Large-scale inference of liver fat with neural networks on UK Biobank body MRI

The UK Biobank Imaging Study has acquired medical scans of more than 40,000 volunteer participants. The resulting wealth of anatomical information has been made available for research, together with extensive metadata including measurements of liver fat. These values play an important role in metabolic disease, but are only available for a minority of imaged subjects as their collection requires the careful work of image analysts on dedicated liver MRI. Another UK Biobank protocol is neck-to-knee body MRI for analysis of body composition. The resulting volumes can also quantify fat fractions, even though they were reconstructed with a two- instead of a three-point Dixon technique. In this work, a novel framework for automated inference of liver fat from UK Biobank neck-to-knee body MRI is proposed. A ResNet50 was trained for regression on two-dimensional slices from these scans and the reference values as target, without any need for ground truth segmentations. Once trained, it performs fast, objective, and fully automated predictions that require no manual intervention. On the given data, it closely emulates the reference method, reaching a level of agreement comparable to different gold standard techniques. The network learned to rectify non-linearities in the fat fraction values and identified several outliers in the reference. It outperformed a multi-atlas segmentation baseline and inferred new estimates for all imaged subjects lacking reference values, expanding the total number of liver fat measurements by factor six

Obesity and pronated foot type may increase the risk of chronic plantar heel pain : a matched case-control study

Background : Chronic plantar heel pain (CPHP) is one of the most common musculoskeletal disorders of the foot, yet its aetiology is poorly understood. The purpose of this study was to examine the association between CPHP and a number of commonly hypothesised causative factors.Methods : Eighty participants with CPHP (33 males, 47 females, mean age 52.3 years, S.D. 11.7) were matched by age (&plusmn; 2 years) and sex to 80 control participants (33 males, 47 females, mean age 51.9 years, S.D. 11.8). The two groups were then compared on body mass index (BMI), foot posture as measured by the Foot Posture Index (FPI), ankle dorsiflexion range of motion (ROM) as measured by the Dorsiflexion Lunge Test, occupational lower limb stress using the Occupational Rating Scale and calf endurance using the Standing Heel Rise Test.Results : Univariate analysis demonstrated that the CPHP group had significantly greater BMI (29.8 &plusmn; 5.4 kg/m2 vs. 27.5 &plusmn; 4.9 kg/m2; P &lt; 0.01), a more pronated foot posture (FPI score 2.4 &plusmn; 3.3 vs. 1.1 &plusmn; 2.3; P &lt; 0.01) and greater ankle dorsiflexion ROM (45.1 &plusmn; 7.1&deg; vs. 40.5 &plusmn; 6.6&deg;; P &lt; 0.01) than the control group. No difference was identified between the groups for calf endurance or time spent sitting, standing, walking on uneven ground, squatting, climbing or lifting. Multivariate logistic regression revealed that those with CPHP were more likely to be obese (BMI &ge; 30 kg/m2) (OR 2.9, 95% CI 1.4 &ndash; 6.1, P &lt; 0.01) and to have a pronated foot posture (FPI &ge; 4) (OR 3.7, 95% CI 1.6 &ndash; 8.7, P &lt; 0.01).Conclusion : Obesity and pronated foot posture are associated with CPHP and may be risk factors for the development of the condition. Decreased ankle dorsiflexion, calf endurance and occupational lower limb stress may not play a role in CPHP.<br /

Plantar calcaneal spurs in older people: longitudinal traction or vertical compression?

<p>Abstract</p> <p>Background</p> <p>Plantar calcaneal spurs are common, however their pathophysiology is poorly understood. This study aimed to evaluate the prevalence and correlates of plantar calcaneal spurs in a large sample of older people.</p> <p>Methods</p> <p>Weightbearing lateral foot radiographs of 216 people (140 women and 76 men) aged 62 to 94 years (mean age 75.9, <smcaps>SD</smcaps> 6.6) were examined for plantar calcaneal and Achilles tendon spurs. Associations between the presence of spurs and sex, body mass index, radiographic measures of foot posture, self-reported co-morbidities and current or previous heel pain were then explored.</p> <p>Results</p> <p>Of the 216 participants, 119 (55%) had at least one plantar calcaneal spur and 103 (48%) had at least one Achilles tendon spur. Those with plantar calcaneal spurs were more likely to have Achilles tendon spurs (odds ratio [OR] = 2.0, 95% confidence interval [CI] 1.2 to 3.5). Prevalence of spurs did not differ according to sex. Participants with plantar calcaneal spurs were more likely to be obese (OR = 7.9, 95% CI 3.6 to 17.0), report osteoarthritis (OR = 2.6, 95% CI 1.6 to 4.8) and have current or previous heel pain (OR = 4.6, 95% CI 2.3 to 9.4). No relationship was found between the presence of calcaneal spurs and radiographic measures of foot posture.</p> <p>Conclusion</p> <p>Calcaneal spurs are common in older men and women and are related to obesity, osteoarthritis and current or previous heel pain, but are unrelated to radiographic measurements of foot posture. These findings support the theory that plantar calcaneal spurs may be an adaptive response to vertical compression of the heel rather than longitudinal traction at the calcaneal enthesis.</p

Should public health interventions aimed at reducing childhood overweight and obesity be gender-focused?

<p>Abstract</p> <p>Background</p> <p>Overweight in childhood is a major public health concern that calls for immediate preventative action. An increasing number of reports suggest that gender specific approaches to prevention may be more effective. However, there is a paucity of information to guide gender-sensitive health promotion and population health interventions for the prevention of overweight in childhood. In the present study, we sought to determine gender-differentials in overweight and underlying behaviors, nutrition and physical activity, among pre-adolescents in Alberta, Canada, to inform the discussion on gender-focused interventions for chronic disease prevention.</p> <p>Methods</p> <p>In 2008, we surveyed 3421 grade five students and their parents of 148 randomly selected schools. Students completed the Harvard food frequency questionnaire, questions on physical activities, and had their height and weight measured. Parents completed questions on socio-economic background and child's lifestyle. We applied multilevel regression methods to assess gender differentials in overweight, nutrition and physical activity.</p> <p>Results</p> <p>Overall, the prevalence of overweight was slightly higher among boys (29.1%) than girls (27.9%) with more pronounced differences in towns and urban geographies. Boys reported to be much more physically active relative to girls (OR = 2.12, 95% CI: 1.73-2.60). Diets of boys, relative to those of girls, reportedly constituted more fat and were less likely to meet the recommendation of 6 daily servings of vegetables and fruits (OR = 0.81, 95% CI: 0.71-0.93).</p> <p>Conclusion</p> <p>Our findings confirm the existence of gender differences in physical activity and nutrition, and support gender-focused health promotion whereby priority is given to physical activity among girls and to healthy eating among boys.</p

Selection of Anti-Sulfadimidine Specific ScFvs from a Hybridoma Cell by Eukaryotic Ribosome Display

BACKGROUND:Ribosome display technology has provided an alternative platform technology for the development of novel low-cost antibody based on evaluating antibiotics derived residues in food matrixes. METHODOLOGY/PRINCIPAL FINDINGS:In our current studies, the single chain variable fragments (scFvs) were selected from hybridoma cell lines against sulfadimidine (SM(2)) by using a ribosome library technology. A DNA library of scFv antibody fragments was constructed for ribosome display, and then mRNA-ribosome-antibody (MRA) complexes were produced by a rabbit reticulocyte lysate system. The synthetic sulfadimidine-ovalbumin (SM(2)-OVA) was used as an antigen to pan MRA complexes and putative scFv-encoding genes were recovered by RT-PCR in situ following each panning. After four rounds of ribosome display, the expression vector pCANTAB5E containing the selected specific scFv DNA was constructed and transformed into Escherichia coli HB2151. Three positive clones (SAS14, SAS68 and SAS71) were screened from 100 clones and had higher antibody activity and specificity to SM(2) by indirect ELISA. The three specific soluble scFvs were identified to be the same molecular weight (approximately 30 kDa) by Western-blotting analysis using anti-E tag antibodies, but they had different amino acids sequence by sequence analysis. CONCLUSIONS/SIGNIFICANCE:The selection of anti-SM(2) specific scFv by in vitro ribosome display technology will have an important significance for the development of novel immunodetection strategies for residual veterinary drugs

Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity

Receptor phosphorylation is thought to be tightly regulated because phosphorylated receptors initiate signaling cascades leading to cellular activation. The T cell antigen receptor (TCR) on the surface of T cells is phosphorylated by the kinase Lck and dephosphorylated by the phosphatase CD45 on multiple immunoreceptor tyrosine-based activation motifs (ITAMs). Intriguingly, Lck sequentially phosphorylates ITAMs and ZAP-70, a cytosolic kinase, binds to phosphorylated ITAMs with differential affinities. The purpose of multiple ITAMs, their sequential phosphorylation, and the differential ZAP-70 affinities are unknown. Here, we use a systems model to show that this signaling architecture produces emergent ultrasensitivity resulting in switch-like responses at the scale of individual TCRs. Importantly, this switch-like response is an emergent property, so that removal of multiple ITAMs, sequential phosphorylation, or differential affinities abolishes the switch. We propose that highly regulated TCR phosphorylation is achieved by an emergent switch-like response and use the systems model to design novel chimeric antigen receptors for therapy

Polymorphism of SERPINE2 gene is associated with pulmonary emphysema in consecutive autopsy cases

<p>Abstract</p> <p>Background</p> <p>The <it>SERPINA1</it>, <it>SERPINA3</it>, and <it>SERPINE2 </it>genes, which encode antiproteases, have been proposed to be susceptible genes for of chronic obstructive pulmonary disease (COPD) and related phenotypes. Whether they are associated with emphysema is not known.</p> <p>Methods</p> <p>Twelve previously reported single nucleotide polymorphisms (SNPs) in <it>SERPINA1 </it>(rs8004738, rs17751769, rs709932, rs11832, rs1303, rs28929474, and rs17580), <it>SERPINA3 </it>(rs4934, rs17473, and rs1800463), and <it>SERPINE2 </it>(rs840088 and rs975278) were genotyped in samples obtained from 1,335 consecutive autopsies of elderly Japanese people. The association between these SNPs and the severity of emphysema, as assessed using macroscopic scores, was determined.</p> <p>Results</p> <p>Emphysema of more than moderate degree was detected in 189 subjects (14.1%) and showed a significant gender difference (males, 20.5% and females, 7.0%; p < 0.0001). Among the 12 examined SNPs, only rs975278 in the <it>SERPINE2 </it>gene was positively associated with emphysema. Unlike the major alleles, homozygous minor alleles of rs975278 were associated with emphysema (odds ratio (OR) = 1.54; 95% confidence interval (CI) = 1.02-2.30; p = 0.037) and the association was very prominent in smokers (OR = 2.02; 95% CI = 1.29-3.15; p = 0.002).</p> <p>Conclusions</p> <p><it>SERPINE2 </it>may be a risk factor for the development of emphysema and its association with emphysema may be stronger in smokers.</p

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a non-neoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known provocation. IPF is a rare disease which affects approximately 5 million persons worldwide. The prevalence is estimated to be slightly greater in men (20.2/100,000) than in women (13.2/100,000). The mean age at presentation is 66 years. IPF initially manifests with symptoms of exercise-induced breathless and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones upon physical exam. Clubbing is found in approximately 50% of IPF patients. Cor pulmonale develops in association with end-stage disease. In that case, classic signs of right heart failure may be present. Etiology remains incompletely understood. Some environmental factors may be associated with IPF (cigarette smoking, exposure to silica and livestock). IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP). The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images and a lung biopsy. In the absence of lung biopsy, the diagnosis of IPF can be made by defined clinical criteria that were published in guidelines endorsed by several professional societies. Differential diagnosis includes other idiopathic interstitial pneumonia, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis and other environmental (sometimes occupational) exposures. IPF is typically progressive and leads to significant disability. The median survival is 2 to 5 years from the time of diagnosis. Medical therapy is ineffective in the treatment of IPF. New molecular therapeutic targets have been identified and several clinical trials are investigating the efficacy of novel medication. Meanwhile, pulmonary transplantation remains a viable option for patients with IPF. It is expected that, during the next decade, considerable progress will be made toward the understanding and treatment of this devastating illness

A new model of development of the mammalian ovary and follicles

Ovarian follicular granulosa cells surround and nurture oocytes, and produce sex steroid hormones. It is believed that during development the ovarian surface epithelial cells penetrate into the ovary and develop into granulosa cells when associating with oogonia to form follicles. Using bovine fetal ovaries (n = 80) we identified a novel cell type, termed GREL for Gonadal Ridge Epithelial-Like. Using 26 markers for GREL and other cells and extracellular matrix we conducted immunohistochemistry and electron microscopy and chronologically tracked all somatic cell types during development. Before 70 days of gestation the gonadal ridge/ovarian primordium is formed by proliferation of GREL cells at the surface epithelium of the mesonephros. Primordial germ cells (PGCs) migrate into the ovarian primordium. After 70 days, stroma from the underlying mesonephros begins to penetrate the primordium, partitioning the developing ovary into irregularly-shaped ovigerous cords composed of GREL cells and PGCs/oogonia. Importantly we identified that the cords are always separated from the stroma by a basal lamina. Around 130 days of gestation the stroma expands laterally below the outermost layers of GREL cells forming a sub-epithelial basal lamina and establishing an epithelial-stromal interface. It is at this stage that a mature surface epithelium develops from the GREL cells on the surface of the ovary primordium. Expansion of the stroma continues to partition the ovigerous cords into smaller groups of cells eventually forming follicles containing an oogonium/oocyte surrounded by GREL cells, which become granulosa cells, all enclosed by a basal lamina. Thus in contrast to the prevailing theory, the ovarian surface epithelial cells do not penetrate into the ovary to form the granulosa cells of follicles, instead ovarian surface epithelial cells and granulosa cells have a common precursor, the GREL cell.Katja Hummitzsch, Helen F. Irving-Rodgers, Nicholas Hatzirodos, Wendy Bonner, Laetitia Sabatier, Dieter P. Reinhardt, Yoshikazu Sado, Yoshifumi Ninomiya, Dagmar Wilhelm and Raymond J. Rodger

Rise and Fall of an Anti-MUC1 Specific Antibody

So far, human antibodies with good affinity and specificity for MUC1, a transmembrane protein overexpressed on breast cancers and ovarian carcinomas, and thus a promising target for therapy, were very difficult to generate.A human scFv antibody was isolated from an immune library derived from breast cancer patients immunised with MUC1. The anti-MUC1 scFv reacted with tumour cells in more than 80% of 228 tissue sections of mamma carcinoma samples, while showing very low reactivity with a large panel of non-tumour tissues. By mutagenesis and phage display, affinity of scFvs was increased up to 500fold to 5,7×10(-10) M. Half-life in serum was improved from below 1 day to more than 4 weeks and was correlated with the dimerisation tendency of the individual scFvs. The scFv bound to T47D and MCF-7 mammalian cancer cell lines were recloned into the scFv-Fc and IgG format resulting in decrease of affinity of one binder. The IgG variants with the highest affinity were tested in mouse xenograft models using MCF-7 and OVCAR tumour cells. However, the experiments showed no significant decrease in tumour growth or increase in the survival rates. To study the reasons for the failure of the xenograft experiments, ADCC was analysed in vitro using MCF-7 and OVCAR3 target cells, revealing a low ADCC, possibly due to internalisation, as detected for MCF-7 cells.Antibody phage display starting with immune libraries and followed by affinity maturation is a powerful strategy to generate high affinity human antibodies to difficult targets, in this case shown by the creation of a highly specific antibody with subnanomolar affinity to a very small epitope consisting of four amino acids. Despite these "best in class" binding parameters, the therapeutic success of this antibody was prevented by the target biology