Ivan Soldatovic

Major salivary gland sonography in Sjögren's syndrome: diagnostic value of a novel ultrasonography score (0–12) for parenchymal inhomogeneity

Objective: To validate ultrasonographic criteria for examination of the major salivary glands in the diagnosis of primary Sjögrens syndrome (SS). Method: A total of 209 consecutive patients with rheumatic diseases were selected according to the American–European Consensus Group (AECG) classification criteria for SS. One hundred and fifteen patients had primary SS, 44 had secondary SS, and 50 had sicca symptoms, and 36 subjects served as asymptomatic controls. This cohort was analysed for size, echogenicity, parenchymal inhomogeneity, focal changes, and posterior borders of the major salivary glands by ultrasonography (US). A novel US score for parenchymal inhomogeneity (0–12) was assigned and its diagnostic accuracy evaluated. Results: Ultrasonographic abnormalities of salivary glands were detected in 107/115 (93.0%) patients with primary SS, in 12/44 (27.3%) with secondary SS, in 25/50 (50.0%) with sicca symptoms, and in 4/36 (11.1%) asymptomatic controls. Area under the receiver operating characteristic curve (AUC-ROC) for US inhomogeneity score was highly significant [0.96 ± 0.01; 95% confidence interval (CI) 0.94–0.99, p < 0.000] for primary SS, with a sensitivity to specificity ratio of 91/83 for parotid and 93/90 for submandibular glands. Setting the cut-off US inhomogeneity score at 6 resulted in the best ratio of specificity (90.0%) to sensitivity (95.1%), with a positive predictive value of 72% and a negative predictive value of 96%. A US inhomogeneity score ≥ 6 was closely correlated with positive biopsy (p < 0.000) and scintigraphy findings (p < 0.000). Conclusions: We demonstrate the high diagnostic value of a novel US score for parenchymal inhomogeneity (0–12) that could serve as a useful single US criterion in the evaluation of salivary gland involvement in primary SS.

Neuroendocrine dysfunction in patients recovering from subarachnoid hemorrhage.

OBJECTIVE: Subarachnoid hemorrhage (SAH) is a recently identified risk factor for hypopituitarism, particularly growth hormone (GH) and corticotrophins deficiencies. The aim of our study was to identify possible predictor(s) for neuroendocrine dysfunction in SAH survivors. DESIGN: Pituitary function was evaluated in 93 patients (30 males, 63 females), aged 48.0±1.1 years (mean±SE), and with a Glasgow Outcome Scale score of 4.6±0.6 (mean±SE) more than one year following SAH. In the acute phase, SAH was complicated by vasospasm (VS) in 18 and by hydrocephalus (HDC) in 9 patients. Baseline serum values of Insulin Growth Factor 1 (IGF-I), cortisol, Thyroxine (T4), Thyroid Stimulating Hormone (TSH), Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), testosterone (in males), estradiol (in females) and prolactin were determined. RESULTS: According to the results of baseline hormonal evaluation, 47 patients (50.5%) had no hormonal abnormalities. Seven patients (7.5%) had multiple pituitary hormone deficiencies: Four patients (4.3%) had two (GH and cortisol), one patient had three (gonadal, adrenal and GH) and two patients had deficiency of all pituitary axes. Thirty-nine patients (42%) had one abnormal axis (13 adrenal, 2 thyroid, 4 gonadal and 20 GH). None of the subjects was treated with desmopressin or exhibited symptomatic polyuria. The VS and HDC during the acute phase of SAH were related to abnormal pituitary status (VS with low IGF-I levels and HDC with low cortisol levels). CONCLUSION: Through a screening procedure, neuroendocrine dysfunction was identified in a substantial number of asymptomatic patients with previous SAH. Cerebral VS and HDC at the time of SAH emerged as risk factors possibly predicting development of pituitary dysfunction. Low basal levels of IGF 1 and cortisol may help in selecting patients requiring further evaluation of pituitary function.

Correlation between procalcitonin and intra-abdominal pressure and their role in prediction of the severity of acute pancreatitis.

BACKGROUND/AIMS Early assessment of disease severity and vigilant patient monitoring are key factors for adequate treatment of acute pancreatitis (AP). The aim of this study was to determine the correlation of procalcitonin (PCT) serum concentrations and intra-abdominal pressure (IAP) as prognostic markers in early stages of AP. METHODS This prospective observational study included 51 patients, of which 29 had severe AP (SAP). Patients were evaluated with the Acute Physiology And Chronic Health Evaluation (APACHE II) score, C-reactive protein (CRP) and PCT serum concentrations and IAP at 24 h from admission. PCT was measured three times in the 1st week of disease and three times afterward, while IAP was measured daily. PCT and IAP values correlated with each other, and also compared with APACHE II score and CRP values. RESULTS PCT, IAP, CRP values and APACHE II score at 24 h after hospital admission were significantly elevated in patients with SAP. There was significant correlation between PCT and IAP values measured at 24 h of admission, and between maximal PCT and IAP values. Sensitivity/specificity for predicting AP severity at 24 h after admission was 89%/69% for APACHE II score, 75%/86% for CRP, 86%/63% for PCT and 75%/77% for IAP. CONCLUSIONS Increased IAP was accompanied by increased PCT serum concentration in patients with AP. PCT and IAP can both be used as early markers of AP severity.

Echocardiographic study of early left ventricular remodeling in highly trained preadolescent footballers.

Almost all the studies of athletes heart have been carried out on adult and older adolescent players; hence the limited data on the cardiac response to exercise in the beginning of the active sports career in the youngest athletes. The study was designed to examine the physiological limits of left ventricle (LV) cavity size and wall thickness in elite footballers at the preadolescent age, it the beginning of the active sports career. Ninety-four highly trained male footballers (mean aged 12.85±0.84) competing in the Serbian Football League and 47 age-matched healthy male controls, aged 12-14, were enrolled in the study. All the echocardiographic findings were adjusted to BSA(-0.5), while left ventricle mass (LVM) was additionally adjusted to BSA(-1.5). Reference ranges were defined as values of 5-95th centile according to the mean values in both groups. The proportions of the footballers with LV dimensions outside expected ranges were additionally noted. The data indicate significant increases in absolute values of LV dimensions, aortic root size and left atrium (p<0.001) in preadolescent professional footballers compared with the values expected for age-matched controls, whereas there are no differences in absolute values of ventricular septal and posterior wall thickness, LV wall thickness and LVM (p>0.05). Upon body-size adjustments, significant increases were observed in all echocardiographic parameters (p<0.001). Our data indicate an early cardiac remodeling, already apparent in pre-adolescence, even after a short period of training.

Current status and perspectives of interventional clinical trials for glioblastoma – analysis of ClinicalTrials.gov

The records of 208.777 (100%) clinical trials registered at ClinicalTrials.gov were downloaded on the 19th of February 2016. Phase II and III trials including patients with glioblastoma were selected for further classification and analysis. Based on the disease settings, trials were classified into three groups: newly diagnosed glioblastoma, recurrent disease and trials with no differentiation according to disease setting. Furthermore, we categorized trials according to the experimental interventions, the primary sponsor, the source of financial support and trial design elements. Trends were evaluated using the autoregressive integrated moving average model. Two hundred sixteen (0.1%) trials were selected for further analysis. Academic centers (investigator initiated trials) were recorded as primary sponsors in 56.9% of trials, followed by industry 25.9%. Industry was the leading source of monetary support for the selected trials in 44.4%, followed by 25% of trials with primarily academic financial support. The number of newly initiated trials between 2005 and 2015 shows a positive trend, mainly through an increase in phase II trials, whereas phase III trials show a negative trend. The vast majority of trials evaluate forms of different systemic treatments (91.2%). In total, one hundred different molecular entities or biologicals were identified. Of those, 60% were involving drugs specifically designed for central nervous system malignancies. Trials that specifically address radiotherapy, surgery, imaging and other therapeutic or diagnostic methods appear to be rare. Current research in glioblastoma is mainly driven or sponsored by industry, academic medical oncologists and neuro-oncologists, with the majority of trials evaluating forms of systemic therapies. Few trials reach phase III. Imaging, radiation therapy and surgical procedures are underrepresented in current trials portfolios. Optimization in research portfolio for glioblastoma is needed.

Tumor Necrosis Factor Blockade Differentially Affects Innate Inflammatory and Th17 Cytokines in Rheumatoid Arthritis

Objective. To evaluate the effect of a tumor necrosis factor-α (TNF-α) inhibitor (etanercept) on innate inflammatory and Th17 cytokines in patients with rheumatoid arthritis (RA). Methods. Serum samples were collected from 40 patients with active RA refractory to conventional disease-modifying antirheumatic drugs who initiated therapy with etanercept plus methotrexate (MTX). Treatment response was assessed at Week 24 according to the European League Against Rheumatism response criteria. Serum levels of interleukin 6 (IL-6), TNF-α, IL-32, IL-23, IL-17A, IL-21, and IL-22 were measured in patients with RA and 25 healthy controls. Results. Patients with RA had increased levels of IL-6 (p < 0.001), IL-32 (p < 0.001), IL-23 (p < 0.001), and a trend toward increased IL-21 in the sera compared to controls. At 24 weeks’ posttreatment, followup serum samples of etanercept responders had decreased levels of IL-6 (p < 0.001) and increased IL-21 (p < 0.05) and IL-32 (p < 0.001), while there were no differences in cytokine levels in non-responders. Serum IL-6 levels were positively correlated with levels of erythrocyte sedimentation rate (r = 0.458, p < 0.01), C-reactive protein (r = 0.593, p < 0.01), and 28-joint Disease Activity Score (r = 0.432, p < 0.01) at baseline. Serum IL-21 levels were positively correlated with levels of rheumatoid factor (r = 0.513, r = 0.633, both p < 0.01) and antimutated citrullinated vimentin antibodies (r = 0.515, p < 0.01; r = 0.428, p < 0.05) at baseline and after 24 weeks of treatment with etanercept. Conclusion. Multiple inflammatory pathways contribute to persistent chronic inflammation in RA. In contrast to nonresponders, etanercept therapy modulated serum cytokine levels and caused a marked decrease of IL-6 levels in responders. IL-21 might be involved in the regulation of autoantibody production in RA.

Phosphorylation of leukocyte glucocorticoid receptor in patients with current episode of major depressive disorder.

The impaired glucocorticoid receptor (GR) signaling has long been considered one of the cornerstones in understanding the pathophysiology of depression. Since the phosphorylation of GR is very important for GR function, in this study we investigated whether GR phosphorylation at serine 211 (pGR-S211) and serine 226 (pGR-S226) is altered in patients with current episode of major depressive disorder (MDD). Particularly, in 30 MDD patients and 35 controls we assessed the levels of nuclear total GR (tGR), pGR-S211 and pGR-S226 in peripheral blood mononuclear cells (PBMC) using Western blot technique, along with plasma cortisol concentrations from the same blood samples. Our results demonstrated increased phosphorylation of GR at S226 (p<0.001) and, to a less extent, at S211 (p<0.05) in MDD patients compared to controls. Consequently, the pGR-S211/pGR-S226 ratio was decreased (p<0.05) implying reduced transcriptional activity of GR in MDD patients. MDD subjects had higher cortisol levels than controls and cortisol concentrations were positively correlated with PBMC pGR-S226 levels from the same blood samples. There was no difference in the levels of tGR between MDD and control subjects. The study showed that altered phosphorylation of GR could contribute to impaired GR function related to the pathophysiology of depression.

Homocysteine is a marker for metabolic syndrome and atherosclerosis.

BACKGROUND It has been documented that patients with metabolic syndrome (MS) and vascular complications have higher homocysteine levels. Hyperhomocysteinemia correlates with IR, increasing oxidative stress, which causes lesions of vascular endothelium leading to endothelial dysfunction, hypertension and atherosclerosis. OBJECTIVE The objectives of the study were to examine homocysteine values, along with cardiovascular risk factors (lipid and apolipoprotein status, CRP, blood pressure), indicators of renal function (microalbuminuria/24h), glucose regulation and insulin resistance (glucose and insulin level, HbA1c, HOMA-IR, uric acid) and anthropometric parameters (BMI, WC, HC, WHR) in patients with and without MS as a correlation between homocysteine and MS factors. METHODS The study included obese and overweight individuals, aged of 30-75 yrs. classified into two groups: with MS (n=35) and without MS (n=41). RESULTS Patients with MS had increased WC, BMI, BP, glycaemia, HOMA-IR, TG, CRP, microalbuminuria, homocysteine and decreased HDL-C (p<0.05). Statistically significant difference between groups was found for WC, BMI, sBP and dBP, TG, HDL-C (p<0.01) and glycaemia, CRP, Apo B, HOMA-IR (p<0.05). Significant positive correlations were found between homocysteine and sBP (p=0.036), dBP (p=0.04), Apo B (p=0.038) and hyperlipoproteinemia (type IIa, type IIb and type IV) (p=0.04). CONCLUSION Patients with MS had increased abdominal obesity, hypertension, hypertriglyceridemia, inflammation factors, IR, homocysteine and microalbuminuria as markers of endothelial dysfunction. A correlation between homocysteine and hypertension and hyperlipoproteinemia showed that homocysteine could be used as a potential marker for atherosclerosis progression.

Nondiabetic patients with either subclinical Cushing's or nonfunctional adrenal incidentalomas have lower insulin sensitivity than healthy controls: clinical implications.

OBJECTIVE The aim of this study was to estimate insulin sensitivity (IS) in nondiabetic patients with adrenal incidentalomas (AI): nonfunctional adrenal incidentalomas (NAI) and patients with AI and subclinical Cushings syndrome (SCS). METHODS Based on the inclusion criteria (normal fasting glucose levels, no previous history of impaired fasting glucose and/or diabetes, and no medications or concomitant relevant diseases) and the exclusion criteria (pheochromocytoma, overt hypercortisolism, hyperaldosteronism, adrenal carcinoma, metastasis of extra-adrenal tumors, extra-adrenal malignancies), 142 subjects were drawn from a series of patients with AI. The subjects were age-, sex- and body mass index (BMI)-matched: 70 with NAI (50 women and 20 men), 37 with AI and SCS (31 women and 6 men) and 35 healthy control (HC) subjects (30 women and 5 men). The oral glucose tolerance test (OGTT) and several indices of insulin sensitivity (IS) were used: homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI), triglycerides and glucose index (TyG), index of whole-body insulin sensitivity (ISI-composite) and glucose to insulin ratio (G/I). RESULTS There was a significant difference in IS between subjects with NAI and HC (HOMA, p=0.049; QUICKI, p=0.036; TyG, p=0.002; ISI-composite, p=0.024) and subjects with SCS and HC (AUC insulin, p=0.01; HOMA, p=0.003; QUICKI, p=0.042; TyG, p=0.008; ISI-composite, p=0.002). There was no difference in the tested indices of IS between subjects with NAI and SCS (p>0.05). However, subjects with SCS had a significantly higher prevalence of impaired glucose tolerance and higher area under the curve for glucose than subjects with NAI (p=0.0174). The linear regression analysis showed that 1 mg-DST cannot be used as a predictor of HOMA (R(2)=0.004, F=0.407, p=0.525). Significant relationship was found between 1 mg-DST and ISI-composite (R(2)=0.042, F=4.981, p=0.028) but this relationship was weak and standard error of estimate was high. The linear regression model also showed that ACTH cannot be used as a predictor of HOMA (R(2)=0.001, F=0.005, p=0.943) or ISI-composite (R(2)=0.015, F=1.819, p=0.187). CONCLUSIONS Insulin resistance is a major cardiovascular risk factor; therefore, the assessment of IS in patients with AI, even nonfunctional, has a valuable place in the endocrine workup of these patients.

Human Cytomegalovirus and Epstein-Barr Virus Genotypes in Apical Periodontitis Lesions

INTRODUCTION Different genotypes of human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) possess specific pathogenic abilities because of various interactions with the hosts immune system and differences in cell tropism. The aim of this study was to determine the distribution of HCMV and EBV genotypes in apical periodontitis lesions in relation to their clinical and histopathologic features. METHODS One hundred samples of apical periodontitis lesions and 25 control samples (healthy pulp tissue) were collected. The presence of HCMV glycoprotein B (gB) and EBV nuclear antigen-2 genotypes was analyzed by nested polymerase chain reaction and restriction fragment length polymorphisms analysis. RESULTS EBV and HCMV were detected in apical periodontitis lesions at significantly higher frequencies than in healthy pulp controls (P = .020 and P = .020, respectively). HCMV gB type II was significantly more frequent compared with gB type I in the examined groups (P = .036). No HCMV gB type III or IV products were found. In both periapical lesions and controls, EBV-1 occurred more often compared with EBV-2 (P = .001). Dual EBV and HCMV coinfection was more frequently detected in large-size periapical lesions (P = .038). CONCLUSIONS Both HCMV and EBV are associated with inflammatory processes of periapical bone destruction. HCMV gB type II and EBV-1 are the most prevalent genotypes in apical periodontitis lesions.