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Maja Karin, M. Bevanda, Emil Babić, M. Mimica, Daniela Bevanda-Glibo, Mile Volaric, Ante Bogut, D. Pravdić

AIM The main goal of this study was to compare the biochemical and histopathological findings in patients with sustained virological response (SVR) before and two years after the therapy with pegylated interferon α-2a and ribavirin in chronic hepatitis C. SUBJECTS AND METHODS The study was conducted at the Department of Internal Medicine and the Clinic for Infectious Diseases of the Clinical Hospital Mostar. The study included 48 patients whose treatment for chronic hepatitis C with pegylated interferon α-2a and ribavirin was finished two years prior to the achieved SVR at the end of the treatment. The main criterion for inclusion was a negative result of HCV RNA, determined by the RealTime HCV assay. After taking a history, physical examination, laboratory tests: AST, ALT, GGT, a liver biopsy were performed with the help of the ultrasound. The assessment of necroinflamatory score was determined by histologic activity index (HAI) score, and the stage of fibrosis according to Knodell's numerical score. RESULTS The values of AST and ALT levels were statistically significantly decreased after the successful treatment (p<0.001), as well as the value of HAI score (p=0.001) and the stage of fibrosis (p=0.010), in contrast to GGT (p=0.054). For the components of HAI score like focal necrosis (0.001) and portal inflammation (0.042) the result showed that they were significantly higher before the therapy, which was not true for the piecemeal (p=0.054) and confluated necrosis (p=0.078). The improvement of HAI score after therapy was found in 36 patients (75.0%), and 27 patients (56.2%) showed an improvement in the degree of fibrosis with the most common improvement of 1 degree (85.7%). One third of patients (31.3%) had the same result in the degree of fibrosis before and after the therapy. Before the treatment, a positive correlation was observed between ALT (p=0.039) and AST (p=0.04) with HAI, AST and the stage of fibrosis (p=0.04). In contrast, after the treatment the only correlation was observed between AST and the stage of fibrosis (p=0.042). CONCLUSION Virological and biochemical responses in patients with SVR may not reflect the histopathological effects of the treatment and therefore these patients should be monitored for the possible development of the liver cirrhosis and hepatocellular carcinoma.

Over the years, an electrocardiogram had become the basic tool to study the heart physiology and pathophysiology. Many authors gave a substantial contribution in understanding the electrophysiological basis for numerous electrocardiographic changes. Some of them were named after authors themselves, or others used the names of scientists who first discovered or explained the nature of a particular electrocardiographic finding. In this article, electrocardiographic phenomena and eponyms used in today's electrocardiography are described.

M. Mimica, D. Pravdić, E. Nakas-ićindić, Maja Karin, Emil Babić, M. Tomić, M. Bevanda

Introduction. Multiple symmetric lipomatosis, or Madelung's disease, is a rare condition which is characterized with large symmetrical accumulation of noncapsulated fat tissue in upper arms, neck, and shoulder areas. The disease etiology is unknown, with the highest incidence in the Mediterranean region. Case Presentation. Here, we present the case of Madelung's disease with symmetric fat distribution throughout the neck and history of alcoholism. The patient was treated from several diseases associated with alcoholism and hospitalized several times, but the diagnosis of Madelung's disease was omitted. The thyroid gland disease was excluded, while enlargement of the neck adipose tissue was attributed to obesity. Conclusions. This study points out possible diagnostic mistakes when a physician is not aware of a differentiation diagnosis of symmetrically enlarged neck masses, especially in geographic regions with high incidence of this disease.

J. Kraljević, J. Marinovic, D. Pravdić, Petra Zubin, Ž. Dujić, U. Wisløff, M. Ljubković

AIMS Following a large myocardial infarction (MI), remaining viable muscle often undergoes pathological remodelling and progresses towards chronic heart failure. Mitochondria may also be affected by this process and, due to their functional importance, likely contribute to the progression of the disease. Aerobic interval training (AIT) has been shown effective in diminishing pathological myocardial transformation, but the effects of AIT on mitochondrial function in hearts undergoing remodelling are not known. METHODS AND RESULTS Adult female Sprague-Dawley rats were randomized to either 8 weeks of aerobic interval treadmill running (5 days/week), which started 4 weeks after left coronary artery ligation (MI-Trained), or a sedentary group (MI-Sedentary). Echocardiography was performed before and after the 8-week period, at which point the left ventricles (LVs) were also harvested. Twelve weeks after surgery, MI-Sedentary rats had significantly lower LV fractional shortening compared with MI-Trained rats. Complex I-dependent respiration assessed in isolated LV mitochondria was decreased by ∼37% in MI-Sedentary and 17% in MI-Trained animals (group differences P < 0.05), compared with sham-operated animals. This was paralleled with diminished ATP production and increased degree of protein oxidation in MI-Sedentary rats. The enzymatic activity of complex I was also decreased to a greater extent in MI-Sedentary than in MI-Trained animals, with no evidence of its reduced expression. When complex II substrate was used, no differences among the three groups were observed. CONCLUSION Exercise reduces LV contractile deterioration in post-infarction heart failure and alleviates the extent of mitochondrial dysfunction, which is paralleled with preserved complex I activity.

D. Pravdić, Nikolina Vladić, I. Čavar, Z. Bosnjak

Previous studies suggest that exogenous nitric oxide (NO) and NO‐dependent signalling pathways modulate intracellular pH (pHi) in different cell types, but the role of NO in pHi regulation in the heart is poorly understood. Therefore, in the present study we investigated the effect of the NO donors S‐nitroso‐N‐acetyl‐dl‐penicillamine, spermine NONOate and propylamine propylamine NONOate on pHi in rat isolated ventricular myocytes. Cells were isolated from the hearts of adult Wistar rats and pHi was monitored using the pH‐sensitive fluorescent indicator 5‐(and‐6)‐carboxy seminaphtharhodafluor (SNARF)‐1 (10 μmol/L) and a confocal microscope. To test the effect of NO donors on the Na+/H+ exchanger (NHE), basal pHi in Na+‐free buffer and pHi recovery from intracellular acidosis after an ammonium chloride (10 mmol/L) prepulse were monitored. The role of carbonic anhydrase was tested using acetazolamide (50 μmol/L). 4,4‐Diisothiocyanatostilbene‐2,2′‐disulphonic acid (0.5 mmol/L; DIDS) was used to inhibit the Cl−/OH− and Cl−/ HCO3− exchangers. Acetazolamide and DIDS were applied via the superfusion system 1 and 5 min before the NO donors. All three NO donors acutely decreased pHi and this effect persisted until the NO donor was removed. In Na+‐free buffer, the decrease in basal pHi was increased, whereas inhibition of carbonic anhydrase and Cl−/OH− and Cl−/ HCO3− exchangers did not alter the effects of the NO donors on pHi. After an ammonium preload, pHi recovery was accelerated in the presence of the NO donors. In conclusion, exogenous NO decreases basal pHi, leading to increased NHE activity. Carbonic anhydrase and chloride‐dependent sarcolemmal HCO3− and OH− transporters are not involved in the NO‐induced decrease in pHi in rat isolated ventricular myocytes.

I. Čavar, T. Kelava, D. Pravdić, F. Culo

Prostanoids are lipid compounds that mediate a variety of physiological and pathological functions in almost all body tissues and organs. Thromboxane (TX) A2 is a powerful inducer of platelet aggregation and vasoconstriction and it has ulcerogenic activity in the gastrointestinal tract. Overdose or chronic use of a high dose of acetaminophen (N-acetyl-paminophenol, APAP) is a major cause of acute liver failure in the Western world. We investigated whether TXA2 plays a role in host response to toxic effect of APAP. CBA/H Zg mice of both sexes were intoxicated with a single lethal or high sublethal dose of APAP, which was administered to animals by oral gavage. The toxicity of APAP was determined by observing the survival of mice during 48 h, by measuring concentration of alanine-aminotransferase (ALT) in plasma 20-22 h after APAP administration and by liver histology. The results have shown that anti-thromboxane (TX) B2 antibodies (anti-TXB2) and a selective inhibitor of thromboxane (TX) synthase, benzylimidazole (BZI), were significantly hepatoprotective, while a selective thromboxane receptor (TPR) antagonist, daltroban, was slightly protective in this model of acute liver injury. A stabile metabolite of TXA2, TXB2, and a stabile agonist of TPR, U-46619, had no influence on APAP-induced liver damage. Our findings suggest that TXA2 has a pathogenic role in acute liver toxicity induced with APAP, which was highly abrogated by administration of anti-TXB2. According to our results, this protection is mediated, at least in part, through decreased production of TXB2 by liver fragments ex vivo .

N. Hirata, Y. Shim, D. Pravdić, Nicole L Lohr, P. Pratt, D. Weihrauch, J. Kersten, D. Warltier et al.

Background: Reactive oxygen species (ROS) mediate the effects of anesthetic precondition to protect against ischemia and reperfusion injury, but the mechanisms of ROS generation remain unclear. In this study, the authors investigated if mitochondria-targeted antioxidant (mitotempol) abolishes the cardioprotective effects of anesthetic preconditioning. Further, the authors investigated the mechanism by which isoflurane alters ROS generation in isolated mitochondria and submitochondrial particles. Methods: Rats were pretreated with 0.9% saline, 3.0 mg/kg mitotempol in the absence or presence of 30 min exposure to isoflurane. Myocardial infarction was induced by left anterior descending artery occlusion for 30 min followed by reperfusion for 2 h and infarct size measurements. Mitochondrial ROS production was determined spectrofluorometrically. The effect of isoflurane on enzymatic activity of mitochondrial respiratory complexes was also determined. Results: Isoflurane reduced myocardial infarct size (40 ± 9% = mean ± SD) compared with control experiments (60 ± 4%). Mitotempol abolished the cardioprotective effects of anesthetic preconditioning (60 ± 9%). Isoflurane enhanced ROS generation in submitochondrial particles with nicotinamide adenine dinucleotide (reduced form), but not with succinate, as substrate. In intact mitochondria, isoflurane enhanced ROS production in the presence of rotenone, antimycin A, or ubiquinone when pyruvate and malate were substrates, but isoflurane attenuated ROS production when succinate was substrate. Mitochondrial respiratory experiments and electron transport chain complex assays revealed that isoflurane inhibited only complex I activity. Conclusions: The results demonstrated that isoflurane produces ROS at complex I and III of the respiratory chain via the attenuation of complex I activity. The action on complex I decreases unfavorable reverse electron flow and ROS release in myocardium during reperfusion.

Z. Ge, I. Ionova, Nikolina Vladić, D. Pravdić, N. Hirata, J. Vasquez-Vivar, P. Pratt, D. Warltier et al.

AIMS Hyperglycaemia (HG) decreases intracellular tetrahydrobiopterin (BH(4)) concentrations, and this action may contribute to injury during myocardial ischaemia and reperfusion. We investigated whether increased BH(4) by cardiomyocyte-specific overexpression of the GTP cyclohydrolase (GTPCH) 1 gene rescues myocardial and mitochondrial protection by ischaemic preconditioning (IPC) during HG through a nitric oxide (NO)-dependent pathway. METHODS AND RESULTS Mice underwent 30 min of myocardial ischaemia followed by 2 h of reperfusion with or without IPC elicited with four cycles of 5 min ischaemia/5 min of reperfusion in the presence or absence of HG produced by d-glucose. In C57BL/6 wild-type mice, IPC increased myocardial BH(4) and NO concentrations and decreased myocardial infarct size (30 ± 3% of risk area) compared with control (56 ± 5%) experiments. This protective effect was inhibited by HG (48 ± 3%) but not hyperosmolarity. GTPCH-1 overexpression increased myocardial BH(4) and NO concentrations and restored cardioprotection by IPC during HG (32 ± 4%). In contrast, a non-selective NO synthase inhibitor N(G)-nitro-l-arginine methyl ester attenuated the favourable effects of GTPCH-1 overexpression (52 ± 3%) during HG. Mitochondria isolated from myocardium subjected to IPC required significantly higher in vitro Ca(2+) concentrations (184 ± 14 µmol mg(-1) protein) to open the mitochondrial permeability transition pore when compared with mitochondria isolated from control experiments (142 ± 10 µmol mg(-1) protein). This beneficial effect of IPC was reversed by HG and rescued by GTPCH-1 overexpression. CONCLUSION Increased BH(4) by cardiomyocyte-specific overexpression of GTPCH-1 preserves the ability of IPC to elicit myocardial and mitochondrial protection that is impaired by HG, and this action appears to be dependent on NO.

Nitin T. Aggarwal, D. Pravdić, E. McNally, Z. Bosnjak, N. Shi, J. Makielski

The sulfonylurea receptor-2 (SUR2) is a subunit of ATP-sensitive potassium channels (K(ATP)) in heart. Mice with the SUR2 gene disrupted (SUR2m) are constitutively protected from ischemia-reperfusion (I/R) cardiac injury. This was surprising because K(ATP), either sarcolemmal or mitochondrial or both, are thought to be important for cardioprotection. We hypothesized that SUR2m mice have an altered mitochondrial phenotype that protects against I/R. Mitochondrial membrane potential (ΔΨ(m)), tolerance to Ca(2+) load, and reactive oxygen species (ROS) generation were studied by fluorescence-based assays, and volumetric changes in response to K(+) were measured by light scattering in isolated mitochondria. For resting SUR2m mitochondria compared with wild type, the ΔΨ(m) was less polarized (46.1 ± 0.4 vs. 51.9 ± 0.6%), tolerance to Ca(2+) loading was increased (163 ± 2 vs. 116 ± 2 μM), and ROS generation was enhanced with complex I [8.5 ± 1.2 vs. 4.9 ± 0.2 arbitrary fluorescence units (afu)/s] or complex II (351 ± 51.3 vs. 166 ± 36.2 afu/s) substrates. SUR2m mitochondria had greater swelling in K(+) medium (30.2 ± 3.1%) compared with wild type (14.5 ± 0.6%), indicating greater K(+) influx. Additionally, ΔΨ(m) decreased and swelling increased in the absence of ATP in SUR2m, but the sensitivity to ATP was less compared with wild type. When the mitochondria were subjected to hypoxia-reoxygenation, the decrease in respiration rates and respiratory control index was less in SUR2m. ΔΨ(m) maintenance in the SUR2m intact myocytes was also more tolerant to metabolic inhibition. In conclusion, the cardioprotection observed in the SUR2m mice is associated with a protected mitochondrial phenotype resulting from enhanced K(+) conductance that partially dissipated ΔΨ(m). These results have implications for possible SUR2 participation in mitochondrial K(ATP).

F. Sedlic, A. Šepac, D. Pravdić, A. Camara, M. Bienengraeber, Anna K. Brzezinska, T. Wakatsuki, Z. Bosnjak

During reperfusion, the interplay between excess reactive oxygen species (ROS) production, mitochondrial Ca(2+) overload, and mitochondrial permeability transition pore (mPTP) opening, as the crucial mechanism of cardiomyocyte injury, remains intriguing. Here, we investigated whether an induction of a partial decrease in mitochondrial membrane potential (DeltaPsi(m)) is an underlying mechanism of protection by anesthetic-induced preconditioning (APC) with isoflurane, specifically addressing the interplay between ROS, Ca(2+), and mPTP opening. The magnitude of APC-induced decrease in DeltaPsi(m) was mimicked with the protonophore 2,4-dinitrophenol (DNP), and the addition of pyruvate was used to reverse APC- and DNP-induced decrease in DeltaPsi(m). In cardiomyocytes, DeltaPsi(m), ROS, mPTP opening, and cytosolic and mitochondrial Ca(2+) were measured using confocal microscope, and cardiomyocyte survival was assessed by Trypan blue exclusion. In isolated cardiac mitochondria, antimycin A-induced ROS production and Ca(2+) uptake were determined spectrofluorometrically. In cells exposed to oxidative stress, APC and DNP increased cell survival, delayed mPTP opening, and attenuated ROS production, which was reversed by mitochondrial repolarization with pyruvate. In isolated mitochondria, depolarization by APC and DNP attenuated ROS production, but not Ca(2+) uptake. However, in stressed cardiomyocytes, a similar decrease in DeltaPsi(m) attenuated both cytosolic and mitochondrial Ca(2+) accumulation. In conclusion, a partial decrease in DeltaPsi(m) underlies cardioprotective effects of APC by attenuating excess ROS production, resulting in a delay in mPTP opening and an increase in cell survival. Such decrease in DeltaPsi(m) primarily attenuates mitochondrial ROS production, with consequential decrease in mitochondrial Ca(2+) uptake.

D. Pravdić, Y. Mio, Y. Mio, F. Sedlic, Phillip F. Pratt, D. Warltier, Zeljko J. Bosnjak, M. Bienengraeber

Background and purpose:  The volatile anaesthetic isoflurane protects the heart from ischaemia and reperfusion (I/R) injury when applied at the onset of reperfusion [anaesthetic postconditioning (APoC)]. However, the mechanism of APoC‐mediated protection is unknown. In this study, we examined the effect of APoC on mitochondrial bioenergetics, mitochondrial matrix pH (pHm) and cytosolic pH (pHi), and intracellular Ca2+.

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