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Volume XVII, Number 3, 2013 - Therapeutics Pharmacology and Clinical Toxicology


Original Papers

Metabolic profiles in a cohort of chronically HCV infected patients

Radulescu Mihaela Andreea, Arama Victoria, Munteanu Daniela Ioana, Mihailescu Raluca Ioana, Popescu Cristina, Lapadat Irina, Poghirc Viorica, Streinu-Cercel A.
Abstract: Multiple reports in the recent years suggest the role of metabolic disturbances in fibrosis progression in HCV-infected patients, although literature data are controversed. This study aimed to characterize lipid and carbohydrate metabolic patterns in chronically HCV-infected patients and to evaluate the cardiovascular risk (CVR) factors in relation to fibrosis. Methods. We conducted a non-interventional cross-sectional analysis on chronically HCV-infected patients monitored in a tertiary hospital in Bucharest. We recorded demographic data, family and personal history of CVR and HCV infection. Blood samples were collected for lipid profile, serum glucose, liver enzymes, plasma HCV viral load (VL). Liver histology was assessed by Fibromax (Biopredictive, Paris, France). Results. Seventy-six patients were included, with a median age of 51 years, sex ratio F/M = 1.53. Median Framingham score was 2%, median lipid profiles within normal limits. Median VL was 5.07 log IU/ml, Fibrosis score was F0 in 25%, F1-2 in 51.3%, F3 in 6.5% and F4 in 17.1%. We compared patients with and without fibrosis (F0vsF1-4), low fibrosis versus high fibrosis (F0-2vsF3-4), with or without cirrhosis (F0-3vsF4) in relation to various risk factors. Patients in F0 group were significantly younger (p=0.000) and more frequently females (p=0.015), had lower VL (p=0.017), higher cholesterol and low density lipoprotein (LDL) (p=0.014, respectively 0.009). CVR was significantly lower in F0 group (p=0.000). In F0-2vsF3-4 comparison the lower fibrosis group had more females and younger age (p=0.052, respectively p=0.032), lower VL (p=0.002), also lower CVR (p=0.038). Also non-cirrhotic patients in F0-3vsF4 comparison were more frequently females and younger (p=0.027, respectively p=0.011), and had lower VL (p=0.011). In multivariate analysis, only correlation between fibrosis and sex and age remained significant for all comparisons. In F0-3vsF4 comparison presence of cirrhosis correlated to cholesterol (OR=11.48, IC95%=1.37-95.83) and LDL levels (OR=0.07, IC95%=0.01-0.78). There was no significant correlation between fibrosis score and CVR. Conclusions. Although higher fibrosis patients had better lipid profiles, there was no difference in CVR. Higher LDL levels in patients with no fibrosis, and the sub-unitary odds ratio in cirrhotic patients suggest that low LDL might be used as predictor for fibrosis progression in chronic HCV-infected patients.

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Diagnostic performances of APRI and FIB-4 score for the evaluation of liver fibrosis in patients with chronic hepatitis C

Munteanu I. Daniela, Radulescu A. Mihaela, Arama Victoria, Mihailescu I. Raluca, Negru Anca, Arama S.St.
Abstract: The evaluation of liver fibrosis (LF) represents the key for an individualized management of chronic hepatitis C (CHC). Liver biopsy is an imperfect gold standard, as it is an invasive procedure, with possible complications and high results variability. Subsequently there were developed algorithms, like Fibrotest, AST-to-platelet-index (APRI) and FIB-4, using different biomarkers, allowing a non-invasive assessment of LF. Our aim was to evaluate the diagnostic accuracy of APRI and FIB-4 in comparison with Fibrotest in patients with CHC. Methods: cross-sectional study in a tertiary care hospital in Bucharest, in patients with CHC, between Nov.2012-Apr.2013. Blood samples were collected for AST, ALT and PLT determination. We performed Fibrotest in all patients. APRI and FIB-4 were calculated with the formulas (AST / UNL AST)*100/PLT(109/L) and (Age*AST)/(PLT*vALT) respectively. For statistical analysis we used SPSS. Results: we enrolled 76 patients (sex ratio M/F=0.65/1, median age 51[44-58] years). According to Fibrotest half of the patients had F1 and F2 fibrosis. For differentiating F0 vs. F1234 APRI and FIB-4 had AUC mean (95%CI) of 0.763(0.635-0.890) (p=0.001) and 0.883(0.771-0.967) (p<0.001). For differentiating F0123 vs. F4 APRI and FIB-4 had AUC mean (95%CI) 0.818(0.701-0.935) (p<0.001) and 0.832(0.709-0.954) (p<0.001). The validated cut-offs for APRI, 0.5 for significant fibrosis and 1.5 for cirrhosis, had the following sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV): 50%, 90%, 62%, 93% and 30%, 97%, 6%, 81% respectively. The validated cut-offs for FIB-4, 1.45 for significant fibrosis and 3.25 for cirrhosis had the following sensitivity, specificity, PPV and NPV: 56%, 95%, 64%, 95% and 38%, 95%, 7%, 72% respectively. Conclusions: APRI and FIB-4, compared with Fibrotest, showed good performance in detecting the patients without LF and were less satisfactory in detecting cirrhosis. These scores should be use in combination with other non-invasive scores for an accurate assessment of LF.

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Human diabetic nephropathy: TRADD-positive and BCL2-negative podocytes

Balasescu E., Duta I., Rusu M.C.
Abstract: In vivo proof of apoptosis in diabetic nephropathy is limited, even though podocyte apoptosis was demonstrated in different in vitro studies. This study aimed to identify markers suggestive for apoptosis in human diabetic kidneys. The study was conducted on six human autopsy samples, from patients with type 2 Diabetes Mellitus, who died secondary to various complications of diabetes. Control samples were obtained from two non-diabetic cases. Immunohistochemistry on paraffin-embedded samples was performed and used antibodies for the tumour necrosis factor receptor-1 associated death domain (TRADD) protein, for the anti-apoptotic protein bcl2, and for caspases -3 and -8. Histopatologically, the renal system of tubules presented necrotic changes, thus the immune phenotypes were ignored in such situations; only immune labelling in histologically undamaged tubular epithelia was taken into account. In diabetic samples we found TRADD-positive podocytes with bcl2-negative renal corpuscles; in control samples we identified a positive staining on the parietal cells of the capsule of Bowman for bcl2. In proximal tubules we found bcl2-positive cells. We identified caspase-8-positive podocytes, and caspase-3 staining was negative on all structures. Thus, an apoptotic mechanism of podocytes death was strongly suggested. The caspase-3-negative phenotype of podocytes can equally suggest either the urinary loss of still viable podocytes, or a delay in execution of apoptosis, or a different cell death mechanism which kills the podocytes.

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Water and sodium imbalance associated with arterial hypertension in chronic kidney diseases

Lepar Zoe, Radulescu Daniela, Peride Ileana, Niculae A., Checherita I. Al., Ciocalteu Al.
Abstract: Although hypervolemia and sodium retention are consider to be the main factors responsible for systemic hypertension in chronic kidney diseases, various hemodynamic and electrolytic abnormalities associated with hypertension or inducing hypertensive crises are emphasized in clinical practice. Material and methods. The present article highlights the available literature data concerning water and sodium imbalance associated with hypertension in chronic kidney diseases, and illustrates these abnormalities in a personal study that included 454 patients with chronic kidney disease stage 3 or 4, who were admitted for hypertensive crises. Results. Most of the subjects were hypervolemic (71%), and in the hypovolemic and hyponatremic group, chronic kidney disease stage 3 significantly prevailed versus stage 4 (Z test, p = 3.96). Conclusions. There is an increased prevalence of hypovolemic and hyponatremic patients and the optimal treatment is challenging because of the classical medical attitude: restrictive salt diet in HT patients.

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Etravirine discontinuation caused by rash

Cambrea Simona Claudia, Ilie Maria Margareta, Halichidis Stelat
Abstract: Introduction: Among the side effects of etravirine (ETV) rash occurs with a frequency of about 15%, while about 2% of the cases require the discontinuation of drug due to rashes. Results: Between January 2008- December 2009, 21 patients received ETV in Constanta HIV Day Clinic. These patients were multi-experienced in combined antiretroviral treatment (cARV) and had received different optimized antiretroviral regimens. Of all the patients who received ETV, two presented with rash leading to drug discontinuation. In both patients, rash appeared after 10-12 days from the initiation of therapy with ETV. The first patient who experienced rash was a 19-year-old man who received an antiretroviral regimen of DRV/r + FTC/TFV + ETV. The second patient was a 20 year old woman who received a regimen of DRV/r + ABC/3TC + ETV. In both cases generalized rash was accompanied by fever and mucosal manifestations, but none of the patients had increased level of eosinophils or changes in liver transaminase. In the second case, the first two attempts to renew antiretroviral therapy were followed by the appearance of rash (after the first episode of rash from ARV regimens both ETV and ABC were excluded) and only the third attempt to reinitiate ART could be continued. Conclusions: The occurrence of severe rash to ETV requires discontinuation of the drug therapy.

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Assessment of two groups of HIV/TB co-infected patients

Dumitru Irina Magdalena, Petcu Andra Elena, Cernat Roxana Carmen, Balas Iulia, Serban Iulia Gabriela, Rugina S.
Abstract: The purpose of this research was to see to what extent the treatment of both infections in the two groups of patients co-infected HIV/TB influenced the evolution of HIV and tuberculosis. Materials and methods. The research was retrospective, included 56 patients co-infected HIV/TB, registered at the Centre of Excellence of HIV-SIDA Constanta, whom we divided in two groups: 1. patients diagnosed simultaneously with TB/HIV (31 patients), and 2. patients diagnosed with TB after they were diagnosed with HIV (25 patients). Monitoring followed: CD4 cells and viral load, clinical forms of TB, incidence of MDR TB and XDR TB, TB recurrence, ART and TB therapy, evolution of HIV and TB. Results. In the first group, 28 patients were late presenters, while 23 from the second group had virologic failure. The incidence of extra pulmonary TB and of mixed forms in group 2 was double compared to the incidence in the first group. TB recurrence was 40% in the second group. Ten patients (40%) from the second group were diagnosed with XDR TB and MDR TB, only one with XDR TB. The evolution of HIV infection was favourable for 19 patients in the first group, while poor outcomes of TB leading to death were higher in the second group (7 patients, 28%). At the moment of TB diagnosis ART was initiated in group 2 and included NNRTI for 24 patients, 13 of which had had NNRTI previously. For patients having PIs, with forms of MDR TB and XDR TB, TB therapy consisted in DOTS I regimen and individualized TB therapy. The ART and TB therapy for a co-infected patient needs to be considered in the context of resistance, drug-drug interactions which limit the options related to the use of the old ARV classes. Therefore, the use of new drugs (ENF, RAL, MVC) in the treatment of experienced patients, co-infected HIV/TB, is necessary. Conclusions. If TB is diagnosed in patients with prior ART, the resulting problems involving therapy for both HIV and TB, are very important for the evolution of both infections. A favourable outcome was perceived in a large number of cases although relapse did occur in a smaller number of patients from the first group. The main cause of mortality in the second group was MDR TB.

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Results in advanced gastric cancer surgery in patients over 60 years old - a cohort study

Popescu B.A., Iordache F., Turculet C., Vartic Mihaela, Beuran M.
Abstract: In our institution locally advanced gastric cancer is prevalent among patients with gastric malignancy. In the last years there has been a trend toward more extensive surgery but controversies still exist. Our aim was to evaluate the impact of this trend and the early outcome for these patients. Materials and Methods: This is an observational retrospective study on 110 patients with advanced gastric cancer operated on, in the General Surgery Department of the Emergency Clinical Hospital Bucharest. We took in account the fact that 74 of these patients were over 60 years old. Results: Male patients had a higher prevalence in our study group (63,51%). The median age of all patients was 72. Most of our tumour locations were distal and 17,51% proximal. Based upon the TNM staging, 56,75% were T4 tumours, N2 was most frequent 47,29%, and 16,21% had metastases (M1). Total gastrectomy with Roux-en-Y anastomosis and distal gastrectomy with gastroduodenal anastomosis were the preferred surgical resections and types of anastomosis. D2 lymphadenectomy (depends on what type of resection we are performing, total or distal gastrectomy and consists of dissection of the most important lymph nodes) was performed in 22 patients and eight patients had only a palliative resection. There were five deceased patients, four of them having reoperations; and three of those were from the D1 subgroup and two from the D2. All three patients from the D1 group had postoperative leaks. One patient from the D2 group had an anastomotic leak and both of them had splenectomies. Morbidity was 45,45% for the D1 cases and 31,81% for D2 (p=0,2137). Conclusions: Gastric cancer is a pathology mainly encountered at patients over 60. Mortality and morbidity rates are not increased when performing D2 instead of D1. D2 lymphadenectomy has good immediate results so it should be employed every time when a radical gastrectomy is needed. We consider that a radical resection associated with a D2 lymphadenectomy is a safe procedure, even for older patients.

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Therapeutical Practice

Neurotrophin related neurotoxicity of general anesthetics

Buraga Ioana, Papacocea T., Buraga I., Papacocea R.
Abstract: General anesthetics have an extensive use in clinical practice which made possible the highlighting of their neurotoxic effects. To limitate these effects was necessary to identify the pathological mechanisms, so a serie of hypotheses was released to explain the anesthetics related neurotoxicity. Surpassing the old theories, the neurotrophins hypotheses bring in atention the complex changes induced by general anesthetics on neurotrophin expression and roles.

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Case Report

Complex extrahepatic manifestations in a case of chronic hepatitis C viral infection

Daha Ioana Cristina, Ionescu R.A., Dunareanu O., Tanaseanu S., Arama Victoria
Abstract: Chronic hepatitis C viral (HCV) infection has a wide range of clinical manifestations, some of which are immune in their nature, due to the interaction between the virus and the human bodies immune system. This material reports the case of a 67 year old female patient, previously diagnosed with idiopathic polimyositis and tlater discovered infected with HCV. Due to the numerous and various clinical manifestations, potential HCV infection must be accounted for especially in patients with immune/autoimmune manifestations. Moreover, knowing the potential serious adverse events of the therapy, the treatment of such patients can prove to be a real challenge to every day clinical practice.

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BK virus-associated progressive multifocal leukoencephalopathy and cryptococcal meningitis in an hiv infected patient

Dumitru Irina Magdalena, Petcu Andra Elena, Cernat Roxana Carmen, Florea D., Pascu Corina, Rugina S.
Abstract: BK virus infections are an important diagnostic and therapeutic challenge in immunocompromised patients. This virus is responsible for infections with various clinical profiles including nephropathy, renal failure, hemorrhagic cystitis, retinopathy or encephalitis (Heritage et al., 1981). We present a rare case of an HIV-infected patient diagnosed with Cryptococcal meningitis and BK-virus associated progressive multifocal leukoencephalopathy.

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Primary surgical treatment of a complete unilateral cleft lip and palate

Stoicescu Simona, Enescu D. M
Abstract: Cleft lip and palate are the most common congenital craniofacial malformations treated by the plastic surgeons. The aim of this study is to present a typical case of cleft lip and palate and its complex treatment, from birth to adulthood, emphasizing on the importance of a multidisciplinary management. Case report: We present a 5 years old boy with a right unilateral complete cleft lip and palate, who finished the primary surgical treatment: cleft lip repair at 12 months, soft palate closure at 1 year and 10 months and hard palate closure at 2 years and 9 months. Speech therapy was inconstant. Now, at five years old, he is scheduled for short and long-term secondary surgeries based on his own particularities. Conclusion: The reported case is a very typical one, but is a good opportunity to present our management protocol for cleft lip and palate. The aim of the protocol is a normal speech, hearing, occlusion, maxillofacial growth, appearance and psychosocial well-being of each and every case.

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