well known for their high purine content [1]. The contribution of purine in the diet to the serum urate concentration is generally not more than 1.0 mg/dl (60 lmol/l). Nonetheless, moderation in dietary purine consumption rather than a constant, low-purine diet, is warranted in gout patients [1]. In drawing attention to this clinical picture, we underscore the fact that arthritis attacks in gout can usually be anticipated and indeed prevented through compliance with the correct diet. Far from ordering less savory meals for gout patients, we orient them towards vigilance against predictable consequences, and we also believe that flavor can be recovered by using alternative recipes.

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-β 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 p53s 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.

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.