Pharmacogenetics aspects of oral anticoagulants therapy.

RATIONALE: Vitamin K antagonists (VKA), such as warfarin and acenocoumarol, are widely used for the prevention and treatment of thromboembolic diseases and they are some of the most commonly prescribed types of medications. They are characterized by narrow therapeutic indices and inter-individual or intra-individual variability in response to the treatment. OBJECTIVE: to establish the influence of several genetic factors on VKA efficacy and adverse reactions. METHODS AND RESULTS: The metabolism of VKA differs depending on their chemical structure: indandiones derivatives (fluindione) or coumarin derivatives (acenocoumarol, phenprocoumon or warfarin). They are mostly metabolized in hepatocytes via a monooxygenase, cytochrome P450 2C9 (CYP2C9), resulting in inactive products. The gene encoding CYP2C9 is polymorphic, its genetic variants being associated with differences in the enzymatic activity of CYP2C9. The most important in terms of their frequency in the general population are CYP2C9*2 and CYP2C9*3. Both alleles are associated with a marked decrease in CYP2C9 enzyme activity. VK epoxide reductase (VKOR) is an enzyme with an important role in VK metabolism. Various polymorphisms in the VKORC1 gene have been described. VKORC1*2 haplotype seems to be the most important in relation to the variability in response to VKA. DISCUSSIONS: Various studies have shown a relationship between the genotype and the mean warfarin maintenance dosing: in patients carrying 2C9*1/*2 alleles, the dose is reduced by 18-40% in patients carrying 2C9*2/*2 alleles, by 21-49% in patients carrying 2C9*1/*3 alleles. The A allele of the c.-1639G>A polymorphism in the VKORC1 gene is associated with the need for a lower dose of acenocoumarol in patients on anticoagulant therapy. ABBREVIATIONS: SNP = Single Nucleotide Polymorphism, VKA = vitamin K antagonists, C1 - VKORC1 = vitamin K epoxide reductase complex subunit, INR = International Normalized Ratio.

Multiple malignant tumors.

BACKGROUND: Due to the improvement in diagnosis and therapy for certain malignant tumors, we are now faced with patients who develop in time multiple malignancies. METHODS: We conducted a retrospective analysis of the patients diagnosed with at least two primary cancers that were admitted and treated in Cluj-Napoca Municipal Hospital. The study followed patients for a period of 7.5 years. RESULTS: We included in the present study 217 patients (4.33%) with two or more malignant primary tumors from 5003 cases diagnosed with a primary cancer. The most common sites for multiple malignant tumors were related to the breast, colorectum, urinary bladder, prostate and kidneys. CONCLUSIONS: We should always take into consideration the possibility of synchronous tumors and we have to keep in mind that a successful treatment of cancer might not prevent the onset of another primary mass.

GST gene variants in synchronous colorectal cancers and synchronous association of colorectal cancers with other cancers.

BACKGROUND: the present study evaluates genetic polymorphisms of three glutathione S-transferases (GSTM1, GSTT1and GSTP1) in patients with synchronous malignant colorectal tumors and the association of synchronous colorectal cancers with other cancers. MATERIAL AND METHODS: from 420 patients with a colorectal cancer admitted to our hospital between 2005-2012, we selected for genetic analysis 20 patients with multiple synchronous malignant colorectal tumors and 9 patients with asynchronous association of colorectal cancer with another cancer. We searched for GST genotypes, comparing the results with controls. RESULTS: the genetic analysis was possible only in 19 patients with colorectal synchronous cancers and 9 patients with asynchronous association of colorectal cancer with another cancer; we found a statistically significant difference for null GSTM1 genotype frequency between these patients and the control group; we found no differences regarding the frequency of null GSTT1 genotype and Ile105Val polymorphism of GSTP1 in patients with synchronous cancers compared with the control group. CONCLUSION: in our study we found the null GSTM1 genotype as a risk factor for multiple colorectal synchronous cancers and for an association of synchronous colorectal with other cancers

Eosinophilic esophagitis.

Eosinophilic esophagitis is a chronic, immune-mediated disorder, isolated to the esophagus. Current theory suggests that the former may be caused by cell-mediated food hypersensitivity or may be a subset of eosinophilic gastrointestinal disease, an autoimmune disorder. During the last decade, the increasing prevalence of EoE has been recognized in pediatric populations. Reports support the efficacy of dietary restriction or corticosteroid therapy. Aditional research is needed to determine etiology, allow earlier clinical recognition and improve treatment. Because no single symptom, endoscopic finding or histopathologic feature is pathognomonic, the diagnosis can frequently be challenging. The current article reviews the possible etiology, clinical presentation, diagnosis, and treatment of this disorder, which has been called not only allergic esophagitis (which may be the most important cause), but also eosinophilic esophagitis, primary eosinophilic esophagitis, and idiopathic eosinophilic esophagitis.

Granulomatous cheilitis of Miescher: the diagnostic proof for a Melkersson-Rosenthal syndrome.

BACKGROUND: The Melkersson-Rosenthal syndrome (MRS) is a very rare clinical entity and its classical form is being characterized by the following triad: facial nerve palsy, swelling of the lips and fissured tongue. However, the monosymptomatic form is more common and the typical manifestation is facial edema and/or enlargement of the lips. CASE REPORT: We report a case of monosymptomatic MRS with a positive biopsy of granulomatous cheilitis. CONCLUSIONS: In the daily practice as a pediatrician, it is not usual to diagnose a patient as having MRS. We consider that this is partly because of misdiagnosis. We therefore believe that this case report will supply additional information, in the scope of recurrent facial paralysis and orofacial edema in both children and adults.

Metformin plus PIAF combination chemotherapy for hepatocellular carcinoma.

OBJECTIVES: Metformin, the most used oral antidiabetic drug for the treatment of type 2 diabetus mellitus, has proved encouraging results when used in the treatment of various types of cancer such as triple-negative breast cancer. Despite compelling evidence of a role of metformin as an anticancer drug, the mechanisms by which metformin exerts its oncostatic actions are not fully understood yet. Therefore, we tried to bring new insights by analyzing the anti-neoplastic effect of metformin for hepatocellular carcinoma-derived stem-like cells treated with conventional combination chemotherapy. METHODS: Cancer stem-like cells previusly isolated from a hepatocellular carcinoma biopsy were treated with metformin, PIAF chemotherapy regimen and the combination of these two protocols. Measurements of lipid peroxidation, reduced glutathione, fluorescein diacetate and proliferation rates were determined, apart from the autophagy assay and apoptosis determination by chip flow cytometry. RESULTS: Metformin alone and especially metformin in association with PIAF increases oxidative stress within the cells by increasing the levels of lipid peroxids as well as decreasing the levels of reduced glutathione. The MTT cell proliferation assay showed decreased prolife-ration rates for the arm treated with metformin and with the combination of drugs in comparison with the control arm, proving high correlation with the oxidative stress results. The autophagy assay and determination of apoptosis by chip flow cytometry confirmed the results obtained in the previous assays. CONCLUSION: Metformin could be used in chemotherapy treatments to induce reactive oxygen species and increase the cytostatics effects within the tumor cell. Still, further experiments must be carried out on murine models before we can move on and use this drugs in the adjuvant setting for unresectable primary liver cancer.

[TIVA-TCI (Total IntraVenous Anesthesia-Target Controlled Infusion) versus isoflurane anesthesia for laparoscopic cholecystectomy. Postoperative nausea and vomiting, and patient satisfaction]. / TIVA-tCI vs. anestezia inhalatorie pentru colecistectomia laparoscopica. Incidenta sindromului emetic postoperator si satisfactia pacientilor.

UNLABELLED: Numerous studies have shown that TIVA is followed by a significant reduction in the incidence of PONV in day-case surgery, including laparoscopic cholecystectomy, where the incidence of PONV can reach 70% according to some studies. TCI is the TIVA technique that maintain a constant plasma concentration due to pharmacokynetic models incorporated in TCI device that inject the anesthetic agent. Besides implementing TIVA-TCI in clinical practice in Romania, our study was designed to evaluate the impact of TIVA-TCI on postoperative outcome and our patient satisfaction after laparoscopic cholecystectomy. PATIENTS AND METHODS: After informed consent, 70 patients ASAI/II undergoing laparoscopic cholecystectomy were randomized in 2 equal study groups: group 1 (n = 35) included patients with TIVA-TCI with propofol (Cpi = 4 microg/ml) and remifentanil, and group 2 (n = 35) were patients undergoing Isoflurane anesthesia. In both groups propofol was administered during induction and remifentanil followed the same protocol: 0.5 microg/kg/min in the first minute during induction, followed by 0.25 microg/kg/min. This infusion was modified by 0.05 microg/kg/min steps according to analgesic needs. PONV (evaluated as both incidence and number of episodes), severity of pain and patient satisfaction score IOWA were compared between study groups. RESULTS: Both the incidence of PONV (p = 0.03) and the number of episodes/24 h/patients (p = 0.01) were significantly lower in TIVA-TCI group, while there was no significant difference in opioid requirements in study groups (p = 0.21). Patients IOWA satisfaction score at 24 hours postoperatively was significantly higher in TIVA-TCI groups (p = 0.0001). CONCLUSIONS: Compared with Isoflurane, TIVA-TCI was followed by significantly lower incidence of PONV and significantly greater patients satisfaction.

Impact of food advertising on food purchases by students in primary and secondary schools in south-eastern Poland.

AIM: The aim of the present study was to determine the impact of food advertising in primary and secondary schools on the food purchasing habits of children. METHODS: All forty-four primary and secondary schools in Rzeszow, Poland were included in the investigation; 15000 children attend primary and secondary schools in the region. Schools were visited by members of the research team, who filled in a questionnaire regarding the type of food products displayed or advertised in the school shop window and recorded the presence of direct corporate advertising in the proximity of the school shop. Shop owners were asked to fill in a form describing food purchases by students within the week preceding the visit. The school principal (or one of teachers) completed a form describing the school's policy regarding food advertising and the sponsorship of school activities by food companies. RESULTS: Recommended foods like milk, yogurts and fruit were offered by only 40.9 % of shops. There was a correlation between foods offered in the shop and foods purchased by students. In schools, 40.9% (95% CI 25.8, 56.0%) of shop windows displayed or advertised 'healthy' foods while 9.1% (95% CI 0.0, 17.9%) of shops displayed advertisements of food companies. The difference between display of 'healthy' food in shop windows and display of food on company advertisements was significant (likelihood ratio chi2 test, P < 0.04). Type of school (primary v. secondary) was not significant factor in advertising or purchasing pattern. CONCLUSIONS: Educational programmes should be introduced in schools with the aim of improving the understanding of nutritional principles among pupils, teachers and parents.

[Endovenous laser treatment (EVLT) for treatment of great saphenous vein insufficiency]. / Tratamentul laser endovenos în insuficienta venei safene interne.

OBJECTIVE: To assess the efficacy and rate of complications of endovenous laser treatment (EVLT) of the great saphenous vein (GSV) insufficiency. METHOD: Between august 2002 and june 2007, 341 of the lower limbs of 322 patients were treated with EVLT using a 980-nm diode laser. Duplex ultrasound and clinical examinations were performed on the day of the procedure, the next day, and 6 to 12 months after the procedure. RESULTS: All procedures were technically successful, and at the 3 months follow-up the Doppler ultrasound indicated the complete obstruction in all cases. 67 of the 70 lower limbs presented a complete obstruction at the 2 year follow-up. Only in two cases (2.85%) the GSV recanalization was observed after 6 months. As side effects reversible paresthesia, transient postoperative pain and ecchymosis were observed. CONCLUSION: EVLT is a safe technique, with low incidence of recanalization and postoperative complications.

Early MR changes in vertebral bone marrow for patients following radiotherapy.

Our study aimed to evaluate the vertebral marrow changes in patients following radiotherapy (RT) by measuring the T2 relaxation times before and during RT. We were mostly interested in evaluating early MR marrow changes during RT. Fifteen patients treated by RT for cervical cancer were submitted to MR examination before and during RT (5-23 days of RT). T2 values were calculated for irradiated and non-irradiated tissues (lumbar and sacral vertebral bone marrow, symphysis pubis marrow, and regional muscle). Fourteen patients presented increased T2 values for irradiated vertebral bone marrow (VBM), and 3 patients showed increased T2 values even for non-irradiated VBM. We found T2 variations for VBM as early as in the fifth day of RT for an absorbed dose as small as 9 Gy. Calculated T2 values in irradiated and also in non-irradiated tissues prove very early tissue alterations.

Assessment of heart disease using fuzzy classification techniques.

In this paper we discuss the classification results of cardiac patients of ischemical cardiopathy, valvular heart disease, and arterial hypertension, based on 19 characteristics (descriptors) including ECHO data, effort testings, and age and weight. In this order we have used different fuzzy clustering algorithms, namely hierarchical fuzzy clustering, hierarchical and horizontal fuzzy characteristics clustering, and a new clustering technique, fuzzy hierarchical cross-classification. The characteristics clustering techniques produce fuzzy partitions of the characteristics involved and, thus, are useful tools for studying the similarities between different characteristics and for essential characteristics selection. The cross-classification algorithm produces not only a fuzzy partition of the cardiac patients analyzed, but also a fuzzy partition of their considered characteristics. In this way it is possible to identify which characteristics are responsible for the similarities or dissimilarities observed between different groups of patients.

[Traumatic diaphragmatic hernia. 2 case reports and review of the literature]. / Herniile diafragmatice posttraumatice. Observatii în legatura cu doua cazuri operate si discutia literaturii.

We have presented two cases of traumatic diaphragmatic hernia which have been diagnosed and operated in late stages, 6 months and 4 years, respectively, after the abdominal and thoracical traumatism causing diaphragmatic injure. The diagnosis was based on clinical and imaging results, while the treatment was meant to reduce the herniated organs in the abdomen and the closing up of the diaphragmatic defect, followed by good postoperative results. We have discussed the peculiarities of both case, the difficulty of early diagnosis and the techniques used to treat these cases. We have also presented data regarding posttraumatic diaphragmatic hernia and their treatment techniques.

[Congenital choledochal cysts. Observations on 2 operated cases]. / Chisturile congenitale coledociene. Observatii în legatura cu doua cazuri operate.

The authors present two cases of congenital choledochal cysts treated by cyst excision with Roux-en-Y hepaticojejunostomy, followed by good postoperative results. One of the patients has been treated by early excisional procedure, while the other has initially undergone an enteric drainage by cystoduodenostomy, followed by complications, which required reoperations after 18 months. We have evaluated the peculiarities of both cases, the present data revealed by literature regarding biliary carcinogenesis related to congenital choledochal cysts, their classification according to pancreatobiliary malunion, as well as the treatment of choice in choledochal cysts, meaning excisional procedure with Roux-en-Y hepaticojejunostomy to prevent the risk of postoperatory complications which might appear after plain enteric drainage of the cyst.

[Long term course over 10 years after balloon dilatation in stable and unstable angina pectoris]. / Langzeitverlauf über 10 Jahre nach Ballondilatation bei stabiler und instabiler Angina pectoris.

OBJECTIVE: To assess the cardiac status of patients ten years after percutaneous transluminal coronary artery angioplasty (PTCA). PATIENTS AND METHODS: Data of 534 patients (436 men, 98 women; mean age 53.2 +/- 8 years) in whom a PTCA had been performed between 1983 and 1986 were analysed, based on a questionnaire answered 121 +/- 11 months after the initial procedure. At the time of PTCA 184 patients (35%) had unstable angina, 350 (65%) stable angina. RESULTS: 116 patients (63%) with unstable angina and 164 (47%) with stable angina had at least one cardiac event after the initial PTCA (repeat PTCA, bypass operation, myocardial infarction, death). None of these events occurred in 68 patients (37%) with unstable or in 186 (53%) with stable angina (P < 0.001). After 10 years 196 of the 302 surviving patients with stable angina (65%) and 104 of the 153 surviving patients with unstable angina (68%) were symptom-free. CONCLUSIONS: Ten-year follow-up after PTCA has shown that cardiac events are significantly more frequent in patients who had had unstable angina than in those with stable angina. This difference already develops in the first year post-PTCA, with no increase later. Symptoms are lastingly improved after 10 years in both groups of patients.

Long-term follow-up of global and regional left ventricular function by two-dimensional echocardiography after thrombolytic therapy in acute myocardial infarction.

In order to evaluate changes in left ventricular volumes and regional left ventricular function after thrombolytic therapy in acute myocardial infarction serial two-dimensional echocardiography was performed during a follow-up of 2 years in 206 consecutive patients treated with streptokinase and adjunctive angioplasty in a randomized group of patients. Unexpected progressive left ventricular enlargement was detected both with and without angioplasty. In anterior wall infarction, end-diastolic volume index increased from 55 +/- 14 to 91 +/- 28 ml/m2 (+65%, P < 0.01) and end-systolic volume index increased from 31 +/- 11 to 55 +/- 23 ml/m2 (+79%, P < 0.01), whereas ejection fraction decreased from 45 +/- 9 to 41 +/- 7% (-9%, P = NS). Averaged regional anterior wall motion improved during the first 4 weeks (11 +/- 10 to 16 +/- 12%), but subsequently deteriorated (16 +/- 12 to 10 +/- 6, P < 0.05). The number of segments with pathological wall motion increased. Similar volumetric and regional wall motion data were demonstrated in inferior wall infarction. We believe this reflects a chronic ventricular remodelling phenomenon. This process takes place predominantly during the first 3 months, but continues over the whole follow-up period. Forty percent of the patients suffered symptoms of heart failure on long-term follow-up. Attenuation of progressive ventricular enlargement remains a therapeutic challenge in the long-term care of these patients. Angiotensin-converting enzyme inhibitors are promising agents in this regard.

[Long-term follow-up of thrombolytic treatment of acute infarct in combination with acute and elective revascularization]. / Langzeitverlauf nach thrombolytischer Behandlung des akuten Infarktes in Kombination mit akuter und elektiver Revaskularisation.

From March 1983 to June 1986 in 206 patients with acute transmural myocardial infarction, combined intravenous and intracoronary therapy with streptokinase was initiated. After intravenous thrombolysis and randomization in two groups we performed a coronary angiography with selective intracoronary lysis. Infarct related vessels still occluded after intracoronary streptokinase application were opened mechanically in group I. In group II we performed additionally a percutaneous transluminal coronary angioplasty (PTCA) after mechanical recanalisation (occluded vessels) or after thrombolysis (open vessels). In 85 of 87 cases in group II, PTCA could be performed in the acute phase. Elective PTCA was performed in 22 patients of group I (21%) and in nine patients of group II (9%). Up to five years after myocardial infarction, coronary artery bypass grafting (CABG) was necessary in 22 patients (21%) of group I and in 23 patients (22%) of group II. Within four weeks after infarction CABG was performed in 32% and 17% of group I and II respectively. The six-year survival rate was 78% in group I and 82% in group II. Taken all patients together, the six-year survival rate was significantly higher (p = 0.002) for those with early reperfusion (less than or equal to 3.5 h). The survival rates of CABG-patients, PTCA-patients and patients without reperfusion were 91%, 74% and 65% respectively. Streptokinase thrombolysis results, combined with acute or elective PTCA and/or coronary bypass surgery, in a high six-year survival rate after acute transmural myocardial infarction. This rate is about 20% higher than ten years ago.