Peroxisome Proliferator Activated Receptor Gamma Controls Mature Brown Adipocyte Inducibility through Glycerol Kinase.
Cell Rep. 2018 Jan 16;22(3):760-773
Authors: Lasar D, Rosenwald M, Kiehlmann E, Balaz M, Tall B, Opitz L, Lidell ME, Zamboni N, Krznar P, Sun W, Varga L, Stefanicka P, Ukropec J, Nuutila P, Virtanen K, Amri EZ, Enerbäck S, Wahli W, Wolfrum C
Peroxisome proliferator-activated receptors (PPARs) have been suggested as the master regulators of adipose tissue formation. However, their role in regulating brown fat functionality has not been resolved. To address this question, we generated mice with inducible brown fat-specific deletions of PPARα, β/δ, and γ, respectively. We found that both PPARα and β/δδ are dispensable for brown fat function. In contrast, we could show that ablation of PPARγ in vitro and in vivo led to a reduced thermogenic capacity accompanied by a loss of inducibility by β-adrenergic signaling, as well as a shift from oxidative fatty acid metabolism to glucose utilization. We identified glycerol kinase (Gyk) as a partial mediator of PPARγ function and could show that Gyk expression correlates with brown fat thermogenic capacity in human brown fat biopsies. Thus, Gyk might constitute the link between PPARγ-mediated regulation of brown fat function and activation by β-adrenergic signaling.
PMID: 29346772 [PubMed - in process]
Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder.
Cell Rep. 2018 Jan 16;22(3):734-747
Authors: Takata A, Miyake N, Tsurusaki Y, Fukai R, Miyatake S, Koshimizu E, Kushima I, Okada T, Morikawa M, Uno Y, Ishizuka K, Nakamura K, Tsujii M, Yoshikawa T, Toyota T, Okamoto N, Hiraki Y, Hashimoto R, Yasuda Y, Saitoh S, Ohashi K, Sakai Y, Ohga S, Hara T, Kato M, Nakamura K, Ito A, Seiwa C, Shirahata E, Osaka H, Matsumoto A, Takeshita S, Tohyama J, Saikusa T, Matsuishi T, Nakamura T, Tsuboi T, Kato T, Suzuki T, Saitsu H, Nakashima M, Mizuguchi T, Tanaka F, Mori N, Ozaki N, Matsumoto N
Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the "de novo paradigm" of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.
PMID: 29346770 [PubMed - in process]
Activation of AMPK-Regulated CRH Neurons in the PVH is Sufficient and Necessary to Induce Dietary Preference for Carbohydrate over Fat.
Cell Rep. 2018 Jan 16;22(3):706-721
Authors: Okamoto S, Sato T, Tateyama M, Kageyama H, Maejima Y, Nakata M, Hirako S, Matsuo T, Kyaw S, Shiuchi T, Toda C, Sedbazar U, Saito K, Asgar NF, Zhang B, Yokota S, Kobayashi K, Foufelle F, Ferré P, Nakazato M, Masuzaki H, Shioda S, Yada T, Kahn BB, Minokoshi Y
Food selection is essential for metabolic homeostasis and is influenced by nutritional state, food palatability, and social factors such as stress. However, the mechanism responsible for selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) remains unknown. Here, we show that activation of a subset of corticotropin-releasing hormone (CRH)-positive neurons in the rostral region of the paraventricular hypothalamus (PVH) induces selection of an HCD over an HFD in mice during refeeding after fasting, resulting in a rapid recovery from the change in ketone metabolism. These neurons manifest activation of AMP-activated protein kinase (AMPK) during food deprivation, and this activation is necessary and sufficient for selection of an HCD over an HFD. Furthermore, this effect is mediated by carnitine palmitoyltransferase 1c (CPT1c). Thus, our results identify the specific neurons and intracellular signaling pathway responsible for regulation of the complex behavior of selection between an HCD and an HFD. VIDEO ABSTRACT.
PMID: 29346768 [PubMed - in process]
Transcriptome and DNA Methylome Analysis in a Mouse Model of Diet-Induced Obesity Predicts Increased Risk of Colorectal Cancer.
Cell Rep. 2018 Jan 16;22(3):624-637
Authors: Li R, Grimm SA, Mav D, Gu H, Djukovic D, Shah R, Merrick BA, Raftery D, Wade PA
Colorectal cancer (CRC) tends to occur at older age; however, CRC incidence rates have been rising sharply among young age groups. The increasing prevalence of obesity is recognized as a major risk, yet the mechanistic underpinnings remain poorly understood. Using a diet-induced obesity mouse model, we identified obesity-associated molecular changes in the colonic epithelium of young and aged mice, and we further investigated whether the changes were reversed after weight loss. Transcriptome analysis indicated that obesity-related colonic cellular metabolic switch favoring long-chain fatty acid oxidation happened in young mice, while obesity-associated downregulation of negative feedback regulators of pro-proliferative signaling pathways occurred in older mice. Strikingly, colonic DNA methylome was pre-programmed by obesity at young age, priming for a tumor-prone gene signature after aging. Furthermore, obesity-related changes were substantially preserved after short-term weight loss, but they were largely reversed after long-term weight loss. We provided mechanistic insights into increased CRC risk in obesity.
PMID: 29346762 [PubMed - in process]
A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis.
Hum Mol Genet. 2018 Jan 16;:
Authors: Munz M, Willenborg C, Richter GM, Jockel-Schneider Y, Graetz C, Staufenbiel I, Wellmann J, Berger K, Krone B, Hoffmann P, van der Velde N, Uitterlinden AG, de Groot LCPGM, Sawalha AH, Direskeneli H, Saruhan-Direskeneli G, Guzeldemir-Akcakanat E, Keceli HG, Laudes M, Noack B, Teumer A, Holtfreter B, Kocher T, Eickholz P, Meyle J, Doerfer C, Bruckmann C, Lieb W, Franke A, Schreiber S, Nohutcu RM, Erdmann J, Loos BG, Jepsen S, Dommisch H, Schaefer AS
PMID: 29346566 [PubMed - as supplied by publisher]
Whole Genome Sequencing Analysis for Cancer Genomics and Precision Medicine.
Cancer Sci. 2018 Jan 18;:
Authors: Nakagawa H, Fujita M
Explosive advances of next-generation sequencer (NGS) and computational analyses have been exploring somatic protein-altered mutations in most cancer types and these coding mutation data are intensively accumulated. However, there is limited information on somatic mutations in non-coding regions including introns, regulatory elements, and non-coding RNAs, structural variants and pathogen in cancer genomes remain widely unexplored. Whole genome sequencing (WGS) approaches can comprehensively explore all types of genomic alterations in cancer and help us to better understand the whole landscape of driver mutations and mutational signature in cancer genomes and elucidate functional or clinical implications of these unexplored genomic regions and mutational signature. This review describes recent technical approaches for cancer WGS and the future direction of cancer WGS, and discuss its utility and limitation of an analysis platform and mutation interpretation for cancer genomics and cancer precision medicine. Taking into account the diversity of cancer genomes and phenotypes, interpretation of abundant mutation information from WGS, especially non-coding and structure variants, requires the analysis of large-scale WGS data integrated with RNA-Seq, epigenomics, immuno-genomic and clinic-pathological information. This article is protected by copyright. All rights reserved.
PMID: 29345757 [PubMed - as supplied by publisher]
Statistical analysis of human microarray data shows that dietary intervention with n-3 fatty acids, flavonoids and resveratrol enriches for immune response and disease pathways.
Br J Nutr. 2018 Jan 18;:1-11
Authors: Warburton A, Vasieva O, Quinn P, Stewart JP, Quinn JP
n-3 Fatty acids, flavonoids and resveratrol are well publicised for their beneficial effects on human health and wellbeing. Identifying common, underlying biological mechanisms targeted by these functional foods would therefore be informative for the public health sector for advising on nutritional health and disease, food and drug product development and consumer interest. The aim of this study was to explore the potential effects of gene expression changes associated with n-3 fatty acids EPA and DHA, flavonoids and resveratrol on modifying biological systems and disease pathways. To test this, publicly available human microarray data for significant gene expression changes associated with dietary intervention with EPA/DHA, flavonoids and resveratrol was subjected to pathway analysis and significance testing for overlap with signals from genome-wide association studies (GWAS) for common non-communicable diseases and biological functions. There was an enrichment of genes implicated in immune responses and disease pathways which was common to all of the treatment conditions tested. Analysis of biological functions and disease pathways indicated anti-tumorigenic properties for EPA/DHA. In line with this, significance testing of the intersection of genes associated with these functional foods and GWAS hits for common biological functions (ageing and cognition) and non-communicable diseases (breast cancer, CVD, diabesity, neurodegeneration and psychiatric disorders) identified significant overlap between the EPA/DHA and breast cancer gene sets. Dietary intervention with EPA/DHA, flavonoids and resveratrol can target important biological and disease pathways suggesting a potentially important role for these bioactive compounds in the prevention and treatment of dietary-related diseases.
PMID: 29345217 [PubMed - as supplied by publisher]
Effectiveness of smartphone technologies on glycaemic control in patients with type 2 diabetes: systematic review with meta-analysis of 17 trials.
Obes Rev. 2018 Jan 17;:
Authors: Wu IXY, Kee JCY, Threapleton DE, Ma R, Lam VCK, Lee EKP, Wong SYS, Chung VCH
Patient education and behavioural interventions for self-management of type 2 diabetes mellitus (T2DM) are effective but place demands on manpower resources. This systematic review aimed to investigate the effectiveness of smartphone technologies (STs) for improving glycaemic control among T2DM patients. CENTRAL, MEDLINE, Embase, CINAHL and ScienceDirect were searched through December 2016. Randomized controlled trials comparing STs with usual diabetes care among T2DM patients and reporting change in glycated haemoglobin (HbA1c) level were included. Seventeen trials (2,225 participants) were included. There was a significant reduction in HbA1c (pooled weighted mean difference: -0.51%; 95% confidence interval: -0.71% to -0.30%; p < 0.001), favouring ST intervention. The pooled weighted mean difference was -0.83% in patients with T2DM <8.5 years and -0.22% in patients with T2DM ≥8.5 years, with significant subgroup difference (p = 0.007). No subgroup differences were found among different follow-up durations, trial locations, patients' age, healthcare provider contract time, baseline body mass index and baseline HbA1c. Compared with usual diabetes care, STs improved glycaemic control among T2DM patients, especially for patients at earlier disease stages (duration of diagnosis <8.5 years). STs could be a complement or alternative to labour-intensive patient education and behavioural interventions, but more studies on up-to-date technologies are needed.
PMID: 29345109 [PubMed - as supplied by publisher]
Association of Combined Patterns of Tobacco and Cannabis Use in Adolescence With Psychotic Experiences.
JAMA Psychiatry. 2018 Jan 17;:
Authors: Jones HJ, Gage SH, Heron J, Hickman M, Lewis G, Munafò MR, Zammit S
Importance: There is concern about potentially causal effects of tobacco use on psychosis, but epidemiological studies have been less robust in attempts to minimize effects of confounding than studies of cannabis use have been.
Objectives: To examine the association of patterns of cigarette and cannabis use with preceding and subsequent psychotic experiences, and to compare effects of confounding across these patterns.
Design, Setting, and Participants: This cohort study used data from the Avon Longitudinal Study of Parents and Children, which initially consisted of 14 062 children. Data were collected periodically from September 6, 1990, with collection ongoing, and analyzed from August 8, 2016, through June 14, 2017. Cigarette and cannabis use data were summarized using longitudinal latent class analysis to identify longitudinal classes of substance use. Associations between classes and psychotic experiences at age 18 years were assessed.
Exposures: Depending on the analysis model, exposures were longitudinal classes of substance use or psychotic experiences at age 12 years.
Main Outcomes and Measures: Logistic regression was used to examine the associations between substance use longitudinal classes and subsequent onset of psychotic experiences.
Results: Longitudinal classes were derived using 5300 participants (56.1% female) who had at least 3 measures of cigarette and cannabis use from ages 14 to 19 years. Prior to adjusting for a range of potential confounders, there was strong evidence that early-onset cigarette-only use (4.3%), early-onset cannabis use (3.2%), and late-onset cannabis use (11.9%) (but not later-onset cigarette-only use [14.8%]) latent classes were associated with increased psychotic experiences compared with nonusers (65.9%) (omnibus P < .001). After adjusting for confounders, the association for early-onset cigarette-only use attenuated substantially (unadjusted odds ratio [OR], 3.03; 95% CI, 1.13-8.14; adjusted OR, 1.78; 95% CI, 0.54-5.88), whereas those for early-onset cannabis use (adjusted OR, 3.70; 95% CI, 1.66-8.25) and late-onset cannabis use (adjusted OR, 2.97; 95% CI, 1.63-5.40) remained consistent.
Conclusions and Relevance: In this study, our findings indicate that while individuals who use cannabis or cigarettes during adolescence have an increased risk of subsequent psychotic experiences, epidemiological evidence is substantively more robust for cannabis use than it is for tobacco use.
PMID: 29344610 [PubMed - as supplied by publisher]
The Effect of Traditional Chinese Medicine on Neural Stem Cell Proliferation and Differentiation.
Aging Dis. 2017 Dec;8(6):792-811
Authors: Qin W, Chen S, Yang S, Xu Q, Xu C, Cai J
Neural stem cells (NSCs) are special types of cells with the potential for self-renewal and multi-directional differentiation. NSCs are regulated by multiple pathways and pathway related transcription factors during the process of proliferation and differentiation. Numerous studies have shown that the compound medicinal preparations, single herbs, and herb extracts in traditional Chinese medicine (TCM) have specific roles in regulating the proliferation and differentiation of NSCs. In this study, we investigate the markers of NSCs in various stages of differentiation, the related pathways regulating the proliferation and differentiation, and the corresponding transcription factors in the pathways. We also review the influence of TCM on NSC proliferation and differentiation, to facilitate the development of TCM in neural regeneration and neurodegenerative diseases.
PMID: 29344417 [PubMed]
Hedyotis diffusa willd extract suppresses colorectal cancer growth through multiple cellular pathways.
Oncol Lett. 2017 Dec;14(6):8197-8205
Authors: Feng J, Jin Y, Peng J, Wei L, Cai Q, Yan Z, Lai Z, Lin J
The development of colorectal cancer (CRC) is strongly associated with the imbalance of various intracellular signal transduction cascades, including protein kinase B (AKT), mitogen-activated protein kinase 1 (MAPK), signal transducer and activator of transcription 3 (STAT3), as well as crosstalk between these signaling networks. At present, anti-tumor agents are often single-targeted and therefore are not always therapeutically effective. Moreover, long-term use of these anti-tumor agents often generates drug resistance and potential side effects. These problems highlight the urgent need for the development of novel and more effective anti-cancer drugs. Hedyotis diffusa Willd (HDW) has been used as a major component in traditional Chinese medicine for the clinical treatment of colorectal cancer, with a limited number of adverse effects. However, the molecular mechanisms, which underlie its anti-cancer activity, still require further elucidation. In the present study, using xenograft models and various different human CRC cell lines, the efficacy of the ethanol extract of HDW (EEHDW) against tumor growth was evaluated, and its underlying molecular mechanisms of action were investigated. It was demonstrated that EEHDW was able to inhibit cancer growth in vivo and in vitro. Furthermore, EEHDW was able to suppress the activation of several CRC-associated signaling pathways and was able to regulate the expression of various inflammatory and angiogenic factors. This resulted in the induction of apoptosis and inhibition of cellular proliferation, as well as tumor angiogenesis. The present study demonstrated that EEHDW is able to exhibit anti-cancer activity due to its ability to affect multiple intracellular targets, which suggests that it may be a novel multi-potent therapeutic agent for the treatment of colorectal cancer.
PMID: 29344262 [PubMed]
Pien Tze Huang inhibits the growth of hepatocellular carcinoma cells by upregulating miR-16 expression.
Oncol Lett. 2017 Dec;14(6):8132-8137
Authors: Qi F, Zhou S, Li L, Wei L, Shen A, Liu L, Wang Y, Peng J
Hepatocellular carcinoma (HCC) is characterized by uncontrolled proliferation and the deregulation of apoptotic signaling, although its molecular pathogenesis is not fully characterized. The ability to inhibit excessive proliferation and induce the apoptosis of cancer cells are crucial characteristics of anticancer drugs. Pien Tze Huang (PZH) is a widely used traditional Chinese medicine for the treatment of various types of cancer, and has exhibited promising therapeutic effects in clinical trials of HCC. However, the underlying mechanisms for its action are unclear. In the present study, the aim was to explore the effect of PZH on the proliferation and apoptosis of the BEL-7402 HCC cell line, and the associated mechanisms. PZH treatment significantly inhibited BEL-7402 cell viability, confluence and clonogenicity, inducing cell cycle arrest and promoting apoptosis. In addition, PZH treatment suppressed the expression of the pro-proliferative genes cyclin D1 and cyclin-dependent kinase 4, and decreased the expression of the anti-apoptotic gene Bcl-2. PZH treatment also upregulated the expression of a key microRNA (miR), miR-16. The study demonstrated that PZH can effectively inhibit cancer cell proliferation and induce apoptosis in BEL-7402 HCC cells via the upregulation of the tumor suppressor miR-16.
PMID: 29344256 [PubMed]
Chloroform extract of Hedyotis diffusa Willd inhibits viability of human colorectal cancer cells via suppression of AKT and ERK signaling pathways.
Oncol Lett. 2017 Dec;14(6):7923-7930
Authors: Yan Z, Feng J, Peng J, Lai Z, Zhang L, Jin Y, Yang H, Chen W, Lin J
Hedyotis diffusa Willd (HDW) is a widely used traditional Chinese medicine in clinical therapy to treat various types of cancer, including colorectal cancer (CRC), but its effective polar fractions and functional mechanisms remain unclear. The aim of the present study was to determine the most effective extract of HDW and to investigate its effects on the regulation of CRC cell proliferation and apoptosis, as well as to investigate the underlying molecular mechanisms. The results demonstrated that the chloroform extract of HDW (CEHDW) exhibited the most anticancer ability. Furthermore, results of the MTT assay, colony formation, carboxyfluorescein diacetate succinimidyl ester assay and annexin V/propidium iodide staining suggested that CEHDW significantly inhibits proliferation and promotes apoptosis in the SW620 CRC cell line. Additionally, reverse transcription-polymerase chain reaction and western blot analysis demonstrated that CEHDW treatment downregulated the expression of Survivin, proliferating cell nuclear antigen, Cyclin D1, cyclin-dependent kinase 4 and B-cell lymphoma 2 (Bcl-2), and upregulated the expression of Bcl-2-associated X protein at the mRNA and protein levels. CEHDW also decreased the phosphorylation of protein kinase B (AKT) and extracellular-signal-regulated kinase (ERK), which indicated that the suppression of the AKT and ERK signaling pathways may be one of the underlying molecular mechanisms by which CEHDW exhibited its anticancer effect. Thus, CEHDW may be a promising agent for anticancer therapy.
PMID: 29344237 [PubMed]
Effect of Lipodox in combination with bevacizumab in a patient with a metastatic malignant phyllodes breast tumor: A case report.
Oncol Lett. 2017 Dec;14(6):6685-6689
Authors: Su CC, Chen CJ, Kuo SJ
A 76-year-old female patient with a malignant phyllodes tumor underwent modified radical mastectomy and wide excision. Multiple nodules were observed in the operated wound area. Positron emission tomography-computed tomography (PET-CT) revealed recurrent disease in the left breast, the adjacent left third rib, the left internal mammary region and the left ilium. A novel formulation of bevacizumab (5 mg/m2, first day) in combination with liposomal doxorubicin (Lipodox, 30 mg/m2, second day) was administered for 3 cycles every 2 weeks, and subsequently wide excision was performed. Lipodox (40 mg/m2) was administered for 3 cycles every 3 weeks, starting 4 weeks after the surgery. Follow-up whole body PET-CT scanning, 3 and 6 months later, indicated no sign of residual hypermetabolic malignancy. Malignant phyllodes tumors do not usually respond to chemotherapy or radiotherapy. In the present case report, a novel formulation of bevacizumab in combination with Lipodox was administered as neoadjuvant chemotherapy in a patient with a malignant phyllodes tumor and preoperative tumor shrinkage was achieved, resulting in clear resection margins.
PMID: 29344119 [PubMed]
CINdex: A Bioconductor Package for Analysis of Chromosome Instability in DNA Copy Number Data.
Cancer Inform. 2017;16:1176935117746637
Authors: Song L, Bhuvaneshwar K, Wang Y, Feng Y, Shih IM, Madhavan S, Gusev Y
The CINdex Bioconductor package addresses an important area of high-throughput genomic analysis. It calculates the chromosome instability (CIN) index, a novel measurement that quantitatively characterizes genome-wide copy number alterations (CNAs) as a measure of CIN. The advantage of this package is an ability to compare CIN index values between several groups for patients (case and control groups), which is a typical use case in translational research. The differentially changed cytobands or chromosomes can then be linked to genes located in the affected genomic regions, as well as pathways. This enables in-depth systems biology-based network analysis and assessment of the impact of CNA on various biological processes or clinical outcomes. This package was successfully applied to analysis of DNA copy number data in colorectal cancer as a part of multi-omics integrative study as well as for analysis of several other cancer types. The source code, along with an end-to-end tutorial, and example data are freely available in Bioconductor at http://bioconductor.org/packages/CINdex/.
PMID: 29343938 [PubMed]
Yoga into Cancer Care: A Review of the Evidence-based Research.
Int J Yoga. 2018 Jan-Apr;11(1):3-29
Authors: Agarwal RP, Maroko-Afek A
To cope with cancer and its treatment-related side effects and toxicities, people are increasingly using complementary and alternative medicine (CAM). Consequently, integrative oncology, which combines conventional therapies and evidence-based CAM practices, is an emerging discipline in cancer care. The use of yoga as a CAM is proving to be beneficial and increasingly gaining popularity. An electronic database search (PubMed), through December 15, 2016, revealed 138 relevant clinical trials (single-armed, nonrandomized, and randomized controlled trials) on the use of yoga in cancer patients. A total of 10,660 cancer patients from 20 countries were recruited in these studies. Regardless of some methodological deficiencies, most of the studies reported that yoga improved the physical and psychological symptoms, quality of life, and markers of immunity of the patients, providing a strong support for yoga's integration into conventional cancer care. This review article presents the published clinical research on the prevalence of yoga's use in cancer patients so that oncologists, researchers, and the patients are aware of the evidence supporting the use of this relatively safe modality in cancer care.
PMID: 29343927 [PubMed]
Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.
Nat Commun. 2018 Jan 17;9(1):260
Authors: Jiang X, O'Reilly PF, Aschard H, Hsu YH, Richards JB, Dupuis J, Ingelsson E, Karasik D, Pilz S, Berry D, Kestenbaum B, Zheng J, Luan J, Sofianopoulou E, Streeten EA, Albanes D, Lutsey PL, Yao L, Tang W, Econs MJ, Wallaschofski H, Völzke H, Zhou A, Power C, McCarthy MI, Michos ED, Boerwinkle E, Weinstein SJ, Freedman ND, Huang WY, Van Schoor NM, van der Velde N, Groot LCPGM, Enneman A, Cupples LA, Booth SL, Vasan RS, Liu CT, Zhou Y, Ripatti S, Ohlsson C, Vandenput L, Lorentzon M, Eriksson JG, Shea MK, Houston DK, Kritchevsky SB, Liu Y, Lohman KK, Ferrucci L, Peacock M, Gieger C, Beekman M, Slagboom E, Deelen J, Heemst DV, Kleber ME, März W, de Boer IH, Wood AC, Rotter JI, Rich SS, Robinson-Cohen C, den Heijer M, Jarvelin MR, Cavadino A, Joshi PK, Wilson JF, Hayward C, Lind L, Michaëlsson K, Trompet S, Zillikens MC, Uitterlinden AG, Rivadeneira F, Broer L, Zgaga L, Campbell H, Theodoratou E, Farrington SM, Timofeeva M, Dunlop MG, Valdes AM, Tikkanen E, Lehtimäki T, Lyytikäinen LP, Kähönen M, Raitakari OT, Mikkilä V, Ikram MA, Sattar N, Jukema JW, Wareham NJ, Langenberg C, Forouhi NG, Gundersen TE, Khaw KT, Butterworth AS, Danesh J, Spector T, Wang TJ, Hyppönen E, Kraft P, Kiel DP
Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
PMID: 29343764 [PubMed - in process]
The neural correlates of the unified percept of alcohol-related craving: a fMRI and EEG study.
Sci Rep. 2018 Jan 17;8(1):923
Authors: Huang Y, Mohan A, De Ridder D, Sunaert S, Vanneste S
Alcohol addiction is accompanied by aberrant neural activity. Previously, task-based fMRI and resting-state EEG studies have revealed that craving, a critical component of addiction, is linked to abnormal activity in cortical regions including the dorsal anterior cingulate cortex (dACC), nucleus accumbens (NAcc), posterior cingulate cortex (PCC) and pregenual anterior cingulate cortex (pgACC), etc. In this study, we combine these two imaging techniques to investigate a group of alcohol-addicted patients and provide convergent evidence for the neural correlates of craving not only in alcohol but substance abuse in general. We observe abnormal BOLD signal levels in the dACC, NAcc, pgACC, PCC, amygdala, and parahippocampus (PHC) in a cue-reactivity fMRI experiment. These findings are consistent with increased beta-band activity in the dACC and pgACC in resting-state EEG. We further observe desynchronization characterized by decreased functional connectivity in cue-based fMRI and hypersynchronization characterized by increased functional connectivity between these regions in the theta frequency band. The results of our study show a consistent pattern of alcohol craving elicited by external cues and internal desires. Given the advantage of superior spatial and temporal resolution, we hypothesize a "central craving network" that integrates the different aspects of alcohol addiction into a unified percept.
PMID: 29343732 [PubMed - in process]
Intestinal epithelial cell-specific deletion of α-mannosidase II ameliorates experimental colitis.
Cell Struct Funct. 2018 Jan 18;:
Authors: Suzuki K, Yamada T, Yamazaki K, Hirota M, Ishihara N, Sakamoto M, Takahashi D, Iijima H, Hase K
Inflammatory bowel disease (IBD) is a refractory disease of the gastrointestinal tract that is believed to develop in genetically susceptible individuals. Glycosylation, a type of post-translational modification, is involved in the development of a wide range of diseases, including IBD, by modulating the function of various glycoproteins. To identify novel genes contributing to the development of IBD, we analyzed single nucleotide polymorphisms (SNPs) of glycosylation-related genes in IBD patients and identified MAN2A1, encoding alpha-mannosidase II (α-MII), as a candidate gene. α-MII plays a crucial, but not exclusive, role in the maturation of N-glycans. We also observed that intestinal epithelial cells (IECs), which establish the first-line barrier and regulate gut immunity, selectively expressed α-MII with minimal expression of its isozyme, alpha-mannosidase IIx (α-MIIx). This led us to hypothesize that IEC-intrinsic α-MII is implicated in the pathogenesis of IBD. To test this hypothesis, we generated IEC-specific α-MII-deficient (α-MIIΔIEC) mice. Although α-MII deficiency has been shown to have a minimal effect on N-glycan maturation in most cell types due to the compensation by α-MIIx, ablation of α-MII impaired the maturation of N-glycans in IECs. α-MIIΔIEC mice were less susceptible to dextran sulfate sodium-induced colitis compared with control littermates. In accordance with this, neutrophil infiltration in the colonic mucosa was attenuated in α-MIIΔIEC mice. Furthermore, gene expression levels of neutrophil-attracting chemokines were downregulated in the colonic tissue. These results suggest that IEC-intrinsic α-MII promotes intestinal inflammation by facilitating chemokine expression. We propose SNPs in MAN2A1 as a novel genetic factor for IBD. Key words: inflammatory bowel disease, alpha-mannosidase II, intestinal epithelial cell, N-glycosylation.
PMID: 29343654 [PubMed - as supplied by publisher]
Structural study of the C-terminal domain of non-structural protein 1 from Japanese encephalitis virus.
J Virol. 2018 Jan 17;:
Authors: Poonsiri T, Wright GSA, Diamond MS, Turtle L, Solomon T, Antonyuk SV
Japanese encephalitis virus (JEV) is a mosquito-transmitted Flavivirus that is closely related to other emerging viral pathogens including dengue, West Nile (WNV) and Zika viruses. JEV infection can result in meningitis and encephalitis, which in severe cases cause permanent brain damage and death. JEV occurs predominantly in rural areas throughout Southeast Asia, the Pacific islands and the Far East, causing around 68,000 cases worldwide each year. In this study, we present a 2.1 Å resolution crystal structure of the C-terminal β-ladder domain of JEV non-structural protein 1 (NS1-C). The surface charge distribution of JEV NS1-C is similar to WNV and ZIKV but differs form DENV. Analysis of the JEV NS1-C structure, with in silico molecular dynamics simulation and experimental solution small angle X-ray scattering, indicates extensive loop flexibility on the exterior of the protein. This, together with the surface charge distribution, indicates flexibility influences the protein-protein interactions that govern pathogenicity. These factors also affect the interaction of NS1 with the monoclonal antibody, 22NS1, which is protective against West Nile virus infection. Liposome and heparin binding assays indicate that only the N-terminal region of NS1 mediates interaction with membranes, and that sulfate binding sites common to NS1 structures are not glycosaminoglycan binding interfaces. This study highlights several differences between flavivirus NS1 proteins and contributes to our understanding of their structure-pathogenic function relationships.IMPORTANCE JEV is a major cause of viral encephalitis in Asia. Despite extensive vaccination, epidemics still occur. Non-structural protein 1 (NS1) plays a role in viral replication and, because it is secreted, it can exhibit a wide range of interations with host proteins. NS1 sequence and protein folds are conserved within the Flavivirus genus, but variations in NS1 protein-protein interactions among viruses likely contribute to differences in pathogenesis. Here, we compared characteristics of the the C-terminal β-ladder domain of NS1 between flaviviruses including surface charge, loop flexibility, epitope cross-reactivity, membrane adherence, and glycosaminoglycan binding. These structural features are central to NS1 functionality and may provide insight into the development of diagnostic tests and therapeutics.
PMID: 29343583 [PubMed - as supplied by publisher]
Development, regulation, metabolism and function of bone marrow adipose tissues.
Bone. 2018 Jan 14;:
Authors: Li Z, Hardij J, Bagchi DP, Scheller EL, MacDougald OA
Most adipocytes exist in discrete depots throughout the body, notably in well-defined white and brown adipose tissues. However, adipocytes also reside within specialized niches, of which the most abundant is within bone marrow. Whereas bone marrow adipose tissue (BMAT) shares many properties in common with white adipose tissue, the distinct functions of BMAT are reflected by its development, regulation, protein secretion, and lipid composition. In addition to its potential role as a local energy reservoir, BMAT also secretes proteins, including adiponectin, RANK ligand, dipeptidyl peptidase-4, and stem cell factor, which contribute to local marrow niche functions and which may also influence global metabolism. The characteristics of BMAT are also distinct depending on whether marrow adipocytes are contained within yellow or red marrow, as these can be thought of as 'constitutive' and 'regulated', respectively. The rBMAT for instance can be expanded or depleted by myriad factors, including age, nutrition, endocrine status and pharmaceuticals. Herein we review the site specificity, age-related development, metabolic characteristics and regulation of BMAT under various metabolic conditions, including the functional interactions with bone and hematopoietic cells.
PMID: 29343445 [PubMed - as supplied by publisher]
Microglial activation mediates chronic mild stress-induced depressive- and anxiety-like behavior in adult rats.
J Neuroinflammation. 2018 Jan 17;15(1):21
Authors: Wang YL, Han QQ, Gong WQ, Pan DH, Wang LZ, Hu W, Yang M, Li B, Yu J, Liu Q
BACKGROUND: Depression is a heterogeneous disorder, with the exact neuronal mechanisms causing the disease yet to be discovered. Recent work suggests it is accompanied by neuro-inflammation, characterized, in particular, by microglial activation. However, microglial activation and its involvement in neuro-inflammation and stress-related depressive disorders are far from understood.
METHODS: We utilized multiple detection methods to detect the neuro-inflammation in the hippocampus of rats after exposure to chronic mild stress (CMS). Male Sprague Dawley (SD) rats were subjected to chronic mild stressors for 12 weeks. Microglial activation and hippocampal neuro-inflammation were detected by using a combinatory approach of in vivo [18F] DPA-714 positron emission computed tomography (PET) imaging, ionized calcium-binding adapter molecule 1 and translocator protein (TSPO) immunohistochemistry, and detection of NOD-like receptor protein 3 (NLRP3) inflammasome and some inflammatory mediators. Then, the rats were treated with minocycline during the last 4 weeks to observe its effect on hippocampal neuro-inflammation and depressive-like behavior induced by chronic mild stress.
RESULTS: The results show that 12 weeks of chronic mild stress induced remarkable depressive- and anxiety-like behavior, simultaneously causing hippocampal microglial activation detected by PET, immunofluorescence staining, and western blotting. Likewise, activation of NLRP3 inflammasome and upregulation of inflammatory mediators, such as interleukin-1β (IL-1β), IL-6, and IL-18, were also observed in the hippocampus after exposure to chronic stress. Interestingly, the anti-inflammatory mediators, such as IL-4 and IL-10, were also increased in the hippocampus following chronic mild stress, which may hint that chronic stress activates different types of microglia, which produce pro-inflammatory cytokines or anti-inflammatory cytokines. Furthermore, chronic minocycline treatment alleviated the depressive-like behavior induced by chronic stress and significantly inhibited microglial activation. Similarly, the activation of NLRP3 inflammasome and the increase of inflammatory mediators were not exhibited or significantly less marked in the minocycline treatment group.
CONCLUSION: These results together indicate that microglial activation mediates the chronic mild stress-induced depressive- and anxiety-like behavior and hippocampal neuro-inflammation.
PMID: 29343269 [PubMed - in process]
Interstitial Glucose and Physical Exercise in Type 1 Diabetes: Integrative Physiology, Technology, and the Gap In-Between.
Nutrients. 2018 Jan 15;10(1):
Authors: Moser O, Yardley JE, Bracken RM
Continuous and flash glucose monitoring systems measure interstitial fluid glucose concentrations within a body compartment that is dramatically altered by posture and is responsive to the physiological and metabolic changes that enable exercise performance in individuals with type 1 diabetes. Body fluid redistribution within the interstitial compartment, alterations in interstitial fluid volume, changes in rate and direction of fluid flow between the vasculature, interstitium and lymphatics, as well as alterations in the rate of glucose production and uptake by exercising tissues, make for caution when interpreting device read-outs in a rapidly changing internal environment during acute exercise. We present an understanding of the physiological and metabolic changes taking place with acute exercise and detail the blood and interstitial glucose responses with different forms of exercise, namely sustained endurance, high-intensity, and strength exercises in individuals with type 1 diabetes. Further, we detail novel technical information on currently available patient devices. As more health services and insurance companies advocate their use, understanding continuous and flash glucose monitoring for its strengths and limitations may offer more confidence for patients aiming to manage glycemia around exercise.
PMID: 29342932 [PubMed - in process]
Trans-ethnic meta-regression of genome-wide association studies accounting for ancestry increases power for discovery and improves fine-mapping resolution.
Hum Mol Genet. 2017 Sep 15;26(18):3639-3650
Authors: Mägi R, Horikoshi M, Sofer T, Mahajan A, Kitajima H, Franceschini N, McCarthy MI, COGENT-Kidney Consortium, T2D-GENES Consortium, Morris AP
Trans-ethnic meta-analysis of genome-wide association studies (GWAS) across diverse populations can increase power to detect complex trait loci when the underlying causal variants are shared between ancestry groups. However, heterogeneity in allelic effects between GWAS at these loci can occur that is correlated with ancestry. Here, a novel approach is presented to detect SNP association and quantify the extent of heterogeneity in allelic effects that is correlated with ancestry. We employ trans-ethnic meta-regression to model allelic effects as a function of axes of genetic variation, derived from a matrix of mean pairwise allele frequency differences between GWAS, and implemented in the MR-MEGA software. Through detailed simulations, we demonstrate increased power to detect association for MR-MEGA over fixed- and random-effects meta-analysis across a range of scenarios of heterogeneity in allelic effects between ethnic groups. We also demonstrate improved fine-mapping resolution, in loci containing a single causal variant, compared to these meta-analysis approaches and PAINTOR, and equivalent performance to MANTRA at reduced computational cost. Application of MR-MEGA to trans-ethnic GWAS of kidney function in 71,461 individuals indicates stronger signals of association than fixed-effects meta-analysis when heterogeneity in allelic effects is correlated with ancestry. Application of MR-MEGA to fine-mapping four type 2 diabetes susceptibility loci in 22,086 cases and 42,539 controls highlights: (i) strong evidence for heterogeneity in allelic effects that is correlated with ancestry only at the index SNP for the association signal at the CDKAL1 locus; and (ii) 99% credible sets with six or fewer variants for five distinct association signals.
PMID: 28911207 [PubMed - indexed for MEDLINE]
Epigenomic Consequences of Coding and Noncoding Driver Mutations.
Trends Cancer. 2016 Oct;2(10):585-605
Authors: Yao X, Xing M, Ooi WF, Tan P, Teh BT
Chromatin alterations are integral to the pathogenic process of cancer, as demonstrated by recent discoveries of frequent mutations in chromatin-modifier genes and aberrant DNA methylation states in different cancer types. Progress is being made on elucidating how chromatin alterations, and how proteins catalyzing these alterations, mechanistically contribute to tissue-specific tumorigenesis. In parallel, technologies enabling the genome-wide profiling of histone modifications have revealed the existence of noncoding driver genetic alterations in cancer. In this review, we survey the current knowledge of coding and noncoding cancer drivers, and discuss their impact on the chromatin landscape. Translational implications of these findings for novel cancer therapies are also presented.
PMID: 28741489 [PubMed - indexed for MEDLINE]
Death-associated protein kinase 1 phosphorylates NDRG2 and induces neuronal cell death.
Cell Death Differ. 2017 Feb;24(2):238-250
Authors: You MH, Kim BM, Chen CH, Begley MJ, Cantley LC, Lee TH
Death-associated protein kinase 1 (DAPK1) has been shown to have important roles in neuronal cell death in several model systems and has been implicated in multiple diseases, including Alzheimer's disease (AD). However, little is known about the molecular mechanisms by which DAPK1 signals neuronal cell death. In this study, N-myc downstream-regulated gene 2 (NDRG2) was identified as a novel substrate of DAPK1 using phospho-peptide library screening. DAPK1 interacted with NDRG2 and directly phosphorylated the Ser350 residue in vitro and in vivo. Moreover, DAPK1 overexpression increased neuronal cell death through NDRG2 phosphorylation after ceramide treatment. In contrast, inhibition of DAPK1 by overexpression of a DAPK1 kinase-deficient mutant and small hairpin RNA, or by treatment with a DAPK1 inhibitor significantly decreased neuronal cell death, and abolished NDRG2 phosphorylation in cell culture and in primary neurons. Furthermore, NDRG2-mediated cell death by DAPK1 was required for a caspase-dependent poly-ADP-ribose polymerase cleavage. In addition, DAPK1 ablation suppressed ceramide-induced cell death in mouse brain and neuronal cell death in Tg2576 APPswe-overexpressing mice. Finally, levels of phosphorylated NDRG2 Ser350 and DAPK1 were significantly increased in human AD brain samples. Thus, phosphorylation of NDRG2 on Ser350 by DAPK1 is a novel mechanism activating NDRG2 function and involved in neuronal cell death regulation in vivo.
PMID: 28141794 [PubMed - indexed for MEDLINE]
Mitochondria mediate cell membrane repair and contribute to Duchenne muscular dystrophy.
Cell Death Differ. 2017 Feb;24(2):330-342
Authors: Vila MC, Rayavarapu S, Hogarth MW, Van der Meulen JH, Horn A, Defour A, Takeda S, Brown KJ, Hathout Y, Nagaraju K, Jaiswal JK
Dystrophin deficiency is the genetic basis for Duchenne muscular dystrophy (DMD), but the cellular basis of progressive myofiber death in DMD is not fully understood. Using two dystrophin-deficient mdx mouse models, we find that the mitochondrial dysfunction is among the earliest cellular deficits of mdx muscles. Mitochondria in dystrophic myofibers also respond poorly to sarcolemmal injury. These mitochondrial deficits reduce the ability of dystrophic muscle cell membranes to repair and are associated with a compensatory increase in dysferlin-mediated membrane repair proteins. Dysferlin deficit in mdx mice further compromises myofiber cell membrane repair and enhances the muscle pathology at an asymptomatic age for dysferlin-deficient mice. Restoring partial dystrophin expression by exon skipping improves mitochondrial function and offers potential to improve myofiber repair. These findings identify that mitochondrial deficit in muscular dystrophy compromises the repair of injured myofibers and show that this repair mechanism is distinct from and complimentary to the dysferlin-mediated repair of injured myofibers.
PMID: 27834955 [PubMed - indexed for MEDLINE]
Photoimmunotheranostic agents for triple-negative breast cancer diagnosis and therapy that can be activated on demand.
Oncotarget. 2016 Aug 23;7(34):54925-54936
Authors: Amoury M, Bauerschlag D, Zeppernick F, von Felbert V, Berges N, Di Fiore S, Mintert I, Bleilevens A, Maass N, Bräutigam K, Meinhold-Heerlein I, Stickeler E, Barth S, Fischer R, Hussain AF
Triple-negative breast cancer (TNBC) is a heterogeneous disease in which the tumors do not express estrogen receptor (ER), progesterone receptor (PgR) or human epidermal growth factor receptor 2 (HER2). Classical receptor-targeted therapies such as tamoxifen or trastuzumab are therefore unsuitable and combinations of surgery, chemotherapy and/or radiotherapy are required. Photoimmunotheranostics is a minimally invasive approach in which antibodies deliver nontoxic photosensitizers that emit light to facilitate diagnosis and produce cytotoxic reactive oxygen species to induce apoptosis and/or necrosis in cancer cells. We developed a panel of photoimmunotheranostic agents against three TNBC-associated cell surface antigens. Antibodies against epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM) and chondroitin sulfate proteoglycan 4 (CSPG4) were conjugated to the highly potent near-infrared imaging agent/photosensitizer IRDye®700DX phthalocyanine using SNAP-tag technology achieving clear imaging in both breast cancer cell lines and human biopsies and highly potent phototherapeutic activity with IC50values of 62-165 nM against five different cell lines expressing different levels of EGFR, EpCAM and CSPG4. A combination of all three reagents increased the therapeutic activity against TNBC cells by up to 40%.
PMID: 27448975 [PubMed - indexed for MEDLINE]
Identification of rs671, a common variant of ALDH2, as a gout susceptibility locus.
Sci Rep. 2016 05 16;6:25360
Authors: Sakiyama M, Matsuo H, Nakaoka H, Yamamoto K, Nakayama A, Nakamura T, Kawai S, Okada R, Ooyama H, Shimizu T, Shinomiya N
Gout is a common disease resulting from hyperuricemia. Recently, a genome-wide association study identified an association between gout and a single nucleotide polymorphism (SNP) rs2188380, located on an intergenic region between MYL2 and CUX2 on chromosome 12. However, other genes around rs2188380 could possibly be gout susceptibility genes. Therefore, we performed a fine-mapping study of the MYL2-CUX2 region. From 8,595 SNPs in the MYL2-CUX2 region, 9 tag SNPs were selected, and genotyping of 1,048 male gout patients and 1,334 male controls was performed by TaqMan method. Eight SNPs showed significant associations with gout after Bonferroni correction. rs671 (Glu504Lys) of ALDH2 had the most significant association with gout (P = 1.7 × 10(-18), odds ratio = 0.53). After adjustment for rs671, the other 8 SNPs no longer showed a significant association with gout, while the significant association of rs671 remained. rs671 has been reportedly associated with alcohol drinking behavior, and it is well-known that alcohol drinking elevates serum uric acid levels. These data suggest that rs671, a common functional SNP of ALDH2, is a genuine gout-associated SNP in the MYL2-CUX2 locus and that "A" allele (Lys) of rs671 plays a protective role in the development of gout.
PMID: 27181629 [PubMed - indexed for MEDLINE]
Impact of body composition changes on risk of all-cause mortality in older adults.
Clin Nutr. 2016 Dec;35(6):1499-1505
Authors: Graf CE, Herrmann FR, Spoerri A, Makhlouf AM, Sørensen TIA, Ho S, Karsegard VL, Genton L
PURPOSE: This study evaluates the relationship between body mass index (BMI), fat mass index (FMI) and fat-free mass index (FFMI) changes and mortality in persons ≥65 years.
METHODS: Adults ≥65 years with at least two body composition measurements (BCM) between 1990 and 2011 were included. We excluded persons who died within one month of the second BCM and who had two single BCM in a one-month timeframe. Mortality data was retrieved until December 2012. For each person, we calculated the regression slopes for BMI, FMI and FFMI changes. Significant positive slopes were categorized as "gain", negative slopes as "loss" and the others as "maintenance". The impact of body composition changes was evaluated by Cox regression models while adjusting for sex, age, co-morbidities and body composition at the last measurement.
RESULTS: We included 791 persons with 3049 BCM. After adjustment for sex, and age and co-morbidities, a loss of FFMI, but not of FMI or BMI, increased the risk of mortality (HR 2.02, 95%CI 1.28-3.19). The prediction of mortality with FFMI loss remained significant when further adjusting for FMI loss and the last available body composition (HR 1.68, 95%CI 1.04-2.70).
CONCLUSIONS: FFMI loss is related to increased mortality in older persons.
PMID: 27126709 [PubMed - indexed for MEDLINE]
ZNF224, Krüppel like zinc finger protein, induces cell growth and apoptosis-resistance by down-regulation of p21 and p53 via miR-663a.
Oncotarget. 2016 May 24;7(21):31177-90
Authors: Cho JG, Park S, Lim CH, Kim HS, Song SY, Roh TY, Sung JH, Suh W, Ham SJ, Lim KH, Park SG
ZNF224 is a Krüppel-associated box-containing zinc-finger protein which represses gene transcription by interacting with various co-repressors. However, its consensus DNA sequences and target genes are not fully identified. In this study, we identified and characterized consensus DNA sequences containing 5'-CAGC-3' recognized by ZNF224 through ChIP-sequencing, which further confirmed by ELISA, SPR, qPCR, and luciferase activity assay. ZNF224 increased miR-663a transcription by binding to miR-663a promoter, which in turn binds to 3' UTR of p53 and p21 to decrease their expression. miR-663a antagonist abolished ZNF224-mediated suppression of p21 and p53, resulting in the enhanced apoptosis by CPT. The analyses using human breast ductal carcinoma tissues exhibited that the expression of ZNF224 and miR-663a was increased in cancer compared to non-cancer region. Consequently, ZNF224 increases cell survival and decreases apoptosis by decreasing the expression of p53 and p21 via miR-663a as a transcriptional activator. Taken together, we identified and characterized DNA binding element of ZNF224, and its target genes, miR-663a, which provides a novel insight in the down-regulation of p21 and p53 via miR-663a by ZNF224 in breast cancer.
PMID: 27105517 [PubMed - indexed for MEDLINE]
Integrated multidisciplinary care of headache disorders: A narrative review.
Cephalalgia. 2016 Oct;36(12):1181-1191
Authors: Gaul C, Liesering-Latta E, Schäfer B, Fritsche G, Holle D
Background Recent evidence shows that multidisciplinary treatment is effective in chronic pain syndromes, especially in headache disorders. Aim The aim of this review is to summarize current knowledge on integrative care concepts in headache patients regarding the optimal and necessary treatment parts, optimal duration and setting. Methods We present a narrative review reporting current literature and personal experience. Results and conclusion Based on current knowledge, multidisciplinary treatment programs appear to be reasonable and efficient in headache disorders. Sufficient controlled studies regarding the need for individual parts of the integrative care approach are missing as yet. Recommendations are therefore at least partly based on personal experiences. It seems to be unambiguous that patients should be referred to a specialized headache center offering such a program instead of being sent sequentially to various medical specialists. The extent and kind of required therapy (e.g. personal consultation versus group sessions) is not known yet. All patients should learn relaxation training, although it is unclear yet which training is the best for which patient. Physiotherapy with guidance on more activity and individual exercises should be used in all patients. Some patients might benefit from cognitive behavioral therapy. However, therapies often depend more on country-specific health care systems than on clinical needs or scientific data.
PMID: 26646785 [PubMed - indexed for MEDLINE]
16p11.2 Locus modulates response to satiety before the onset of obesity.
Int J Obes (Lond). 2016 05;40(5):870-6
Authors: Maillard AM, Hippolyte L, Rodriguez-Herreros B, Chawner SJ, Dremmel D, Agüera Z, Fagundo AB, Pain A, Martin-Brevet S, Hilbert A, Kurz S, Etienne R, Draganski B, Jimenez-Murcia S, Männik K, Metspalu A, Reigo A, Isidor B, Le Caignec C, David A, Mignot C, Keren B, 16p11.2 European Consortium, van den Bree MB, Munsch S, Fernandez-Aranda F, Beckmann JS, Reymond A, Jacquemont S
BACKGROUND: The 600 kb BP4-BP5 copy number variants (CNVs) at the 16p11.2 locus have been associated with a range of neurodevelopmental conditions including autism spectrum disorders and schizophrenia. The number of genomic copies in this region is inversely correlated with body mass index (BMI): the deletion is associated with a highly penetrant form of obesity (present in 50% of carriers by the age of 7 years and in 70% of adults), and the duplication with being underweight. Mechanisms underlying this energy imbalance remain unknown.
OBJECTIVE: This study aims to investigate eating behavior, cognitive traits and their relationships with BMI in carriers of 16p11.2 CNVs.
METHODS: We assessed individuals carrying a 16p11.2 deletion or duplication and their intrafamilial controls using food-related behavior questionnaires and cognitive measures. We also compared these carriers with cohorts of individuals presenting with obesity, binge eating disorder or bulimia.
RESULTS: Response to satiety is gene dosage-dependent in pediatric CNV carriers. Altered satiety response is present in young deletion carriers before the onset of obesity. It remains altered in adolescent carriers and correlates with obesity. Adult deletion carriers exhibit eating behavior similar to that seen in a cohort of obesity without eating disorders such as bulimia or binge eating. None of the cognitive measures are associated with eating behavior or BMI.
CONCLUSIONS: These findings suggest that abnormal satiety response is a strong contributor to the energy imbalance in 16p11.2 CNV carriers, and, akin to other genetic forms of obesity, altered satiety responsiveness in children precedes the increase in BMI observed later in adolescence.
PMID: 26620891 [PubMed - indexed for MEDLINE]