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Sarajlic A.,Imperial College London | Gligorijevic V.,Imperial College London | Radak D.,Institute for Cardiovascular Diseases Dedinje | Przulj N.,Imperial College London
Integrative Biology (United Kingdom) | Year: 2014

Recent studies suggest a protective role of diabetes in the development of aneurysm, but the biological mechanisms behind this are still unknown. This type of association is not present in the case of diabetes and atherosclerosis despite similar risk factors for aneurysm and atherosclerosis. We postulate the existence of genes that disrupt the pathways needed for the onset of aneurysm in the presence of diabetes. Motivated by the significance of genetic interactions in understanding disease-disease associations, we tackle this problem by integrating protein-protein interaction and genetic interaction data, i.e., we examine the biological pathways related to the three diseases that contain genes involved in the following genetic interactions: one gene in a genetic interaction is part of a diabetes pathway, the other gene is part of an aneurysm, or an atherosclerosis pathway. We create a protein-protein interaction sub-network that contains disease pathways described above. We then use a "brokerage" measure-a topological measure that identifies proteins in this sub-network whose removal severely affects the interconnectedness of their neighbourhood, enabling such proteins to disrupt the pathway they are in. We identify a set of proteins with high brokerage values and find this set to be enriched in biological functions, including cell-matrix adhesion, which facilitates mechanisms that have already been suggested as possible causes of diabetes-aneurysm association. We further narrow down our set to 16 proteins that are involved in an aneurysm or an atherosclerosis pathway and are encoded by genes participating in genetic interactions with a gene in a diabetes pathway. This set is enriched in kinases and phosphorylation processes, with two pleiotropic kinases that are involved in both aneurysm and atherosclerosis pathways. Kinases can turn on or off proteins, explaining how functional changes of such proteins could result in the disruption of pathways. So if in an aneurysm-related pathway a gene is turned off, the onset of the disease could be prevented. However, mutations of pleiotropic genes could have effects only on one of the traits, which explains why pleiotropic kinases that are involved in both aneurysm and atherosclerosis pathways could disrupt aneurysm pathways explaining the reduced risk of aneurysm in diabetes patients, but not affect the atherosclerosis pathways. © 2014 the Partner Organisations.

Nikolic B.,University of Belgrade | Ljubic A.,University of Belgrade | Ljubic A.,Institute for Gynecology and Obstetrics | Terzic M.,University of Belgrade | And 6 more authors.
Vojnosanitetski Pregled | Year: 2012

Introduction. Choriocarcinoma is a malignant form of gestational trophoblastic neoplasm (GTN). It is a rare event but also a curable malignancy. In the majority of instancies it developes after any gestational event. In some cases it developes as non-gestational extrauterine malignancy. Prognosis of choriocarcinoma is poor when invasion and metastases appear early and spread fast. This form of choriocarcinoma can lead to incurable and letal outcome. Case report. We presented a 20-year-old patient with abdominal and retroperitoneal malignancy - anaplastic carcinoma combined with choriocarcinoma metastases in. Tumor developed three months after left adnexectomy which had been done because of adnexal tumor. Choriocarcinoma was immunohistochemicaly confirmed in adnexal masses. Two courses of chemotherapy, metotrexate + folic acid (MTX+FA) regimen, were administrated. The initial serum beta human chorionic gonadotropin level stayed unknown as well as the last one after the treatment. The patient came from the other country and was hospitalized because of pelvic and abdominal pain and palpable abdominal masses in hypogastrium with progressive anemia. The human chorionic gonadotropin level was 38 mIU/L. Tumor biopsy was done and choriocarcinoma metastases were immunohistochemicaly confirmed with predominant anaplastic carcinoma. Five day course of MTX + cyclophosphamide regimen was administrated and the patient was prepared for operative treatment. Relaparotomy was perforemed and tumor completely exceeded. Tumor mass mostly developed retroperitonely and partialy in abdominal cavity infiltrating intestinal wall with rupture of sigmoid colon. Anaplastic carcinoma, with large fields of necrosis and bleeding, was confirmed after histological examination. Immunohistochemical examination excluded choriocarcinoma in tumor mass. After 20 blood units transfusion, one course of chemotherapy and tumor excision, the patient left hospital on the 9th postoperative day. The patient rejected chemotherapy which was recommended according to the protocol and died one month after the operation. Conclusion. Non-gestational metastatic choriocarcinoma complicated with another type of malignancy with early spread of the disease and low responsiriness to chemotherapy has poor prognosis and leads to lethal outocome.

Grdinic A.,Clinical Hospital Center Dr Dragisa Misovic Dedinje | Vojvodic D.,Military Medical Academy | Djukanovic N.,Institute for Cardiovascular Diseases | Colic M.,Institute for Cardiovascular Diseases Dedinje | And 7 more authors.
Acta Cardiologica | Year: 2011

Objective This study on responsiveness to clopidogrel and aspirin evaluates its interaction with: (i) patient characteristics; (ii) procedure characteristics; (iii) antiplatelet dose. Methods and results After elective PCI, 60 patients receiving aspirin 100 mg daily, and clopidogrel 75mg daily were monitored with the PFA 100 test and VASP assay. Non-responsiveness to aspirin and clopidogrel was found in 23 (38%) and 18 (30%) of 60 patients, respectively. Seven (12%) patients were dual non- responders. Non-responders to both aspirin and clopidogrel were more often smokers. Non-responders to clopidogrel, in addition had elevated inflammatory markers (P < 0.05). Dual non-responders had (i) a higher platelet count, LDL, and CRP; (ii) a lower HDL (P < 0.05). Clopidogrel non-responders were receiving 150 mg clopidogrel, with a positive response in 72%. Eighty % of non-responders to 150 mg clopidogrel were also non-responders to aspirin. Conclusion Baseline patient characteristics and clopidogrel dose modify the antiplatelet response. Also, patients resistant to both aspirin and clopidogrel do no benefit from an increased clopidogrel dose.

Wiemer M.,Ruhr University Bochum | Danzi G.B.,Ospedale Maggiore Policlinico | West N.,Papworth Hospital | Voudris V.,Onassis Cardiac Surgery Center | And 6 more authors.
Medical Devices: Evidence and Research | Year: 2015

Objective: This study investigates the safety and efficacy of a third-generation drug-eluting stent (DES) with biodegradable polymer in the complex patient population of diabetes mellitus (DM). Clinical trial registration: ISRCTN81649913. Background: Percutaneous coronary interventions in patients with DM are associated with a higher incidence of death, restenosis, and stent thrombosis as compared to non-diabetic patients. The use of a DES has been shown to improve outcomes in diabetic patients. Methods: Out of 3,067 patients, enrolled in 126 centers worldwide in the NOBORI 2 registry, 888 patients suffered from DM, 213 of them (14%) being insulin-dependent DM (IDDM). Two years’ follow-up has been completed in this study. Results: At 1- and 2-year follow-up, 97% and 95% of the patients, respectively, were available. The reported target lesion failure (TLF) rates at 1- and 2-year follow-up were 6.0% and 7.2% in the DM group, respectively, and 3.0% and 4.2% in the non-DM group, respectively (P,0.001 for both years). Inside the DM group, the TLF rates of 9.9% and 11.7% at the 1- and 2-year follow-ups, respectively, in patients with IDDM were significantly higher than the TLF rates of 4.7% and 5.8%, respectively, in the non-IDDM subgroup (P,0.01 for both years). The rate of stent thrombosis at the 2-year follow-up was 1.0% in the DM group and 0.7% in non-DM patients. There were no cases of late, or very late stent thrombosis in IDDM patients. Conclusion: The Nobori DES performed well in patients with DM. As expected, patients with DM, particularly those with IDDM, had worse outcomes. However, the absence of late, and very late stent thrombosis in IDDM patients merits further investigation, as this finding might have significant clinical value. © 2015 Wiemer et al.

Kotarac M.,The Surgical Center | Radovanovic N.,The Surgical Center | Radovanovic N.,University of Belgrade | Lekic N.,The Surgical Center | And 5 more authors.
Srpski Arhiv za Celokupno Lekarstvo | Year: 2015

Introduction Median arcuate ligament (MAL) syndrome, also called celiac trunk compression syndrome (CACS) or Dunbar syndrome is a rare disorder caused by compression of the celiac artery by median arcuate ligament of the diaphragm, which leads to mesenteric ischemia and chronic abdominal angina. The typical clinical triad of symptoms includes postprandial epigastric pain, weight loss and vomiting. The gold standard for MAL syndrome diagnosis is selective angiography, while in symptomatic patients with angiographically verified stenosis the optimal therapy is surgical treatment. Case Outline A 40-year-old male patient was presented with epigastric pain, followed by dyspepsia and weight loss. The upper endoscopy showed gastric and duodenal distention with prominent folds of gastric mucosa and slow peristalsis. Selective angiography showed stenosis (90%) of initial segment of the celiac trunk. Adhesiolysis with the transection of the median arcuate ligament was performed. Due to repeated symptoms, the patient was reoperated on the 10th postoperative day with performed adhesiolysis and gastrostomy for gastric nutrition. Two months later, the patient was rehospitalized for closure of gastrostomy. At five years follow-up, selective angiography showed no stenosis of the initial segment of the celiac artery. Conclusion Despite the existing controversy concerning pathophysiological mechanism, the clinical presentation and treatment modalities of patients with MAL syndrome, it is evident that careful selection and adequate surgical treatment may significantly reduce symptoms in these patients.

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