The role of hemochromatosis susceptibility gene mutations in protecting against iron deficiency in celiac disease

BACKGROUND & AIMS: Celiac disease and hereditary hemochromatosis are common HLA-defined conditions in northwestern Europe. We sought to determine whether there is a genetic relationship between the 2 diseases and if hemochromatosis susceptibility gene (HFE) mutations are protective against iron deficiency in celiac disease. METHODS: Polymerase chain reaction amplification using sequence-specific primers capable of identifying the 2 HFE gene mutations (H63D and C282Y) and the HLA class I and II alleles was used to type 145 white patients with celiac disease and 187 matched controls. Hemoglobin and fasting serum iron levels in celiac patients were measured at diagnosis. RESULTS: HFE gene mutations, H63D or C282Y, were identified in 70 celiac patients (48.3%) and 61 controls (32.6%) (P = 0.004). The C282Y mutation was associated with HLA-A*03 and B*07 alleles in controls and with A*01, A*03, B*08, and DRB1*0301 alleles in celiac patients; the H63D mutation was associated with HLA-A*25 and DRB1*03 alleles in controls and A*29 and DRB1*03 alleles in celiac patients. At diagnosis, celiac patients with the C282Y mutation had higher mean hemoglobin and fasting serum iron levels compared with the HFE wild type (P = 0.0002 and 0.006, respectively). This was not observed with the H63D mutation. CONCLUSIONS: In celiac disease, HFE gene mutations are common and are in linkage disequilibrium with different HLA alleles compared with controls. A disease-specific haplotype that carries C282Y and DQB1*02 is suggested. We propose that HFE gene mutations provide a survival advantage by ameliorating the iron deficiency seen in celiac patients.     

Cultural Differences in Specificity of Autobiographical Memories: Implications for Asylum Decisions

Current knowledge about cultural differences in the trauma autobiographical memory is limited. Such a limitation reduces the body of empirical evidence that can be drawn upon to inform decisions about asylum. The objective of this study was to explore the impact of cultural differences in self-construal on the specificity of autobiographical memories. Research participants from independent and interdependent cultures were asked to provide autobiographical memories of everyday events, trauma events and self-defining memories. Those from independent cultures consistently provided more specific autobiographical memories than those from interdependent cultures. The findings indicate that specificity has an essential role in enhancing the dominant self-focus and needs to be considered when deeming a memory as credible.     

Is your patient taking the medicine? A simple assay to measure compliance with 5‐aminosalicylic acid‐containing compounds

BACKGROUND: Poor compliance with 5-aminosalicylic acid therapy has been reported amongst patients with inflammatory bowel disease. Currently, there is no easy method to monitor 5-aminosalicylic acid; however, the chemical similarity between 5-aminosalicylic acid and salicylate might provide a solution. AIM: To determine the feasibility of using salicylate levels to monitor compliance with 5-aminosalicylic acid medication. METHODS: Thirty-six patients with inflammatory bowel disease, taking maintenance 5-aminosalicylic acid, provided either a paired serum and urine sample or an intestinal biopsy. Samples were split into two: half were sent to the hospital biochemistry department for salicylate measurement, and half were analysed for 5-aminosalicylic acid and its metabolite, N-acetyl-5-aminosalicylic acid, using high performance liquid chromatography. Correlation between the results was calculated. RESULTS: Serum and urine were available for 25 patients. Serum salicylate was undetectable, but urinary salicylate ranged from 31 to 3254 microg/mL. The correlations between urinary salicylate and 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid were 0.96 (95% confidence interval, 0.91-0.98) and 0.9 (95% confidence interval, 0.77-0.96), respectively. Sixteen biopsies were available from 13 patients. The 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid concentrations were 0.2-657 ng/mg and 1.6-1598 ng/mg, respectively; there was no correlation with bowel salicylate. CONCLUSIONS: The close correlation between 5-aminosalicylic acid and salicylate levels offers a simple method to assess compliance with 5-aminosalicylic acid therapy.     

Adaptive evolution of cytochrome c oxidase: Infrastructure for a carnivorous plant radiation

Much recent attention in the study of adaptation of organismal form has centered on developmental regulation. As such, the highly conserved respiratory machinery of eukaryotic cells might seem an unlikely target for selection supporting novel morphologies. We demonstrate that a dramatic molecular evolutionary rate increase in subunit I of cytochrome c oxidase (COX) from an active-trapping lineage of carnivorous plants is caused by positive Darwinian selection. Bladderworts (Utricularia) trap plankton when water-immersed, negatively pressured suction bladders are triggered. The resetting of traps involves active ion transport, requiring considerable energy expenditure. As judged from the quaternary structure of bovine COX, the most profound adaptive substitutions are two contiguous cysteines absent in approximately 99.9% of databased COX I sequences from Eukaryota, Archaea, and Bacteria. This motif lies directly at the docking point of COX I helix 3 and cytochrome c, and modeling of bovine COX I suggests the possibility of an unprecedented helix-terminating disulfide bridge that could alter COX/cytochrome c dissociation kinetics. Thus, the key adaptation in Utricularia likely lies in molecular energetic changes that buttressed the mechanisms responsible for the bladderworts' radical morphological evolution. Along with evidence for COX evolution underlying expansion of the anthropoid neocortex, our findings underscore that important morphological and physiological innovations must often be accompanied by specific adaptations in proteins with basic cellular functions.     

Human lymphocyte antigens in hypertrophic cardiomyopathy

An increasing number of genetic studies in hypertrophic cardiomyopathy challenge conventional views on inheritance and suggest genetic heterogeneity or non-genetic disease. We have found changes in relative risk for some antigens with significantly increased frequency of HLA antigen DR4 in this condition. These findings are consistent with there being a genetic component in susceptibility to hypertrophic cardiomyopathy. No evidence was found for HLA linkage using either sib pair analysis or lod scores. This suggests that hypertrophic cardiomyopathy does not have a disease susceptibility gene related to the HLA region on the short arm of chromosome number six. Population HLA associations with hypertrophic cardiomyopathy must thus be explained by other influences of the genetic background on disease susceptibility.     

Iodine-123 labeled reboxetine analogues for imaging of noradrenaline transporter in brain using single photon emission computed tomography

Preliminary investigation of the radioiodinated (S,S)‐reboxetine analogue, ¹²³I‐INER, in baboons showed this tracer to have promise for imaging the noradrenaline transporter (NAT) using single photon emission computed tomography (SPECT). More recently, the radioiodinated (R,S)‐stereoisomer of ¹²³I‐INER, ¹²³I‐NKJ64, has been synthesized and preliminary evaluation in rats has been reported. This article reports the brain distribution and pharmacokinetic properties of ¹²³I‐NKJ64 in baboons and compares results with ¹²³I‐INER data in the same species. SPECT studies were conducted in two ovariectomized adult female baboons using two different protocols: (1) bolus of ¹²³I‐INER or ¹²³I‐NKJ64; and (2) bolus plus constant infusion of ¹²³I‐NKJ64 with reboxetine (2.0 mg/kg) administration at equilibrium. Following bolus injection, both radiotracers rapidly and avidly entered the baboon brain. The regional brain accumulation of ¹²³I‐NKJ64 did not match the known distribution of NAT in baboon brain, contrasting with previous results obtained in rats. Conversely, the regional distribution of ¹²³I‐INER was consistent with known distribution of NAT in baboon brain. No displacement of ¹²³I‐NKJ64 was observed following administration of reboxetine. This contrasts with previous data obtained for ¹²³I‐INER, where 60% of specific binding was displaced by a lower dose of reboxetine. These data suggest that ¹²³I‐NKJ64 may lack affinity and selectivity for NAT in baboon brain and ¹²³I‐INER is the most promising iodinated reboxetine analogue developed to date for in vivo imaging of NAT in brain using SPECT. This study highlights the importance of species differences during radiotracer development and the stereochemical configuration of analogues of reboxetine in vivo. Synapse 66:923–930, 2012. © 2012 Wiley Periodicals, Inc.