Ivana Petrovic

Galectin-3 expression in papillary thyroid carcinoma: relation to histomorphologic growth pattern, lymph node metastasis, extrathyroid invasion, and tumor size.

Galectin‐3 has been recently recognized as a promising presurgical marker of thyroid malignancy.

Galectin‐3 expression in papillary microcarcinoma of the thyroid

Aims :u2002Galectin‐3 is a β‐galactoside binding protein, recently recognized as a promising molecular marker of thyroid malignancy. As reported in several studies, galectin‐3 is highly expressed in papillary thyroid carcinoma, but its expression has not been investigated in papillary microcarcinoma, which is a variant of papillary thyroid carcinoma.

Apoptosis and proliferation related molecules (Bcl-2, Bax, p53, PCNA) in papillary microcarcinoma versus papillary carcinoma of the thyroid.

Aim: To gain a better insight into the differences in biological behaviour between papillary microcarcinoma (PMC) and clinically evident papillary thyroid carcinoma (PTC). Methods: Immunohistochemical analysis of apoptosis related molecules (Bcl‐2, Bax, p53) and proliferation related marker (PCNA) in 39 archival cases of PMC and 46 cases of PTC. Results: Bcl‐2 and Bax were expressed in most PMCs and PTCs. The average Bcl‐2 staining score did not differ significantly between PMCs and PTCs (p > 0.05), but the average Bax score was significantly lower in PMCs (p < 0.05). The Bcl‐2/Bax ratio was significantly higher in PMCs than in PTCs (p < 0.05). The expression of p53 was similar in PMCs and PTCs, without a correlation with clinical data, but was associated with high Bax expression (p < 0.05) in these cases in both groups. Non‐malignant tissue expressed only Bcl‐2, but not p53 or Bax. PCNA expression was significantly lower (p < 0.05) in PMC than in PTC and positively correlated with tumour size (p < 0.05). Conclusions: The higher Bcl‐2/Bax ratio and lower proliferative activity in PMC suggest differences from PTC in the balance between apoptosis and proliferation. However, the presence of p53 and Bax in PMC indicates malignant potential, and thus PMC should be treated with caution.

Thyroid peroxidase immunohistochemistry in differential diagnosis of thyroid tumors.

Thyroperoxidase (TPO) is a thyroid-specific enzyme expressed by differentiated thyroid cells. Initial immunohistochemical studies claimed that TPO expression, detected by the monoclonal antibody mAb 47, may be a potentially important diagnostic tool in differentiating malignant from benign lesions. However, some recent studies have failed to reproduce the earlier results, suggesting the limitations for TPO immunohistochemistry. To assess these observations we have evaluated the immunohistochemical expression of TPO in thyroid tissue from 215 patients. The studied material included 87 nonmalignant thyroid lesions and 128 thyroid carcinomas. TPO expression was investigated using newly available mAb 47 and staining of less than 80% of the follicular cells/specimen as the threshold indicating a malignant lesion. We found that TPO had a sensitivity of 89.9% for cancer and a specificity of 64.4% for nonmalignant lesions, showing that it does not give a sufficient degree of diagnostic certainty that the lesion is benign. In addition, the variability in the degree of TPO expression found within and between follicular carcinomas, and the significant number of benign adenomas having similar immunostaining patterns, assured us that TPO immunostaining is not sufficiently discriminatory in the differential diagnosis of thyroid cancer versus benign lesions.

The interface of hypothalamic–pituitary–adrenocortical axis and circulating brain natriuretic peptide in prediction of cardiopulmonary performance during physical stress

Brain natriuretic peptide (NT-pro-BNP) was implicated in the regulation of hypothalamic-pituitary-adrenocortical (HPA) responses to psychological stressors. However, HPA axis activation in different physical stress models and its interface with NT-pro-BNP in the prediction of cardiopulmonary performance is unclear. Cardiopulmonary test on a treadmill was used to assess cardiopulmonary parameters in 16 elite male wrestlers (W), 21 water polo player (WP) and 20 sedentary age-matched subjects (C). Plasma levels of NT-pro-BNP, cortisol and adrenocorticotropic hormone (ACTH) were measured using immunoassay sandwich technique, radioimmunoassay and radioimmunometric techniques, respectively, 10min before test (1), at beginning (2), at maximal effort (3), at 3rdmin of recovery (4). In all groups, NT-pro-BNP decreased between 1 and 2; increased from 2 to 3; and remained unchanged until 4. ACTH increased from 1 to 4, whereas cortisol increased from 1 to 3 and stayed elevated at 4. In all groups together, ΔNT-pro-BNP2/1 predicted peak oxygen consumption (B=37.40, r=0.38, p=0.007); cortisol at 3 predicted heart rate increase between 2 and 3 (r=-0.38,B=-0.06, p=0.005); cortisol at 2 predicted peak carbon-dioxide output (B=2.27, r=0.35, p<0.001); ΔACTH3/2 predicted peak ventilatory equivalent for carbon-dioxide (B=0.03, r=0.33, p=0.003). The relation of cortisol at 1 with NT-pro-BNP at 1 and 3 was demonstrated using logistic function in all the participants together (for 1/cortisol at 1 B=63.40, 58.52; r=0.41, 0.34; p=0.003, 0.013, respectively). ΔNT-pro-BNP2/1 linearly correlated with ΔACTH4/3 in WP and W (r=-0.45, -0.48; p=0.04, 0.04, respectively). These results demonstrate for the first time that HPA axis and NT-pro-BNP interface in physical stress probably contribute to integrative regulation of cardiopulmonary performance.

Oxidized Low-Density Lipoprotein Predicts the Development of Renal Dysfunction in Atrial Fibrillation

Background/Aim: To investigate the role of oxidative stress (OS) in the development of chronic kidney disease (CKD) in atrial fibrillation (AF). Methods: We compared OS burden, determined at study inclusion as plasma concentrations of oxidized low-density lipoprotein (oxLDL), between stable AF patients (n = 256, mean age: 62.8 ± 9.3 years; 60.9% males) with preserved renal function, defined as an estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2, and a matched control group in sinus rhythm (n = 138, mean age: 61.5 ± 11.2 years; 60.9% males). During the prospective follow-up of AF patients, we investigated the association and prognostic validity of oxLDL for CKD development, diagnosed as a sustained decline in eGFR to <60 ml/min/1.73 m2. Results: AF patients had a higher mean oxLDL (76.2 ± 21.7 U/l) compared to sinus rhythm controls (61.6 ± 13.1 U/l; p < 0.001). AF presence independently predicted increased oxLDL levels in the study cohort [β = 14.7; 95% confidence interval (CI), 10.7-18.7; p < 0.001]. Over a median 4-year follow-up, 19.9% of AF patients developed CKD. Adjusting for all clinical covariates, oxLDL (per tertile) was associated with a hazard ratio of 2.17 for CKD occurrence (95% CI, 1.40-3.35; p < 0.001). AF patients in the upper oxLDL tertile (≥88.7 U/l) had a 3.70-fold (95% CI, 1.55-8.81) higher risk for CKD compared to the lower oxLDL tertile (<67.0 U/l) patients (p < 0.001). oxLDL improved discriminative validity (c-statistic increment: 0.041, 95% CI, 0.007-0.075, p = 0.017), and increased the net reclassification and integrated discrimination for CKD risk by 12.4 and 6.0%, respectively (both p < 0.001). Conclusions: oxLDL is increased in AF patients compared to sinus rhythm controls. oxLDL has an independent association and an incremental predictive value that might complement clinical CKD risk assessment in AF patients following further research.

The Relationship of Myocardial Collagen Metabolism and Reverse Remodeling after Cardiac Resynchronization Therapy

Summary Background: In the majority of patients with a wide QRS complex and heart failure resistant to optimal medical therapy, cardiac resynchronization therapy (CRT) leads to rever se ventricular remodeling and possibly to changes in cardiac collagen synthesis and degradation. We investigated the relationship of biomarkers of myocardial collagen meta bolism and volumetric response to CRT. Methods: We prospectively studied 46 heart failure patients (mean age 61±9 years, 87% male) who underwent CRT im plantation. Plasma concentrations of amino-terminal pro peptide type I (PINP), a marker of collagen synthesis, and carboxy-terminal collagen telopeptide (CITP), a marker of collagen degradation, were measured before and 6 months after CRT. Response to CRT was defined as 15% or greater reduction in left ventricular end-systolic volume at 6-month follow-up. Results: Baseline PINP levels showed a negative correlation with both left ventricular end-diastolic volume (r=−0.51; p=0.032), and end-systolic diameter (r=−0.47; p=0.049). After 6 months of device implantation, 28 patients (61%) responded to CRT. No significant differences in the base-line levels of PINP and CITP between responders and nonresponders were observed (p>0.05 for both). During follow-up, responders demonstrated a significant increase in serum PINP level from 31.37±18.40 to 39.2±19.19 μg/L (p=0.049), whereas in non-responders serum PINP levels did not significantly change (from 28.12±21.55 to 34.47±18.64 μg/L; p=0.125). There were no significant changes in CITP levels in both responders and non-responders (p>0.05). Conclusions: Left ventricular reverse remodeling induced by CRT is associated with an increased collagen synthesis in the first 6 months of CRT implantation.

Polyphenolic Content and Biological Activities of Post-Distillation Waste of Three Sage Species from the Republic of Macedonia

This research was aimed at investigating polyphenolic content, antioxidant and anti-neurodegenerative activities of post-distillation waste extracts of Macedonian Salvia amplexicaulis, S. jurisicii and S. ringens, for the first time. Total phenolic and flavonoid contents varied in a broad range (3.92-146.49 mg GAE/g and 7.11-67.51 mg QE/g, respectively), with the highest values obtained for S. amplexicaulis and S. ringens extracts. Certain S. amplexicaulis and S. ringens extracts neutralized more than 80% of DPPH radicals at the highest concentration, while S. amplexicaulis extracts showed up to ≈50% inhibition of β-carotene oxidation in β-carotene/linoleic acid assay. Post-distillation waste extracts inhibited acetylcholinesterase (25.94-38.15%) and tyrosinase (18.84-59.52%), with the strongest inhibition of S. amplexicaulis extracts. The obtained results suggest that post-distillation waste of tested species, especially of S. amplexicaulis, show antioxidant and anti-neurodegenerative activities and could be considered as potential raw material rich in polyphenols.

The relationship between causative microorganisms and cardiac lesions caused by infective endocarditis: New perspectives from the contemporary cohort of patients

BACKGROUNDnThe etiology of infective endocarditis (IE) is changing. More aggressive forms with multiple IE cardiac lesions have become more frequent. This study sought to explore the relationship between contemporary causative microorganisms and IE cardiac lesions and to analyze the impact of multiple lesions on treatment choice.nnnMETHODSnIn 246 patients hospitalized for IE between 2008 and 2015, cardiac lesions caused by IE were analyzed by echocardiography, classified according to the 2015 European Society of Cardiology guidelines and correlated with microbiological data. We defined a new parameter, the Echo IE Sum, to summarize all IE cardiac lesions in a single patient, enabling comprehensive comparisons between different etiologies and treatment strategies.nnnRESULTSnStaphylococcus aureus was associated with the development of large vegetation (OR 2.442; 95% CI 1.220-4.889; p=0.012), non-HACEK bacteria with large vegetation (OR 13.662; 95% CI 2.801-66.639; p=0.001), perivalvular abscess or perivalvular pseudoaneurysm (OR 5.283; 95% CI 1.069-26.096; p=0.041), and coagulase-negative staphylococci (CoNS) with leaflet abscess or aneurysm (OR 3.451; 95% CI 1.285-9.266, p=0.014), and perivalvular abscess or perivalvular pseudoaneurysm (OR 4.290; 95% CI 1.583-11.627; p=0.004). The Echo IE Sum significantly differed between different etiologies (p<0.001), with the highest value in non-HACEK and the lowest in streptococcal endocarditis. Patients operated for IE had a significantly higher Echo IE Sum vs those who were medically treated (p<0.001).nnnCONCLUSIONnNone of the IE cardiac lesions is microorganism-specific. However, more severe lesions were caused by S. aureus, CoNS, and non-HACEK bacteria. The highest propensity to develop multiple lesions was shown by the non-HACEK group. Higher Echo IE Sum in patients sent to surgery emphasized the importance of multiple IE cardiac lesions on treatment choice and potential usage of Echo IE Sum in patient management.

Gauging the response to cardiac resynchronization therapy: The important interplay between predictor variables and definition of a favorable outcome

Selection of patients who are viable candidates for cardiac resynchronization therapy (CRT), prediction of the response to CRT as well as an optimal definition of a favorable response, all require further exploration. The purpose of this study was to evaluate the interplay between the prediction of the response to CRT and the definition of a favorable outcome.