Feasibility of identifying proliferative active bone marrow with fat fraction MRI and multi-energy CT.

Objective.Active bone marrow (ABM) can serve as both an organ at risk and a target in external beam radiotherapy.18F-fluorothymidine (FLT) PET is the current gold standard for identifying proliferative ABM but it is not approved for human use, and PET scanners are not always available to radiotherapy clinics. Identifying ABM through other, more accessible imaging modalities will allow more patients to receive treatment specific to their ABM distribution. Multi-energy CT (MECT) and fat-fraction MRI (FFMRI) show promise in their ability to characterize bone marrow adiposity, but these methods require validation for identifying proliferative ABM.Approach.Six swine subjects were imaged using FFMRI, fast-kVp switching (FKS) MECT and sequential-scanning (SS) MECT to identify ABM volumes relative to FLT PET-derived ABM volumes. ABM was contoured on FLT PET images as the region within the bone marrow with a SUV above the mean. Bone marrow was then contoured on the FFMRI and MECT images, and thresholds were applied within these contours to determine which threshold produced the best agreement with the FLT PET determined ABM contour. Agreement between contours was measured using the Dice similarity coefficient (DSC).Main results.FFMRI produced the best estimate of the PET ABM contour. Compared to FLT PET ABM volumes, the FFMRI, SS MECT and FKS MECT ABM contours produced average peak DSC of 0.722 ± 0.080, 0.619 ± 0.070, and 0.464 ± 0.080, respectively. The ABM volume was overestimated by 40.51%, 97.63%, and 140.13% by FFMRI, SS MECT and FKS MECT, respectively.Significance.This study explored the ability of FFMRI and MECT to identify the proliferative relative to ABM defined by FLT PET. Of the methods investigated, FFMRI emerged as the most accurate approximation to FLT PET-derived active marrow contour, demonstrating superior performance by both DSC and volume comparison metrics. Both FFMRI and SS MECT show promise for providing patient-specific ABM treatments.

Multiple interventions following an acute coronary syndrome event increase uptake into cardiac rehabilitation.

AIMS: Cardiac rehabilitation (CR) improves morbidity and mortality. Uptake varies for patients following acute coronary syndrome (ACS). Entry into CR is often dependent on the management strategy received, lower following percutaneous coronary intervention (PCI), higher following coronary artery bypass grafting (CABG). This study sought to investigate differences in CR uptake following an ACS event for those patients receiving multiple treatments. METHODS: Data was from the National Audit of CR between 2016 and 2019. Patients with ACS were categorised as: no intervention; one treatment (such as any PCI, CABG, any valve surgery and any device therapy); two treatments; or three or more treatments. Baseline demographics and logistic regression were used to analyse the effect of multiple treatment intervention on uptake into CR. RESULTS: A total of 6833 ACS patients were included in the analysis (0 treatments 2014, 1 treatment 3104, ≥2 treatments 2799). Patients who received ≥2 therapeutic interventions were more likely to be male, partnered and >2 comorbidities. Logistic regression showed a positive relationship between uptake total intervention. Similar associations were seen: being younger, male, partnered and having any comorbidity. The hospital stay, history of angina, diabetes and stroke was negatively correlated with an uptake. CONCLUSION: This study showed for the first time that multiple interventions following ACS is a significant predictor of uptake into CR. The findings align with recent trends with medically managed myocardial infarction uptake. Our findings identify factors associated with poor uptake to CR which should be considered as part of strategy to increase participation.

On the use of the Cu2+-iminodiacetic acid complex for double histidine based distance measurements by pulsed ESR.

Cu2+ based distance measurements using the double-histidine (dHis) motif by pulsed ESR present an attractive strategy to obtain precise, narrow distance distributions that can be easily related to protein backbone structure (Cunningham et al., Angew. Chem., Int. Ed., 2015, 54, 633). The Cu2+-ion is introduced as a complex with the iminodiacetic acid (IDA) chelating agent, which enhances binding selectivity to the two histidine residues that are site-selectively placed on the protein through mutagenesis. However, initial results of this method produced weak dipolar modulations. To enhance applicability of the double histidine motif using IDA, we perform a systematic examination of the possible causes of these weak dipolar modulations. We examine the efficiency of the Cu2+-ion to form the Cu2+-IDA complex in solution. In addition, we analyze the selectivity of Cu2+-IDA binding to dHis sites at both α-helical and ß-strand environments. Our results indicate that the dHis motif on the ß-sheet sites have high affinity towards Cu2+-IDA while the dHis sites on α-helices show poor affinity for the metal-ion complex. We are able to use our new findings to optimize conditions to maximize dHis loading while minimizing both free Cu2+ and unbound Cu2+-IDA complex in solution, allowing us to double the sensitivity of the Double Electron-Electron Resonance (DEER) experiment. Finally, we illustrate how Cu2+-based CW-ESR and DEER can be combined to obtain information on populations of different Cu2+-complexes in solution.

An evaluation of community-based cognitive stimulation therapy: a pilot study with an Irish population of people with dementia.

OBJECTIVES: Research shows that cognitive stimulation therapy (CST) improves cognitive function, quality of life, and well-being of people with mild-moderate dementia. Despite consistent evidence and recommendations, CST is not routinely available in Ireland post-diagnosis. The aim of the current research was to develop and evaluate community-based CST for people with mild-moderate dementia, run by the Alzheimer Society of Ireland across four pilot sites in Ireland. METHODS: Participants with mild-moderate dementia attended once weekly CST sessions for 14 weeks. Baseline and post-intervention assessments were completed by CST participants, carers, and CST facilitators. Primary outcomes of interest for CST participants included quality of life (Quality of Life in Alzheimer Disease Scale), cognitive function (Montreal Cognitive Assessment), and subjective cognitive function (Memory Awareness Rating Scale-Functioning Subscale). Secondary outcomes included well-being, cognitive ability, satisfaction with cognitive performance, and engagement and confidence of CST participants; well-being of carers; and job satisfaction of facilitators. Post-intervention interviews supplemented quantitative analyses. RESULTS: In total, 20 CST participants, 17 carers, and six CST facilitators completed evaluation assessments. Results showed that CST improved participants' satisfaction with cognitive performance (p=0.002), level of engagement (p=0.046), level of confidence (p=0.026). Improvements on subjective cognitive function just fell short of significance (p=0.055). Qualitative analysis of interview data identified consistent themes of cognitive and overall benefits of CST; and provided support for quantitative data. CONCLUSIONS: Community-based CST positively impacted the lives of people with dementia and their families. This study supports prior recommendations that CST should be made routinely available to people with mild-moderate dementia, particularly in light of the lack of post-diagnostic interventions currently offered in Ireland.

Screening for asymptomatic urogenital Chlamydia trachomatis infection at a large Dublin maternity hospital: results of a pilot study.

BACKGROUND: There are currently no Irish guidelines on screening for Chlamydia trachomatis infection in pregnancy. Prevalence rates in the antenatal population are not known which has prevented the development of screening recommendations for this group. AIMS: The objective of this study was to determine the prevalence of asymptomatic urogenital C. trachomatis infection in young women attending for care at a large maternity hospital. METHODS: All patients aged 25 years and under attending the Hospital between December 2011 and December 2013 were offered screening for urogenital C. trachomatis infection. Nucleic acid amplification testing of the C. trachomatis cryptic plasmid was performed on either endocervical swabs or first void urine samples. RESULTS: There were 2687 women tested for C. trachomatis infection, 83.4 % (2241/2687) through the antenatal clinics, 7.1 % (193/2687) through the gynaecology clinic, and 9.4 % (253/2687) through the emergency department. The rate of a positive test result was 5.6 % (151/2687) overall. The rates in women ages 16-18, 19-21 and 22-25 years were 9.1 % (31/340), 6.5 % (50/774) and 4.4 % (69/1561), respectively. A positive test result was more likely in those who were unemployed (p = 0.04), those who were Irish (p = 0.03) and those who were unmarried (p < 0.01). There were no cases of neonatal C. trachomatis infection in babies born to mothers who were screened in early pregnancy. CONCLUSIONS: The prevalence rate of detected C. trachomatis infection was 5.6 % in the study population. Screening of antenatal patients may have a role in preventing vertical transmission of infection to the neonate.

Investigating the emotional response to room acoustics: A functional magnetic resonance imaging study.

While previous research has demonstrated the powerful influence of pleasant and unpleasant music on emotions, the present study utilizes functional magnetic resonance imaging (fMRI) to assess the positive and negative emotional responses as demonstrated in the brain when listening to music convolved with varying room acoustic conditions. During fMRI scans, subjects rated auralizations created in a simulated concert hall with varying reverberation times. The analysis detected activations in the dorsal striatum, a region associated with anticipation of reward, for two individuals for the highest rated stimulus, though no activations were found for regions associated with negative emotions in any subject.

Risk assessment for anterior cruciate ligament injury.

INTRODUCTION: Anterior cruciate ligament tears are one of the most frequent soft tissue injuries of the knee. A torn anterior cruciate ligament leaves the knee joint unstable and at risk for further damage to other soft tissues manifested as pain, dislocation, and osteoarthritis. A better understanding of the anatomical details of knee joints suffering anterior cruciate ligament tears is needed to understand and develop prediction models for anterior cruciate ligament injury and/or tear. MATERIALS AND METHODS: Magnetic resonance images of 32 patients with anterior cruciate ligament tears and 40 patients with non-tears were evaluated from a physician group practice. Digital measurements of femoral condyle length, femoral notch width, anterior cruciate ligament width in the frontal and sagittal plane, and the anterior cruciate ligament length in the sagittal plane were taken in both groups to identify trends. Monte Carlo simulations were performed (n = 2000) to evaluate the relationship between notch width index and sagittal width and to establish functional relationships among the anatomical parameters for potential injury risk. Sensitivity analysis performed shows the risk of anterior cruciate ligament injury a function of force and notch width index. RESULTS: Females have a significantly shorter anterior cruciate ligament when compared to that of males. The notch width index was also significantly different between torn and non-torn individuals. The NWI was not significantly different between genders (p value = 0.40). CONCLUSIONS: Anterior cruciate ligament injury has been shown to be caused by the forces which act on the ligament. These forces can result from hyperextension of the tibia or the internal rotation of tibia. The anatomical parameters of the knee joint (i.e., notch width index, anterior cruciate ligament width and length) have no role in the cause of an injury.

Educational influences on early retirement through disability in Ireland.

BACKGROUND: Studies suggest a higher prevalence of early retirement through disability among older people with lower educational attainment. There have been no national studies in Ireland on the factors that affect early withdrawal from the labour force through disability or long-term illness. AIMS: To identify and analyse potential impacts of education on early retirement through disability in the over 50 age cohort of the Irish Labour force. METHODS: We analysed the educational attainment of participants using The Irish Longitudinal Study of Ageing (TILDA). The group of interest were those aged 50-75 who had retired early. The sample was dichotomized on disability. Examination of interviewer-recorded information on background influences determining early retirement decisions included the following factors: age, gender, education, family and socio-economic circumstances, including parental education. RESULTS: A total of 334 of 1179 study subjects (28%) retired early through disability. Comparison of those retired early with and without disability showed a significantly higher frequency of lower educational attainment both personally and for parents. Men with lower educational attainment and from a non-professional background were more likely to retire early through disability. Non-professional disabled respondents with less well-educated parents had lower educational attainment than non-disabled respondents. CONCLUSIONS: Among TILDA participants, educational attainment appears to influence early retirement through disability. The sector of previous employment was also a significant factor. Behaviour, lifestyle and employment choice are influenced by educational level, which may affect cognitive ability to process health information. Factors affecting the education-disability relationship could include parental education, employment status and socio-economic characteristics.

Lamivudine treatment and outcome in pregnant women with high hepatitis B viral loads.

Perinatal transmission is the most common mode of hepatitis B virus (HBV) transmission and is a leading cause of chronic infection worldwide. Maternal treatment with lamivudine (LAM) can result in a rapid and significant reduction in HBV viral load (VL) and, thus, mitigate the risk of mother-to-child transmission (MTCT). The aim of this study was to retrospectively evaluate the safety of LAM treatment administered in the third trimester of pregnancy and determine the influence, if any, on infant outcome. The medical charts of all HBV surface antigen (HBsAg)-positive women eligible for treatment with LAM and who registered for antenatal care between 2007 and 2012 were retrospectively reviewed. During the 6-year period, 45 women met the criteria for LAM treatment. Thirty-six women (80 %) accepted treatment; the remaining women declined treatment (5), defaulted from care (3) or transferred to another maternity unit (1). The median duration of treatment was 11.4 weeks (range 5.3-17.4) and the median baseline VL was 1.4 × 10(8) IU/mL (range 1.8 × 10(7)-1.7 × 10(8)). The median VL at delivery was 2.3 × 10(5) IU/mL and 60 % of women achieved a VL reduction >2 log10 IU/mL before delivery. No cases of perinatal transmission occurred in the infants born to mothers who received treatment; however, one infant, born to a mother who defaulted from care, was HBV-infected at 8 months. The results suggest that LAM therapy in highly viraemic HBV-infected pregnant women could lower the rate of vertical transmission.

Toll-like receptor signalling in liver disease: ER stress the missing link?

Toll-like receptors induce a complex inflammatory response that can function to alert the body to infection, neutralize pathogens and repair damaged tissues. Toll-like receptors are expressed on kupffer, endothelial, dendritic, biliary epithelial, hepatic stellate cells, and hepatocytes in the liver. The endoplasmic reticulum (ER) is a central organelle of eukaryotic cells that exists as a place of lipid synthesis, protein folding and protein maturation. The ER is a major signal transduction organelle that senses and responds to changes in homeostasis. Conditions interfering with the function of the ER are collectively known as ER stress and can be induced by accumulation of unfolded protein aggregates or by excessive protein traffic as can occur during viral infection. The ability of ER stress to induce an inflammatory response is considered to play a role in disease pathogenesis. Importantly, ER stress is viewed as a contributor to the pathogenesis of liver diseases with evidence linking components of ER homeostasis as requirements for optimal Toll-like receptor function. In this context this review discusses the association of Toll-like receptors with ER stress. This is an emerging paradigm in the understanding of Toll-like receptor signalling which may have an underlying role in the pathogenesis of liver disease.

Correlation between patella and patellar tendon width: An anatomic study.

Anterior cruciate ligament (ACL) rupture is a common injury among orthopaedic patients with many different treatment modalities including bone-patella-bone autograft (BPBA) ACL reconstruction. Patella tendon width has been reported to be a predictor of recovery speed and success following BPBA repair. This study reports on the strength of the relationship between patella width and patella tendon width. Twenty fresh frozen cadavers were included in the study. Patella and patellar tendon measurements were recorded at the midpoint of the patellar tendon. Pearson correlation and linear regression were used to determine the relationship between patella width and patellar tendon width. Bivariate correlations with 95% confidence intervals and coefficients of determination (R(2) ) are reported. The study used 20 cadavers, 12 men and 8 women with a mean age of 72 (standard deviation [SD] = 12; range = 44 to 87). The mean patella width was 49.24mm (SD = 4.11; range 42.33mm-56.33mm) while the mean patellar tendon width was 26.10mm (SD = 3.31; range 18.33mm-33.33mm). The correlation between patella width and patellar tendon width was 0.67 (95% confidence interval = 0.45 - 0.81). R(2), the percent of variance in patellar tendon width accounted for by patella width, was 0.45. The regression equation for predicting patellar tendon width (y) yielded a formula of y = 0.536 + -0.316 × patella width. A moderate correlation exists between patella width and patellar tendon width. Our data suggests that this correlation is strongest with wider patellas and is more loosely associated with smaller patellas.

SU-E-T-137: The Response of TLD-100 in Mixed Fields of Photons and Electrons.

PURPOSE: Thermoluminescent dosimeters are used routinely for dosimetric measurements of photon and electron fields. However, no work has been published characterizing TLDs for use in combined photon and electron fields. This work investigates the response of TLD-100 (LiF:Mg,Ti) in mixed fields of photon and electron beam qualities. METHODS: TLDs were irradiated in a 6 MV photon beam, 6 MeV electron beam, and a NIST traceable cobalt-60 beam. TLDs were also irradiated in a mixed field of the electron and photon beams. All irradiations were normalized to absorbed dose to water as defined in the AAPM TG-51 report. The average response per dose (nC/Gy) for each linac beam quality was normalized to the average response per dose of the TLDs irradiated by the cobalt-60 standard.Irradiations were performed in a water tank and a Virtual Water™ phantom. Two TLD dose calibration curves for determining absorbed dose to water were generated using photon and electron field TLD response data. These individual beam quality dose calibration curves were applied to the TLDs irradiated in the mixed field. RESULTS: The TLD response in the mixed field was less sensitive than the response in the photon field and more sensitive than the response in the electron field. TLD determination of dose in the mixed field using the dose calibration curve generated by TLDs irradiated by photons resulted in an underestimation of the delivered dose, while the use of a dose calibration curve generated using electrons resulted in an overestimation of the delivered dose. CONCLUSIONS: The relative response of TLD-100 in mixed fields fell consistently between the photon nd electron relative responses. When using TLD-100 in mixed fields, the user must account for this intermediate response to avoid an over- or underestimation of the dose due to calibration in a single photon or electron field.

QSAR in the pharmaceutical research setting: QSAR models for broad, large problems.

The field of quantitative structure activity relationships (QSAR) has evolved into an integral tool for pharmaceutical discovery. It is presently an accessible technology, as can be shown by the number papers which are easily found through PubMed literature searches. At one level, QSAR is used routinely and invisibly as an aid for the bench chemist for logP, logS, pK(a)/pK(b), metabolic stability and other such properties. Chemoinformaticians and computational chemists develop models from scratch for less routine purposes associated with lead optimization around a single target or library design around a target family such as kinase, ion channel or GPCR inhibitors. Regardless of the differences in frequency of use and the end user, any successful QSAR is successful because it rests on appropriate mathematics linking valid data and relevant descriptors. Though success is defined by the end user, the QSAR originator is well advised to validate his model and understand how it performs in different situations. The present review will cover QSAR from the ground up as it is used in pharmaceutical research environments. It will focus towards larger dataset methodologies (a minimum 100 of compounds) and by consequence will focus on 2D descriptors. It will start with the critical base of data, descriptors, equations and validation methods. It will review the broadly used and invisible QSARs for logP, pKa/pKb and metabolic stability. The review will then present progress in QSARs of broad interest which are under active development: 1) hERG liability models, 2) modeling for 2a) drug-likeness and related properties, 2b) kinase ligand likeness and 2c) GPCR ligand likeness.

Highly sensitivity adhesion molecules detection in hereditary haemochromatosis patients reveals altered expression.

Several abnormalities in the immune status of patients with hereditary haemochromatosis (HH) have been reported, suggesting an imbalance in their immune function. This may include persistent production of, or exposure to, altered immune signalling contributing to the pathogenesis of this disorder. Adhesion molecules L-, E- and P-Selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) are some of the major regulators of the immune processes and altered levels of these proteins have been found in pathological states including cardiovascular diseases, arthritis and liver cancer. The aim of this study was to assess L-, E- and P-Selectin, ICAM-1 and VCAM-1 expression in patients with HH and correlate these results with HFE mutation status and iron indexes. A total of 139 subjects were diagnosed with HH (C282Y homozygotes = 87, C282Y/H63D = 26 heterozygotes, H63D homozygotes = 26), 27 healthy control subjects with no HFE mutation (N/N), 18 normal subjects heterozygous for the H63D mutation served as age-sex-matched controls. We observed a significant decrease in L-selectin (P = 0.0002) and increased E-selectin and ICAM-1 (P = 0.0006 and P = 0.0059) expression in HH patients compared with healthy controls. This study observes for the first time that an altered adhesion molecules profile occurs in patients with HH that is associated with specific HFE genetic component for iron overload, suggesting that differential expression of adhesion molecules may play a role in the pathogenesis of HH.

Histone deacetylase inhibitors target diabetes via chromatin remodeling or as chemical chaperones?

Globally, obesity and diabetes (particularly type 2 diabetes) represents a major challenge to world health. Despite decades of intense research efforts, the genetic basis involved in diabetes pathogenesis & conditions associated with obesity are still poorly understood. Recent advances have led to exciting new developments implicating epigenetics as an important mechanism underpinning diabetes and obesity related disease. One epigenetic mechanism known as the "histone code" describes the idea that specific patterns of post-translational modifications to histones act like a molecular "code" recognised and used by non-histone proteins to regulate specific chromatin functions. One modification which has received significant attention is that of histone acetylation. The enzymes which regulate this modification are described as lysine acetyltransferases or KATs and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. Some of the known inhibitors of HDACs (HDACi) have also been shown to act as "chemical chaperones" to alleviate diabetic symptoms. In this review, we discuss the available evidence concerning the roles of HDACs in regulating chaperone function and how this may have implications in the management of diabetes.

Targeting histone deacetylases for the treatment of immune, endocrine & metabolic disorders.

The 'histone code' is a well-established hypothesis describing the idea that specific patterns of post-translational modifications to histones act like a molecular "code" recognised and used by non-histone proteins to regulate specific chromatin functions. One modification which has received significant attention is that of histone acetylation. The enzymes which regulate this modification are described as histone acetyltransferases or HATs, and histone deacetylases or HDACs [1]. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The pro-inflammatory environment is increasingly being recognised as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential & current development of histone deacetylases for the treatment of diseases for which a proinflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the proinflammatory environment.

Targeting histone deacetylases for the treatment of disease.

The 'histone code' is a well-established hypothesis describing the idea that specific patterns of post-translational modifications to histones act like a molecular 'code' recognized and used by non-histone proteins to regulate specific chromatin functions. One modification, which has received significant attention, is that of histone acetylation. The enzymes that regulate this modification are described as lysine acetyltransferases or KATs, and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The pro-inflammatory environment is increasingly being recognized as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential and current development of histone deacetylases for the treatment of diseases for which a pro-inflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the pro-inflammatory environment.

Characterization of tumour necrosis factor-alpha genetic variants and mRNA expression in patients with severe sepsis.

Tumour necrosis factor-alpha (TNFalpha) has been implicated in the pathogenicity of severe sepsis by both genetic association studies and animal models. Conflicting functional data have emerged in relation to genetic variants and TNFalpha protein production. Therefore, we assessed the functionality of TNFalpha genetic variants in terms of mRNA production and their potential influence on outcome in the setting of severe sepsis. Sixty-two Irish Caucasian patients presenting with severe sepsis were recruited and TNFalpha mRNA and protein levels were quantified. Patient DNA was analysed for the presence of common promoter polymorphisms and haplotypes were inferred. An A allele at position -863 was associated with more TNFalpha mRNA on day 1 compared to C homozygotes (P = 0.037). There was a trend for G homozygotes at position -308 to produce more TNFalpha mRNA on day 1 than those carrying an A allele (P = 0.059). The presence of an A allele at -863 was associated with greater levels of TNFalpha mRNA in comparison with patients carrying the A allele at -308 on day 1 (P = 0.02). Patients homozygous for the A allele at position -308 had a higher mortality than those carrying the G allele (P = 0.01). Our data are consistent with recent reports suggesting that a deficient proinflammatory response may be harmful in human sepsis. This deficient inflammatory response may be mediated in part by polymorphisms in the TNFalpha promoter.

Alpha-1 antitrypsin deficiency: a conformational disease associated with lung and liver manifestations.

Alpha-1 antitrypsin (A1AT) is a serine anti-protease produced chiefly by the liver. A1AT deficiency is a genetic disorder characterized by serum levels of less than 11 mumol/L and is associated with liver and lung manifestations. The liver disease, which occurs in up to 15% of A1AT-deficient individuals, is a result of toxic gain-of-function mutations in the A1AT gene, which cause the A1AT protein to fold aberrantly and accumulate in the endoplasmic reticulum of hepatocytes. The lung disease is associated with loss-of-function, specifically decreased anti-protease protection on the airway epithelial surface. The so-called 'Z' mutation in A1AT deficiency encodes a glutamic acid-to-lysine substitution at position 342 in A1AT and is the most common A1AT allele associated with disease. Here we review the current understanding of the molecular pathogenesis of A1AT deficiency and the best clinical management protocols.

Elevated MCP-1 serum levels are associated with the H63D mutation and not the C282Y mutation in hereditary hemochromatosis.

Monocyte chemoattractant protein-1 (MCP-1) is a major lymphocyte and inflammatory chemokine associated with persistent inflammatory states. Several abnormalities in the immune status of patients with hereditary hemochromatosis (HH) have been reported, suggesting an imbalance in their immune function. This may include persistent production of, or exposure to, inflammatory cytokines contributing to the pathogenesis of this disorder. The aim of this study was to assess MCP-1 levels in patients with HH and correlate these results with HFE status and iron indexes. One hundred and thirty-nine subjects diagnosed with HH (C282Y homozygotes = 87, C282Y/H63D = 26 heterozygotes, H63D homozygotes = 26), 27 healthy control subjects with no HFE mutation (N/N), and 18 normal subjects heterozygous for the H63D mutation served as age- and sex-matched controls. Ferritin and transferrin saturation and the presence of HFE mutation status were correlated with MCP-1 levels. Full white blood cell count analysis was also performed. We found a strongly significant decrease in MCP-1 protein levels in the C282Y homozygotes compared with the H63D homozygotes (P = 0.0009) and C282Y/H63D heterozygotes (P = 0.002). Similarly, MCP-1 protein levels in the C282Y homozygotes were decreased compared with the healthy controls (P = 0.00076). Furthermore, MCP-1 serum levels were elevated in H63D patients compared with the healthy controls (P = 0.0008). This study suggests for the first time that a differential expression of MCP-1 protein in patients with HH is associated with the specific HFE genetic component for iron overload. Therefore, these findings offer a possible explanation in the variable clinical spectrum of pathogenesis in patients with HH through abnormalities of an imbalance in the immune states of patients with HH.