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A Terzic

Publications and source records attributed to A Terzic.

At least 19 recordsLinked to original sources
PubMed2007

Aminoglycoside-induced translational read-through in disease: overcoming nonsense mutations by pharmacogenetic therapy.

A third of inherited diseases result from premature termination codon mutations. Aminoglycosides have emerged as vanguard pharmacogenetic agents in treating human genetic disorders due to their unique ability to suppress gene translation termination induced by nonsense mutations. In preclinical and pilot clinical studies, this therapeutic approach shows promise in phenotype correction by promoting otherwise defective protein synthesis. The challenge ahead is to maximize efficacy while preventing interaction with normal protein production and function.

Aminoglycosides↗
PubMed2006

[Laparoscopic pancreatic resection].

UNLABELLED: Over a long time laparascopy for pancreatic diseases was performed only as staging laparoscopy in order to find hidden metastasis. The laparoscopic pyloric preserving duodeno-pancreatectomy showed many problems and could not establish. Laparoscopic distal resection of pancreas is much more feasible due to lack of intestinal anastomoses. Anyway there is only few literature about laparoscopic left pancreatic resection found. We demonstrate our experiences in four cases of the last months. RESULTS: In all four cases laparoscopic distal pancreatic resection was performed for tumor. In three cases the resection of the spleen was necessary. In another case we performed a laparoscopic hemifundoplicaton (DOR) for GERD in the same session. Histologic examination showed a neuroendocrine carcinoma, a serous-microcystic adenoma, a low differentiated ductal adenocarcinoma and an intraductal papillary-mucinous tumor of borderline type. Postoperative stay was between eight and ten days. There was no patient suffering from intra- or postoperative complications. CONCLUSION: Laparoscopic resection of distal pancreas shows the common benefit of minimal invasive surgery for the early postoperative period and is an attractive alternative for treatment of benign and semimalign pancreatic tumors.

Adenoma↗
PubMed2006

[Laparoscopic Dor-hemifundoplication for therapy of gastroesophageal reflux disease].

INTRODUCTION: Gastroesophageal reflux disease is a major health problem in western industrial nations. Several prospective randomized studies showed the operative therapy of GERD superior to a steady medication with omeprazole regarding recurrence rate as well as rate of side effects. The today most performed 360 degrees fundoplication (Nissen-Rossetti) leads in 10-30% to a persisting postoperative dysphagia. We prefer the anterior semifundoplication by Dor. Aim of our study is to find out if our results are comparable to current literature and to open procedure. PATIENTS: Between 1.1.03 and 30.6.05 one operator performed on 100 consecutive patients (57 female, 43 male) between 29 and 86 years of age an anterior Dor-semifundoplication with posterior hiatal repair. In 37 cases we performed a cholecystectomy simultaneously, on two patients a sigmoid resection and in one case a left pancreatic resection. 52 Patients were re-evaluated after six months (median follow up nine months). RESULTS: Median operation time was 71 min (30-250 min). The learning curve showed a time reduction of initially 102 to 40 min in the last 10 cases. Blood loss was between 10 and 300 ml (median 40 ml). No conversion was necessary). As intraoperative complication in one case the right pleural cavity was opened. Postoperative complications were found to be wound infection in one case and urinary tract infection in another. Postoperative stay was four days (2-19 d) and eight days respectively for patients after sigmoid resection or left pancreatic resection. After median follow up of nine months 45 of 52 re-evaluated patients (86%) were free of reflux symptoms, 47 (90%) were pleased or very pleased with the result of the operation. Four patients felt at least a reduction of preoperative symptoms. CONCLUSION: The anterior Dor semifundoplication is a technically easy and low risk procedure, which has a lower side effect rate than the 360 degrees operation and will heal 90% of the patients from their reflux disease.

Adult↗
PubMed2006

[Extent of lymphnode dissection with minimally invasive esophageal resection].

UNLABELLED: Esophageal resection is still today associated with a high morbidity and mortality. Minimally invasive procedures show a significantly lower rate of such complications and therefore might also be associated with a lower surgical risk. However, publications till date contain little or no data on the extent of lymph node dissection. The aim of our study was to evaluate the morbidity and mortality rate of minimally invasive esophageal resection. MATERIAL AND METHODS: In the last two years, we carried out 25 minimally invasive esophageal resections on five women and 20 men with a median age of 63 years (range 41-74 years). All data were accrued prospectively. RESULTS: Nine patients were operated upon transhiatally and 12 combined laparocopic-thoracoscopic. On four patients, a thoracotomy was necessary. The average surgical time for the transhiatal approach was calculated at 164 minutes (range 150-180 min) and for the combined laparoscopic-thoracoscopic procedure 285 minutes (240-360 min). The thoracoscopic esophageal resection itself lasted 105 minutes on average; the last five resections each lasting 70 minutes. A median of 24,5 lymph nodes (19-26) was calculated in the laparoscopic-thoracoscopic technique. The transhiatal procedure revealed a median of 14 lymph nodes (12-17). Postoperatively, we had three cases of anastomotic and two cases of bronchial leakages, most probably associated with the use of monopolar current; complications no longer seen since usage of the HARMONIC ACE for surgical preparation. There was no 30 day letality. CONCLUSION: Our experience with 25 successful minimally invasive esophageal resections shows that with increasing experience and better surgical equipment, the extent of lymph node dissection does not differ from open procedure.

Adenocarcinoma↗
PubMed2005

Analysis of mRNA in hemophilia A patients with undetectable mutations reveals normal splicing in the factor VIII gene.

BACKGROUND: haemophilia A (HA) is characterized by partial or total deficiency of factor VIII (FVIII) protein activity. It is caused by a broad spectrum of mutations in the FVIII gene. Despite tremendous improvements in mutation screening methods, in about 2% of HA patients no DNA change could be found, even after sequencing the whole coding part of the FVIII gene including the flanking splice sites, as well as the promotor and the 3' UTR regions. OBJECTIVES, PATIENTS AND METHODS: In the present study we performed a detailed RNA analysis of three groups of patients. The first included control patients with known splicing defects, the second included two patients with already identified nucleotide changes close to splicing sites, that could potentially alter the normal splicing process, and a third group of 11 unrelated patients whose genomic DNA have already been screened for mutations by DHPLC and direct sequencing with no mutation being identified. RESULTS: Both candidate splice site mutations were shown to result in either skipping or alternative splicing of at least one exon, therefore these DNA changes must be considered as causal for the patients' HA phenotype. In contrast, no abnormalities on the RNA level were observed in any of 11 unrelated patients without mutations in the FVIII gene. CONCLUSIONS: These findings exclude mutations that could be located deep in the introns and affecting either normal splicing or lead to mechanisms causing some unknown rearrangements of the FVIII gene. In fact, our results point to the presence of still unknown factor(s) causing HA, which might be either allelic or in the close proximity of the FVIII gene or non-allelic associated with other genetic loci that are involved in the processing of the FVIII protein.

DNA Mutational Analysis↗
PubMed2005

Angiotensin II antagonism fails to ameliorate bleomycin-induced pulmonary fibrosis in mice.

Based on current evidence, transforming growth factor (TGF)-beta plays a central pathogenic role in the development of pulmonary fibrosis. There is growing evidence that angiotensin II can serve as a stimulus for TGF-beta-mediated lung fibrosis. However, the role of angiotensin II in the pathobiology of pulmonary fibrosis in vivo remains unclear and the therapeutic potential for targeting angiotensin II in a bleomycin-induced pulmonary fibrosis model is not well known. Therefore, the aim of this study was to test whether the angiotensin II antagonist, losartan, attenuated the development of bleomycin-induced pulmonary fibrosis in two distinct murine strains, C57/BL6 and Sv129. This was determined by histopathology and quantification of collagen content by hydroxyproline assay. Despite demonstrable angiotensin II antagonism in vivo and a reduction in measures of acute lung injury, losartan therapy, at a dose shown to reduce renal and cardiac fibrosis in mice, failed to significantly ameliorate bleomycin-induced pulmonary fibrosis. In conclusion, these data suggest that the pulmonary fibrotic disease process in vivo is not solely dependent on angiotensin II activity and the potential for angiotensin II receptor blockers as a therapeutic strategy in patients with pulmonary fibrosis may be limited.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2004

Inguinal hernia: measurement of the biomechanics of the lower abdominal wall and the inguinal canal.

BACKGROUND: The stability of the lower abdominal wall may play a considerable role in the development of inguinal hernia. Therefore, the strength of the individual wall layers needs to be quantified. Despite numerous advances in hernia repair, comparatively few systematic biomechanic and morphometric analyses have been performed. Our aim was to establish and apply a standardised procedure for testing the abdominal wall layers' stability. METHODS: After dissecting the abdominal walls of 16 cadavers into separate layers, we used a spherical punch and a force transducer to investigate the forces necessary to foraminate the layer. In addition, maximum tensile-strength and suction tests and histologic morphometry were performed. RESULTS: The transversalis fascia was torn up on an average of 10.5 N, the peritoneum including pre- and subperitoneal tissue on 46.6 N, the aponeurosis of obliquus internus abdominis muscle on 51.7 N, and the aponeurosis of obliquus externus abdominis muscle on 92.6 N. Tensile tests of tissue strips obtained from defined areas showed comparable results. In contrast, surgical mesh revealed values between 60 and 150 N in punching tests. Left-right comparisons, as well as comparisons of the individual areas, revealed considerable intra- and inter-individual differences. CONCLUSIONS: Biological hernia repair should focus on a reinforcement of the tissue layers with the highest biomechanic stability. Reinforcement of the transversal fascia must be questioned according to our results of poor mechanical resistance.

Abdominal Wall↗
PubMed2004

[Selection of patients with rectal tumors for local excision based on preoperative diagnosis. Results of a consecutive evaluation study of 552 patients].

INTRODUCTION: The aim of our study was to evaluate the accuracy of clinical staging (CS), biopsies, and endoluminal ultrasonic examination (EUS) in preoperative staging of rectal tumors treated with transanal local excision. This local excision is an adequate procedure for benign rectal polyps and low-risk T1 carcinoma. PATIENTS AND METHODS: The study included 552 patients with rectal adenocarcinoma, villous adenoma, or tumors with other histologic characteristics who underwent a transanal excision (transanal endoscopic microsurgery n=513 or transanal excision n=39). We compared the results of CS, biopsies, and EUS with postoperative pathology findings. RESULTS: Preoperative histological diagnosis of the rectal carcinoma depended on tumor size (52% in cancers <3 cm, 25% in cancers >3 cm; p=0.001) and was correct in 56% of cases. Transanal ultrasonography (uT0/1) had superior sensitivity (95% vs 78%) and a higher positive predictive value (93% vs 85%) than clinical staging (CS I) in detecting adenoma or T1 rectal carcinoma, whereas specificity was similar in both (62% vs 58%). In patients in whom preoperative histological analysis revealed adenomas, transanal ultrasonography was accurate (uT0/1) for the postoperatively assessed adenoma pT1 in 97%, whereas diagnosis (uT0/1) was correct in only 71% of cases in which preoperative histological analyses showed rectal carcinomas. CONCLUSIONS: In patients with rectal tumors, preoperative staging with transanal ultrasonography and biopsy is essential for the indication and allows selection of patients for transanal local excision.

Adenocarcinoma↗
PubMed2003

Bacterial enterotoxins are associated with resistance to colon cancer.

One half million patients suffer from colorectal cancer in industrialized nations, yet this disease exhibits a low incidence in under-developed countries. This geographic imbalance suggests an environmental contribution to the resistance of endemic populations to intestinal neoplasia. A common epidemiological characteristic of these colon cancer-spared regions is the prevalence of enterotoxigenic bacteria associated with diarrheal disease. Here, a bacterial heat-stable enterotoxin was demonstrated to suppress colon cancer cell proliferation by a guanylyl cyclase C-mediated signaling cascade. The heat-stable enterotoxin suppressed proliferation by increasing intracellular cGMP, an effect mimicked by the cell-permeant analog 8-br-cGMP. The antiproliferative effects of the enterotoxin and 8-br-cGMP were reversed by L-cis-diltiazem, a cyclic nucleotide-gated channel inhibitor, as well as by removal of extracellular Ca(2+), or chelation of intracellular Ca(2+). In fact, both the enterotoxin and 8-br-cGMP induced an L-cis-diltiazem-sensitive conductance, promoting Ca(2+) influx and inhibition of DNA synthesis in colon cancer cells. Induction of this previously unrecognized antiproliferative signaling pathway by bacterial enterotoxin could contribute to the resistance of endemic populations to intestinal neoplasia, and offers a paradigm for targeted prevention and therapy of primary and metastatic colorectal cancer.

Bacterial Toxins↗
PubMed2001

Cellular energetics in the preconditioned state: protective role for phosphotransfer reactions captured by 18O-assisted 31P NMR.

Cell survival is critically dependent on the preservation of cellular bioenergetics. However, the metabolic mechanisms that confer resistance to injury are poorly understood. Phosphotransfer reactions integrate ATP-consuming with ATP-producing processes and could thereby contribute to the generation of a protective phenotype. Here, we used ischemic preconditioning to induce a stress-tolerant state and (18)O-assisted (31)P nuclear magnetic resonance spectroscopy to capture intracellular phosphotransfer dynamics. Preconditioning of isolated perfused hearts triggered a redistribution in phosphotransfer flux with significant increase in creatine kinase and glycolytic rates. High energy phosphoryl fluxes through creatine kinase, adenylate kinase, and glycolysis in preconditioned hearts correlated tightly with post-ischemic functional recovery. This was associated with enhanced metabolite exchange between subcellular compartments, manifested by augmented transfer of inorganic phosphate from cellular ATPases to mitochondrial ATP synthase. Preconditioning-induced energetic remodeling protected cellular ATP synthesis and ATP consumption, improving contractile performance following ischemia-reperfusion insult. Thus, the plasticity of phosphotransfer networks contributes to the effective functioning of the cellular energetic system, providing a mechanism for increased tolerance toward injury.

Adenosine Triphosphate↗
PubMed2001

Pneumatosis cystoides intestinalis as a complication of celiac disease.

Pneumatosis cystoides intestinalis (PCI) is an uncommon but important condition characterized by the presence of gas-filled cysts in the submucosa and subserosa of the gastrointestinal tract. PCI has been associated with several clinical settings. We report a case where PCI developed in a patient with known celiac disease. To our knowledge, this type of coincidence has been described in seven prior cases. Since PCI often results in pneumoperitoneum through rupture of the cysts, it is important to differentiate the benign form of pneumoperitoneum, in which no intervention is indicated, from the life-threatening form with intestinal infarction and/or perforation, in which immediate surgery is mandatory. Differentiating between them can be difficult; this explains the high rate of negative laparotomy, which, in the past, occurred in 27% of cases. By performing diagnostic laparoscopy, we were able to establish the diagnosis of PCI and exclude intestinal perforation or infarction, thus permitting the patient to avoid an unnecessary laparotomy. Although diagnostic laparoscopy is not routinely indicated as a diagnostic tool for the detection of PCI, it proved to be a safe and accurate method to differentiate between the benign form of PCI and the life-threatening form. Whenever this differentiation has to be made, we recommend that diagnostic laparoscopy be performed first rather than primary laparotomy. Herein, the laparoscopic features of PCI are described and the coincidence of PCI with celiac disease is reviewed.

Aged↗
PubMed2001

Signaling in channel/enzyme multimers: ATPase transitions in SUR module gate ATP-sensitive K+ conductance.

ATP-sensitive potassium (K(ATP)) channels are bifunctional multimers assembled by an ion conductor and a sulfonylurea receptor (SUR) ATPase. Sensitive to ATP/ADP, K(ATP) channels are vital metabolic sensors. However, channel regulation by competitive ATP/ADP binding would require oscillations in intracellular nucleotides incompatible with cell survival. We found that channel behavior is determined by the ATPase-driven engagement of SUR into discrete conformations. Capture of the SUR catalytic cycle in prehydrolytic states facilitated pore closure, while recruitment of posthydrolytic intermediates translated in pore opening. In the cell, channel openers stabilized posthydrolytic states promoting K(ATP) channel activation. Nucleotide exchange between intrinsic ATPase and ATP/ADP-scavenging systems defined the lifetimes of specific SUR conformations gating K(ATP) channels. Signal transduction through the catalytic module provides a paradigm for channel/enzyme operation and integrates membrane excitability with metabolic cascades.

ATP-Binding Cassette Transporters↗
PubMed2001

Increased calcium vulnerability of senescent cardiac mitochondria: protective role for a mitochondrial potassium channel opener.

In senescence, endogenous mechanisms of cardioprotection are apparently attenuated resulting in increased vulnerability to ischemia-reperfusion. In particular, mitochondria, which are essential in maintaining cardiac energetic and ionic homeostasis, are susceptible to Ca2+ overload, a component of metabolic injury. However, effective means of protecting senescent mitochondria are lacking. Here, mitochondrial function and structure were assessed using ion-selective mini-electrodes, high-performance liquid chromatography and electron microscopy. Aging decreased ADP-induced oxygen consumption and prolonged the time associated with ADP to ATP conversion, which manifested as a reduced rate of oxidative phosphorylation. Aging also reduced mitochondrial Ca2+ handling, and increased Ca2+-induced mitochondrial damage. Diazoxide, a potassium channel opener, reduced Ca2+ loading and protected the functional and structural integrity of senescent mitochondria from Ca2+-induced injury. In this way, the present study identifies the potential usefulness for pharmacotherapy in protecting vulnerable senescent mitochondria from conditions of Ca2+ overload, such as ischemia-reperfusion.

Aging↗
PubMed2001

Adenylate kinase phosphotransfer communicates cellular energetic signals to ATP-sensitive potassium channels.

Transduction of energetic signals into membrane electrical events governs vital cellular functions, ranging from hormone secretion and cytoprotection to appetite control and hair growth. Central to the regulation of such diverse cellular processes are the metabolism sensing ATP-sensitive K+ (K(ATP)) channels. However, the mechanism that communicates metabolic signals and integrates cellular energetics with K(ATP) channel-dependent membrane excitability remains elusive. Here, we identify that the response of K(ATP) channels to metabolic challenge is regulated by adenylate kinase phosphotransfer. Adenylate kinase associates with the K(ATP) channel complex, anchoring cellular phosphotransfer networks and facilitating delivery of mitochondrial signals to the membrane environment. Deletion of the adenylate kinase gene compromised nucleotide exchange at the channel site and impeded communication between mitochondria and K(ATP) channels, rendering cellular metabolic sensing defective. Assigning a signal processing role to adenylate kinase identifies a phosphorelay mechanism essential for efficient coupling of cellular energetics with K(ATP) channels and associated functions.

Adenosine Diphosphate↗
PubMed2001

Directed inhibition of nuclear import in cellular hypertrophy.

Each nuclear pore is responsible for both nuclear import and export with a finite capacity for bidirectional transport across the nuclear envelope. It remains poorly understood how the nuclear transport pathway responds to increased demands for nucleocytoplasmic communication. A case in point is cellular hypertrophy in which increased amounts of genetic material need to be transported from the nucleus to the cytosol. Here, we report an adaptive down-regulation of nuclear import supporting such an increased demand for nuclear export. The induction of cardiac cell hypertrophy by phenylephrine or angiotensin II inhibited the nuclear translocation of H1 histones. The removal of hypertrophic stimuli reversed the hypertrophic phenotype and restored nuclear import. Moreover, the inhibition of nuclear export by leptomycin B rescued import. Hypertrophic reprogramming increased the intracellular GTP/GDP ratio and promoted the nuclear redistribution of the GTP-binding transport factor Ran, favoring export over import. Further, in hypertrophy, the reduced creatine kinase and adenylate kinase activities limited energy delivery to the nuclear pore. The reduction of activities was associated with the closure of the cytoplasmic phase of the nuclear pore preventing import at the translocation step. Thus, to overcome the limited capacity for nucleocytoplasmic transport, cells requiring increased nuclear export regulate the nuclear transport pathway by undergoing a metabolic and structural restriction of nuclear import.

Animals↗