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S Jovanovic

Publications and source records attributed to S Jovanovic.

At least 19 recordsLinked to original sources
PubMed2001

Delivery of genes encoding cardiac K(ATP) channel subunits in conjunction with pinacidil prevents membrane depolarization in cells exposed to chemical hypoxia-reoxygenation.

Metabolic injury is a complex process affecting various: tissues with membrane depolarisation recognised as a common trigger event leading to cell death. To examine whether, under metabolic challenge, membrane potential homeostasis can be maintained by an activator of channel proteins, we here delivered Kir6.2 and SUR2A genes, which encode cardiac K(ATP) channel subunits, into a somatic cell line lacking native K(ATP) channels (COS-7 cells). Chemical hypoxia-reoxygenation was simulated in COS-7 cells by addition and removal of the mitochondrial poison 2,4 dinitrophenol (DNP). The membrane potential of COS-7 cells at rest was -31 +/- 3 mV. This value did not change following 3 min-long exposure to DNP (-32 +/- 4 mV). In contrast, washout of DNP induced significant membrane depolarisation (-17 +/- 2 mV). Delivery of Kir6.2/SUR2A genes did not change cellular response to hypoxia-reoxygenation. Similarly, pinacidil, potassium channel opener, did not have effect on hypoxia-reoxygenation-induced membrane depolarisation in cells lacking recombinant K(ATP) channel subunits. However, gene delivery combined with pinacidil prevented membrane depolarisation induced by hypoxia-reoxygenation. This effect of pinacidil, in cells expressing Kir6.2/SUR2A, was observed regardless of whether pinacidil was added only during hypoxia or reoxygenation. The present study demonstrates that combined use of K(ATP) channel subunits gene delivery and pharmacological targeting of recombinant proteins can be used to efficiently control membrane potential under hypoxia-reoxygenation.

2,4-Dinitrophenol↗
PubMed2000

Mechanical unloading versus neurohumoral stimulation on myocardial structure and endocrine function In vivo.

BACKGROUND-Mechanical load and humoral stimuli such as endothelin (ET) and angiotensin II (Ang II) are potent modulators of cardiac structure and endocrine function, specifically gene expression and production and release of atrial natriuretic peptide (ANP). We define the contribution of mechanical load compared with neurohumoral stimulation in vivo with specific focus on myocardial and circulating ANP during chronic myocardial unloading produced by thoracic inferior vena caval constriction (TIVCC). METHODS AND RESULTS-TIVCC was produced by banding the IVC for 10 days in 7 dogs, whereas in the 6 control dogs, the band was not constricted. TIVCC was characterized by a decrease in cardiac output, right atrial pressure, and left ventricular (LV) end-diastolic diameter and marked activation of ET and Ang II in plasma and atrial and ventricular myocardium. Despite neurohumoral stimulation, LV mass index and myocyte diameters in unloaded hearts decreased, reflecting myocyte atrophy. The total number of myocytes in the LV remained unchanged. Atrial stores of ANP increased, but plasma ANP did not change, in association with a trend toward ANP gene expression to decrease in unloaded hearts. CONCLUSIONS-Chronic mechanical unloading of the heart results in myocardial atrophy and lack of activation of ANP synthesis despite marked neurohumoral stimulation by the growth promoters ET and Ang II.

Angiotensin II↗
PubMed2000

[Enlarged ventricular sacculus in laryngeal carcinoma--in increased risk in tumor surgery].

The case of a 60-year-old female patient with a supraglottic larynx carcinoma (T3N2CM0) and bilateral enlargement of the laryngeal sacculus is presented. On one side, the sacculus opened atypically into the left vestibular fold. The sacculus is a physiologic part of the roof of Morgagni's ventricle, the size of which can vary greatly. These canal-like structures can be the point of origin of cysts, laryngoceles, mucoceles, and pyoceles. Laryngoceles are present in about 5% of larynx carcinomas; their cause is not precisely known. Frequently, a computer tomogram suggests the coincidence of larynx carcinoma and laryngoceles or a large laryngeal sacculus. In oral panendoscopy, these ventricular distensions are difficult to detect even using 70 degrees rigid endoscopes. A planned supraglottic partial resection must take into account early tumor growth along the performed canals in the preepiglottic space. In this patient, a laryngectomy was performed due to the bilateral involvement of the vocal process and the anterior commissure.

Carcinoma, Squamous Cell↗
PubMed2000

[Experimental and clinical experiences with the Er:YAG laser otoscope].

BACKGROUND AND OBJECTIVE: Laserotoscopes are suitable for low-pain outpatient surgery of otitis media with effusion (OME) under topical anesthesia. The myringotomy perforations should have a diameter greater than 2 mm to ventilate the middle ear for approximately 3 weeks. PATIENTS/METHODS: In this study, the clinical applicability of a prototype of an Er:YAG laserotoscope (Baasel Lasertechnik, Starnberg, Germany) was tested. Formalin-fixed human tympanic membranes yielded the parameters suitable for clinical application of an Er:YAG laserotoscope in patients. With a focussed laser beam (beam diameter 500 microns), one is able to achieve perforations of 50-micron diameter with one single laser pulse applying pulse energies of 70 mJ (energy density 36 J/cm2). The ablation rate, i.e., the tissue layer that is ablated per laser pulse, is 100 microns using pulse energies of 70 mJ. This means that formalin-fixed human tympanic membrane can be perforated with one single laser pulse. RESULTS: Ten patients with OME (otitis media with effusion) were treated under topical anesthesia of the tympanic membrane (8% tetracainbase in Isopropanol for 15 min) with focussed laser pulses (beam diameter 500 microns) with energies of 100 mJ (energy density 52 J/cm2). A sufficient perforation diameter of 2 mm could be achieved with an average of 15 juxtaposed laser applications. The enlargement of the perforations was made difficult by extruding middle ear secretions and slight bleeding of the tympanic membrane. Between laser applications, the target tissue had to be cleaned by suctioning using the operation microscope. The healing of the tympanic membrane was verified and compared in postoperative clinical follow-ups. With a perforation diameter of 2 mm, the Er:YAG laser myringotomies healed within 14 days. The used parameters did not generate side effects such as inner ear hearing loss. CONCLUSIONS: An effective, easy, and practical performance of laser myringotomy is not currently possible with the Er:YAG laserotoscope.

Adult↗
PubMed2000

Influence of pulsed laser irradiation on the morphology and function of the guinea pig cochlea.

Recent experimental and clinical studies have demonstrated that several pulsed laser systems are also suitable for stapedotomy. The aim of the study was to investigate morphological and functional inner ear changes after irradiating the basal turn of the guinea pig cochlea with two pulsed laser systems of different wavelengths. The Er:YSGG (lambda=2.78 mcm) and Ho:YAG (lambda=2.1 mcm) lasers were used applying the laser energies necessary for perforating a human stapes footplate. The cochleas were removed 90 min, 1 day, 2 weeks, or 4 weeks after laser application. Acoustic evoked potentials (compound action potentials) were measured before and after laser application and at the above times immediately before removal of the cochleas. The organ of Corti was examined by scanning electron microscopy. Application of Er:YSGG laser parameters effective for stapedotomy had no adverse effects on Corti's organ in the guinea pig cochlea. On the other hand, effective Ho:YAG laser parameters cause damage to the outer hair cells with fusion of stereocilia and formation of giant cilia leading to partial or total cell loss. The inner hair cells and supporting cells were usually normal. These morphological data show a good correlation with the electrophysiological measurements. Our results clearly demonstrate that, besides achieving efficient bone management, the Er:YSGG laser has high application safety. On the other hand, the Ho:YAG laser is not well tolerated in our animal study. Its use in stapedotomy would be unreliable and dangerous for the inner ear.

Action Potentials↗
PubMed2000

Pregnancy is associated with altered response to neuropeptide Y in uterine artery.

Pregnancy is associated with a significant increase in uterine blood flow which contributes to optimal fetal development. Although neuropeptide Y (NPY) is considered to be an important regulator of uterine blood flow, it is not known whether: (i) products from the vascular endothelium modulate NPY action in the uterine artery; (ii) pregnancy changes the responsiveness of the uterine artery to NPY, or (iii) NPY interacts with noradrenaline and acetylcholine on the uterine artery, with pregnancy regulating this possible interaction. In the present study, NPY induced a concentration-dependent contraction of guinea pig uterine arterial rings both intact and denuded of endothelium. Pregnancy significantly decreased the potency of NPY to contract uterine artery with and without endothelium. In all preparations, addition of N(G)-monomethyl-l-arginine acetate (l-NMMA), indomethacin and diethylcarbamazine did not modify the effect of NPY. In the presence of NPY concentration-response curves for acetylcholine and noradrenaline were significantly shifted to the right and left respectively. This effect of NPY was independent of endothelial condition or pregnancy status. The receptor reserve (K(A)/EC(50)) for acetylcholine was decreased and for noradrenaline was increased in the presence of NPY, although no changes in the dissociation constants of the neurotransmitter-receptor complexes were observed. Thus, this study has shown that: (i) NPY induces contraction of guinea pig uterine arteries acting on receptors localized in smooth muscle; (ii) pregnancy alters the response of guinea pig uterine arteries to NPY in such a way as to promote vasorelaxation, and (iii) NPY modulates the effect of neurotransmitters on guinea pig uterine arteries, but pregnancy is not associated with the changes at the level of NPY-neurotransmitter interaction.

Acetylcholine↗
PubMed2000

Pregnancy does not alter the response of uterine arteries to vasoactive intestinal polypeptide.

In order to provide sufficient nutrients for fetal development, pregnancy is associated with a significant increase in uterine blood flow. Although vasoactive intestinal polypeptide (VIP) is considered to be an important regulator of uterine blood flow it is not known whether endothelium-derived relaxing factors contribute to VIP action in the uterine artery, whether pregnancy alters the effect of VIP in the uterine artery and/or whether VIP interacts with noradrenaline and acetylcholine on the uterine artery and whether pregnancy regulates this possible interaction. In the present study, VIP induced a concentration-dependent relaxation of guinea pig uterine arterial rings, both intact and denuded of endothelium. Pregnancy did not alter the relaxation of uterine artery in response to VIP. In all preparations, addition of N(G)-monomethyl-L-arginine (L-NMMA), indomethacin and diethylcarbamazine did not modify the effect of VIP in uterine arteries. The VIP-receptor complex dissociation constant did not differ significantly between studied vessels, and in all experimental groups the relationship between receptor occupancy and the response was linear, with the receptor reserve (K(A)/EC(50)) close to unity. VIP did not modulate acetylcholine-induced relaxation or noradrenaline-induced contraction in both non-pregnant and pregnant guinea pig uterine arteries. This study has shown that: (i) VIP induces relaxation of guinea pig uterine artery acting as a partial agonist on receptors localized in smooth muscle; (ii) pregnancy does not alter the response of guinea pig uterine arteries to VIP and does not change the receptor affinity for VIP, the efficiency of the receptor coupling or the VIP receptor density; and (iii) VIP does not modulate effects of neurotransmitters on guinea pig uterine arteries and pregnancy is not associated with the changes of VIP-neurotransmitter interaction.

Acetylcholine↗
PubMed2000

Redo cardiac surgery in a Jehovah's Witness, the importance of a multidisciplinary approach to blood conservation.

Although Jehovah's Witnesses present a particular problem when undergoing surgery because of their refusal to accept stored blood, it is now quite common to undertake uncomplicated cardiac surgery in these patients. Complex or redo cardiac surgery however, is often associated with major blood loss, and is conventionally contraindicated in Jehovah's Witnesses. We describe the perioperative management of a Jehovah's Witness who underwent a resternotomy for mitral valve replacement and coronary artery bypass grafting having previously had an aortic valve replacement and mitral valve repair. The importance of a multidisciplinary approach to blood conservation is discussed.

Blood Loss, Surgical↗
PubMed2000

Differential regulation of leptin transport by the choroid plexus and blood-brain barrier and high affinity transport systems for entry into hypothalamus and across the blood-cerebrospinal fluid barrier.

Leptin is a circulating hormone that controls food intake and energy homeostasis. Little is known about leptin entry into the central nervous system (CNS). The blood-cerebrospinal fluid (CSF) barrier at the choroid plexus and the blood-brain barrier (BBB) at the cerebral endothelium are two major controlling sites for entry of circulating proteins into the brain. In the present study, we characterized leptin transport across the blood-CSF barrier and the BBB by using a brain perfusion model in lean rats. Rapid, high-affinity transport systems mediated leptin uptake by the hypothalamus (KM = 0.2 ng/ml) and across the blood-CSF barrier (KM = 1.1 ng/ml). High affinity in vivo binding of leptin was also detected in the choroid plexus (KD = 2.6 ng/ml). In contrast, low affinity carriers for leptin (KM = 88 to 345 ng/ml) were found at the BBB in the CNS regions outside the hypothalamus (e.g. cerebral cortex, caudate nucleus, hippocampus). Our findings suggest a key role of high affinity leptin transporters in the hypothalamus and choroid plexus in regulating leptin entry into the CNS and CSF under physiological conditions. Low affinity transporters at the BBB outside the hypothalamus could potentially contribute to overall neuropharmacological effects of exogenous leptin.

Animals↗
PubMed1999

Regulation of nitric oxide-responsive recombinant soluble guanylyl cyclase by calcium.

Calcium (Ca2+) and cyclic GMP (cGMP) subserve antagonistic functions that are reflected in their coordinated reciprocal regulation in physiological systems. However, molecular mechanisms by which Ca2+ regulates cGMP-dependent signaling remain incompletely defined. In this study, the inhibition of recombinant nitric oxide (NO)-stimulated soluble guanylyl cyclase (SGC) by Ca2+ was demonstrated. The alpha- and beta-subunits of recombinant rat SGC were heterologously coexpressed in HEK 293 cells which do not express NO synthase, whose Ca2+-stimulated activity can confound the effects of that cation on SGC. Ca2+ inhibited basal and NO-stimulated SGC in a concentration- and guanine nucleotide-dependent fashion. This cation inhibited SGC in crude cell extracts and immunopurified preparations. Ca2+ lowered both the Vmax and Km of SGC via an uncompetitive mechanism through direct interaction with the enzyme. In intact HEK 293 cells, increases in the intracellular Ca2+ concentration induced by ionomycin, a Ca2+ ionophore, and thapsigargin, which releases intracellular stores of that cation, inhibited NO-stimulated intracellular cGMP accumulation. Similarly, carbachol-induced elevation of the intracellular Ca2+ concentration inhibited NO-stimulated intracellular cGMP accumulation in HEK 293 cells. These data demonstrate that SGC behaves as a sensitive Ca2+ detector that may play a central role in coordinating the reciprocal regulation of Ca2+- and cGMP-dependent signaling mechanisms.

Animals↗
PubMed1999

[Manifestation of epidermolysis bullosa acquisita (EBA) in the ENT area].

Epidermolysis bullosa acquisita (EBA) is a rare, chronic, acquired bullous autoimmune dermatosis. It is characterized by the formation of IgG autoantibodies against type VII procollagen of anchoring fibrils with subepidermal formation of bullous lesions and consequent scarring. The epidemiology of this disease and its characteristic clinical findings cannot be completely surveyed at present due to the limited number of available publications. In general, bullous lesions form on the entire integument and can also involve mucosa. The development of scar-related adhesions on the mucosa of the upper airways and esophagus can lead to serious complications that are difficult to treat. We report our experience in managing a 44-year-old male patient in whom the diagnosis of EBA was established in 1993 on the basis of multiple persistent bullous lesions involving the eye, nose, skin and oral, pharyngeal and laryngeal mucosa. After failing previous medical and surgical therapies, interdisciplinary management resulted in the control of active lesions with extracorporal phototherapy and cyclosporin A.

Adult↗
PubMed1999

Cereport (RMP-7) increases the permeability of human brain microvascular endothelial cell monolayers.

PURPOSE: To study Cereport (RMP-7, bradykinin B2 agonist) effects on human brain microvascular endothelial cell (HBMEC) monolayer permeability. METHODS: HBMEC grown on transwell membranes were exposed to Cereport. The monolayer permeability was determined with [14C]-inulin (MW. 5,200) and [3H]-dextran (MW. 70,000). RESULTS: Cereport increased the HBMEC permeability to [14C]-inulin, but not to [3H]-dextran. The effect was transient, maximal at 15 min (i.e., 79.3% increase), and polarized to the basolateral membrane. An inverted U, dose-response curve was observed with active concentrations of Cereport from 0.01 to 0.5 nmol/L, the plateau maximal effect between 0.5 and 10 nmol/L, and loss of activity at the highest concentration, i.e., 20 nmol/L. Cyclic AMP-specific phosphodiesterase 3 (PDE3) inhibitor rolipram (10 micromol/L) abolished Cereport effects, while cGMP-specific PDE5 inhibitor, zaniprast (50 micromol/L) enhanced by 31% (p < 0.05) the effect of 0.1 nmolL Cereport. Unlabeled Cereport displaced [125I]-bradykinin and/or [125I]-Cereport from the basolateral side. There was no specific Cereport binding to the apical side. CONCLUSIONS: Cereport exerts specific time, dose and size dependent actions on HMBEC monolayer that are restricted to the basolateral membrane. Its effects can be further modulated through changes in cAMP and cGMP second messenger systems.

Binding, Competitive↗
PubMed1999

Combined intratumor cisplatinum injection and Nd:YAG laser therapy.

OBJECTIVES/HYPOTHESIS: Interstitial laser therapy (ILT) has become useful for tumor palliation in patients with advanced head and neck cancer. Cisplatinum chemotherapy also is a frequent adjuvant treatment for recurrent tumors, but systemic toxicity limits application. Intratumor cisplatinum injection combined with ILT may improve therapy of these recurrent tumors with reduced toxicity. STUDY DESIGN: Prospective. Tumor transplants were injected with cisplatinum in a gel implant before ILT to evaluate treatment response and toxicity in a preclinical study. METHODS: UCLA-P3 human squamous cell carcinoma tumors were grown as subcutaneous transplants in nude mice and treated by intratumor injection of 2 mg/mL cisplatinum in a slow-release, collagen-based gel carrier 4 hours before interstitial implantation of Nd:YAG laser fiberoptics to induce local tumor hyperthermia. Treatment efficacy and toxicity were followed for 12 weeks after combined drug and laser therapy compared with ILT alone. RESULTS: Combined cisplatinum gel and ILT was a significant improvement (P < .01 by chi-square test) and induced 57% complete responses without regrowth in 21 transplanted tumors compared with only 24% in 21 tumors after ILT alone during 12-week follow-up. Recurrences in both cases appeared to result from nonuniform laser energy delivery within tumors via the implanted fiberoptic tip. CONCLUSIONS: The results of this experimental combined cisplatinum and ILT study suggest it may be possible to improve treatment of advanced head and neck cancer by intratumor injection of gel implants containing the drug followed by interstitial Nd:YAG laser hyperthermia.

Animals↗
PubMed1999

Increased number of cardiomyocytes in cross-sections from tachycardia-induced cardiomyopathic hearts.

Based on positive identification of DNA replication and mitotic division in cardiomyocytes isolated from failing hearts, it has been proposed that adult ventricular cardiomyocytes can gain the capacity to proliferate with progression of heart failure. However, due to the lack of a reliable method to distinctly image individual cardiac cells within the myocardial syntitium, such a concept still remains largely controversial. In the present study, we used laser confocal microscopy, to image cross-sections of intact myocardium stained with fluorescein-conjugated wheat germ agglutinin and propidium iodide. This approach allowed to clearly separate the profile of individual myocytes within cardiac tissue sections. We found that in the left ventricles of dogs, subjected to tachycardia-induced cardiomyopathy, the number of cells was significantly increased in both longitudinal and transversal sections. Treatment with the angiotensin-converting enzyme inhibitor, enalapril, reversed these changes to values similar to those found in controls. Therefore, this study provides evidence, at the in situ level, for cellular hyperplasia in heart failure. This supports the more general notion that adult cardiomyocytes may not be terminally differentiated, and that an increase in cell number could contribute to the increase in left ventricular mass observed with progression of disease.

Animals↗
PubMed1999

Influence of CO2 laser application to the guinea-pig cochlea on compound action potentials.

HYPOTHESIS: Experiments in guinea pigs were performed to clarify which, if any, of the CO2 lasers in different modes (continuous wave [cw] and superpulse) can damage the inner ear on application of the laser parameters required for stapedotomy and to determine their application safety. METHODS: The laser effect connected with perforating the basal convolution of the guinea-pig cochlea (cochleostomy) was examined. Acoustic evoked potentials (compound action potentials [CAPs]) yielded information on inner-ear function. RESULTS: In cw mode, even single applications of an approximately four times higher power density (60,000 W/cm2) than necessary for stapedotomy at a pulse duration of 50 msec (energies up to 1 J) and 20-fold applications of effective parameters for a footplate perforation (power density 16,000 W/cm2; energy 0.2 J) did not cause CAP changes. Experimental studies with the CO2 superpulse laser used (peak pulse powers: ca. 300 W) have demonstrated that irreversible CAP alterations already occur in the effective laser range in > 40% of the animals. CONCLUSIONS: Because damage is expected only at much higher energies (> 2 J) than those used clinically, the CO2 laser in cw mode has a high application safety for laser stapedotomy. The application of the CO2 laser in superpulse mode with peak pulse powers of approximately 300 W in stapedotomy appears to be more unreliable and dangerous for the inner ear.

Animals↗
PubMed1999

Wartime amputations.

This paper outlines the causative factors, incidence, and localization of extremity amputations of wounded persons treated at the Osijek University Hospital (Eastern Slavonia) during 1991 and 1992. The medical documentation of 5,024 patients was analyzed. Of these, 1,560 patients were treated in the hospital (31.0%). A total of 1,916 extremity injuries were found in hospitalized wounded patients. Injuries of the lower extremities were found in 1,226 patients and injuries of the upper extremities in 690 patients. Gunshot-explosive fractures of the extremity bones were diagnosed in 1,122 patients (71.9%): 735 (47.1%) in the lower extremities and 387 (25.8%) in the upper extremities. In 90 cases (4.6%), amputation of the extremities (including the fingers) using an open circular or flap technique was performed. Large amputations (above the wrist and ankle joints) were performed on 40 patients (2.6%). Amputation of the upper extremities was performed on 53 patients (58.9%), and amputation of the lower extremities was performed on 37 patients (41.1%). Injuries of the major blood vessels were treated with primary reconstruction in the upper extremities in 44 patients and in the lower extremities in 96 patients. Unstable gunshot-explosive fractures of the long bones were stabilized with external fixation, and fractures of the short bones were stabilized by means of minimal osteosynthesis or external fixation. Secondary amputations (on the lower extremities) were performed on 2 patients because of vascular insufficiency. Not a single secondary amputation procedure was performed because of infection, secondary uncontrolled hemorrhage, or gas gangrene. Amputation is a radical and irreversible intervention, and indications for amputation must be determined by those with great surgical experience and good knowledge of military-surgical doctrine.

Amputation, Surgical↗
PubMed1998

Intravenous RMP-7 increases delivery of ganciclovir into rat brain tumors and enhances the effects of herpes simplex virus thymidine kinase gene therapy.

Herpes simplex virus thymidine kinase (HSV-tk) gene therapy for brain tumors depends on ganciclovir (GCV) and its transport across the blood-brain tumor barrier (BBTB). We examined whether RMP-7, the bradykinin analog and potent BBTB permeabilizer, could enhance the efficacy of GCV treatment of brain tumors by increasing the BBTB delivery of GCV. In vitro, a significant bystander cytocidal effect of GCV was shown in mixed HSV-tk-transduced (HSV-tk+) and control vector-transduced (HSV-tk-) C6 glioma cultures. A dose-dependent cytotoxic effect of GCV on untransformed C6 cells was also shown. In vivo, rats with 100% HSV-tk+ or 100% HSV-tk- intracerebral C6 gliomas were treated for 7 days with intravenous infusions of GCV alone or with GCV and RMP-7 (2.5 microg/kg/day). The growth of HSV-tk+ and HSV-tk- gliomas decreased with increasing doses of GCV. A high dosage (100 mg of GCV/kg/day) eradicated all HSV-tk- and HSV-tk+ tumors. An intermediate dosage (5 mg of GCV/kg/day) reduced the growth of HSV-tk- gliomas by 42% if given alone, and by 88% in combination with RMP-7. A low dosage (0.5 mg of GCV/kg/day) in combination with RMP-7 enhanced the regression of HSV-tk+ gliomas by 87% compared with GCV alone. Low-dose GCV was ineffective in HSV-tk- tumors. RMP-7 increased [3H] GCV tumoral uptake by 2.6- and 1.7-fold in the tumor center and periphery, respectively. We conclude that RMP-7 could be an important adjunctive treatment for suicide gene therapy of brain tumors, while an RMP-7/GCV combination may also have a significant antitumor effect in untransfected gliomas.

3T3 Cells↗