Tracking physical activity using smart phone apps: assessing the ability of a current app and systematically collecting patient recommendations for future development.

BACKGROUND: Within the United Kingdom's National Health System (NHS), patients suffering from obesity may be provided with bariatric surgery. After receiving surgery many of these patients require further support to continue to lose more weight or to maintain a healthy weight. Remotely monitoring such patients' physical activity and other health-related variables could provide healthworkers with a more 'ecologically valid' picture of these patients' behaviours to then provide more personalised support. The current study assesses the feasibility of two smartphone apps to do so. In addition, the study looks at the barriers and facilitators patients experience to using these apps effectively. METHODS: Participants with a BMI > 35 kg/m2 being considered for and who had previously undergone bariatric surgery were recruited. Participants were asked to install two mobile phone apps. The 'Moves' app automatically tracked participants' physical activity and the 'WLCompanion' app prompted participants to set goals and input other health-related information. Then, to learn about participants' facilitators and barriers to using the apps, some participants were asked to complete a survey informed by the Theoretical Domains Framework. The data were analysed using regressions and descriptive statistics. RESULTS: Of the 494 participants originally enrolled, 274 participants data were included in the analyses about their activity pre- and/or post-bariatric surgery (ages 18-65, M = 44.02, SD ± 11.29). Further analyses were performed on those 36 participants whose activity was tracked both pre- and post-surgery. Participants' activity levels pre- and post-surgery did not differ. In addition, 54 participants' survey responses suggested that the main facilitator to their continued use of the Moves app was its automatic nature, and the main barrier was its battery drain. CONCLUSIONS: The current study tracked physical activity in patients considered for and who had previously undergone bariatric surgery. The results should be interpreted with caution because of the small number of participants whose data meet the inclusion criteria and the barriers participants encountered to using the apps. Future studies should take note of the barriers to develop more user-friendly apps. TRIAL REGISTRATION: ClinicalTrials.gov- NCT01365416 on the 3rd of June 2011.

Cortical Lewy bodies and Aß burden are associated with prevalence and timing of dementia in Lewy body diseases.

AIMS: Our main objective was to determine the neuropathological correlates of dementia in patients with Lewy body disease (LBD). Furthermore, we used data derived from clinical, neuropathological and genetic studies to investigate boundary issues between Dementia with Lewy bodies (DLB) and Parkinson's disease with (PDD) and without (PDND) dementia. METHODS: One hundred and twenty-one cases with a neuropathological diagnosis of LBD and clinical information on dementia status were included in the analysis (55 PDD, 17 DLB and 49 PDND). We carried out topographical and semi-quantitative assessment of Lewy bodies (LB), Aß plaques and tau-positive neuropil threads (NT). The APOE genotype and MAPT haplotype status were also determined. RESULTS: The cortical LB (CLB) burden was the only independent predictor of dementia (OR: 4.12, P < 0.001). The total cortical Aß plaque burden was an independent predictor of a shorter latency to dementia from onset of motor signs (P = 0.001). DLB cases had a higher LB burden in the parietal and temporal cortex, compared to PDD. Carrying at least one APOE ϵ4 allele was associated with a higher cortical LB burden (P = 0.02), particularly in the neocortical frontal, parietal and temporal regions. CONCLUSIONS: High CLB burden is a key neuropathological substrate of dementia in LBD. Elevated cortical LB pathology and Aß plaque deposition are both correlated with a faster progression to dementia. The higher CLB load in the temporal and parietal regions, which seems to be a distinguishing feature of DLB, may account for the shorter latency to dementia and could be mediated by the APOE ϵ4 allele.

Replication of 13 obesity loci among Singaporean Chinese, Malay and Asian-Indian populations.

OBJECTIVE: Recent genome-wide association studies (GWAS) have identified 38 obesity-associated loci among European populations. However, their contribution to obesity in other ethnicities is largely unknown. METHODS: We utilised five GWAS (N=10 482) from Chinese (three cohorts, including one with type 2 diabetes and another one of children), Malay and Indian ethnic groups from Singapore. Data sets were analysed individually and subsequently in combined meta-analysis for Z-score body-mass index (BMI) associations. RESULTS: Variants at the FTO locus showed the strongest associations with BMI Z-score after meta-analysis (P-values 1.16 × 10(-7)-7.95 × 10(-7)). We further detected associations with nine other index obesity variants close to the MC4R, GNPDA2, TMEM18, QPCTL/GIPR, BDNF, ETV5, MAP2K5/SKOR1, SEC16B and TNKS/MSRA loci (meta-analysis P-values ranging from 3.58 × 10(-4)-1.44 × 10(-2)). Three other single-nucleotide polymorphisms (SNPs) from CADM2, PTBP2 and FAIM2 were associated with BMI (P-value ≤ 0.0418) in at least one dataset. The neurotrophin/TRK pathway (P-value=0.029) was highlighted by pathway-based analysis of loci that had statistically significant associations among Singaporean populations. CONCLUSION: Our data confirm the role of FTO in obesity predisposition among Chinese, Malays and Indians, the three major Asian ethnic groups. We additionally detected associations for 12 obesity-associated SNPs among Singaporeans. Thus, it is likely that Europeans and Asians share some of the genetic predisposition to obesity. Furthermore, the neurotrophin/TRK signalling may have a central role for common obesity among Asians.

Genetic Obesity and Bariatric Surgery Outcome in 1014 Patients with Morbid Obesity.

BACKGROUND: Mutations in the leptin-melanocortin pathway genes are known to cause monogenic obesity. The prevalence of these gene mutations and their effect on weight loss response after bariatric surgery are still largely unknown. OBJECTIVE: To determine the prevalence of genetic obesity in a large bariatric cohort and evaluate their response to bariatric surgery. METHODS: Mutation analysis of 52 obesity-associated genes. Patient inclusion criteria were a BMI > 50 kg/m2, an indication for revisional surgery or an early onset of obesity (< 10 years of age). RESULTS: A total of 1014 patients were included, of whom 30 (3%) were diagnosed with genetic obesity, caused by pathogenic heterozygous mutations in either MC4R, POMC, PCSK1, SIM1, or PTEN. The percentage total body weight loss (%TBWL) after Roux-en-Y gastric bypass (RYGB) surgery was not significantly different for patients with a mutation in MC4R, POMC, and PCSK1 compared with patients lacking a molecular diagnosis. Of the confirmed genetic obesity cases, only patients with MC4R mutations receiving a sleeve gastrectomy (SG) showed significantly lower %TBWL compared with patients lacking a molecular diagnosis, during 2 years of follow-up. CONCLUSIONS: In this cohort of morbid obese bariatric patients, an estimated prevalence of monogenic obesity of 3% is reported. Among these patients, the clinical effects of heterozygous mutations in POMC and PCSK1 do not interfere with the effectiveness of most commonly performed bariatric procedures within the first 2 years of follow-up. Patients with MC4R mutations achieved superior weight loss after primary RYGB compared with SG.

Human genes involved in copy number variation: mechanisms of origin, functional effects and implications for disease.

Copy number variants (CNVs) overlap over 7000 genes, many of which are pivotal in biological pathways. The implications of this are profound, with consequences for evolutionary studies, population genetics, gene function and human phenotype, including elucidation of genetic susceptibility to major common diseases, the heritability of which has thus far defied full explanation. Even though this research is still in its infancy, CNVs have already been associated with a number of monogenic, syndromic and complex diseases: the development of high throughput and high resolution techniques for CNV screening is likely to bring further new insights into the contribution of copy number variation to common diseases. Amongst genes overlapped by CNVs, significant enrichments for certain gene ontology categories have been identified, including those related to immune responses and interactions with the environment. Genes in both of these categories are thought to be important in evolutionary adaptation and to be particular targets of natural selection. Thus, a full appreciation of copy number variation may be important for our understanding of human evolution.

Transforming growth factor-beta1 SNPs: genetic and phenotypic correlations in progressive kidney insufficiency.

Associations have been described between polymorphisms of cytokine and growth factor genes and susceptibility to, or progression of, an increasing number of diseases. TGF-beta1 plays an important role in the pathogenesis of experimental and clinical glomerulosclerosis and tubulointerstitial fibrosis. In this study, single nucleotide polymorphisms (SNPs) in the TGFbeta1 gene were investigated as possible markers for the progression of chronic kidney failure (CKF). 145 Caucasian patients with CKF were screened for four TGFbeta1 SNPs: T-509C in the promoter region; Arg25Pro and Leu10Pro in exon 1 and Thr263Ile in exon 5. There were significant differences between CKF patients and controls in allele frequencies of two of the SNPs, Leu10Pro (p = 0.038) and C-509T (p = 0.02) and in haplotype distributions (p = 0.0175), indicating an association with susceptibility to CKF. We also observed a significant association between progression of CKF and homozygosity for Arg25 (odds ratio 3.77, 95% confidence interval 1.57-9.04, p = 0.002). Homozygosity for Arg25 was also associated with severity of proteinuria at diagnosis (p = 0.038), plasma TGF-beta1 protein levels (p = 0.01), and severity of glomerulosclerosis (p = 0.04). Homozygosity for -509T was associated with severity of proteinuria at diagnosis (p = 0.0017), level of renal tubular TGF-beta1 immunostaining (p = 0.0006) and with severity of renal interstitial inflammatory cellular infiltration (p = 0.01). Tubular TGF-beta1 immunostaining was significantly higher in biopsies with inflammatory cellular infiltration compared those without inflammation (p = 0.0048). There was a significant difference in haplotype distributions between CKF patients with progressive, as opposed to non-progressive disease (p = 0.0484). TGFbeta1 SNPs may be useful prognostic indicators for the progression of CKF.

Severity of alopecia areata is associated with a polymorphism in the interleukin-1 receptor antagonist gene.

One of the most potent pro-inflammatory mediators is the early-acting cytokine interleukin-1. Its actions are regulated by a structurally related anti-inflammatory cytokine known as the interleukin-1 receptor antagonist. We have previously characterized a DNA polymorphism in this gene (IL-1rn) and have found associations between allele 2 and several chronic inflammatory diseases. In the present study, we tested the frequency of allele 2 of the IL-1rn gene in 90 patients with alopecia areata compared with 261 healthy controls. There was a significant association between allele 2 of the polymorphism and the severity of alopecia areata. The frequency of allele 2 increased from 24.1% in the control population to 25.9% in patchy alopecia areata, 36.1% in alopecia totalis, and 47.2% in alopecia universalis (p = 0.005). This severity association is similar to that found in other epithelial-related diseases, including inflammatory bowel disease, lichen sclerosus, and systemic lupus erythematosus.

Association of Graves' disease with an allele of the interleukin-1 receptor antagonist gene.

The proinflammatory cytokine, interleukin-1 (IL-1), has been implicated in the pathogenesis of several autoimmune and inflammatory diseases. One of its natural inhibitors, IL-1 receptor antagonist, is a potent antiinflammatory agent. We have previously described genetic associations between an allele of the IL-1 receptor antagonist gene (IL1RN*2) and several autoimmune and inflammatory diseases. In the present study, we tested the association of this polymorphism with thyroid diseases. We genotyped 2 separate cohorts (total of 100 patients) with Graves' disease and 58 patients with Hashimoto's thyroiditis and compared IL1RN*2 frequencies with those in 261 ethnically matched controls. There was a significant increase in IL1RN*2 frequency and carriage rate in Graves' disease, but this was not associated with thyroid antibody levels, T4 levels, thyroid-associated ophthalmopathy, or outcome after antithyroid drug treatment. In contrast, there was no difference in the frequency of IL1RN*2 between patients with Hashimoto's thyroiditis and the control group. Whether the IL1RN polymorphism makes a direct functional contribution to the pathogenesis of Graves' disease or is acting as a marker for a linked gene is being investigated.

Leptin binding activity changes with age: the link between leptin and puberty.

The timing of the physical transition from child to adult is determined by a biological clock that switches off the pituitary gonadal axis during infancy until puberty. Body composition (and in particular, fat mass), through leptin, are critical signals to this clock. However, no direct relationship between leptin and puberty has been demonstrated. Leptin is bound in the circulation by a high-affinity binding protein, which has been identified as a soluble leptin receptor. We found circulating levels of leptin binding activity (LBA) to be low at birth, to be high in the prepubertal years, to fall through puberty, and then to remain stable during adult life. LBA correlated with pubertal status in both boys and girls. We postulate that the fall in LBA, associated with increasing age and puberty, reflects a reduction in expression of truncated leptin receptors, and leptin is then available to the full-length receptor, which transmits the biological signal for leptin. The high levels of LBA occur during the years when the pituitary gonadal axis is quiescent. Thus, the change in LBA could explain how leptin regulates puberty.

Expression of interleukin-11 receptor alpha and interleukin-11 protein in the endometrium of normal fertile women and women with recurrent miscarriage.

Interleukin-11 (IL-11) is a member of the IL-6 family of cytokines. Previous studies have suggested that IL-11 may play a role in human endometrial function. In this study, we have used immunocytochemistry to compare endometrial IL-11Ralpha and IL-11 expression in precisely timed peri-implantation biopsies from 9 normal fertile women and 16 recurrent miscarriage (RM) women. Immunocytochemistry was semi-quantified by obtaining an H-score value, which showed increased expression of both IL-11 and IL-11Ralpha in epithelial cells compared to stromal cells in all biopsies. There was a significant (P<0.01) reduction in epithelial cell IL-11, but not stromal cell IL-11, expression in endometrium from RM women compared to normal fertile women. There were no significant differences in expression of IL-11Ralpha protein in both stromal and epithelial cells in endometrium from the two groups of women. This work shows the presence of IL-11 and IL-11Ralpha within the endometrium of RM women during the peri-implantation period. The decreased expression of IL-11 in epithelial endometrium in RM women suggests that this cytokine may play a role in preventing miscarriage.

Single nucleotide polymorphisms in the leptin receptor gene: studies in anorexia nervosa.

Anorexia nervosa is an eating disorder of unknown aetiology. There is significant evidence for a genetic component in the pathogenesis of this disorder. A region on chromosome 1 has been identified as a susceptibility locus. The leptin receptor has been mapped to a similar region, further upstream of this susceptibility locus. Leptin and its receptor are known to be important factors in the control and regulation of body weight. Single nucleotide polymorphisms (SNPs) in the leptin receptor are associated with measures of body weight. In the present study, SNPs in the coding region of the leptin receptor were analysed and their possible association with anorexia nervosa was investigated. Two cohorts of young women, 176 Caucasian anorexia nervosa patients and 152 normal Caucasian females, were genotyped for three SNPs in the leptin receptor. There was no significant difference in allele or genotype frequency, for any SNP, between the normal controls and the cohort of anorexia subjects. There were no significant associations with any genotype and body mass index in either the control or anorexic cohorts. When the anorexic cohort was subdivided into restricting and bingeing/purging behaviours, we found no significant association with any genotype. Analysis of haplotypes showed no significant evidence of association with anorexia. In summary, leptin receptor SNPs do not appear to be important factors in the regulation of body weight in young, pre-menopausal women or have any significant association with anorexia nervosa.

Specific diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in dried blood spots by a polymerase chain reaction (PCR) assay detecting a point-mutation (G985) in the MCAD gene.

The discovery of a point-mutation, adenine-to-guanine, at position 985 in the gene coding for MCAD (G985), gave the basis for an easy and specific polymerase chain reaction test. We tested the specificity of such a PCR based assay and detected correctly G985 and A985 in sequence verified cDNA clones. We showed that the G985 mutation is present in genomic DNA from 48 of 50 patients with confirmed MCAD deficiency, originating from various European countries, Australia and the USA. On the basis of this high frequency of the G985 mutation among patients, we improved and optimized the assay with respect to reliability and convenience for routine diagnostic and screening purposes. As little as 2 microliters blood from filter-paper blood-spots (Guthrie spots) is sufficient for the test.

Serum leptin levels during the menstrual cycle of healthy fertile women.

Leptin is a protein, produced by adipose tissue, which has cytokine and hormonal properties. Serum leptin levels can be considered as a measure of body fat mass, and are involved in regulation of body weight. Previous studies suggest that leptin may have an additional role in reproduction, and there is also evidence for involvement in the hypothalamic-pituitary-gonadal axis. In this study, we investigate the possible changes in serum leptin concentration throughout the menstrual cycle. Samples were collected from apparently healthy, fertile women at different stages in their menstrual cycle, timed precisely according to the luteinising hormone (LH) surge. Mean serum leptin levels were significantly higher in the luteal phase (median 11.4 ng/mL) than in the follicular phase (median 10.0 ng/mL) (P < 0.001). In addition, mean serum leptin levels correlated with body mass index (r = 0.54, P < 0.05), but showed no correlation with luteal-phase progesterone levels. Results showed that levels of serum leptin vary during the menstrual cycle, and add to the mounting evidence that leptin has a role in reproduction. These fluctuations should be taken into account whenever studies are performed using female subjects.

A mechanistic role for leptin in human dendritic cell migration: differences between ileum and colon in health and Crohn's disease.

Dendritic cells (DC) migrate to lymph nodes on expression of C-C motif chemokine receptor 7 (CCR7) and control immune activity. Leptin, an immunomodulatory adipokine, functions via leptin receptors, signaling via the long isoform of receptor, LepRb. Leptin promotes DC maturation and increases CCR7 expression on blood DC. Increased mesenteric fat and leptin occur early in Crohn's disease (CD), suggesting leptin-mediated change in intestinal CCR7 expression on DC as a pro-inflammatory mechanism. We have demonstrated CCR7 expression and capacity to migrate to its ligand macrophage inflammatory protein 3ß in normal human ileal DC but not colonic or blood DC. In CD, functional CCR7 was expressed on DC from all sites. Only DC populations containing CCR7-expressing cells produced LepRb; in vitro exposure to leptin also increased expression of functional CCR7 in intestinal DC in a dose-dependent manner. In conclusion, leptin may regulate DC migration from gut, in homeostatic and inflammatory conditions, providing a link between mesenteric obesity and inflammation.

Localisation of RFLPs of the medium chain acyl-CoA dehydrogenase gene.

Six restriction fragment length polymorphisms (RFLPs) of the gene are described. Three of these are in linkage disequilibrium. Hybridisation with sub-probes allowed localisation of the RFLPs to different regions of the gene.

Genetic polymorphism of human interleukin-1 alpha.

Interleukin-1 alpha (IL-1 alpha) has been implicated in the pathogenesis of infectious, autoimmune and inflammatory diseases. There is, however, very little information on the cis-acting sequences involved in IL-1 alpha regulation or whether there is any variation in the structure of the gene. It is known that intron 6 of IL-1 alpha shows a 5 x 46 bp tandem repeat in the genomic sequence. We have studied this region of the gene. Amplification by polymerase chain reaction showed different sized products from different individuals, most being of higher molecular weight than the expected size of 620 bp. Sequencing demonstrated that the polymorphism was due to a variable number of repeats of the 46 bp sequence. This was confirmed by restriction fragment length analysis of genomic DNA. Altogether, 72 unrelated individuals were tested and 6 alleles ranging from 5 to 18 repeats were found, the most frequent allele (62%) containing 9 repeats. This polymorphism may be of interest in gene function, since each repeat contains three potential binding sites for transcriptional factors: an SP1 site, a viral enhancer element and a glucocorticoid-responsive element. The latter, at least, demonstrates site-specific protein binding by electromobility shift assay. The functional significance of the polymorphism and its allelic frequency in inflammatory and autoimmune diseases are currently under investigation.

Interleukin (IL)-10, IL-1ra and IL-12 profiles in active and quiescent systemic lupus erythematosus: could longitudinal studies reveal patient subgroups of differing pathology?

Several cytokines have been implicated individually in the pathogenesis of systemic lupus erythematosus (SLE) and some, including interleukin (IL)-10, IL-12 and IL-1ra are raised during flares of disease activity. Few studies have been directed at examining the interactions between these cytokines and how their combined profile relates to disease activity. We have examined serum levels of IL-10, IL-12 and IL-1ra in a cohort of SLE patients obtained from the Queen Elizabeth Hospital, Birmingham in cross-sectional and, in a smaller group, longitudinal analyses. In the cross-sectional study, there were significant correlations between levels of the three cytokines. There were also significant correlations between levels of each cytokine and measures of disease activity. IL-10 levels correlated with ESR, anti-dsDNA antibody titres and C3D, IL-12 levels with anti-dsDNA antibody titres and IL-1ra levels with ESR, anti-dsDNA antibody titres and C3D. IL-1ra levels also correlated with CRP. Circulating IL-10 and IL-1ra levels were higher in patients with SLE than in normal controls, although in this study group they did not reach significance. Circulating IL-12 levels were, however, significantly higher in SLE compared to controls. This was true both in patients with active disease and those sampled during a quiescent phase. These data add to the evidence that cytokines such as IL-10, IL-12 and IL-1ra are important in SLE pathogenesis. In a retrospective study of serial serum samples from seven patients, we found two patients whose cytokine profile was very different from the rest of the group. In most patients normalized IL-10, IL-12 and IL-1ra levels mirrored BILAG scores closely, but in these two patients, IL-10, IL-12 and IL-1ra levels did not fluctuate with disease activity. It is possible that there is a subgroup of SLE patients whose cytokine profile could be an important indicator of their pathology. In order to confirm this and determine the frequency of such patients this study needs to be repeated with a much larger subject group. The coexistence of patient groups with different patterns of cytokine activity might explain conflicting reports of associations of levels of particular cytokines with SLE. As the observed differences could reflect different aetiologies of SLE, this information could reveal valuable endophenotypes for genetic and functional studies of SLE and might, ultimately, inform therapeutic management.

Leptin and leptin-binding activity in women with recurrent miscarriage: correlation with pregnancy outcome.

BACKGROUND: Previous studies in humans and mice have suggested the importance of leptin in fetal growth. Recurrent miscarriage may be a result of abnormal placental and/or fetal development and therefore abnormal leptin levels may be associated with this form of pregnancy loss. METHODS: Leptin and leptin-binding activity (LBA) were measured in blood obtained from women who had a history of recurrent miscarriage (n = 53) during weeks 5-6 and 7-8 of pregnancy, and the concentrations were correlated with subsequent pregnancy outcome. RESULTS: Concentrations of leptin ranged from 1.4-62.8 ng/ml, but there was a strong correlation (r = 0.825, P < 0.001) between leptin values at weeks 5-6 and 7-8 in the same woman. Women who subsequently miscarried had significantly lower plasma leptin concentrations on both weeks 5-6 (13.34 +/- 2.1 ng/ml) (P < 0.05) and 7-8 (13.71 +/- 2.4 ng/ml) (P < 0.01) of pregnancy, than women who subsequently had a term birth (22.04 +/- 2.43 ng/ml week 5-6, 24.76 +/- 3.66 ng/ml week 7-8). LBA values ranged from 1-8.5% but there was no significant difference in LBA in blood obtained from women who subsequently miscarried or had a live birth. CONCLUSIONS: The significantly lower concentrations of leptin in women who subsequently miscarried suggest that leptin may play a role in preventing miscarriage. However, as there was a considerable overlap between the values of leptin in women who subsequently miscarried, and those that had a live birth, these measurements are of limited use in the prediction of pregnancy outcome in these women.

A single nucleotide polymorphism (SNP) in the leptin receptor is associated with BMI, fat mass and leptin levels in postmenopausal Caucasian women.

The human leptin (obese) receptor gene contains a number of single nucleotide polymorphisms, including GLN223ARG, which changes an amino acid on the extracellular region common to all isoforms of the receptor. Here, we demonstrate that, in postmenopausal Caucasian women, genotypes at that locus are associated with differences in body mass index (BMI), fat mass and serum leptin levels. Measurement of serum leptin-binding activity indicates that this may reflect changed receptor function associated with genotype. These observations indicate that functional variations in the leptin receptor gene are important factors in the regulation of adiposity and BMI.