The window of opportunity: A relevant concept for axial spondyloarthritis

The window of opportunity is a concept critical to rheumatoid arthritis treatment. Early treatment changes the outcome of rheumatoid arthritis treatment, in that response rates are higher with earlier disease-modifying anti-rheumatic drug treatment and damage is substantially reduced. Axial spondyloarthritis is an inflammatory axial disease encompassing both nonradiographic axial spondyloarthritis and established ankylosing spondylitis. In axial spondyloarthritis, studies of magnetic resonance imaging as well as tumor necrosis factor inhibitor treatment and withdrawal studies all suggest that early effective suppression of inflammation has the potential to reduce radiographic damage. This potential would suggest that the concept of a window of opportunity is relevant not only to rheumatoid arthritis but also to axial spondyloarthritis. The challenge now remains to identify high-risk patients early and to commence treatment without delay. Developments in risk stratification include new classification criteria, identification of clinical risk factors, biomarkers, genetic associations, potential antibody associations and an ankylosing spondylitis-specific microbiome signature. Further research needs to focus on the evidence for early intervention and the early identification of high-risk individuals.

Burden attributable to child maltreatment in Australia

Child maltreatment is a complex phenomenon, with four main types (childhood sexual abuse, physical abuse, emotional abuse, and neglect) highly interrelated. All types of maltreatment have been linked to adverse health consequences and exposure to multiple forms of maltreatment increases risk. In Australia to date, only burden attributable to childhood sexual abuse has been estimated. This study synthesized the national evidence and quantified the burden attributable to the four main types of child maltreatment. Meta-analyses, based on quality-effects models, generated pooled prevalence estimates for each maltreatment type. Exposure to child maltreatment was examined as a risk factor for depressive disorders, anxiety disorders and intentional self-harm using counterfactual estimation and comparative risk assessment methods. Adjustments were made for co-occurrence of multiple forms of child maltreatment. Overall, an estimated 23.5% of self-harm, 20.9% of anxiety disorders and 15.7% of depressive disorders burden in males; and 33.0% of self-harm, 30.6% of anxiety disorders and 22.8% of depressive disorders burden in females was attributable to child maltreatment. Child maltreatment was estimated to cause 1.4% (95% uncertainty interval 0.4–2.3%) of all disability-adjusted life years (DALYs) in males, and 2.4% (0.7–4.1%) of all DALYs in females in Australia in 2010. Child maltreatment contributes to a substantial proportion of burden from depressive and anxiety disorders and intentional self-harm in Australia. This study demonstrates the importance of including all forms of child maltreatment as risk factors in future burden of disease studies.

Current trends in the etiology and diagnosis of HPV-related head and neck cancers

Human papilloma virus (HPV) infection is a major risk factor for a distinct subset of head and neck squamous cell carcinoma (HNSCC). The current review summarizes the epidemiology of HNSCC and the disease burden, the infectious cycle of HPV, the roles of viral oncoproteins, E6 and E7, and the downstream cellular events that lead to malignant transformation. Current techniques for the clinical diagnosis of HPV-associated HNSCC will also be discussed, that is, the detection of HPV DNA, RNA, and the HPV surrogate marker, p16 in tumor tissues, as well as HPV-specific antibodies in serum. Such methods do not allow for the early detection of HPV-associated HNSCC and most cases are at an advanced stage upon diagnosis. Novel noninvasive approaches using oral fluid, a clinically relevant biological fluid, allow for the detection of HPV and cellular alterations in infected cells, which may aid in the early detection and HPV-typing of HNSCC tumors. Noninvasive diagnostic methods will enable early detection and intervention, leading to a significant reduction in mortality and morbidity associated with HNSCC.

Effects of Tamoxifen and oestrogen on histology and radiographic density in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers

Mammographic density (MD) is a strong risk factor for breast cancer. It is altered by exogenous endocrine treatments, including hormone replacement therapy and Tamoxifen. Such agents also modify breast cancer (BC) risk. However, the biomolecular basis of how systemic endocrine therapy modifies MD and MD-associated BC risk is poorly understood. This study aims to determine whether our xenograft biochamber model can be used to study the effectiveness of therapies aimed at modulating MD, by examine the effects of Tamoxifen and oestrogen on histologic and radiographic changes in high and low MD tissues maintained within the biochamber model. High and low MD human tissues were precisely sampled under radiographic guidance from prophylactic mastectomy fresh specimens of high-risk women, then inserted into separate vascularized murine biochambers. The murine hosts were concurrently implanted with Tamoxifen, oestrogen or placebo pellets, and the high and low MD biochamber tissues maintained in the murine host environment for 3 months, before the high and low MD biochamber tissues were harvested for histologic and radiographic analyses. The radiographic density of high MD tissue maintained in murine biochambers was decreased in Tamoxifen-treated mice compared to oestrogen-treated mice (p = 0.02). Tamoxifen treatment of high MD tissue in SCID mice led to a decrease in stromal (p = 0.009), and an increase in adipose (p = 0.023) percent areas, compared to placebo-treated mice. No histologic or radiographic differences were observed in low MD biochamber tissue with any treatment. High MD biochamber tissues maintained in mice implanted with Tamoxifen, oestrogen or placebo pellets had dynamic and measurable histologic compositional and radiographic changes. This further validates the dynamic nature of the MD xenograft model, and suggests the biochamber model may be useful for assessing the underlying molecular pathways of Tamoxifen-reduced MD, and in testing of other pharmacologic interventions in a preclinical model of high MD.

Impact of diurnal temperature range on human health: a systematic review

Increasing epidemiological studies have shown that a rapid temperature change within 1 day is an independent risk factor for human health. This paper aimed to systematically review the epidemiological evidence on the relationship between diurnal temperature range (DTR) and human health and to propose future research directions. A literature search was conducted in October 2013 using the databases including PubMed, ScienceDirect, and EBSCO. Empirical studies regarding the relationship between DTR and mortality and morbidity were included. Twenty-five relevant studies were identified, among which, 11 investigated the relationship between DTR and mortality and 14 examined the impact of DTR on morbidity. The majority of existing studies reported that DTR was significantly associated with mortality and morbidity, particularly for cardiovascular and respiratory diseases. Notably, compared with adults, the elderly and children were more vulnerable to DTR effects. However, there were some inconsistencies regarding the susceptible groups, lag time, and threshold of DTR. The impact of DTR on human health may be confounded or modified by season, socioeconomic, and educational status. Further research is needed to further confirm the adverse effects of DTR in different geographical locations; examine the effects of DTR on the health of children aged one or under; explore extreme DTR effects on human health; analyze the difference of DTR effects on human health in different locations and the modified effects of potential confounding factors; and develop detailed preventive measures against large DTR, particularly for susceptible groups

Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: A Mendelian randomisation analysis

Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1α and IL-1β); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0·22 SD (95% CI 0·18–0·25; 12·5%; p=9·3 × 10−33), concentrations of interleukin 6 decreased by 0·02 SD (−0·04 to −0·01; −1·7%; p=3·5 × 10−3), and concentrations of C-reactive protein decreased by 0·03 SD (−0·04 to −0·02; −3·4%; p=7·7 × 10−14). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1·15 (1·08–1·22; p=1·8 × 10−6) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1·03 (1·02–1·04; p=3·9 × 10−10). Per-allele odds ratios were 0·97 (0·95–0·99; p=9·9 × 10−4) for rheumatoid arthritis, 0·99 (0·97–1·01; p=0·47) for type 2 diabetes, 1·00 (0·98–1·02; p=0·92) for ischaemic stroke, and 1·08 (1·04–1·12; p=1·8 × 10−5) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1α/β inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Funding UK Medical Research Council, British Heart Foundation, UK National Institute for Health Research, National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council, and European Commission Framework Programme 7.

Genetics of ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory arthritis that affects the spine and sacroiliac joints. It causes significant disability and is associated with a number of other features including peripheral arthritis, anterior uveitis, psoriasis and inflammatory bowel disease (IBD). Significant progress has been made in the genetics of AS have in the last five years, leading to new treatments in trial, and major leaps in understanding of the aetiopathogenesis of the disease.

Factors associated with depression among male casual laborers in urban Vietnam

This study examined the level, the prevalence of and the factors associated with depression among male casual laborers in Hanoi. Social mapping was done to recruit and interview 450 men aged over 18 years, mostly unskilled and unregistered laborers from 135 street venues across 13 districts of the city using a structured questionnaire. Most were from rural and mountainous provinces and did manual works such as motorbike taxi drivers, porters, construction workers, small traders and others in the current city. The prevalence of self-reported depressive symptoms (25 %) was high. Structural equation modeling showed that marriage, family separation and living with peers or partners were three significant distal risk factors, while illicit drug use and low social connectedness were proximal predictors of depression. Of all factors, social connectedness appeared to be the most important because it plays a mediating role. Drug use was an independent risk factor. This study provides a model to understand the mental health of male casual laborers and to develop culturally appropriate intervention programs for these men

Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

Serum vitamin D levels are lower in Australian children and adolescents with type 1 diabetes than in children without diabetes

Vitamin D is synthesised in the skin through the action of UVB radiation (sunlight), and 25-hydroxy vitamin D (25OHD) measured in serum as a marker of vitamin D status. Several studies, mostly conducted in high latitudes, have shown an association between type 1 diabetes mellitus (T1DM) and low serum 25OHD. We conducted a case-control study to determine whether, in a sub-tropical environment with abundant sunlight (latitude 27.5°S), children with T1DM have lower serum vitamin D than children without diabetes. Fifty-six children with T1DM (14 newly diagnosed) and 46 unrelated control children participated in the study. Serum 25OHD, 1,25-dihydroxy vitamin D (1,25(OH)2D) and selected biochemical indices were measured. Vitamin D receptor (VDR) polymorphisms Taq1, Fok1, and Apa1 were genotyped. Fitzpatrick skin classification, self-reported daily hours of outdoor exposure, and mean UV index over the 35d prior to blood collection were recorded. Serum 25OHD was lower in children with T1DM (n=56) than in controls (n=46) [mean (95%CI)=78.7 (71.8-85.6) nmol/L vs. 91.4 (83.5-98.7) nmol/L, p=0.02]. T1DM children had lower self-reported outdoor exposure and mean UV exposure, but no significant difference in distribution of VDR polymorphisms. 25OHD remained lower in children with T1DM after covariate adjustment. Children newly diagnosed with T1DM had lower 1,25(OH)2D [median (IQR)=89 (68-122) pmol/L] than controls [121 (108-159) pmol/L, p=0.03], or children with established diabetes [137 (113-153) pmol/L, p=0.01]. Children with T1DM have lower 25OHD than controls, even in an environment of abundant sunlight. Whether low vitamin D is a risk factor or consequence of T1DM is unknown. © 2012 John Wiley & Sons A/S.

Signs of driver sleepiness and risky sleepy driving behaviours: the associations with demographic, work and sleep-related factors

Driving while sleepy is regarded as a substantial crash risk factor. Reducing the risk of sleep-related crashes predominately rests with the driver’s awareness of experiencing signs that are common when sleepy; such as yawning, frequent eye blinks, and difficulty keeping eyes open. However the relationship between the signs of sleepiness and risky sleepy driving behaviours is largely unknown. The current study sought to examine the relationships between drivers’ experiences of the signs of sleepiness, risky sleepy driving behaviours, and the associations with demographic, work and sleep-related factors. In total 1,608 participants completed a questionnaire administered via a telephone interview that assessed their experiences and behaviours of driving while sleepy. The results revealed a number of demographic, work and sleep-related factors were associated with experiencing signs of sleepiness when driving. Signs of sleepiness were also found to mediate the relationship between continuing to drive while sleepy and having a sleep-related close call event. A subgroup analysis based on age (under 30 and 30 years or older) found younger drivers were more likely to continue to drive when sleepy despite experiencing more signs of sleepiness. The results suggest participants had considerable experience with the signs of sleepiness and driving while sleepy. Actions to be taken from this research include informing the content of driver education campaigns regarding the importance of the signs of sleepiness. Working together to educate all drivers about the dangerousness of driving when experiencing signs of sleepiness is an important road safety outcome.

Genome-wide association study of intraocular pressure identifies the GLCCI1/ICA1 region as a glaucoma susceptibility locus

To discover quantitative trait loci for intraocular pressure, amajor risk factor for glaucoma and the only modifiable one,weperformed agenome-wide association studyonadiscoverycohort of2175individualsfromSydney, Australia. We found a novel association between intraocular pressure and a common variant at 7p21 near to GLCCI1 and ICA1. The findings in this region were confirmed through two UK replication cohorts totalling 4866 individuals (rs59072263, Pcombined = 1.10 × 10-8). A copy of the G allele at this SNP is associated with an increase in mean IOP of 0.45 mmHg (95%CI = 0.30-0.61 mmHg). These results lend support to the implication of vesicle trafficking and glucocorticoid inducibility pathways in the determination of intraocular pressure and in the pathogenesis of primary open-angle glaucoma.

Immunopathogenesis of ankylosing spondylitis

Ankylosing spondylitis is a model immunogenetic disease with major common and rare genetic risk factors, likely environmental contributors to its pathogenesis and, to date, no treatment that has been shown to induce disease remission in long-term studies. The discovery of the association of HLA-B27 with the disease in the early 1970s triggered extensive efforts to elucidate the mechanism of this association. However, the precise role of HLA-B27 in ankylosing spondylitis pathogenesis remains unclear. In recent years, rapid progress made in the discovery of non-MHC genes involved in susceptibility to ankylosing spondylitis has combined with increasing ability to investigate the immune system to make rapid progress in unraveling the etiopathogenesis of the condition. © 2013 Future Medicine Ltd.

Attainment of early feeding milestones in preterm neonates

Objective: This study aimed to document the ages at which preterm neonates commence suckle-feeds and attain exclusive suckle-feeding, as well as the time taken to transition from commencement of suckle-feeds to exclusive suckle-feeding. It was hypothesized that gestational age (GA) at birth and degree of neonatal morbidity would influence the timing of these early feeding milestones. Study Design: A chart review was conducted for all neonates born <37;0 weeks GA admitted to a tertiary level perinatal facility over a 12-month period (n=735). Complete data relating to attainment of feeding milestones were available on 472 neonates. Results: Correlation analysis indicated that both a low GA at birth and a high neonatal morbidity rating were statistically significantly correlated with an increased transition time from commencement of suckle-feeds to exclusive suckle-feeding. Cox regression indicated that both of these variables were statistically significant risk factors for a delayed GA at attainment of exclusive suckle-feeding. Conclusion: Preterm neonates who were less mature at birth and/or who displayed a greater degree of neonatal morbidity took longer to transition from starting suckle-feeds to achieving independent suckle-feeding, and were more mature at attainment of independent suckle-feeding.

Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21

We performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in an additional cohort of 1039 French PD cases and 1984 controls for the 27 regions showing the strongest evidence of association (P < 10 4). We replicated published associations in the 4q22/SNCA and 17q21/MAPT chromosome regions (P < 10 10) and found evidence for an additional independent association in 4q22/SNCA.A detailed analysis of the haplotype structure at 17q21 showed that there are three separate risk groups within this region. We found weak but consistent evidence of association for common variants located in three previously published associated regions (4p15/BST1, 4p16/GAK and 1q32/PARK16). We found no support for the previously reported SNP association in 12q12/LRRK2. We also found an association of the two SNPs in 4q22/SNCA with the age of onset of the disease. © The Author 2010. Published by Oxford University Press.