The effect of metformin and myoinositol on metabolic outcomes in women with polycystic ovary syndrome: role of body mass and adiponectin in a randomized controlled trial.

PURPOSE: To compare the effects of insulin sensitizers metformin (MET) and myo-inositol (MI) on adiponectin levels and metabolic characteristics in women with polycystic ovary syndrome (PCOS) with respect to their body mass index (BMI). METHODS: In this open label, parallel randomized clinical trial, 66 women with PCOS (33 normal-weight and 33 overweight/obese) were randomized to either MI (4 g/day) or MET (1500 mg/day) for a period of 6 months. Serum concentration of adiponectin, hormonal and metabolic laboratory outcomes and clinical assessment of BMI, body composition and Ferriman-Gallwey score (FG score) were evaluated before and after treatment. RESULTS: After the 6-month intervention, comparison between MET and MI in time to treatment analysis showed no significant differences between the two treatments for all analyzed parameters. Only borderline significantly lower AUC glucose was found in the MET group in comparison to the MI group (p = 0.071). The main effect of treatment was shown for glucose concentration at 120 min OGTT (p = 0.032) and testosterone (p = 0.002). The main effect of time was shown for body mass (p = 0.004), waist circumference (p < 0.001), BMI (p = 0.003), body fat mass (p = 0.001), adiponectin (p = 0.020), fasting glucose (p = 0.001), testosterone (p = 0.015), SHBG (p = 0.013), 17OH progesterone (p = 0.008), LH (p = 0.004) and estradiol (p = 0.014). CONCLUSION: Our study showed similar effects of MET and MI on BMI, body composition, hormonal profile, metabolism of glucose and insulin, and adiponectin level. The two insulin sensitizers, MET and MI, were useful in reducing BMI and improving body composition without significant differences between the two treatments in PCOS women. TRIAL REGISTRATION: ISRCTN13199265. Trial registration date: 14.04.2021. (ISRCTN Registry), retrospectively registered.

THE EFFECT OF MYOINOSITOL AND METFORMIN ON CARDIOVASCULAR RISK FACTORS IN WOMEN WITH POLYCYSTIC OVARY SYNDROME: A RANDOMIZED CONTROLLED TRIAL.

CONTEXT: Cardiovascular risk is increased in women with polycystic ovary syndrome (PCOS). Do insulin sensitizing agents such as metformin (MET) and myoinositol (MI) ameliorate biomarkers of cardiovascular risk? OBJECTIVE: To compare the effects of MET and MI on blood pressure, lipid profile and high sensitive C-reactive protein (hs-CRP) in women with PCOS in respect to their body mass index (BMI). DESIGN: Open label, parallel randomized, single center study. SUBJECTS AND METHODS: Sixty six women with PCOS (33 normal-weight and 33 overweight/obese) were randomized to either MI (4 g/day) or MET (1500 mg/day) for a period of 6 months. Serum concentration of hormones, lipid profile, oxidized LDL (ox-LDL), hs-CRP, blood pressure measurement and clinical assessment of BMI, waist circumference (WC) and Ferriman Gallwey score (FG score) were performed before and after treatment. RESULTS: Thirty patients in each group completed the trial. Compared with MET, MI significantly decreased diastolic blood pressure (DBP) (p=0.036) and significantly increased serum hs-CRP (p=0.043). No differences between groups in total cholesterol (TC), HDL-cholesterol, LDL-cholesterol, ox-LDL and triglycerides were reported after 6 months. Treatment with MI reduced BMI (p=0.037), WC (p=0.005), DBP (p=0.021) and TC (p=0.008). During MET treatment a significant decrease in BMI (p=0.005), WC (p=0.004), FG score (p=0.001), testosterone (p=0.013) and free androgen index (FAI) (p=0.006) was observed. CONCLUSIONS: Our study showed an advantage of MI in reduction of DBP and TC thus predicting favorable metabolic and cardiovascular outcomes in PCOS women. MET more effectively decrease indices of hyperandrogenism.

Effects of cinchonine, a Cinchona bark alkaloid, on spontaneous and induced rat ileum contractions.

AIM: Quinine, a frequently used anti-malaria alkaloid isolated from the Cinchona bark, possesses numerous toxic properties, the majority of which arrive from a dysfunction of the gastrointestinal tract. Similarly, cinchonine, another alkaloid from the Cinchona bark, displays a great potential for treating malaria (especially the resistant forms). METHODS: In this work, we aimed to evaluate the effects of cinchonine on spontaneous and induced Wistar rat ileum contractions in order to uncover potential side effects that might arise after its application. RESULTS: Cinchonine produced a concentration-dependent spasmolytic activity, which was found to be reversible (i.e. disappeared after tissue wash-up), with an IC50 value of 273 µM. Furthermore, the mechanism of action of cinchonine at IC50 elucidated through experiments with acetylcholine and Ca2+-induced ileum contractions. The applied IC50 concentration of cinchonine statistically significantly prevented the occurrence of contractions after the application of specific agonist. The obtained results are in a range with the effects seen with standard receptor antagonists, i.e. atropine and verapamil. CONCLUSIONS: The obtained results showed that cinchonine inhibited both types of induced contractions, suggesting a Ca2+-channels mediated modus operandi (Fig. 4, Ref. 19).

Acute and Late Genitourinary Toxicity after 72 Gy of Conventionally Fractionated Conformal Radiotherapy for Localised Prostate Cancer: Impact of Individual and Clinical Parameters.

AIM: Our aim was to estimate the incidence of acute and late genitourinary toxicity in patients treated with three-dimensional conformal radiotherapy (3DCRT) for localised prostate cancer and to estimate the possible influence of individual and clinical characteristics. MATERIALS AND METHODS: Between September 2009 and September 2013, 225 patients with localised prostate cancer were treated with 3DCRT. Ninety-four patients with an estimated risk of lymph node involvement ≤15%, according to the Roach formula, were evaluated in this study. All patients received a total dose of 72 Gy in 36 fractions. Acute and late genitourinary toxicity were graded according to the European Organization for Research and Treatment of Cancer radiation morbidity scoring scale. Characteristics such as age, smoking status, previous abdominal or pelvic surgery (PAPS), diabetes mellitus and the use of diuretics were analysed as possible predictive factors of toxicity. The median follow-up was 27 months. RESULTS: Grade ≥2 acute toxicity during 3DCRT developed in 25 of 94 patients (26.5%). Predictive factors of acute genitourinary toxicity grade ≥2 in the multivariate logistic regression analysis (MVA) were current smoking status (P = 0.003), PAPS (P = 0.012) and the use of diuretics (P = 0.017). The 2 and 3 year cumulative risk of late genitourinary toxicity grade ≥1 was 25.3% and 30.2%, respectively. In the MVA, acute genitourinary toxicity was significantly associated with late genitourinary toxicity (P = 0.024). CONCLUSION: Current smoking status, PAPS and the use of diuretics have a significant effect on the occurrence of acute genitourinary toxicity grade ≥2. The occurrence of any grade of acute genitourinary toxicity has a significant influence on the development of any grade of late genitourinary toxicity.

Structural and biological evaluation of lignin addition to simple and silver-doped hydroxyapatite thin films synthesized by matrix-assisted pulsed laser evaporation.

We report on thin film deposition by matrix-assisted pulsed laser evaporation of simple hydroxyapatite (HA) or silver (Ag) doped HA combined with the natural biopolymer organosolv lignin (Lig) (Ag:HA-Lig). Solid cryogenic target of aqueous dispersions of Ag:HA-Lig composite and its counterpart without silver (HA-Lig) were prepared for evaporation using a KrF* excimer laser source. The expulsed material was assembled onto TiO2/Ti substrata or silicon wafers and subjected to physical-chemical investigations. Smooth, uniform films adherent to substratum were observed. The chemical analyses confirmed the presence of the HA components, but also evidenced traces of Ag and Lig. Deposited HA was Ca deficient, which is indicative of a film with increased solubility. Recorded X-ray Diffraction patterns were characteristic for amorphous films. Lig presence in thin films was undoubtedly proved by both X-ray Photoelectron and Fourier Transform Infra-Red Spectroscopy analyses. The microbiological evaluation showed that the newly assembled surfaces exhibited an inhibitory activity both on the initial steps of biofilm forming, and on mature bacterial and fungal biofilm development. The intensity of the anti-biofilm activity was positively influenced by the presence of the Lig and/or Ag, in the case of Staphylococcus aureus, Pseudomonas aeruginosa and Candida famata biofilms. The obtained surfaces exhibited a low cytotoxicity toward human mesenchymal stem cells, being therefore promising candidates for fabricating implantable biomaterials with increased biocompatibility and resistance to microbial colonization and further biofilm development.

Calcitonin gene-related peptide (CGRP) - microadenomas of the thyroid gland induced by cadmium toxicity. Experimental study.

PURPOSE: The objective of our study was to make morphological and functional analysis of thyroid C cells in rats chronically exposed to cadmium (Cd). METHODS: The study was carried out on female albino Wistar rats (n=22, age=35-37 days, body mass 120-140 g), divided in control (n=11) and experimental group (n=11). The rats of the experimental group were treated with 15 mg/kg Cd dissolved (as CdCl(2)) in drinking water. The animals were sacrificed 3 months later. The thyroid glands were removed and macroscopic, histological and immunocytochemical examinations were done. Monoclonal antibodies for chromogranin A (Chr A), neuron specific enolase (NSE), calcitonin (CT), somatostatin (SST) and calcitonin gene related peptide (CGRP) were used for immunocytochemical examinations. RESULTS: No pathological changes were found in parafollicular cells of the animals of the control group. All the animals of the experimental group showed bilateral diffuse C cell hyperplasia, mostly in the middle and upper thirds of the lobes. Strong immunoreactivity was present to all tested polypeptides (Chr A, CT, NSE, CGRP and SST). In 5 (45%) of the animals of the experimental group, C cell microadenomas were exclusively made of CGRP-secreting cells. CONCLUSION: Chronic Cd exposure causes preneoplastic changes and functional differentiation of parafollicular cells of the thyroid gland, the first cell type being present in the area of diffuse hyperplasia, and the other C cell type being the constituent of microadenomas secreting CGRP exclusively. The results of this study indicate that chronic Cd exposure disturbs the structure and function of C cells of the thyroid gland.

Co-overexpression of bcl-2 and c-myc in uterine cervix carcinomas and premalignant lesions.

To establish the role of co-overexpression of bcl-2 and c-myc protooncogenes in uterine cervix carcinogenesis, we examined 138 tissue samples of low grade cervical squamous intraepithelial lesions (SIL), high grade SIL, portio vaginalis uteri (PVU) carcinoma in situ and PVU carcinoma invasive, stage IA-IIA (study group) and 36 samples without SIL or malignancy (control group). The expression of bcl-2 and c-myc was detected immunohistochemically using a monoclonal antibody. Fisher’s exact test (P<0.05) was used to assess statistical significance. Overexpression of bcl-2 was found to increase in direct relation to the grade of the cervical lesions. High sensitivity was of great diagnostic significance for the detection of these types of changes in the uterine cervix. On the basis of high predictive values it can be said that in patients with bcl-2 overexpression there is a great possibility that they have premalignant or malignant changes in the uterine cervix. Co-overexpression of bcl-2 and c-myc oncogenes was found only in patients with PVU invasive carcinoma (6/26-23.0%). Statistically significant difference was not found in the frequency of co-overexpression in patients with PVU invasive carcinoma in relation to the control group (Fisher’s test; P=0.064). The method's sensitivity of determining these oncogenes with the aim of detecting PVU invasive carcinoma was 23%, while specificity was 72.2%. On the basis of high predictive values (100%), speaking in statistical terms, it can be concluded that all patients with co-overexpression of bcl-2 and c-myc oncogenes will have PVU invasive carcinoma. We confirmed in our research that co-overexpression of bcl-2 and c-myc oncogenes was increased only in PVU invasive carcinoma. However, a more extensive series of samples and additional tests are required to establish the prognostic significance of bcl-2 and c-myc co-overexpression in cervical carcinogenesis.

Monitoring levels of nephrotoxicity of different aminoglycosides during febrile neutropenia caused by nephrotoxic chemotherapy: a single centre study.

PURPOSE: To investigate the possible existence of increased nephrotoxicity caused by once-daily aminoglycosides in febrile neutropenic patients who were previously treated with cisplatin-based nephrotoxic chemotherapy. METHODS: Thirty-one patients with metastatic tumors received chemotherapy and, as a result, developed febrile neutropenia. Patients were stratified with regard to chemotherapy with cisplatin (n=15) or without cisplatin (n=16). Both groups received i.v. empiric antibiotic treatment which included combinations of once-daily aminoglycosides (amikacin vs. gentamicin) with beta-lactams. RESULTS: Increased nephrotoxicity due to administered aminoglycosides appeared significantly more frequently (p<0.05) in patients who received cisplatin-based chemotherapy. Increased nephrotoxicity differed significantly between various aminoglycosides regimens (p<0.05), being greater in the gentamicin group. CONCLUSION: These results showed that cisplatin-based chemotherapy followed by a once-daily aminoglycosides regimen caused increased renal toxicity, which was more pronounced in patients treated with gentamicin vs. those treated with amikacin.

Adsorption of heavy metal ions by sawdust of deciduous trees.

The adsorption of heavy metal ions from synthetic solutions was performed using sawdust of beech, linden and poplar trees. The adsorption depends on the process time, pH of the solution, type of ions, initial concentration of metals and the sawdust concentration in suspension. The kinetics of adsorption was relatively fast, reaching equilibrium for less than 20 min. The adsorption equilibrium follows Langmuir adsorption model. The ion exchange mechanism was confirmed assuming that the alkali-earth metals from the adsorbent are substituted by heavy metal ions and protons. On lowering the initial pH, the adsorption capacity decreased, achieving a zero value at a pH close to unity. The maximum adsorption capacity (7-8 mg g(-1) of sawdust) was achieved at a pH between 3.5 and 5 for all the studied kinds of sawdust. The initial concentration of the adsorbate and the concentration of sawdust strongly affect the process. No influence of particles size was evidenced. A degree of adsorption higher than 80% can be achieved for Cu(2+) ions but it is very low for Fe(2+) ions, not exceeding 10%.

Copper electrowinning from acid mine drainage: a case study from the closed mine "Cerovo".

Copper removal from acid mine drainage originating from closed copper mine "Cerovo" RTB Bor, Serbia and containing approximately 1.3 g dm(-3) of copper and a very small amount of Fe2+/Fe3+ ions, has been successfully performed by the direct electrowinning method using either a porous copper sheet or carbon felt as the cathode. A cell with a fluidised bed of inert turbulent promoters, also used in this study, may be considered as unacceptable for the purpose view, having a cell voltage between 12 and 14 V. The cells used in the electrowinning experiments were compared in terms of cell voltage, pH and copper concentration. The results showed that it is possible to remove copper successfully from the mine waters with a high degree of electrowinning--higher than 92% and with a satisfactorily average current efficiency (>60%). Depending on the process time and the applied current, a final copper concentration less than 0.1 g dm(-3) was achieved. The specific energy consumption was approximately 7 kWh kg(-1) of deposited copper. A dense copper deposit was obtained when a three-dimensional electrode was used.

[Preoperative chemoradiotherapy in locally advanced esophageal cancer].

Preoperative or definitive chemoradiotherapy defines today the standard treatment of patients with localized or locally advanced esophageal cancer. Preliminary results of our study are presented. 46 patients with locally advanced squamous cell esophageal cancer (T3-4, N0-1, M0) were enrolled. All patients recieved concomitant chemotherapy (Cisplatin/5FU/LV) and radiotherapy (45-50, 4Gy). Clinical response rate was 59% (3 patients (7%) complete response, 24 patients (52%) partial regression, 13 (28%) stabile disease, 6 patients (13%) disease progression). Out of 46 patients, 12 were operated (26%), all with R0 resection. Complete patohistolgical regression (TRG 1) was noted in 5 patients (42%). TRG 2 i TRG 3 in one (8%) and 3 patients (25%), and TRG 4 in 3 patients (25%). Mean survival time in operated group of patients was 9.3 months, and in nonoperated group 5.5 months. Studies show improved survival rate in patients with complete response to chemoradiotherapy and R0 resection. Individualy tailored therapy is essential.

[Combined hormono-radiotherapy in treatment of locally advanced prostate cancer].

Numerous questions regarding combined hormono-radiotherapy in the treatment of locally advanced prostate cancer still remain open. We present results of combined treatment in 133 our patients with locally advanced prostate cancer. All patients recieved hormonotherapy as neoadjuvant, concomitant with radiotherapy (tumor dose range 65-72 Gy), and adjuvant. In six months follow-up time, complete regression (CR) was noted in 120 patients (90%), partial regression (PR) in 6 (4.5%), stabile disease (SD) in 2 (1.5%) and progression of disease (PD) in 5 patients (4%). In mean follow up time of 17 months (6-77), 13 patients relapsed. Five-year time to progression was 70%. Five-year disease-free interval for CR patients was 70%. At the date of last control CR was noted in 116 patients (87%), PR in 2 patients (2%), SD in 7 patients (5%), and 8 patients (6%) had progressive disease. Second malignancy was noted in 4 patients. Multidisciplinary studies directed towards the optimisation of combined treatment are ongoing. There are no definitive conclusions.

[Implementation of 3D- CT based brachytherapy in the postoperative radiotherapy of cervical cancer: treatment technique and dose-volume parameters].

Intracavitary brachytherapy has an important roll in developing complications in postoperative radiotherapy of cervical cancer. 3D- CT based brachytherapy gives precisely estimating doses to organ at risk. In this study, we show our preliminary results in implementation of 3D-imaging based postoperative brachytherapy of cervical cancer: treatment technique and dose-volume parameters. During 2009 year, in 6 patients with early stage I-II of cervical cancer, brachytherapy treatment planning was based on the radiographs and CT imaging brachytherapy technique. Mean values of ICRU reference points of rectum was R max 4,2 Gy and bladder B max 4,5 Gy, while estimated volume-dose parameters D0.1 cm3 D1.0 cm D2.0 cm3 were presented with higher dose.Volume of organ at risk reflected the need for better bladder preparation. Our initial experience in performing CT-based brachytherapy, enabled us to introduce the characteristics of the parameters, assessment of their significance from the aspect of mutual relations applicators and organs at risk. Further analysis are needed, for monitoring the effects of 3D planning on complications.

Biweekly oxaliplatin, fluorouracil and leucovorin versus cisplatin, fluorouracil and leucovorin in patients with advanced gastric cancer.

PURPOSE: To compare a bi-weekly infusion of leucovorin (LV) 5-fluorouracil (5-FU) for 2 days, plus oxaliplatin (LV5- FU2-oxaliplatin) and LV5-FU2-cisplatin (CDDP) regimens with respect to toxicity, objective response rates, time to progression (TTP) and overall survival (OS) in patients with advanced gastric cancer. PATIENTS AND METHODS: Patients received LV5-FU2- oxaliplatin (oxaliplatin 85 mg/m(2), day 1; folinic acid 200 mg/m(2), days 1-2; 5-FU 400 mg/m(2), i.v. bolus, days 1-2; 5-FU 600 mg/m(2), 22-hour continuous infusion, days 1-2) or LV5- FU2-CDDP (CDDP 50 mg/m(2), day 1; plus LV5-FU2). A total of 72 patients were enrolled into this study (36 vs. 36). RESULTS: A total of 305 cycles were administered in the LV5-FU2-oxaliplatin arm (median 8) and 272 cycles in the LV5-FU2-CDDP arm (median 8). Grades 3-4 toxicity were as follows (LV5-FU2-oxaliplatin %/LV5-FU2-CDDP %; p<0.05): neutropenia 5/49, thrombocytopenia 2/6, anemia 6/16 nausea/vomiting 2/15, and mucositis 0/3. Response rate of LV5-FU2-oxaliplatin was 41% (partial response/PR 41%, stable disease/SD 31%, progressive disease/PD 28%; 95% confidence internal/95% CI 27-58) and of LV5-FU2-CDDP was 25% (PR 25%, SD 36%, PD 39%; 95% CI 14-41; p =0.013). The median TTP of the patients in the LV5-FU2-oxaliplatin arm was 8 months and 6 months for those in the LV5- FU2-CDDP arm (p=0.073). The median survival time of the patients in the LV5-FU2-oxaliplatin arm was 10 months and 7 months for those in the LV5-FU2-CDDP arm (p=0.003). CONCLUSION: Our study showed that oxaliplatin may be substituted for cisplatin with LV5-FU2 with favorable safety and efficacy profile. The encouraging results from our study support the effectiveness of oxaliplatin-fluoropyrimidine- containing chemotherapy in gastric cancer and could provide a new core on which to add other agents in future investigations.

[Medullary carcinoma of the thyroid gland: effect of postoperative transcutaneous radiotherapy on local control and results of treatment]. / Medularni karcinom stitaste zlezde: uticaj postoperativne transkutane zracne terapije u lokalnoj kontroli i rezultatima lecenja.

In the period of Octo. 01, 1987. up to Dec. 31, 1998. retrospective-prospective, non-randomized study was conducted at IORS, which included 36 patients diagnosed with thyroid gland medullar cancer. Our study had the following aims: evaluation of treatment results following probability of total survival, survival without signs of disease and disease-free interval until local recurrence of the disease and influence of parameters of transcutaneous radiotherapy (intensity of total tumor dose and length of disease-free interval from date of performed operation to beginning of radiotherapy). After finished treatment, median of the patient follow-up was 37.75 months (3.5 up to 141 months); probability of total five-year survival was 62.61% and of 10 year survival was 23.48%. Probability of 5-year survival, without signs of disease was 37.13%, and of 10-year survival 18.56%. As to radiotherapy parameters intensity of total therapy dose was statistically insignificant, while time interval to beginning of transcutaneous radiotherapy, shorter than 2 months, was statistically significant in relation to prognosis of disease outcome.

[Radiotherapy in malignant tumors of the thyroid gland]. / Radioterapija malignih tumora stitaste zlezde.

The primary treatment of thyroid gland malignoma is surgery. Success of radiotherapy depends of extent of the previous surgery treatment. The types of radiotherapy are: curative (prophylactic and postoperative) and palliative. Tumor dose and radiotherapy tehnique depend on histologica type, extent of the previous surgery treatment, curative or paliative intent and general condition of patient, and they are from 40 Gy to 65 Gy by conventional fractionation. The basis of radiotherapy treatment planning and choice of radiotherapy treatment technique in survey of the region of interest by imaging procedure. On the basis of those data we determine therapeutic volume and structure of risk (spinal cord, lung) and protection of the risky structures is planned.

[Personal experience in the diagnosis and therapy of pulmonary thromboembolism]. / Nasa iskustva u dijagnostici i lecenju tromboembolijske bolesti pluca.

The analysis of both clinical findings and diagnostic procedures results were performed in 26 patients with thromboembolic pulmonary disease in order to determine the incidence of signs indicating pulmonary thromboembolism. Sudden dyspnea, hemoptysis and chest pains are the most common symptoms of the disease. These symptoms associated with radiographically confirmed pulmonary infiltrations with the elevation of hemidiaphragm and pleural effusion, particularly if they are bilateral, are the main clues for the diagnosis of pulmonary embolism. Perfusion defect on the pulmonary scintigraphy makes this diagnosis almost certain. Hypoxemia and hypocapnia and respiratory alkalosis are frequent findings in thromboembolic pulmonary disease, as well. Fever, increases RBC sedimentation rate and leukocytosis are present in a great deal of patients. In addition, the presence of risk factors related to the development of thrombosis of the lower limbs deep veins, and particularly those related to the long term immobilization as well as diagnostically confirmed venous thrombus are basic guidelines for the diagnostic of pulmonary thromboembolism.