Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix.

Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix component collagen type I promotes greater adhesion and decreased migration of CRC cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition and liver metastasis. Overall, our study reveals the potential for PAD4-dependant citrullination to drive the progression of CRC liver metastasis.

Sinus pauses and high-grade atrioventricular block in Albright's hereditary osteodystrophy with pseudopseudohypoparathyroidism.

Albright's hereditary osteodystrophy (AHO) is a rare inherited syndrome involving the molecular defects in the gene encoding the α subunit of the stimulatory G protein (Gsα). AHO has several variants, mainly pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP). We present a family that share the same inactivating GNAS1 mutation, the daughter being affected by PPHP and her late father with PHP. The daughter, in her late teens, presented with a long history of presyncopal and syncopal attacks. Her father died suddenly in his mid-40 s. As expected, her laboratory tests to date have shown normal biochemistry and hormonal levels. Subsequently, an implantable loop recorder was inserted. This demonstrated extreme sinus pauses of >11 s and also high-grade atrioventricular block. A dual-chamber pacemaker was therefore inserted.

Cardiac CT: are we underestimating the dose? A radiation dose study utilizing the 2007 ICRP tissue weighting factors and a cardiac specific scan volume.

AIM: To calculate the effective dose from cardiac multidetector computed tomography (MDCT) using a computer-based model utilizing the latest International Commission on Radiation Protection (ICRP) 103 tissue-weighting factors (2007), to compare this dose with those calculated with previously published chest conversion factors and to produce a conversion factor specific for cardiac MDCT. MATERIALS AND METHODS: An observational study of 152 patients attending for cardiac MDCT as part of their usual clinical care in a university teaching hospital. The dose for each examination was calculated using the computer-based anthropomorphic ImPACT model (the imaging performance assessment of CT scanners) and this was compared with the dose derived from the dose-length product (DLP) and a chest conversion factor. RESULTS: The median effective dose calculated using the ImPACT calculator (4.5 mSv) was significantly higher than the doses calculated with the chest conversion factors (2.2-3 mSv). CONCLUSION: The use of chest conversion factors significantly underestimates the effective dose when compared to the dose calculated using the ImPACT calculator. A conversion factor of 0.028 would give a better estimation of the effective dose from prospectively gated cardiac MDCT.

A comparison of radiation doses between state-of-the-art multislice CT coronary angiography with iterative reconstruction, multislice CT coronary angiography with standard filtered back-projection and invasive diagnostic coronary angiography.

OBJECTIVE: To accurately compare the radiation dose between prospectively gated cardiac multidetector CT (with and without iterative reconstruction) and diagnostic invasive coronary angiography using the latest International Commission on Radiological Protection 103 (ICRP) tissue weightings. DESIGN, SETTING AND PATIENTS: A retrospective analysis of consecutive patients presenting to a university teaching hospital for investigation of coronary artery disease. Radiation doses for each technique were calculated using computational Monte Carlo modelling of a standard Cristy phantom rather than the application of previously published conversion factors. While these have frequently been used in other studies, they are based on out-dated ICRP tissue weightings (ICRP 60) and are for the whole chest rather than for structures irradiated in cardiac imaging. In order to allow a comparison, doses were calculated and expressed in terms of effective dose in millisieverts (mSv). RESULTS: From a population presenting for angiography within a clinical service, the median radiation dose from cardiac CT with standard filtered back-projection (84 patients, 5.4 mSv) was comparable with the dose from invasive diagnostic coronary angiography (94 patients, 6.3 mSv). The dose for cardiac CT using iterative reconstruction was significantly lower (39 patients, 2.5 mSv). CONCLUSION: The median effective dose from cardiac CT with standard filtered back-projection was comparable with the effective dose from invasive coronary angiography, even with application of the most contemporary ICRP tissue weightings and use of cardiac specific volumes. Cardiac CT scanning incorporating iterative reconstruction resulted in a significant reduction in the effective dose.

Early maternal and paternal bonding, childhood physical abuse and adult psychopathic personality.

BACKGROUND: A significant gap in the literature on risk factors for psychopathy is the relative lack of research on parental bonding.MethodThis study examines the cross-sectional relationship between maternal and paternal bonding, childhood physical abuse and psychopathic personality at age 28 years in a community sample of 333 males and females. It also assesses prospectively whether children separated from their parents in the first 3 years of life are more likely to have a psychopathic-like personality 25 years later. RESULTS: Hierarchical regression analyses indicated that: (1) poor parental bonding (lack of maternal care and low paternal overprotection) and childhood physical abuse were both associated with a psychopathic personality; (2) parental bonding was significantly associated with psychopathic personality after taking into account sex, social adversity, ethnicity and abuse; (3) those separated from parents in the first 3 years of life were particularly characterized by low parental bonding and a psychopathic personality in adulthood; and (4) the deviant behavior factor of psychopathy was more related to lack of maternal care whereas the emotional detachment factor was related to both lack of maternal care and paternal overprotection. CONCLUSIONS: Findings draw attention to the importance of different components of early bonding in relation to adult psychopathy, and may have potential implications for early intervention and prevention of psychopathy.

Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles.

BACKGROUND: Autoantibodies to cyclic citrullinated peptides (anti-CCP) are present in most patients with rheumatoid arthritis (RA), and associate with HLA-DRB1 shared epitope (SE) alleles. OBJECTIVE: To investigate reactivities of anti-CCP to various citrullinated proteins/peptides, which represent potential autoantigens in RA, and to examine the relationship between such antibodies, and their association with genetic variants within HLA-DRB1 SE alleles. METHODS: Serum samples from 291 patients with established RA and 100 sex- and age-matched healthy subjects were included in this study. Sera were first analysed for presence of anti-CCP antibodies and further for IgG and IgA antibodies towards candidate autoantigens in both their native and citrullinated form including: fibrinogen, alpha-enolase peptide-1 and the C1-epitope of type II collagen (C1(III)). Antibody specificity was confirmed by cross-reactivity tests. HLA-DR genotyping was performed. RESULTS: 72% of patients with RA were anti-CCP positive. Among the candidate autoantigens examined, IgG antibodies to citrullinated fibrinogen were found in 66% of patients' sera and in 41% for both citrullinated alpha-enolase peptide-1 and citrullinated C1(III). These antibodies were mainly seen in the anti-CCP-positive patient group; they were specific for their respective antigen and displayed limited cross reactivity. IgA responses were also detected, but less frequently than IgG. Anti-CCP and anti-citrullinated protein antibodies were associated with HLA-DRB1*04 rather than with HLA-DRB1*01 alleles. CONCLUSIONS: Antibodies directed against several citrullinated antigens are present in CCP-positive RA, with many patients displaying multireactivity. All specific reactivities were primarily associated with the HLA-DRB1*04 alleles, suggesting common pathways of anti-citrulline immunity.

Management of patients presenting with Sjogren's syndrome.

Sjogren's syndrome is an autoimmune exocrinopathy that predominantly affects salivary and lachrymal glands, leading to dry eyes and mouth. The most common clinical problems faced by the rheumatologist are those of dry eyes and mouth, parotid swelling, fatigue and extraglandular manifestations. The first stage in management is to make an accurate diagnosis based on the American/European consensus criteria. The most frequent differential diagnoses are dry eyes and mouth symptoms, a variant of chronic fatigue syndrome and fibromyalgia, and sialosis, which causes a non-inflammatory enlargement of the parotid glands. The mainstay of treatment for the sicca symptoms is local therapy, and that for the milder systemic symptoms is hydroxychloroquine. Steroids and immunosuppressive drugs are reserved for more severe extraglandular disease. In spite of intensive research in other systemic treatments including biologic therapies, there is limited evidence to support their use in routine clinical practice.

Mixed connective tissue disease.

Mixed connective tissue disease (MCTD) was first described in 1972 as a disease syndrome with overlapping features of systemic sclerosis, systemic lupus erythematosus (SLE) and polymyositis associated with antibodies to RNAse sensitive extractable nuclear antigen. When the antigen was subsequently characterized as polypeptides on the U1 ribonuclear protein component of the splicesosome (U1RNP), MCTD became the first rheumatic disease syndrome to be defined by a serologic test. Clinical features include a high frequency of Raynaud's syndrome, swollen hands, sclerodactyly, arthritis, polymyositis and interstitial lung disease. Over the last 30 years there has been a continuing debate as to whether MCTD constitutes a 'distinct clinical entity'. Here, I will review the pathological, immunogenetic and clinical features of MCTD and conclude that the debate remains unresolved. The early misconception that it has a relatively good prognosis has not stood the test of time with long-term follow-up studies. These have identified a tendency for MCTD to evolve into SLE or systemic sclerosis and highlighted pulmonary hypertension and scleroderma renal crisis as important causes of death. Providing it is realized that our appreciation of the clinical features associated with anti-U1RNP have evolved over time, MCTD remains a useful concept in clinical practice. Whether it can be credited with the term 'disease' awaits the demonstration of common etiopathological events underlying the development of antibodies to U1 RNP and their associated clinical features.

Conservation and loss of the ERV3 open reading frame in primates.

The human endogenous retrovirus ERV3 possesses an open reading frame for a truncated envelope, which is expressed as mRNA and protein. Here we examine the env sequence in primates for evidence of evolutionary conservation. ERV3 sequences were amplified by PCR from genomic DNA of great ape and Old World primates but not from New World primates or gorilla, suggesting an integration event more than 30 million years ago with a subsequent loss in one species. In the chimpanzee, the protein sequence of Env is 98.18% identical to that of human. In other species the identity falls (93.71% in rhesus macaque) in proportion to the separation from the human lineage. Start and stop codons and domains of functional significance in the envelope protein are conserved. The evolutionary conservation of the ERV3 envelope suggests a beneficial function, though the loss from gorilla shows that it is not essential for survival or reproduction.

Glucose-6-phosphate isomerase is not a specific autoantigen in rheumatoid arthritis.

OBJECTIVE: To test the hypothesis that glucose-6-phosphate isomerase (GPI) is a novel autoantigen in RA. METHODS: Eighty-eight serum samples from 23 patients with rheumatoid arthritis (RA), 25 with Sjögren's syndrome, 20 with systemic lupus erythematosus and 20 healthy controls were tested by enzyme-linked immunosorbent assay (ELISA) using a commercially available, partially purified rabbit GPI as antigen. Beside each duplicate well containing antigen (10 micro g/ml), uncoated blocked duplicate wells (phosphate-buffered saline only) were included as controls for non-specific binding for every serum tested. We also examined antibodies binding to various polypeptides in the GPI preparation by immunoblotting in 73 of the sera. RESULTS: By ELISA, binding levels were low and there was no difference between serum from patients with RA, other rheumatic diseases and normal controls. By immunoblotting, antibodies binding to the GPI polypeptide were present in 70-80% of all groups tested. In addition, we showed that another polypeptide identified as phosphoglucomutase was also present in the preparation and reacted with human immunoglobulins. CONCLUSION: Our findings suggest that GPI is not a specific autoantigen in RA.

Autoantibodies to human endogenous retrovirus-K are frequently detected in health and disease and react with multiple epitopes.

A number of studies have found increased levels of antibodies to human endogenous retroviruses (HERVs) in autoimmune rheumatic diseases. It is not clear whether this immune response is driven by the HERV itself or by cross-reactions with an exogenous virus or an autoantigen. To address this question, we examined the antibody response to the Env protein of two closely related members of the HERV-K family, HERV-K10 and IDDMK1,222. By immunoblotting of recombinant proteins, antibodies were found in 32-47% of 84 sera from patients with autoimmune rheumatic disease, and 29% of 35 normal controls. Epitope mapping with overlapping 15mers identified multiple reactive peptides on both antigens, with one (GKTCPKEIPKGSKNT) containing immunodominant epitope(s). By ELISA, the median titre of antibody to this peptide was significantly increased in 39 patients with SLE compared to 39 healthy controls and 86 patients with other rheumatic diseases (P < 0.003). We have shown that there is a high frequency of IgG antibodies to HERV-K env sequences in human sera, both in health and autoimmune rheumatic disease, and that the response is to multiple epitopes. This supports the hypothesis that the autoimmune response to HERV-K is antigen-driven and may be an early stage in the chain of events that leads to tolerance breakdown to other autoantigens.

Dry eyes and mouth syndrome--a subgroup of patients presenting with sicca symptoms.

OBJECTIVE: To evaluate the characteristics of patients presenting with symptoms suggestive of Sjögren's syndrome (SS) but failing to satisfy diagnostic criteria. METHODS: Clinical, serological and histological data were collected on 34 patients presenting with dry eyes and/or mouth who did not satisfy the Vitali criteria for the diagnosis of SS. They were compared with 136 patients with primary SS, 38 patients with secondary SS, and 13 patients without SS. Questionnaires on symptoms from each group were compared with 43 healthy controls. RESULTS: The 34 patients who did not satisfy the diagnostic criteria for SS or any other connective tissue disease were designated dry eyes and mouth syndrome (DEMS). Their demography including age was similar to that of a primary SS group and there was no more atrophy seen on their biopsies compared with SS and non-SS controls. They scored highly on visual analogue scales of symptoms but had few objective signs. All were negative for anti-Ro and anti-La although the prevalence of antinuclear antibodies (19%) was increased compared with a normal population. There was no excess of SS-associated tissue types. CONCLUSION: There was no evidence that age, salivary gland atrophy or subclinical SS accounted for the symptoms in DEMS. Most of the patients fitted into a spectrum of disease which tended more towards fibromyalgia and/or chronic fatigue syndrome.

Early educational and health enrichment at age 3-5 years is associated with increased autonomic and central nervous system arousal and orienting at age 11 years: evidence from the Mauritius Child Health Project.

Little is known about the effects of environmental enrichment on psychophysiological measures of arousal and orienting in humans. This study tests the hypothesis that early educational and health enrichment is associated with long-term increases in psychophysiological orienting and arousal. One hundred children were experimentally assigned to a two-year enriched nursery school intervention at ages 3-5 years and matched at age 3 years on psychophysiological measures, gender, and ethnicity to 100 comparisons who received the normal educational experience. Children were retested 6-8 years later at age 11 years on skin conductance (SC) and electroencephalogram (EEG) measures of arousal and attention during pre- and postexperimental rest periods and during the continuous performance task. Nursery enrichment was associated with increased SC amplitudes, faster SC rise times, faster SC recovery times, and less slow-wave EEG during both rest and CPT conditions. This is believed to be the first study to show that early environmental enrichment is associated with long-term increases in psychophysiological orienting and arousal in humans. Results draw attention to the important influence of the early environment in shaping later psychophysiological functioning.

Invariance of the MAST across religious groups.

OBJECTIVE: The Michigan Alcoholism Screening Test (MAST), a commonly used instrument of alcohol-related problems, was examined to determine whether it assessed the same constructs in individuals from religions with different proscriptions regarding the use of alcohol. METHOD: The MAST was completed by participants in the longitudinal Joint Child Health Project when they were approximately 23 years old. Subjects of this study (N= 747; 505 men) were 465 Hindus, 223 Catholics and 59 Muslims who reported drinking alcohol. Measurement invariance, the determination that the same constructs are being measured across groups, was tested by comparing factor invariance using multigroup structural equation modeling. RESULTS: The Hindu and Catholic groups had similar factor structures to those found in previous Australian, Canadian and U.S. samples. Metric invariance was obtained for the Hindu and Catholic groups, but not for the Muslim group. CONCLUSIONS: These findings suggest the measurement of MAST factors is invariant across a fairly broad segment of the population in which the MAST might be used. However, the lack of invariance in this sample of Muslims suggests that the MAST is not an appropriate instrument to use among all groups of drinkers. These findings highlight the importance of testing for invariance when using psychological measures to compare heterogeneous samples.

Delta 32 deletion of CCR5 gene and association with asthma or atopy.

The CCR5-delta32 deletion polymorphism (CCR5-delta32) was investigated for linkage and association to asthma and atopy using two panels of nuclear families containing 1284 individuals. No statistically significant linkage to asthma/wheeze or atopy was observed in either of the two panels of families. Multiallelic transmission disequilibrium tests (TDT) of the combined data found no significant association for atopy (52 independent alleles transmitted, 51 non-transmitted) or asthma/wheeze (39 transmitted, 44 non-transmitted). Although functional evidence might suggest that CCR5 is a good candidate gene for atopic asthma, this study provides no genetic evidence from CCR5-delta32 polymorphism to support this hypothesis.

The content and structure of schizotypy: a study using confirmatory factor analysis.

This study examined the content of subscales within a multidimensional scale of self-reported schizotypy and their subsequent interrelationship by means of confirmatory factor analysis (CFA). Neither single-factor nor four-factor models provided good fits to the data; two-factor and three-factor models showed very good fits. On closer look, the three-factor solution was, overall, marginally the best fit and gave credence to a model with positive schizotypy, negative schizotypy, and social impairment as the factors. This model was in contrast to those that have disorganization as the third factor. In the present study, the subscale of disorganization loaded on the factor of positive schizotypy. The three-factor solution proposed here may be seen as giving support to the structures advocated by Meehl (1962), Strauss et al. (1974), and Lenzenweger et al. (1991).