Intestinal alkaline phosphatase activity as a molecular marker of enterotoxicity induced by single dose of 5-fluorouracil and protective role of orally administered glutamine

Background. One of the critical limitations for the administration of the chemotherapy is the toxicity affecting normal tissue. The main target organs for 5-fluorouracil (5-FU) toxicity in humans and experimental animals are the gastrointestinal tract, bone marrow, and skin. The cytotoxic effects of antimetabolite chemotherapy are based on their role as substrates for the same transport processes and enzymes involved in anabolism and catabolism as the natural substrates. The main goal of our study was to analyze the dose-dependent antiproliferative effects of 5-FU on intestinal mucosa, enterotoxic potential of 5-FU in experimental animals and to test possible protective role of glutamine. Methods. In our study, we used Sprague Dawley rats. The control group of rats included 50 animals, while the groups where either 5-fluorouracil (5-FU) alone or 5-FU and glutamine were administered included 200 animals. All experimental animals were further stratified according to the experimental model (25 animals in each of 8 experimental subgroups of animals). The 5-FU was administered by intraperitoneal application in single dose of 0, 100, 200, 300, and 400 mg of 5-FU per kg of body weight. Water solution of 1% glutamine was prepared daily and administered orally, in volume of 200 ml, for 7 days continuously, after the 7th day of 5-FU administration. Experimental animals were sacrificed 7 days after the administration of 5-FU. The isolation of enterocytes was performed according to the method of Kralovansky et al. In cell homogenate obtained by described method, we determined the protein content using the Biuret method and the DNA content using the Burton reagent. The activities of enzymes alkaline phosphatase (ALP), glutathione S-transferase (GST), glutathione reductase (GR), and glutathione peroxidase (GPX) were determined by kinetic method. All paraffin samples of the small intestine were stained by haematoxiline and eosine(HE method). All the experiments were done in duplicate and analyzed by standard statistical methods. All the experiments were done in duplicate and analyzed by standard statistical methods. Results: Our results of enterotoxicity induced by intraperitonealy administered 5-FU showed statistically significant decrease of DNA content in small intestine samples of experimental animals, decrease in activity of intestinal alkaline phosphatase enzyme and the increase in glutathione-dependent enzymes. The glutamine supplementation reduced 5-FU intestinal toxicity. Conclusion: Intestinal alkaline phosphatase is a good marker of the dose-dependent enterotoxicity induced by 5-fluorouracil

Vasilij Vodovozov i Srbija tokom Prvog svetskog rata

U članku se, na osnovu relevantnih izvora i literature, analizira odnos ruskog publiciste Vasilija Vodovozova (1864–1933) prema Srbiji u toku Prvog svetskog rata. Kao ratni dopisnik u Srbiji, Vodovozov je putovao kroz Makedoniju i ispitivao raspoloženje tamošnjeg stanovništva. Usled povoljnih utisaka stečenih na putu i privrženosti načelu samoopredeljenja naroda, u svojim potonjim člancima i knjigama pretežno je podržavao srpske ratne ciljeve

Reprint of “The clinical impact of deficiency in DNA non-homologousend-joining”

DNA non-homologous end-joining (NHEJ) is the major DNA double strand break (DSB) repair pathway inmammalian cells. Defects in NHEJ proteins confer marked radiosensitivity in cell lines and mice models,since radiation potently induces DSBs. The process of V(D)J recombination functions during the devel-opment of the immune response, and involves the introduction and rejoining of programmed DSBs togenerate an array of diverse T and B cells. NHEJ rejoins these programmed DSBs. Consequently, NHEJdeficiency confers (severe) combined immunodeficiency – (S)CID – due to a failure to carry out V(D)Jrecombination efficiently. NHEJ also functions in class switch recombination, another step enhancing Tand B cell diversity. Prompted by these findings, a search for radiosensitivity amongst (S)CID patientsrevealed a radiosensitive sub-class, defined as RS-SCID. Mutations in NHEJ genes, defining human syn-dromes deficient in DNA ligase IV (LIG4 Syndrome), XLF-Cernunnos, Artemis or DNA-PKcs, have beenidentified in such patients. Mutations in XRCC4 or Ku70,80 in patients have not been identified. RS-SCIDpatients frequently display additional characteristics including microcephaly, dysmorphic facial featuresand growth delay. Here, we overview the clinical spectrum of RS-SCID patients and discuss our currentunderstanding of the underlying biology

Sudskomedicinske dileme kod veštačenja trzajnih povreda vrata

Veštačenja u građansko pravnim sporovima, a posebno u sporovima za naknadu nematerijalne štete nastale kao posledica saobraćajne nezgode, u poslednjih nekoliko godina postaju zanimljive zbog činjenice da se u tim parnicama postavlja pitanje uzročne veze između saobraćajne nezgode i nastale posledice, ukoliko je posledica trzajna povreda vrata(eng. whiplash injury - pucanje bičem, odnosno WAD-whiplash associated disorder)). Da li i koliko ubrzanje udarenog vozila izaziva kretanje tela u prostoru i da li je ovo kretanje, kao i brzina kretanja vozila koji je naleteo na udareni automobil, prouzrokuje trzajnu povredu vrata, pitanje je na koje moraju dati odgovor sudski veštaci medicinske struke, u pravilu ortopedi-traumatolozi ili veštaci sudske medicine. A pre nego što se oni upuste u veštačenje, nužno je da veštaci saobraćajne struke izračunaju promenu brzine kod vozila koja su učestvovala u saobraćajnoj nezgodi. Ne postoje opšteprihvaćene tabele koje nam ukazuju da li kod određene brzine vozila može doći ili ne do trzajne povrede vrata, ali manja ili veća brzina može ukazivati na veću ili manju mogućnost ovakve povrede. O uzročno posledičnoj vezi između saobraćajne nezgode i trzajne povrede vrata izjašnjavaju se lekari sudski veštaci, pre svega ortopedi-traumatolozi, isključivo nakon veštačenja od strane sudskih veštaka saobraćajne struke koji utvrđuju promenu brzine kod vozila koja su učestvovala u saobraćajnoj nezgodi (Δv). Ovaj podatak služi sudskim veštacima medicinske struke kao jedan od parametara kojim će dati svoj zaključak o uzročno posledičnoj vezi između saobraćajne nezgode i trzajne povrede vrata, kao i posledicama po zdravlje oštećenog, sa ciljem da ovakav nalaz veštaka posluži sudu prilikom odmeravanja pravične novčane naknade nematerijalne štete

Fibrodysplasia ossificans progressiva: a case report

Fibrodysplasia ossificans progressiva (FOP) is a rare, severely disabling, autosomal dominant disease characterized by recurrent painful episodes of soft tissue swelling and the development of heterotopic ossification. The main target is the axial musculature, but eventually ectopic bone formation occurs in the ligaments, the fascia, the tendons and the joint capsules. Small soft tissue traumas and intramuscular injections exacerbate this extraskeletal bone formation. We present a 16-year-old male patient who has osseous lesions beginning from the left ramus mandible and extending along the sternocleidomastoid muscle, vertebral region and deltoid, with visible restriction in temporomandibuler joint movement. Surgery was not performed due to parental concerns. Unfortunately, no effective medical therapy for FOP is known. These patients may require extra care during some oral surgery and anesthetic procedures. In this report, the importance of the decision to perform surgery has been stressed

Tinnitus and Cochlear Functions in Hearing Impaired and Normal Hearing Individuals

Background: In order to determine the pathophysiology of tinnitus and deciding on treatment, the function of peripheral hearing organs is very important. Objective: To evaluate the cochlear functions in tinnitus patients with or without hearing-loss(HL). Methods: Participants with tinnitus were divided into two groups; 16 participants with accompanying HL were included in the first study group (SG-I), and 15 participants without HL were included in the second group (SG-II). 21 normal-hearing subjects without tinnitus included as control group(CG). Tinnitus discomfort levels was determined with Tinnitus Handicap Inventory(THI). Besides pure-tone audiometry, Otoacoustic Emissions, to evaluate cochlear functions and to decide dead regions (DR), Threshold Equalizing Noise-(TEN) was used. Results: The threshold-shift was observed with TEN in subjects in SG-I and these levels were statistically different from SG-II and CG. There were both threshold-shift and DR in SG-II according to TEN. TEOAEs did not differ between SG-II and CG. The DPOAE results for SG-II showed significant decreases in emission amplitudes at 6 & 8 kHz. Conclusion: While Tinnitus patients with HL can be evaluated with conventional tests, evaluating patients with normal hearing tinnitus with additional tests such as OAE and TEN allows us to get more precise results on the functions of peripheral hearing organs

Association of MDR1 Gene SNPs and Haplotypes with the Tacrolimus Dose Requirements in Han Chinese Liver Transplant Recipients

BACKGROUND: This work seeks to evaluate the association between the C/D ratios (plasma concentration of tacrolimus divided by daily dose of tacrolimus per body weight) of tacrolimus and the haplotypes of MDR1 gene combined by C1236T (rs1128503), G2677A/T (rs2032582) and C3435T (rs1045642), and to further determine the functional significance of haplotypes in the clinical pharmacokinetics of oral tacrolimus in Han Chinese liver transplant recipients. METHODOLOGY/PRINCIPAL FINDINGS: The tacrolimus blood concentrations were continuously recorded for one month after initial administration, and the peripheral blood DNA from a total of 62 liver transplant recipients was extracted. Genotyping of C1236T, G2677A/T and C3435T was performed, and SNP frequency, Hardy-Weinberg equilibrium, linkage disequilibrium, haplotypes analysis and multiple testing were achieved by software PLINK. C/D ratios of different SNP groups or haplotype groups were compared, with a p value<0.05 considered statistically significant. Linkage studies revealed that C1236T, G2677A/T and C3435T are genetically associated with each other. Patients carrying T-T haplotype combined by C1236T and G2677A/T, and an additional T/T homozygote at either position would require higher dose of tacrolimus. Tacrolimus C/D ratios of liver transplant recipients varied significantly among different haplotype groups of MDR1 gene. CONCLUSIONS: Our studies suggest that the genetic polymorphism could be used as a valuable molecular marker for the prediction of tacrolimus C/D ratios of liver transplant recipients

Management of Far-Advanced Otosclerosis: Stapes Surgery or Cochlear Implant

Objective: The aim of this report is to share our experience and treatment outcomes with far-advanced otosclerosis (FAO) patients.Methods: Patients that underwent surgery from 2003 through 2014 at a tertiary referral center were retrospectively reviewed. Nineteen FAO patients were included in the study. Audiological results and the ability to communicate face to face and over telephone were considered as the main outcome measures.Results: Six FAO patients benefited well from stapedotomy with an average of 5.9-decibel (dB) air-bone gap and 86% median speech discrimination. Cochlear implantation (CI) was performed in 13 patients; two had disease progression after stapedotomy, five had failed stapes surgeries elsewhere, and six preferred CI as primary treatment. Median speech discrimination score of CI patients was 78.4%. Overall, all patients had satisfactory face-to-face communication and 90% could use telephone.Conclusion: Bilateral stapedotomy and wearing hearing aid is an effective and cost-effective solution for restoring natural binaural hearing and requires no specific training. Should stapedotomy fail, cochlear implantation is always a successful back-up option