Protein expression of various hepatic uridine 5′‐diphosphate glucuronosyltransferase (UGT) enzymes and their inter‐correlations: a meta‐analysis

Avoiding cytochrome P450 (CYP) related drug interactions in the development of new drug candidates means that glucuronidation by uridine 5′‐diphosphate glucuronosyltransferase (UGT) enzymes is expected to become a more prominent pathway in the metabolism of new drug candidates designed by pharmaceutical companies. Therefore, determining the abundance and activity of these enzymes is of value in the process of scaling in vitro data to in vivo metabolic parameters. Many of the studies involving the measurement of UGTs were conducted with too few samples, which did not provide a good indication of population values and the level of variability. Meta‐analysis is used in the current study to combine all reported values (eight studies that used LC‐MS isotope‐labelled standard targeted quantitative methods), detect inconsistencies between the various datasets and describe correlations of expression between the quantified UGT enzymes. Some heterogeneity was observed between studies, especially in the UGT1A4, 2B7 and 2B10 datasets. However, in the absence of information on the inter‐laboratory consistency of assays, it is difficult to assign these differences to the heterogeneity of the samples. Large inter‐individual variability was observed in the collated data across this family of enzymes. Positive correlations between the expression levels of certain UGT enzymes were found in the collated data. These included the pairs: UGT1A4/2B4 (r_s = 0.71, p < 0.0001, n = 82), UGT2B4/2B15 (r_s = 0.63, p < 0.0001, n = 83), UGT2B7/2B15 (r_s = 0.81, p < 0.0001, n = 99). These correlations can be explained by common regulatory mechanisms involved in the expression of these proteins. Copyright © 2014 John Wiley & Sons, Ltd.     

Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases

CARD15 is a major susceptibility gene for a frequent multifactorial chronic inflammatory bowel disorder, Crohn disease (CD). By using NF-kappaB activation assays, the cytosolic CARD15 was shown to efficiently detect bacterial peptidoglycan (PGN), reminiscent of the PGN recognition protein surveillance mechanism in Drosophila. The 3 CD-associated variants and 13 additional variants carried by CD patients demonstrated impaired PGN-dependent response revealing null, hypomorphic, or dominant-negative properties. Quantitative parametrization of this response, computed from the patients' CARD15 genotypes, was predictive of several variable CD manifestations. In contrast, CARD15 alleles associated with Blau's syndrome promoted PGN-independent NF-kappaB activation, an observation that accounts for the minimal microbial input in the etiology of this dominant, monogenic inflammatory disorder affecting solely aseptic sites.     

Safety and immunogenicity of a canarypox-vectored human immunodeficiency virus Type 1 vaccine with or without gp120: a phase 2 study in higher- and lower-risk volunteers

Live attenuated viral vectors that express human immunodeficiency virus (HIV) antigens are being developed as potential vaccines to prevent HIV infection. The first phase 2 trial with a canarypox vector (vCP205, which expresses gp120, p55, and protease) was conducted in 435 volunteers with and without gp120 boosting, to expand the safety database and to compare the immunogenicity of the vector in volunteers who were at higher risk with that in volunteers at lower risk for HIV infection. Neutralizing antibodies to the MN strain were stimulated in 94% of volunteers given vCP205 plus gp120 and in 56% of volunteers given vCP205 alone. CD8(+) cytotoxic T lymphocyte cells developed at some time point in 33% of volunteers given vCP205, with or without gp120. Phase 3 field trials with these or similar vaccines are needed, to determine whether efficacy in preventing HIV infection or in slowing disease progression among vaccinees who become infected is associated with the level and types of immune responses that were induced by the vaccines in this study.     

Intra-articular methylprednisolone acetate injection at the knee joint and the hypothalamic–pituitary–adrenal axis: a randomized controlled study

The objective of this study was to evaluate the effect of intra-articular corticosteroid injection (IACI) of methylprednisolone acetate (MPA) on the hypothalamic–pituitary–adrenal (HPA) axis in patients with osteoarthritis of the knee. Patients with symptomatic osteoarthritis of the knee who failed to respond to nonsteroidal anti-inflammatory medications and physical therapy were randomized between group 1 and group 2. Group 1 patients had an IACI of 80 mg of MPA at the knee joint and group 2 patients had an intra-articular injection (IAI) of 6 ml (60 mg) of sodium hyaluronate (control group). Immediately prior to the IAI and on weeks 1, 2, 3, 4, and 8 following IAI, patients from both groups underwent a low-dose (1 μg) adrenocorticotropin hormone (ACTH) stimulation test. Demographic, clinical, laboratory, and radiologic variables were documented in all patients. Both criteria of <7 μg/dl increase in the serum cortisol level and absolute levels of <18 μg/dl 30 min following the ACTH stimulation test were used to define secondary adrenal insufficiency (SAI). Twenty patients were randomized in each group. In group 1, 25 % of patients had SAI vs. none in group 2 (p?=?0.0471). The earliest SAI was observed at week 2, and latest SAI was observed at week 4. SAI was observed at one time point, two consecutive time points, or two separate time points in the same patient. There was no correlation between SAI and any of the demographic, clinical, or laboratory variables. An IACI of 80 mg MPA at the knee joint induced a transient SAI in 25 % of the patients, an effect that was observed between week 2 and week 4 following the IACI.     

Adult intestinal intussusception — A report of 2 cases and literature review

Every five years or so a case of adult small bowel intussusception secondary to pathologies such as inflammatory fibroid polyp (IFP) appears in English literature. Likewise rare cases of adult colonic intussusception due to a tumour have been reported including, more recently, their successful management by laparoscopic approach. We describe two such cases, one each of small bowel and large bowel intussusception, due to IFP and caecal tumour respectively and discuss their management. We also suggest role of combined laparoscopy/endoscopy in selected cases of colonic resections.