Thiopurine-methyltransferase variants in inflammatory bowel disease:Prevalence and toxicity in Brazilian patients

AIM:To analyze the prevalence of thiopurine-methyltransferase(TPMT)genotypes and their associationwith drug toxicity in inflammatory bowel disease(IBD)patients from southeastern Brazil.METHODS:A total of 219 consecutive patients with IBD,of which 146 had Crohn’s disease and 73 had ulcerative colitis,regularly seen at the outpatient unit of the Division of Gastroenterology at the University Hospital Pedro Ernesto of the State University of Rio de Janeiro,a tertiary referral center,were enrolled in this study from February 2009 to January 2011.We analyzed the presence of major TPMT genetic variants(TPMT*2,*3A,*3C)in IBD patients by means of a specific allele and RFLP-PCR.Genomic DNA was isolated from peripheral blood leukocytes by proteinase-K/Sodium Dodecyl Sulfate digestion and phenol-chloroform extraction.TPMT*2(C238G),TPMT*3A(G460A/A719G),and TPMT*3C(A719G)genotypes were detected by real-time polymerase chain reaction followed by direct sequencing with specific primers.Clinical data were systematically recorded,and correlated with the genotype results.RESULTS:The distribution of the selected TPMT gene polymorphism TPMT*2(C238G),TPMT*3A(G460A/A719G),and TPMT*3C(A719G)genotypes was 3.6%,5.4%,and 7.7%of the patients,respectively.Among the side effects recorded from patients taking azathioprine,14 patients presented with pancreatitis and/or an elevation of pancreatic enzymes,while 6 patients had liver toxicity,and 2 patients exhibited myelosuppression/neutropenia.TPMT polymorphisms were detected in 37/219 patients(8 heterozygous for*2,11 heterozygous for*3A,and 18 heterozygous for*3C).No homozygotic polymorphisms were found.Despite the prevalence of the TPMT*3C genotype,no differences among the genotype frequencies were significant.Although no association was detected regarding myelotoxicity or hepatotoxicity,a trend towards the elevation of pancreatic enzymes was observed for TPMT*2 and TPMT*3C genotypes.CONCLUSION:The prevalence of TPMT genotypes was high among Brazilian patients.Variants genes*2and*3C may be associated with azathioprine pancreatic toxicity in a IBD southeastern Brazilian population.     

Predictors of hepatitis B surface antigen loss,relapse and retreatment after discontinuation of effective oral antiviral therapy in noncirrhotic HBeAg‐negative chronic hepatitis B

Reliable predictors of outcomes after treatment discontinuation in HBeAg‐negative chronic hepatitis B (CHB) patients have not been established. We investigated the role of hepatitis B surface antigen (HBsAg), interferon‐inducible protein‐10 (IP10) and hepatitis B core‐related antigen (HBcrAg) serum levels as predictors of HBsAg loss, relapse and retreatment in noncirrhotic HBeAg‐negative CHB patients who discontinued long‐term antiviral therapy. All HBsAg‐positive (n = 57) patients of the prospective DARING‐B study were included and followed monthly for 3 months, every 2/3 months until month‐12 and every 3/6 months thereafter. HBsAg, IP10 and HBcrAg levels were measured by enzyme immunoassays, and SCALE‐B score was calculated. Twelve patients achieved HBsAg loss before retreatment with 18‐month cumulative incidence of 25%. Independent predictors of HBsAg loss were baseline HBsAg and month‐1 IP10 levels. Of 10 patients with baseline HBsAg ≤100 IU/mL, 70% cleared HBsAg and 10% required retreatment. Of 23 patients with baseline HBsAg >1000 IU/mL, 4% cleared HBsAg and 43% required retreatment. Of 24 patients with intermediate baseline HBsAg (100‐1000 IU/mL), 17% cleared HBsAg and 21% required retreatment; in this subgroup, month‐1 IP10 was significantly associated with HBsAg loss, which occurred in 30% and 7% of cases with IP10 >150 and ≤150 pg/mL, respectively. Baseline HBcrAg was undetectable in all patients who cleared HBsAg and was associated with retreatment. SCALE‐B was associated with HBsAg loss but not with relapse or retreatment. In conclusion, HBsAg, IP10 and HBcrAg serum levels can be useful for the decisions and management of treatment discontinuation in noncirrhotic Caucasian patients with HBeAg‐negative CHB.     

Evaluation of Hybrid Melamine and Steel Fiber Reinforced Geopolymers Composites

This study investigated the influence of the steel and melamine fibers hybridization on the flexural and compressive strength of a fly ash-based geopolymer. The applied reinforcement reduced the geopolymer brittleness. Currently, there are several types of polymer fibers available on the market. However, the authors did not come across information on the use of melamine fibers in geopolymer composites. Two systems of reinforcement for the composites were investigated in this work. Reinforcement with a single type of fiber and a hybrid system, i.e., two types of fibers. Both systems strengthened the base material. The research results showed the addition of melamine fibers as well as steel fibers increased the compressive and flexural strength in comparison to the plain matrix. In the case of a hybrid system, the achieved results showed a synergistic effect of the introduced fibers, which provided better strength results in relation to composites reinforced with a single type of fiber in the same amount by weight.     

Vitamin B6 in Primary Hyperoxaluria I: First Prospective Trial after 40 Years of Practice

Background and objectives

Primary hyperoxaluria type I (PH I) is caused by deficiency of the liver-specific enzyme alanine-glyoxylate:aminotransferase (AGT). Many mutations are known to perturb AGT protein folding. Vitamin B6 (B6) is the only specific drug available for treatment. Although B6 has been used for >40 years, controlled data on B6 efficacy are lacking. Therefore, this study investigated the absolute and relative change of urinary oxalate (Uox) excretion under increasing dosages of B6, the first prospective trial to do so.

Design, setting, participants, & measurements

B6 response was studied in 12 patients (7 male patients) with genetically confirmed PH I (3 Gly170Arg homozygous, 5 compound Gly170Arg and/or Phe152Ile heterozygous, and 4 negative for Gly170Arg and/or Phe152Ile mutations) and noncompromised renal function. Efficacy was defined as a 30% relative reduction in Uox excretion. B6 was administered orally starting at 5 mg/kg body weight per day and given in increments of 5 mg/kg every 6 weeks, up to a final dosage of 20 mg/kg per day at week 24. Uox and serum B6 levels were measured every 6 weeks.

Results

Mean relative Uox reduction was 25.5%. Uox declined from 2.09±0.55 (mean±SD) at baseline to 1.52±0.60 mmol/1.73 m² per day (P=0.01) at week 24. Serum B6 levels increased from 22.5±8.7 to 1217±776 ng/ml (P<0.001). Six patients showed a ≥30% relative reduction of Uox at week 24.

Conclusion

This first prospective trial confirmed B6 efficacy in 50% of patients (three of three homozygous, one of five heterozygous, and two of four patients negative for the Gly170Arg and/or Phe152Ile mutations). Interestingly, no complete biochemical remission was observed, even in the homozygous Gly170Arg study participants. Future trials are necessary to learn more about genotype-related B6 response and B6 metabolism.     

Building skill in heart failure self-care among community dwelling older adults: Results of a pilot study

Objective

Most of the day-to-day care for heart failure (HF) is done by the patient at home and requires skill in self-care. In this randomized controlled trial (RCT) we tested the efficacy of a community-based skill-building intervention on HF self-care, knowledge and health-related quality of life (HRQL) at 1- and 3-months.

Methods

An ethnically diverse sample (n = 75) of patients with HF (53% female; 32% Hispanic, 27% Black; mean age 69.9 ± 10 years) was randomized to the intervention group (IG) or a wait-list control group (CG). The protocol intervention focused on tactical and situational HF self-care skill development delivered by lay health educators in community senior centers. Data were analyzed using mixed (between–within subjects) ANOVA.

Results

There was a significant improvement in self-care maintenance [F(2, 47) = 3.42, p = .04, (Cohen's f = .38)], self-care management [F(2, 41) = 4.10, p = .02, (Cohen's f = .45) and HF knowledge [F(2, 53) = 8.00, p = .001 (Cohen's f = .54)] in the IG compared to the CG.

Conclusions

The skill-building intervention improved self-care and knowledge but not HRQL in this community-dwelling sample.

Practice implications

Delivering an intervention in a community setting using lay health educators provides an alternative to clinic- or home-based teaching that may be useful across diverse populations and geographically varied settings.     

Prevalence and diversity of Babesia,Hepatozoon, Ehrlichia,and Bartonella in wild and domestic carnivores from Zambia,Africa

A molecular survey was conducted for several hemoparasites of domestic dogs and three species of wild carnivores from two sites in Zambia. Three Babesia spp. were detected including Babesia felis and Babesia leo in lions (Panthera leo) and a Babesia sp. (similar to Babesia lengau) in spotted hyenas (Crocuta crocuta) and a single lion. All wild dogs (Lycaon pictus) and domestic dogs were negative for Babesia. High prevalences for Hepatozoon were noted in all three wild carnivores (38–61 %) and in domestic dogs (13 %). Significantly higher prevalences were noted in hyenas and wild dogs compared with domestic dogs and lions. All carnivores were PCR negative for Ehrlichia canis, Ehrlichia ewingii, and Bartonella spp. Overall, high prevalences and diversity of Babesia and Hepatozoon were noted in wild carnivores from Zambia. This study is the first molecular characterization of Babesia from any hyena species and is the first report of a Babesia sp. closely related to B. lengau, a parasite previously only reported from cheetahs (Acinonyx jubatus), in lions and hyenas. Although usually benign in wild carnivores, these hemoparasites can be pathogenic under certain circumstances. Importantly, data on vectors for these parasites are lacking, so studies are needed to identify vectors as well as determine transmission routes, infection dynamics, and host specificity of these hemoparasites in wildlife in Africa and also the risk of transmission between domestic animals and wildlife.