3alpha-6alpha-Dihydroxy-7alpha-fluoro-5beta-cholanoate (UPF-680), physicochemical and physiological properties of a new fluorinated bile acid that prevents 17alpha-ethynyl-estradiol-induced cholestasis in rats

3alpha-6alpha-Dihydroxy-7alpha-fluoro-5beta-cholanoate (UPF-680), the 7alpha-fluorine analog of hyodeoxycholic acid (HDCA), was synthesized to improve bioavailability and stability of ursodeoxycholic acid (UDCA). Acute rat biliary fistula and chronic cholestasis induced by 17alpha-ethynyl-estradiol (17EE) models were used to study and compare the effects of UPF-680 (dose range 0.6-6.0 micromol/kg min) with UDCA on bile flow, biliary bicarbonate (HCO(3)(-)), lipid output, biliary bile acid composition, hepatic enzymes and organic anion pumps. In acute infusion, UPF-680 increased bile flow in a dose-related manner, by up to 40.9%. Biliary HCO(3)(-) output was similarly increased. Changes were observed in phospholipid secretion only at the highest doses. Treatment with UDCA and UPF-680 reversed chronic cholestasis induced by 17EE; in this model, UDCA had no effect on bile flow in contrast to UPF-680, which significantly increased bile flow. With acute administration of UPF-680, the biliary bile acid pool became enriched with unconjugated and conjugated UPF-680 (71.7%) at the expense of endogenous cholic acid and muricholic isomers. With chronic administration of UPF-680 or UDCA, the main biliary bile acids were tauro conjugates, but modification of biliary bile acid pool was greater with UPF-680. UPF-680 increased the mRNA for cytochrome P450 7A1 (CYP7A1) and cytochrome P450 8B (CYP8B). Both UDCA and UPF-680 increased the mRNA for Na(+) taurocholate co-transporting polypeptide (NCTP). In conclusion, UPF-680 prevented 17EE-induced cholestasis and enriched the biliary bile acid pool with less detergent and cytotoxic bile acids. This novel fluorinated bile acid may have potential in the treatment of cholestatic liver disease.     

Evidence-based review of three-dimensional conformal radiotherapy for localized prostate cancer: an ASTRO outcomes initiative

PURPOSE: To perform a systematic review of the evidence to determine the efficacy and effectiveness of three-dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer; provide a clear presentation of the key clinical outcome questions related to the use of 3D-CRT in the treatment of localized prostate cancer that may be answered by a formal literature review; and provide concise information on whether 3D-CRT improves the clinical outcomes in the treatment of localized prostate cancer compared with conventional RT. METHODS AND MATERIALS: We performed a systematic review of the literature through a structured process developed by the American Society for Therapeutic Radiology and Oncology's Outcomes Committee that involved the creation of a multidisciplinary task force, development of clinical outcome questions, a formal literature review and data abstraction, data review, and outside peer review. RESULTS: Seven key clinical questions were identified. The results and task force conclusions of the literature review for each question are reported. CONCLUSION: The technological goals of reducing morbidity with 3D-CRT have been achieved. Randomized trials and follow-up of completed trials remain necessary to address these clinical outcomes specifically with regard to patient subsets and the use of hormonal therapy.     

Evaluation of prophylactic and therapeutic effects of silymarin on mebendazole-induced hepatotoxicity in cats

The aim of this study was to determine the protective action of silymarin on mebendazole-induced hepatotoxicity in cats. Twenty five healthy cats were randomly allotted into five equal groups. Cats in group A were given mebendazole (single dose 200?mg?kg, p.o.); group B consisted of cats that received silymarin (single dose 30?mg?kg, p.o.) concurrent with mebendazole administration; groups C, D and E were treated as group B, but silymarin was administered 2, 12 and 24?h after mebendazole administration, respectively. The serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and total and direct bilirubin were measured before mebendazole administration and 2, 12, 24 and 72?h later as indices of liver injury. A single oral administration of mebendazole significantly elevated serum concentrations of ALT, AST, ALP, LDH (in all cases), and total and direct bilirubin in one cat in group A, after 24?h (P?<?0.05). In groups B and C, levels of serum enzyme activities and total and direct bilirubin remained within normal values, but in group D, levels of serum enzyme activity (in four cases) were higher than normal values and total and direct bilirubin remained within the normal range. In group E, levels of serum enzyme activities (in all cats) and total and direct bilirubin (in one cat) were higher than normal values. In conclusion, silymarin can protect liver tissue against oxidative stress in cats with mebendazole intoxication particularly in the first 2?h after exposure.     

Comparison of IOPen rebound tonometer with Goldmann applanation tonometer at different IOP levels

AIM:To compare the accuracy of IOPen rebound tonometer with Goldmann applanation tonometer (GAT) in individuals with low, normal and high intraocular pressure (IOP) and to evaluate the effect of central corneal thickness (CCT) on IOP measurements.METHODS:This cross-sectional study consisted of 159 participants. IOP of one eye of each subject was measured consecutively with IOPen and GAT. Then CCT was measured using an ultrasonic pachymeter. Based on GAT IOP readings, participants were divided into low, normal and high IOP groups. Correlation between tonometers and CCT was calculated by spearman’s correlation coefficient. Agreement between tonometers was evaluated using Bland-Altman method.RESULTS: Non-significant underestimation of IOP by IOPen was observed in low IOP group (Mean difference:0.20mmHg; P=0.454) and also in normal IOP group (Mean difference:0.56mmHg; P=0.065). However, IOPen significantly overestimated IOP in high IOP group (Mean difference:1.06mmHg; P=0.038). The 95% limits of agreement (LoA) width between IOPen and GAT IOPs were 7.84, 8.57 and 14.27mmHg in low, normal and high IOP groups, respectively. Low IOP group had thinner corneas compared to high IOP group (P=0.034). IOP measurements taken by IOPen were not influenced by CCT (P=0.099) while poor correlation between CCT and GAT was found (R=0.17, P=0.032). Using receiver operating characteristic (ROC) curve, cutoff value of 18.75mmHg was determined for IOPen with sensitivity of 98.1 and specificity of 97.2%.CONCLUSION:Accuracy of IOPen is comparable to GAT in patients with low or normal IOP but IOPen overestimates IOP at high IOP levels. CCT does not affect IOP readings with IOPen.     

Identification of “substrate fibrillators” and “trigger fibrillators” by pacemaker diagnostics

BACKGROUND: The population of patients likely to respond to selected pacing algorithms for maintenance of sinus rhythm is unknown. OBJECTIVES: The purpose of this study was to identify patients with specific onset patterns of paroxysmal atrial fibrillation (AF). METHODS: Dual-chamber pacemakers with advanced diagnostic functions were implanted in 112 patients with conventional indications for antibradycardia pacing and a history of paroxysmal AF. Pacemaker diagnostic data were analyzed after 97.5 +/- 40.9 days. According to the frequency of premature atrial contractions (PACs) during the 5 minutes before AF onset, patients were assigned to one of three groups: group A (high PAC activity), group B (moderate PAC activity), or group C (low PAC activity). RESULTS: AF burden was lower in group A (4.6% +/- 2.4%) than group B (15.8% +/- 3.0%, P = .003) and group C (15.5% +/- 3.1%, P = .003). Fewer AF episodes occurred in group A (2.1 +/- 1.3 per day) than group B (3.8 +/- 1.2 per day, P = .006). Mean AF episode duration was shorter in group A (11.4 +/- 10.2 hours) than group C (41.4 +/- 27.5 hours, P = .03). CONCLUSION: The coincidence of low PAC activity before AF onset, high AF burden, and extended arrhythmia episode duration appears to be the consequence of a high atrial substrate factor. In these "substrate fibrillators," the efficacy of pacing algorithms for maintenance of sinus rhythm may be limited. In contrast, "trigger fibrillators" exhibiting low AF burden despite high PAC incidence may represent the target population for specific PAC-suppressing pacing algorithms.     

Prevalence of Helicobacter pylori infection in children (south of Iran)

The prevalence of Helicobacter pylori in children ranges from 10% to more than 80%. High prevalence occurs in developing countries, and after colonization it takes an extended period to be eradicated by the immune system. To evaluate the prevalence and age distribution of H. pylori infection in children in Shiraz (a city in the south of Iran), we collected 593 stool samples from children selected randomly from 5 age groups. Infection was determined based on antigen immunoassay in stool using the enzyme-linked immunosorbent assay method. The prevalence rates were 82%, 98%, 88%, 89%, and 57% in age groups of 9 months, and 2, 6, 10, and 15 years, respectively. There were no significant differences between the prevalence of H. pylori infection in the first 4 age groups (P > 0.05), but there was a significant decrease in the 15-year-old group (P < 0.05). The prevalence of H. pylori infection in the south of Iran is very high. The infection begins at infancy and remains high until late childhood.     

Comparative study of cryogen spray cooling with R-134a and R-404a: implications for laser treatment of dark human skin

Cutaneous laser treatment in dark skin patients is challenging due to significant light absorption by the melanin at the basal layer of epidermis, which can result in irreversible nonspecific thermal injury to the epidermis. Cryogen spray cooling (CSC) with R-134a (boiling point approximately -26.2 degrees C at 1 atm), which is currently used during cutaneous laser treatment, has shown poor efficacy in protecting dark human skin. We investigated the potential of CSC with R-404a (boiling point approximately -46.5 degrees C at 1 atm), which has a lower boiling point than R-134a, for improved therapeutic outcome in dark human skin at three levels: in vitro (epoxy resin skin phantom), ex vivo (normal dark human skin sample), and in vivo (skin of the rabbit external ear). The skin phantom was used to acquire the surface and internal temperature profiles in response to CSC with R-134a or R-404a at various spurt durations, based upon which CSC-induced heat removal from the skin phantom was estimated using an algorithm that solved a one-dimensional inverse heat conduction problem. CSC with R-404a increased the temperature reductions within the phantom and subsequently the amount of heat removal from the phantom in comparison to that with R-134a. Normal ex vivo Fitzpatrick types V-VI human skin samples were used to investigate the thermal response of dark human skin epidermis to CSC (R-134a or R-404a) at various spurt durations in conjunction with 595-nm pulsed dye laser irradiation at various radiant exposures. Cryogen R-404a increased the threshold radiant exposures for irreversible thermal injury to the epidermis in dark pigmentation skin. No obvious CSC-induced morphological changes to human skin was observed when sprayed with R404-a spurts using durations up to 300 ms. In vivo rabbit ear vasculature was used as a model of cutaneous anomalies to assess the influences of CSC (with R-134a or R-404a) on the photothermolysis of dermal blood vessels. CSC (R-134a or R-404a) with the spurt durations of 100 to 300 ms increased the most superficial depth of thermally damaged dermal blood vessel compared with the sites without CSC, implying possible nonspecific cooling of superficial dermal blood vessels by the cryogen spurts with the settings applied.