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Biomedical subjects

A Jovanovic

Publications and source records attributed to A Jovanovic.

At least 19 recordsLinked to original sources
PubMed2006

Phaeochromocytomas presenting as acute crises after beta blockade therapy.

OBJECTIVE: Phaeochromocytoma crisis is a life-threatening emergency that may be undiagnosed because of its numerous, nonspecific manifestations. We analysed, retrospectively, the presentation, management and outcome of patients who were admitted to our institution with phaeochromocytoma crises over a 5-year period. RESULTS: Five patients (two males, three females; mean age 34.6 years, range 19-51 years) who presented as emergencies requiring intensive care, with multiple non-specific manifestations and previously undiagnosed pheochromocytoma, were identified. The initial presentation included features of cardiomyopathy (n = 3), atypical pneumonia with myocarditis (n = 1) and acute abdomen (n = 1). Only one of the five cases had a raised blood pressure at the time of the acute presentation. Initiation of beta blockers in four patients was associated with further deterioration in haemodynamic status, labile blood pressure and cardiac arrhythmias, which led to the diagnosis of the underlying phaeochromocytoma. Following intensive supportive therapy and alpha blockade, all five patients recovered and underwent elective surgical removal of phaeochromocytoma, uneventfully. CONCLUSION: Unexplained cardiopulmonary dysfunction, particularly after the institution of beta blockers, should alert clinicians to the possibility of phaeochromocytoma. A high index of suspicion is essential to reduce morbidity and mortality in these patients through early diagnosis and aggressive management.

Acute Disease↗
PubMed2006

[Vertical distraction osteogenesis of the extremely resorbed edentulous mandible. A retrospective description of 16 patients].

This study's objective is to assess long-term results of vertical distraction osteogenesis for the extremely resorbed edentulous mandible by clinically measuring and taking x-rays from the beginning of the treatment of 16 subsequent patients to its final moment in the follow up period (ranging from 2-62 months). Bone height, nerve sensitivity, complications and loss of implant were registered. Average bone resorption after 3 years was 11.2%. Out of 16 patients 5 experienced sensory nerve disturbance; 3 suffered complications. The implant success rate was 89.2%. Distraction osteogenesis appears to be a reliable technique, with which stable bone tissue is developed. Risk of sensory nerve disturbance and complications however, must be taken into consideration.

Aged↗
PubMed2005

The combined use of two endosteal implants and iliac crest onlay grafts in the severely atrophic mandible by a modified surgical approach.

Seventeen patients, who received an iliac crest onlay bone graft augmentation to their severely atrophic mandible with simultaneous placement of two endosteal implants by a modified surgical approach, were studied retrospectively. Follow-up ranged from 0.5 to 7.9 years after implant loading with an average follow-up of 4.3 years. Frequency of wound dehiscences and other postoperative complications, the extend of resorption of the initial graft, and the implant success rate were assessed. Two patients, who had a previous history of preprosthetic and implantological procedures at the surgical site, developed a serious wound dehiscence with loss of two implants in one patient and need for antibiotic treatment and sequestrectomy in the other patient. One implant was lost in two other patients with a negative surgical history, resulting in an implant success rate of 88.2%. The average resorption at the last follow up visit was 15% of the initial graft. Damage of the mental nerve was seen in 14.7% of nerves. Our preliminary data indicate that the procedure presented provides a reliable and predictable method for the construction of an implant-bearing overdenture in patients with a severely atrophic mandible. This one-step procedure can not be recommended for patients with a history of surgery in the anterior mandible.

Adult↗
PubMed2004

Fixion nails for humeral fractures.

Humeral fractures in the setting of multi-trauma are usually managed with internal fixation. We prospectively followed nine patients treated with an expandable nail (Fixion, DiscoTech, Medical Technologies, Herzliya, Israel), until union. Internal fixation rapidly stabilises the injured limb, and the lack of distal cross-bolting in this device markedly reduced our operative time. There were no complications in our series and there was evidence of clinical and radiological union within 6 months. We found the nail easy to use and effective in this clinical setting.

Adolescent↗
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↗
PubMed2001

Stress-induced map kinase Hog1 is part of transcription activation complexes.

In response to hyperosmotic environments, most eukaryotic cells activate a specialized mitogen-activated protein (MAP) kinase pathway. In S. cerevisiae, the key protein kinase, Hog1, coordinates the transcriptional induction of a variety of genes devoted to osmoadaptation and general stress protection. Depending on the promoter context, Hog1 can function through a variety of structurally unrelated transcription factors. Using chromatin precipitation assays, we discovered that the kinase itself becomes intimately linked with promoter regions during stress responses. This interaction is dependent on the presence of stress-mediating transcriptional activators. In turn, Hog1 modulates promoter association of at least one of these factors. Additional findings highlight the possibility that Hog1 constitutes an integral part of the upstream activation complex, perhaps targeting not only the activator but also components of the general transcription machinery.

Catalase↗
PubMed2001

Diadenosine tetraphosphate-gating of recombinant pancreatic ATP-sensitive K(+) channels.

Diadenosine tetraphosphate (Ap4A) has been recently discovered in the pancreatic beta cells where targets ATP-sensitive K(+) (K(ATP)) channels, depolarizes the cell membrane and induces insulin secretion. However, whether Ap4A inhibit pancreatic K(ATP) channels by targeting protein channel complex itself was unknown. Therefore, we coexpressed pancreatic K(ATP) channel subunits, Kir6.2 and SUR1, in COS-7 cells and examined the effect of Ap4A on the single channel behavior using the inside-out configuration of the patch-clamp technique. Ap4A inhibited channel opening in a concentration-dependent manner. Analysis of single channels demonstrated that Ap4A did not change intraburst kinetic behavior of K(ATP) channels, but rather decreased burst duration and increased between-burst duration. It is concluded that Ap4A antagonizes K(ATP) channel opening by targeting channel subunits themselves and by keeping channels longer in closed interburst states.

ATP-Binding Cassette Transporters↗
PubMed2001

Pinacidil prevents membrane depolarisation and intracellular Ca2+ loading in single cardiomyocytes exposed to severe metabolic stress.

Recently, it has been proposed that, besides sarcolemmal K(ATP) channels, the activation of mitochondrial K(ATP) channels may also contribute to the cardioprotective action of potassium channel openers. In this respect, use of drugs that target both mitochondrial and sarcolemmal K(ATP) channels, such as pinacidil, may be a promising therapeutic strategy against metabolic injury of the heart. Therefore, the main objective of the present study was to determine whether pinacidil could maintain the value of resting membrane potential and intracellular Ca2+ homeostasis in cardiac cells exposed to metabolic stress. Experiments were performed on isolated ventricular cardiomyocytes. The membrane potential was monitored during experiments using whole cell patch clamp electrophysiology and the intracellular Ca2+ concentration was measured by a digital epifluorescence imaging. Chemical hypoxia-reoxygenation was induced by application and removal of the mitochondrial poison 2,4 dinitrophenol (DNP). Under hypoxia-reoxygenation, membrane depolarisation and intracellular Ca2+ loading was induced by Ca2+ influx during hypoxia and release of Ca2+ from intracellular stores during reoxygenation. The K(ATP) channel activator, pinacidil, prevented intracellular Ca2+ loading and membrane depolarisation, irrespective of whether the channel opener was applied throughout the duration of hypoxia-reoxygenation or transiently during the hypoxic or reoxygenation stage. Thus, the present study provides evidence that pinacidil, a non-selective K(ATP) channel opener, can handle membrane potential and intracellular Ca2+ homeostasis in cardiomyocytes under hypoxia-reoxygenation irrespective of the stage of the metabolic insult. This provides further evidence, at the single cell level, that targeting K(ATP) channels may be a valuable approach to protect the myocardium against metabolic challenge.

Animals↗
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

Reactive oxygen species and proinflammatory cytokine signaling in endothelial cells: effect of selenium supplementation.

The release of superoxide (O(2)(*-)) and hydrogen peroxide (H(2)O(2)), induced by tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta (IL-1beta), has been studied in the endothelial cell line ECV 304 in the presence and absence of selenium (Se) supplementation. Both cytokines elicit the production of both species. Selenium supplementation, which increases Se-enzyme activity, decreases the amount of H(2)O(2) but not O(2)(*-) detectable in the extracellular medium. Inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by diphenyliodonium (DPI) or phenylarsine oxide (PAO), largely prevents O(2)(*-) production, whereas H(2)O(2) remains above the amount accounted for by disproportion of residual O(2)(*-). Thus, a fraction of H(2)O(2) found in the medium, derives from an intracellular pool, which is under control of selenium-dependent peroxidases. This is further supported by the observation that in Se-supplemented cells, the rate of intracellular glutathione (GSH) depletion induced by cytokine treatment is faster and more extensive. Because Se supplementation decreases cytokine-induced NF-kappaB activity, whereas added H(2)O(2) is inactive and catalase does not affect the activation induced by TNF-alpha, it is concluded that only intracellularly generated H(2)O(2) has a role in transcription factor activation by both TNF-alpha and IL-1beta.

Biphenyl Compounds↗
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↗
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

Risk of second primary cancer following treatment of squamous cell carcinoma of the lower lip.

The risk of second primary cancers (excluding skin cancers) was evaluated among 56 patients who underwent treatment for a squamous cell carcinoma of the lower lip. The mean follow-up was 5.5 years. Ten patients (17.8%) developed at least one new primary cancer. The prevalence of second primary cancers within the respiratory and upper digestive tract, and elsewhere in the body, was 19.4 and 12.9 per 1000 person-years of follow-up, respectively. Patients were at risk for a second primary cancer at a steady rate of 2.7% per year during at least 5 years.

Adult↗
PubMed1999

Inhibition of both Na/H and bicarbonate-dependent exchange is required to prevent recovery of intracellular pH in single cardiomyocytes exposed to metabolic stress.

Although tight regulation of intracellular pH (pHi) is critical for the survival under stress, paradoxically a slowed recovery of pHi under hypoxic injury may be cardioprotective. In this study, we investigated the recovery of pHi after hypoxia-induced intracellular acidosis in cardiomyocytes loaded with the H+-sensitive dye SNARF-1. Exposure of single cardiomyocytes to 2,4-dinitrophenol (DNP), an inhibitor of mitochondrial oxidative phosphorylation, induced significant intracellular acidification. However, within 10-12 min upon removal of DNP, cardiomyocytes restituted their intracellular H+ concentration. The presence either of 5-N-ethyl-N-isopropylamiloride (EIPA) an inhibitor of Na/H antiporter, or 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), an inhibitor of bicarbonate-dependent exchange, did not modify the cellular response to DNP. But, combined use of EIPA and DIDS prevented the restitution of intracellular pH following removal of DNP. This study, thus, demonstrated, for the first time, that blockade of both Na/H and bicarbonate-dependent exchange is necessary and sufficient to maintain the hypoxia-induced intracellular acidification. Therefore, concomitant blockade of both pH-regulating mechanisms deserves to be further considered as a novel strategy against hypoxia-reoxygenation injury in the heart.

2,4-Dinitrophenol↗