Georgios Koukoulis

Resistin serum levels are increased but not correlated with insulin resistance in chronic hemodialysis patients

Background/Aims: Insulin resistance is a well-known phenomenon in uremia. Resistin, a recently discovered insulin inhibitor secreted by adipocytes, is associated with obesity and insulin resistance in mice. Adiponectin, also secreted by adipocytes, is known to reduce insulin resistance in humans. The aim of the present study was to address the hypothesis that changes in resistin or adiponectin serum levels may relate to body composition and to insulin resistance in patients with end-stage renal disease. Methods: In a cross-sectional study, 33 non-diabetic patients (24 males and 9 females, mean age 61.5 ± 15.8 years) with end-stage renal disease on chronic hemodialysis (treatment duration 41 ± 31 months) that lacked signs of infection were enrolled. The control group consisted of 33, matched for age, sex and body mass index (BMI), healthy volunteers (22 males, 11 females, mean age 62.6 ± 12.1 years). BMI (kg/m2) was calculated from body weight and height. Body fat (%) was measured by means of bioelectrical impedance. Blood samples were taken always in the morning after a 12-hour fasting period before and after the hemodialysis session. Resistin and adiponectin serum concentrations were measured by enzyme immunoassays and insulin by an electrochemiluminescence immunoassay. The post-treatment values were corrected regarding the hemoconcentration. The homeostasis model assessment index (HOMA-R) was calculated as an estimate of insulin resistance from the fasting glucose and insulin serum levels. Results: Pre-treatment resistin serum levels were significantly increased in hemodialysis patients compared to healthy controls (19.2 ± 6.2 vs. 3.9 ± 1.8 ng/ml; p < 0.001). Hemodialysis did not alter resistin levels, as pre- and post-treatment levels were not different when corrected for hemoconcentration (19.2 ± 6.2 vs. 18.7 ± 5.0 ng/ml; p = 0.54). Adiponectin levels were also increased in hemodialysis patients compared to healthy controls (25.4 ± 21.5 vs. 10.5 ± 5.9 µg/ml; p < 0.001). A significant inverse correlation was observed between the serum adiponectin levels before the hemodialysis session on the one hand and the BMI (r = –0.527, p = 0.002), the HOMA-R (r = –0.378, p < 0.05) and the fasting insulin levels (r = –0.397, p < 0.05) on the other. However, no significant correlation was observed between serum resistin levels on the one hand versus HOMA-R index (3.2 ± 3.9 mmol·µIU/ml; r = –0.098, p = 0.59), insulin levels (13.3 ± 14.4 mU/l; r = –0.073, p = 0.69), glucose levels (89 ± 13 mg/dl; r = –0.049, p = 0.78), BMI (25.6 ± 3.7 kg/m2; r = –0.041, p = 0.82) and body fat content (26.4 ± 8.4%; r = –0.018, p = 0.94) on the other hand. Conclusion: Resistin serum levels are significantly elevated in non-diabetic patients with end-stage renal disease that are treated by hemodialysis. The hemodialysis procedure does not affect the resistin levels. Along with previous observations in patients with renal insufficiency in the pre-dialysis stage, our findings implicate an important role of the kidney in resistin elimination. However, increased resistin serum levels in hemodialysis patients are not related to reduced insulin sensitivity encountered in uremia.

Sexual Functioning and Distress among Premenopausal Women with Uncomplicated Type 1 Diabetes

INTRODUCTION Current studies indicate that women with type 1 diabetes (T1DM) have a high prevalence of sexual disorders although data on the prevalence of sexual dysfunction are limited when sexual distress is included. AIM The frequency and the possible correlates of distressful sexual disorders in a highly selected group of type 1 diabetic women. METHODS The sexual function, sexual distress, and general health status were assessed in 44 premenopausal women with uncomplicated T1DM and 47 healthy controls, using the Female Sexual Function Index (FSFI), the Female Sexual Distress Scale (FSDS), and the General Health Questionnaire-28 (GHQ-28). MAIN OUTCOME MEASURES The impact of sexual distress on the frequency of female sexual dysfunction (FSD). RESULTS The frequency of sexual disorders according to the FSFI was significantly higher in diabetic compared to control women (25% vs. 8.5%, respectively, P < 0.05). Diabetic women had significantly lower median (first to third quartile) total FSFI score compared to control group (30.55 [26.08-33.08] vs. 33.50 [30.70-34.30], P = 0.001). Desire, arousal, and satisfaction were the sexual domains significantly affected in the diabetic group. Diabetic women had significantly higher median (first to third quartile) FSDS score compared to control group (6.5 [2.3-15.8] vs. 4.0 [1.0-10.5] P = 0.043). FSD (combined pathological FSFI and FSDS scores) was present in higher proportion of diabetic women (15.9%) compared to controls (2.1%) (P = 0.020). GHQ-28 score was comparable between the groups. However, in the diabetic group, FSD was related with anxiety, depression, and low educational level. Diabetes-related factors were not associated with FSD. CONCLUSIONS Pre-menopausal women with uncomplicated T1DM have significantly higher frequency of FSD compared to healthy controls, when the criterion of sexual distress is included. Psychosomatic and contextual factors implicated in sexual distress are correlates of FSD.

A case of membranous nephropathy associated with Sjögren syndrome, polymyositis and autoimmune hepatitis.

Sjögren syndrome (SS) is a chronic systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands, especially lacrimal and salivary. The immunologic process which occurs in this syndrome is B cell hyperactivity, which results in production of autoantibodies and immune complexes. SS can exist as a primary disorder or in association with other autoimmune processes. A usually mild, proximal and insidious inflammatory myopathy can occur in patients with SS with a broad clinical and pathological spectrum. Interstitial nephritis with mild proteinuria and tubular dysfunction is the most common renal manifestation of SS, but glomerular involvement due to immune complex deposition may also rarely occur [Goules et al. 2000]. There is an association of SS with hepatic abnormalities, as evidenced by abnormal liver biochemical tests or histological characteristics of primary biliary cirrhosis (PBC), portal tract fibrosis, or autoimmune hepatitis [Abraham et al. 2004]. The pathogenetic mechanism of liver involvement in SS is not clear, but it is possible that hepatic and salivary gland damage share a similar pathology. The combination of Sjögren syndrome with kidney, liver and muscle involvement in one entity is extremely rare and data in the literature are remarkably sparse. We present a case of a 43-year-old female patient suffering from SS accompanied by polymyositis, membranous nephropathy and autoimmune hepatitis.

The indoleamine 2,3-dioxygenase inhibitor 1-methyl-tryptophan suppresses mitochondrial function, induces aerobic glycolysis and decreases interleukin-10 production in human lymphocytes.

Background: Indoleamine 2,3-dioxygenase (IDO) suppresses adaptive immunity. It is known that IDO induces T-cell differentiation to regulatory T-cells (Treg) through tryptophan depletion and/or kynurenine pathway products. CD4+ effector T-cells require distinct metabolic programs in order to support their function as compared to Treg cells. Furthermore, glucose metabolism is also known to affect B-cell survival and function. The effect of IDO on glucose metabolism of lymphocytes was evaluated by using its inhibitor 1-methyl-DL-tryptophan (1-MT). Methods: Ten healthy volunteers vaccinated against tetanus. Peripheral blood mononuclear cells (PBMC) were cultured with or without tetanus toxoid and/or 1-MT. Cell proliferation was assessed by optical microscopy, glucose uptake by measuring its concentration in the supernatant, aerobic glycolysis by assessing lactate concentration in the supernatant, mitochondrial function by XTT assay, and finally production of Tregs’ signature cytokine IL-10 by means of ELISA. Results: Primarily, IDO decreases glucose uptake by stimulated lymphocytes. Secondly, IDO increases mitochondrial function in stimulated lymphocytes. In addition, IDO decreases aerobic glycolysis in stimulated lymphocytes. Finally, IDO induces the production of the immunosuppressive cytokine IL-10 by stimulated lymphocytes. Conclusion: Considering that cell metabolism plays a significant role in lymphocyte differentiation and function, IDO may exert its immunomodulatory effect by interfering with cell metabolism.

Upregulation of VEGF expression is associated with accumulation of HIF-1α in the skin of naïve scleroderma patients

Systemic sclerosis is a disease hallmarked by microangiopathy; the enlargement and leakage of skin capillaries in active stages develops into extensive avascular areas, clinically associated with severe tissue hypoxia and the formation of digital ulcers. Vascular endothelial growth factor (VEGF) is upregulated in all stages of the disease, with little effect on efficient neovascularization. The oxygen-regulated α-subunit of hypoxia-inducible transcription factor-1 (HIF-1α) represents a key mechanism involved in the transcriptional regulation of VEGF. The aim of this study is to investigate expression of the oxygen-regulated α-subunit of HIF-1 and VEGF in naïve scleroderma patients. For this purpose, skin biopsies (dorsal hand surface) from scleroderma patients were analyzed and compared with control skin biopsies. Immunoreactivity for VEGF was enhanced in scleroderma patients, in contrast to restricted positive immunostaining in suprabasal keratinocytes observed in normal skin. In a similar fashion, all skin biopsies from scleroderma patients were strongly HIF-1α reactive, compared with rare immunoreactivity observed in normal skin. The pattern was similar in all stages of scleroderma. These observations for the first time directly connect constitutive hypoxia with VEGF upregulation in scleroderma patients. The sequence of events needs to be precisely mapped, and the pro- and antiangiogenic switches which may interfere with efficient tissue neovascularization identified, in order to provide meaningful therapeutic strategies.

TNFα induces expression of HIF-1α mRNA and protein but inhibits hypoxic stimulation of HIF-1 transcriptional activity in airway smooth muscle cells.

Airway smooth muscle cells (ASMCs) participate in tissue remodeling characteristic of airway inflammatory diseases like asthma. Inflammation and hypoxia pathways are often interconnected and the regulatory subunit of the hypoxia inducible factor, HIF‐1α, has been recently shown to be induced by cytokines. Here we investigate the effect of individual or combined treatment of ASMCs with the inflammatory mediator TNFα and/or hypoxia on the expression of HIF‐1α, HIF‐1 targets and inflammation markers. TNFα enhances HIF‐1α protein and mRNA levels, under both normoxia and hypoxia. TNFα‐mediated induction of HIF‐1α gene transcription is repressed by inhibition of the NF‐κB pathway. Despite the up‐regulation of HIF‐1α protein, the transcription of HIF‐1 target genes remains low in the presence of TNFα at normoxia and is even reduced at hypoxia. We show that the reduction in HIF‐1 transcriptional activity by TNFα is due to inhibition of the interaction of HIF‐1α with ARNT and subsequent blocking of its binding to HREs. Comparison between hypoxia and TNFα for their effects on the expression of inflammatory markers shows significant differences: hypoxia up‐regulates the expression of IL‐6, but not RANTES or ICAM, and reduces the induction of VCAM by TNFα. Finally, ex vivo treatment of rabbit trachea strips with TNFα increases HIF‐1α protein levels, but reduces the expression of HIF‐1 targets under hypoxia. Overall, TNFα induces HIF‐1α mRNA synthesis via an NF‐κB dependent pathway but inhibits binding of HIF‐1α to ARNT and DNA, while hypoxia and TNFα have distinct effects on ASMC inflammatory gene expression. J. Cell. Physiol. 228: 1745–1753, 2013.

Arterial stiffness predicts risk for long-term recurrence in patients with type 2 diabetes admitted for acute coronary event.

OBJECTIVES to investigate the predictive value of arterial stiffness (AS) estimation for long-term recurrences in patients with type 2 diabetes (DM2) following acute coronary event. PATIENTS AND METHODS prospective observational study involving 119 DM2 patients without history of coronary heart disease admitted with ST-segment elevation myocardial infarction (STEMI). Medical history, anthropometrics, smoking, HbA1c, lipid profile, troponine-I levels, and left ventricular ejection fraction (LVEF) were recorded. Carotid-femoral pulse wave velocity (cf-PWV) was measured 1 month after discharge. Patients were followed up for 36 months or to reach an end-point: cardiovascular death, acute coronary event, angioplasty or hospitalization for acute heart failure. To facilitate analysis, patients were divided into two groups according to cf-PWV, using the accepted cut-off value of 12m/s. RESULTS overall, 34 patients had a recurrence. In Kaplan-Meier analysis patients with cf-PWV>12m/s had mean time-to-event 353±43 days compared to 505±115 days for patients with cf-PWV≤12m/s, log rank=0.0252. In multivariate analysis factors independently associated with recurrence were age (66.53±6.87 vs. 61.54±10.77 years, p=0.015), LVEF (41.66±8.21 vs. 47.58±8.11%, p=0.001) and cf-PWV (13.94±2.91 vs. 12.35±2.77m/s, p=0.008). CONCLUSIONS AS estimation in patients with DM2 after STEMI discriminate patients at higher risk for 3-year recurrence, and maybe valuable for distinguishing patients likely to require a more rigorous therapeutic intervention.

A Primary Hepatic Lymphoma Treated with Liver Resection and Chemotherapy

Primary hepatic lymphoma (PHL) is a rare malignancy, which is frequently misdiagnosed. Although chemotherapy is the treatment of choice there are reports that a combination of surgery and adjuvant chemotherapy can offer better results. Herein we present an interesting case of a large primary non-Hodgkin lymphoma originating from liver was treated with a liver which resection and chemotherapy.

Intestinal Obstruction and Ileocolic Fistula due to Intraluminal Migration of a Gossypiboma

Gossypiboma refers, as a term, to a retained surgical sponge. It is considered as a rare surgical complication which can occur despite precautions. We report a case of a 36-year-old woman who was admitted to our surgical department with symptoms of abdominal pain associated with episodes of nausea and vomiting that lasted for 2 months. Six months ago she had undergone a cesarean section in a private clinic. Computed tomography revealed a high-density mass occupying a portion of the intestinal lumen, which was reported as a “calcified parasite.” The patient was subjected to laparotomy. The intraoperative findings included signs of obstructive ileus and ileosigmoid fistula and a large sponge was found at the resected portion of the small intestine. Although gossypiboma is a rare entity, it should be included in the differential diagnosis.

Fine Needle Aspiration Cytology of a Primary Malignant Peripheral Nerve Sheath Tumor Arising in the Parotid Gland A Case Report

BACKGROUND Malignant peripheral nerve sheath tumor (MPNST) is an uncommon mesenchymal neoplasm showing nerve sheath differentiation, usually arising in large nerves of the trunk and extremities. Primary location in the parotid gland is rare. We describe fine needle aspiration (FNA) findings in a case of MPNST in the parotid gland. Differential diagnostic problems encountered in interpretation are discussed. CASE A 39-year-old man underwent FNA of a well-circumscribed, painless, mobile mass of the parotid gland. Smears were cellular, with clusters of tightly packed spindle or oval cells arranged in a storiform or whorled pattern, showing clearly malignant features. Elongated nuclei with tapered ends and many angulated nuclei were encountered. The background contained abundant necrotic material with dispersed malignant nuclei. Neoplastic cells were positive for vimentin and weakly positive for S-100 and negative for cytokeratins 8 and 18 and HMB-45. Cytologic diagnosis was positive for malignant cells consistent with a spindle cell sarcoma, with morphologic features compatible to neural differentiation, confirmed by histologic examination. CONCLUSION This case illustrates that attention to moiphologic criteria suggestive of nerve sheath phenotype supported by immunocytochemical data is extremely helpful and reliable in the diagnostic approach to MPNSTs, even in rare locations.