Aberrant Motility in Unaffected Small Bowel is Linked to Inflammatory Burden and Patient Symptoms in Crohn's Disease.

BACKGROUND: Inflammation-related enteric dysmotility has been postulated as a cause for abdominal symptoms in Crohn's disease (CD). We investigated the relationship between magnetic resonance imaging-quantified small bowel (SB) motility, inflammatory activity, and patient symptom burden. METHODS: The Harvey-Bradshaw index (HBI) and fecal calprotectin were prospectively measured in 53 patients with CD (median age, 35; range, 18-78 years) the day before magnetic resonance enterography, which included a dynamic (cine), breath-hold motility sequence, repeated to encompass the whole SB volume. A validated registration-based motility quantitation technique produced motility maps, and regions of interest were drawn to include all morphologically normal SB (i.e., excluding diseased bowel). Global SB motility was correlated with calprotectin, HBI, and symptom components (well-being, pain, and diarrhea). Adjustment for age, sex, smoking, and surgical history was made using multivariate linear regression. RESULTS: Median calprotectin was 336 (range, 0-1280). Median HBI, motility mean, and motility variance were 3 (range, 0-16), 0.33 (0.18-0.51), and 0.01 (0.0014-0.034), respectively. Motility variance was significantly negatively correlated with calprotectin (rho = -0.33, P = 0.015), total HBI (rho = -0.45, P 0.05). CONCLUSIONS: Reduced motility variance in morphologically normal SB is associated with patient symptoms and fecal calprotectin levels, supporting the hypothesis that inflammation-related enteric dysmotility may explain refractory abdominal symptoms in CD

Estimation of contrast agent bolus arrival delays for improved reproducibility of liver DCE MRI

Delays between contrast agent (CA) arrival at the site of vascular input function (VIF) sampling and the tissue of interest affect dynamic contrast enhanced (DCE) MRI pharmacokinetic modelling. We investigate effects of altering VIF CA bolus arrival delays on liver DCE MRI perfusion parameters, propose an alternative approach to estimating delays and evaluate reproducibility. Thirteen healthy volunteers (28.7  ±  1.9 years, seven males) underwent liver DCE MRI using dual-input single compartment modelling, with reproducibility (n  =  9) measured at 7 days. Effects of VIF CA bolus arrival delays were assessed for arterial and portal venous input functions. Delays were pre-estimated using linear regression, with restricted free modelling around the pre-estimated delay. Perfusion parameters and 7 days reproducibility were compared using this method, freely modelled delays and no delays using one-way ANOVA. Reproducibility was assessed using Bland–Altman analysis of agreement. Maximum percent change relative to parameters obtained using zero delays, were  −31% for portal venous (PV) perfusion, +43% for total liver blood flow (TLBF), +3247% for hepatic arterial (HA) fraction, +150% for mean transit time and  −10% for distribution volume. Differences were demonstrated between the 3 methods for PV perfusion (p  =  0.0085) and HA fraction (p  <  0.0001), but not other parameters. Improved mean differences and Bland–Altman 95% Limits-of-Agreement for reproducibility of PV perfusion (9.3 ml/min/100 g, ±506.1 ml/min/100 g) and TLBF (43.8 ml/min/100 g, ±586.7 ml/min/100 g) were demonstrated using pre-estimated delays with constrained free modelling. CA bolus arrival delays cause profound differences in liver DCE MRI quantification. Pre-estimation of delays with constrained free modelling improved 7 days reproducibility of perfusion parameters in volunteers

Diffusion-weighted imaging for evaluating inflammatory activity in Crohn's disease: comparison with histopathology, conventional MRI activity scores, and faecal calprotectin

PURPOSE: To evaluate whether the extent of enteric diffusion-weighted imaging (DWI) signal abnormality reflects inflammatory burden in Crohn's disease (CD), and to compare qualitative and quantitative grading. METHODS: 69 CD patients (35 male, age 16-78) undergoing MR enterography with DWI (MRE-D) and the same-day faecal calprotectin (cohort 1) were supplemented by 29 patients (19 male, age 16-70) undergoing MRE-D and terminal ileal biopsy (cohort 2). Global (cohort 1) and terminal ileal (cohort 2) DWI signal was graded (0 to 3) by 2 radiologists and segmental apparent diffusion coefficient (ADC) calculated. Data were compared to calprotectin and a validated MRI activity score [MEGS] (cohort 1), and a histopathological activity score (eAIS) (cohort 2) using nonparametric testing and rank correlation. RESULTS: Patients with normal (grades 0 and 1) DWI signal had lower calprotectin and MEGS than those with abnormal signal (grades 2 and 3) (160 vs. 492 μg/l, p = 0.0004, and 3.3 vs. 21, p  120 μg/l) were 83% and 52%, respectively. There was a negative correlation between ileal MEGS and ADC (r = -0.41, p = 0.017). There was no significant difference in eAIS between qualitative DWI scores (p = 0.42). Mean ADC was not different in those with and without histological inflammation (2077 vs. 1622 × 10(-6)mm(2)/s, p = 0.10) CONCLUSIONS: Qualitative grading of DWI signal has utility in defining the burden of CD activity. Quantitative ADC measurements have poor discriminatory ability for segmental disease activity

The potential role of Antarctic krill faecal pellets in efficient carbon export at the marginal ice zone of the South Orkney Islands in spring

Antarctic krill (Euphausia superba) play a central role in the food web of the Southern Ocean, forming a link between primary production and large predators. Krill produce large, faecal pellets (FP) which can form a large component of mesopelagic particulate organic carbon (POC) fluxes. However, the patchy distribution of krill swarms, highly variable pellet composition, and variable sinking and attenuation rates means that these episodic, but potentially large, carbon fluxes are difficult to sample or model. We measured particle flux and type using Marine Snow Catchers (MSC) in the marginal ice zone near the South Orkneys, Antarctica. Krill FP were the dominant component of the POC flux in the upper 200 m (typically 60–85%). FP sinking velocities measured onboard were highly variable (15–507 m d− 1) but overall high, with mean equivalent velocities of 172, 267, and 161 m d− 1 at our three stations. The high numbers of krill FP sinking through the mesopelagic suggest that krill FP can be transferred efficiently and/or that rates of krill FP production are high. We compared our direct MSC-derived estimates of krill FP POC flux (33–154 mg C m− 2 d− 1) and attenuation to estimates of krill FP production based on previous measurements of krill density and literature FP egestion rates, and estimated net krill FP attenuation rates in the upper mesopelagic. Calculated attenuation rates are sensitive to krill densities in the overlying water column but suggest that krill FP could be transferred efficiently through the upper mesopelagic, and, in agreement with our MSC attenuation estimates, could make large contributions to bathypelagic POC fluxes. Our study contrasts with some others which suggest rapid FP attenuation, highlighting the need for further work to constrain attenuation rates and assess how important the contribution of Antarctic krill FP could be to the Southern Ocean biological carbon pump

Insulin autoantibodies as determined by competitive radiobinding assay are positively correlated with impaired beta-cell function — The Ulm-Frankfurt population study

Out of a random population of 4208 non-diabetic pupils without a family history of Type I diabetes 44 (1.05%) individuals had islet cell antibody (ICA) levels greater or equal to 5 Juvenile Diabetes Foundation (JDF) units. 39 of these ICA-positives could be repeatedly tested for circulating insulin autoantibodies (CIAA) using a competitive radiobinding assay. The results were compared with the insulin responses in the intravenous glucose tolerance tests (IVGTT) and with HLA types. Six pupils were positive for CIAA. All of them had complement-fixing ICA, and 5 of them were HLA-DR4 positive. Three of the 6 showed a first-phase insulin response below the first percentile of normal controls. Our data indicate that in population-based studies CIAA can be considered as a high risk marker for impaired beta-cell function in non-diabetic ICA-positive individuals

Brief Report: AIP Mutation in Pituitary Adenomas in the 18th Century and Today

From New England Journal of Medicine, Volume 364, issue 1, p.43-50. Copyright © (2011) Massachusetts Medical Society. Reprinted with permission.Gigantism results when a growth hormone–secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783,1-3 he noted an enlarged pituitary fossa. We extracted DNA from the patient’s teeth and identified a germline mutation in the aryl hydrocarbon–interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier

Serotonin and corticosterone rhythms in mice exposed to cigarette smoke and in patients with COPD:implication for COPD-associated neuropathogenesis

The circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS) can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD) have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT) is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT) is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT) is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d), sub-chronic (10 d) or chronic (6 mo) CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase) and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Can big data solve a big problem? Reporting the obesity data landscape in line with the Foresight obesity system map.

BACKGROUND: Obesity research at a population level is multifaceted and complex. This has been characterised in the UK by the Foresight obesity systems map, identifying over 100 variables, across seven domain areas which are thought to influence energy balance, and subsequent obesity. Availability of data to consider the whole obesity system is traditionally lacking. However, in an era of big data, new possibilities are emerging. Understanding what data are available can be the first challenge, followed by an inconsistency in data reporting to enable adequate use in the obesity context. In this study we map data sources against the Foresight obesity system map domains and nodes and develop a framework to report big data for obesity research. Opportunities and challenges associated with this new data approach to whole systems obesity research are discussed. METHODS: Expert opinion from the ESRC Strategic Network for Obesity was harnessed in order to develop a data source reporting framework for obesity research. The framework was then tested on a range of data sources. In order to assess availability of data sources relevant to obesity research, a data mapping exercise against the Foresight obesity systems map domains and nodes was carried out. RESULTS: A reporting framework was developed to recommend the reporting of key information in line with these headings: Background; Elements; Exemplars; Content; Ownership; Aggregation; Sharing; Temporality (BEE-COAST). The new BEE-COAST framework was successfully applied to eight exemplar data sources from the UK. 80% coverage of the Foresight obesity systems map is possible using a wide range of big data sources. The remaining 20% were primarily biological measurements often captured by more traditional laboratory based research. CONCLUSIONS: Big data offer great potential across many domains of obesity research and need to be leveraged in conjunction with traditional data for societal benefit and health promotion