Signals elicited at the intestinal epithelium upon chitosan feeding contribute to immunomodulatory activity and biocompatibility of the polysaccharide

Chitosan is a copolymer of N-acetylglucosamine and glucosamine derived from chitin with several applications in pharmaceutical and medical fields. This polysaccharide exhibits adjuvant properties in mucosal immune responses of humans, rats and mice. Characterization of signals elicited by chitosan at the intestinal epithelium could explain its immunomodulatory activity and biocompatibility. We fed normal rats with single doses of chitosan and 16 h later, we purified intestinal epithelial cells (IECs) to assess immune and biochemical parameters. Following chitosan administration, mRNA expression and release of several cytokines and chemokines increased, injury markers maintained constitutive levels and MHC type II molecule expression was augmented. IEC supernatants showed higher levels of IL-10, IL-6 and TGF-β. Arginase activity of IECs increased upon chitosan interaction in vivo and in vitro. Together, after chitosan feeding, mild activation of IECs occurs in vivo, with production of regulatory factors that could be relevant for its biocompatibility and immunomodulatory effects.     

COL1A1 Sp1-binding site polymorphism as a risk factor for genital prolapse

The objective of this study was to verify the possible association between the Sp1-binding site polymorphism and genital prolapse. A case–control study was conducted in 107 patients with stages III and IV genital prolapse. The control group included 209 women with stages 0 and I. The polymorphism of type I collagen Sp1-binding site was identified by amplification of the first intron of the COL1A1 gene. We did not find differences in the prevalence of the GT and TT genotypes between the groups (p = 0.34), even when we grouped patients with at least one polymorphic allele (GT and TT) and compared them with patients without the polymorphic allele (GG; p = 0.17) The presence of at least one vaginal delivery, family history for prolapse, and macrosomatic fetus were independent risk factors for prolapse. In conclusion, the COL1A1 Sp1-binding site was not significantly associated with genital prolapse among our study subjects.     

Guillain Barre syndrome in children: clinical manifestations, laboratory findings, and the results of steroid treatment

We report 28 cases diagnosed as GBS in the Department of Child Health, Medical School, University of Indonesia, DR. Cipto Mangunkusumo General Hospital in 7 years period. There were 17 males and 11 females with a ratio of 1.5:1. The age ranged from 9 months to 9.5 years, with a mean age of 4.57 +/- 2.36 years. Twelve (42.86%) cases were preceded by acute respiratory infection, 8 (28.57%) cases by non specific fever, 1 (9.57%) case by gastrointestinal tract infection and 7 (25%) cases did not have any history of acute infection. The clinical manifestations were motor weakness (100%), cranial nerves involvement (14.29%) and disturbance of sensation (17.80%). Most cases (92.86%) showed albuminocytologic dissociation feature with the CSF protein content more than 40 mg/dl. The number of cells was less than 10 cells/mm3 in 96.43% of cases. The specific NCV feature (peripheral NCV decrease) was found in 96.15% of patients and only 1 patient (3.85%) showed normal peripheral NCV. The severity of the disease was in accordance with the prognosis later. Corticosteroid was not beneficial in the treatment of GBS.     

Quantitative cancer risk assessment based on NIOSH and UCC epidemiological data for workers exposed to ethylene oxide

The most recent epidemiological data on individual workers in the NIOSH and updated UCC occupational studies have been used to characterize the potential excess cancer risks of environmental exposure to ethylene oxide (EO). In addition to refined analyses of the separate cohorts, power has been increased by analyzing the combined cohorts. In previous SMR analyses of the separate studies and the present analyses of the updated and pooled studies of over 19,000 workers, none of the SMRs for any combination of the 12 cancer endpoints and six sub-cohorts analyzed were statistically significantly greater than one including the ones of greatest previous interest: leukemia, lymphohematopoietic tissue, lymphoid tumors, NHL, and breast cancer. In our study, no evidence of a positive cumulative exposure–response relationship was found. Fitted Cox proportional hazards models with cumulative EO exposure do not have statistically significant positive slopes. The lack of increasing trends was corroborated by categorical analyses. Cox model estimates of the concentrations corresponding to a 1-in-a-million extra environmental cancer risk are all greater than approximately 1 ppb and are more than 1500-fold greater than the 0.4 ppt estimate in the 2006 EPA draft IRIS risk assessment. The reasons for this difference are identified and discussed.     

Effect of pH,EDTA, and Anions on Heavy Metal Toxicity Toward a Bioluminescent Cyanobacterial Bioreporter

The bioavailability and therefore toxicity of a metal depends on the chemical species present in a particular environment. We evaluated the effect of a series of factors that could potentially modify metal speciation on the toxicity of Hg, Cu, Zn, and Cd toward a recombinant strain of the freshwater cyanobacterium Anabaena sp. PCC 7120 with cloned lux operon of luminescent terrestrial bacterium Photorhabdus luminescens. The strain, denoted as Anabaena CPB4337, showed a high constitutive luminescence with no need to add exogenous aldehyde. The tested factors were pH, EDTA (as organic ligand), and anions PO₄ ^3–, CO₃ ^2–, and Cl^–. Chemical modeling and correlation analyses were used to predict metal speciation and link it with toxicity. In general, metal toxicity significantly correlated to the predicted metal free-ion concentration, although Zn–EDTA complexes and certain Hg chloro-complexes could also exhibit some toxicity to cyanobacteria. An interesting feature of metal toxicity to strain Anabaena CPB4337 was that low amounts of PO₄ ^3– and CO₃ ^2– increased metal toxicity; this effect could not be related to significant changes in metal speciation and could be attributed to a modulating effect of these anions on metal/uptake toxicity. The combination of toxicity studies that take into account a range of factors that might modulate metal toxicity with chemical modeling to predict changes in metal speciation might be useful for interpreting complex toxicity data. Finally, this cyanobacterial bioreporter, due to its ecological relevance as a primary producer, could be used as a tool for toxicity assessment in freshwater environments.     

The effect of case-based discussion of topics with experts on learners’ opinions: implications for spinal education and training

Purpose

This investigation aimed to examine the extent to which case-based discussion with experts could influence the audience’s opinions on the treatment of patients during a continuing medical education event for spine surgeons.

Methods

We conducted a prospective controlled crossover study of 90 surgeons. During a continuing medical education activity using case-based discussion, quiz questions were used which asked participants (attendants and faculty group) their opinions on the best choices about diagnosis and treatment in a number of cases. No answer was considered correct, but we evaluated the number of participants choosing each specific answer among a number of valid options. Quiz questions were collected with an automated response system at the entry and at the end of each case discussion. Change in participant’s opinions was estimated from the change in the preferred answers between the entry and exit quizzes. Chi-square analysis was performed to determine significance.

Results

Sixty-two attendants out of eighty three (75%) and six faculties out of twelve (50%) responded to the survey. After the case discussion, 68.2% (p < 0.04, Chi-square test) of the attendants changed their opinion on the appropriate treatment. The faculty answers, however, showed no significant change in opinions regarding the identification of the appropriate treatment.

Conclusions

On the basis of our results, case-based discussion driven by experts, as a form of teaching, has a measurable effect in terms of changes in the learners’ opinions.

     

Effects of human immunodeficiency virus protease inhibitors on the intestinal absorption of tenofovir disoproxil fumarate in vitro

Human immunodeficiency virus protease inhibitors (PIs) modestly affect the plasma pharmacokinetics of tenofovir (TFV; -15% to +37% change in exposure) following coadministration with the oral prodrug TFV disoproxil fumarate (TDF) by a previously undefined mechanism. TDF permeation was found to be reduced by the combined action of ester cleavage and efflux transport in vitro. Saturable TDF efflux observed in Caco-2 cells suggests that at pharmacologically relevant intestinal concentrations, transport has only a limited effect on TDF absorption, thus minimizing the magnitude of potential intestinal drug interactions. Most tested PIs increased apical-to-basolateral TDF permeation and decreased secretory transport in MDCKII cells overexpressing P-glycoprotein (Pgp; MDCKII-MDR1 cells) and Caco-2 cells. PIs were found to cause a multifactorial effect on the barriers to TDF absorption. All PIs showed similar levels of inhibition of esterase-dependent degradation of TDF in an intestinal subcellular fraction, except for amprenavir, which was found to be a weaker inhibitor. All PIs caused a dose-dependent increase in the accumulation of a model Pgp substrate in MDCKII-MDR1 cells. Pgp inhibition constants ranged from 10.3 microM (lopinavir) to >100 microM (amprenavir, indinavir, and darunavir). Analogous to hepatic cytochrome P450-mediated drug interactions, we propose that the relative differences in perturbations in TFV plasma levels when TDF is coadministered with PIs are based in part on the net effect of inhibition and induction of intestinal Pgp by PIs. Combined with prior studies, these findings indicate that intestinal absorption is the mechanism for changes in TFV plasma levels when TDF is coadministered with PIs.