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

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

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

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

Spontaneous Herniation of Temporomandibular Joint through the External Auditory Canal

Spontaneous herniation of the temporomandibular joint (TMJ) through the external auditory canal (EAC) is a relatively rare condition. It was first described by Hawke in 1987. In this article, 2 cases with spontaneous herniation of TMJ were reported together with clinical and radiological features, as well as the updated literature.The first case was a 56-year-old female patient, and she applied to our clinic because of itching at the EAC. On physical examination, herniation of the TMJ to the left EAC was detected. On computerized tomography, there was a bony defect at the anterior portion of the left EAC. The second case was a 52-year-old female, and she attended our clinic with sore throat. On routine physical examination, herniation of the TMJ through the left EAC was detected. Both patients were asymptomatic; none of them underwent surgery and follow-up visits were recommended.In the presence of herniation of the TMJ, a bony defect between the posterior wall of the glenoid cavity and anterior part of the EAC should be taken into consideration. Treatment of TMJ herniation through the EAC is controversial, and presence and the degree of the symptoms are the factors which were taken into consideration for management

Perioperative dynamic alterations in peripheral regulatory T and B cells in patients with hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Intratumoral and circulating regulatory T cells (Tregs) have been shown to be critical in the pathogenesis of hepatocellular carcinoma (HCC). However there is limited knowledge on the alterations of regulatory B cells (Bregs). We here investigated perioperative dynamic alterations of peripheral circulating Tregs and Bregs in HCC patients to reveal the relationship between regulatory lymphocytes and its clinical implications.</p> <p>Methods</p> <p>36 patients with HCC, 6 with chronic hepatitis B infection and 10 healthy donors were enrolled for this study. Frequencies of peripheral Tregs and Bregs were measured by flow cytometry with antibodies against CD4, CD25, CD127, CD19 and IL-10 before, and after radical surgery. Then, clinical informatics of HCC patients was achieved through Digital Evaluation Score System (DESS) for the assessment of disease severity. Finally, we analysed correlations between digitalized clinical features and kinetics of circulating regulatory lymphocytes.</p> <p>Results</p> <p>Level of circulating CD4⁺CD25⁺CD127^-Tregs in HCC patients was significantly lower than that in healthy donors and patients with chronic hepatitis B infection before surgery, but was increased after surgery. Preoperative level of CD19⁺IL-10⁺Bregs in HCC patients was also significantly lower than the other groups. However it dramatically was elevated right after surgery and remained elevated compared to controls (about 7 days after surgery, <it>P </it>= 0.04). Frequency of circulating Tregs was correlated with circulating leukocytes, ferritin, and clinical features suggesting tumor aggressiveness including portal vein thrombosis, hepatic vein involvement and advanced clinical stages. Frequency of circulating Bregs was associated with Hepatitis B e Antigen (HBeAg) and Hepatitis B virus (HBV) DNA copy number. In addition, DESS was significantly and positively correlated with other staging systems.</p> <p>Conclusion</p> <p>Frequencies of peripheral Tregs and Bregs in HCC patients increased after surgery. These results suggest that a postoperative combination of therapies against Tregs and Bregs may be beneficial for better outcome of HCC patients after resection.</p

Which Patients Can Benefit from Pillar Palatal Implant Procedure?

Objective:The aim of this prospective study is to determine which patients may benefit from pillar procedure as a treatment for snoring.Methods:A total of 37 patients (25 males and 12 females) with a history of snoring were implanted with 3 pillar palatal implants. Flexible fiberoptic examination was used to evaluate the upper airway, especially the retropalatal and retrolingual areas. Visual analog scale (VAS) and polysomnography were performed on before and 3rd months after the pillar procedure. The implantation was performed under local anesthesia.Results:The mean VAS score was reduced from 9.3±0.6 to 6.2±1.1 at the 3rd month. VAS scores of snoring intensity were reduced >50% in 24 of the patients (64.8%). The mean apnea-hypopnea index (AHI) was 11.7±2.3 before the implantation and was reduced to 8.4±1.6 at the 3rd month. VAS and AHI had a close relation with gender, body weight, and oropharynx class. There were no major complications, such as infection, extrusion, and major bleeding.Conclusion:Pillar procedure has a high success rate if it is done with appropriate patient selection, but overall effectiveness remains limited. Initial AHI and VAS values, oropharynx and tonsil position scores, and gender are important determinants of pillar procedure

Effect of Myostatin Depletion on Weight Gain, Hyperglycemia, and Hepatic Steatosis during Five Months of High-Fat Feeding in Mice

The marked hypermuscularity in mice with constitutive myostatin deficiency reduces fat accumulation and hyperglycemia induced by high-fat feeding, but it is unclear whether the smaller increase in muscle mass caused by postdevelopmental loss of myostatin activity has beneficial metabolic effects during high-fat feeding. We therefore examined how postdevelopmental myostatin knockout influenced effects of high-fat feeding. Male mice with ubiquitous expression of tamoxifen-inducible Cre recombinase were fed tamoxifen for 2 weeks at 4 months of age. This depleted myostatin in mice with floxed myostatin genes, but not in control mice with normal myostatin genes. Some mice were fed a high-fat diet (60% of energy) for 22 weeks, starting 2 weeks after cessation of tamoxifen feeding. Myostatin depletion increased skeletal muscle mass ∼30%. Hypermuscular mice had ∼50% less weight gain than control mice over the first 8 weeks of high-fat feeding. During the subsequent 3 months of high-fat feeding, additional weight gain was similar in control and myostatin-deficient mice. After 5 months of high-fat feeding, the mass of epididymal and retroperitoneal fat pads was similar in control and myostatin-deficient mice even though myostatin depletion reduced the weight gain attributable to the high-fat diet (mean weight with high-fat diet minus mean weight with low-fat diet: 19.9 g in control mice, 14.1 g in myostatin-deficient mice). Myostatin depletion did not alter fasting blood glucose levels after 3 or 5 months of high-fat feeding, but reduced glucose levels measured 90 min after intraperitoneal glucose injection. Myostatin depletion also attenuated hepatic steatosis and accumulation of fat in muscle tissue. We conclude that blocking myostatin signaling after maturity can attenuate some of the adverse effects of a high-fat diet