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1.  PGD for hereditary breast and ovarian cancer: the route to universal tests for BRCA1 and BRCA2 mutation carriers 
European Journal of Human Genetics  2013;21(12):1361-1368.
Preimplantation Genetic Diagnosis (PGD) is a method of testing in vitro embryos as an alternative to prenatal diagnosis with possible termination of pregnancy in case of an affected child. Recently, PGD for hereditary breast and ovarian cancer caused by BRCA1 and BRCA2 mutations has found its way in specialized labs. We describe the route to universal single-cell PGD tests for carriers of BRCA1/2 mutations. Originally, mutation-specific protocols with one or two markers were set up and changed when new couples were not informative. This route of changing protocols was finalized after 2 years with universal tests for both BRCA1 and BRCA2 mutation carriers based on haplotyping of, respectively, 6 (BRCA1) and 8 (BRCA2) microsatellite markers in a multiplex PCR. Using all protocols, 30 couples had a total of 47 PGD cycles performed. Eight cycles were cancelled upon IVF treatment due to hypostimulation. Of the remaining 39 cycles, a total of 261 embryos were biopsied and a genetic diagnosis was obtained in 244 (93%). In 34 of the 39 cycles (84.6%), an embryo transfer was possible and resulted in 8 pregnancies leading to a fetal heart beat per oocyte retrieval of 20.5% and a fetal heart beat per embryonic transfer of 23.5%. The preparation time and costs for set-up and validation of tests are minimized. The informativity of microsatellite markers used in the universal PGD-PCR tests is based on CEPH and deCODE pedigrees, making the tests applicable in 90% of couples coming from these populations.
doi:10.1038/ejhg.2013.50
PMCID: PMC3831069  PMID: 23531862
PGD; HBOC; BRCA1; BRCA2; microsatellites; mutation
2.  Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium 
Milne, Roger L. | Burwinkel, Barbara | Michailidou, Kyriaki | Arias-Perez, Jose-Ignacio | Zamora, M. Pilar | Menéndez-Rodríguez, Primitiva | Hardisson, David | Mendiola, Marta | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Dennis, Joe | Wang, Qin | Bolla, Manjeet K. | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk | Ko, Yon-Dschun | Brauch, Hiltrud | Hamann, Ute | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Li, Jingmei | Brand, Judith S. | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Lambrechts, Diether | Peuteman, Gilian | Christiaens, Marie-Rose | Smeets, Ann | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katazyna | Hartman, Mikael | Hui, Miao | Yen Lim, Wei | Wan Chan, Ching | Marme, Federick | Yang, Rongxi | Bugert, Peter | Lindblom, Annika | Margolin, Sara | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Hooning, Maartje J. | Kriege, Mieke | van den Ouweland, Ans M.W. | Koppert, Linetta B. | Fletcher, Olivia | Johnson, Nichola | dos-Santos-Silva, Isabel | Peto, Julian | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha J. | Long, Jirong | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Cox, Angela | Cross, Simon S. | Reed, Malcolm W.R. | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Braaf, Linde | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K. | Noh, Dong-Young | Simard, Jacques | Dumont, Martine | Goldberg, Mark S. | Labrèche, France | Fasching, Peter A. | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Radice, Paolo | Peterlongo, Paolo | Azzollini, Jacopo | Barile, Monica | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Hopper, John L. | Schmidt, Daniel F. | Makalic, Enes | Southey, Melissa C. | Hwang Teo, Soo | Har Yip, Cheng | Sivanandan, Kavitta | Tay, Wan-Ting | Shen, Chen-Yang | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Hou, Ming-Feng | Guénel, Pascal | Truong, Therese | Sanchez, Marie | Mulot, Claire | Blot, William | Cai, Qiuyin | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Wu, Anna H. | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O. | Bogdanova, Natalia | Dörk, Thilo | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Zhang, Ben | Couch, Fergus J. | Toland, Amanda E. | Yannoukakos, Drakoulis | Sangrajrang, Suleeporn | McKay, James | Wang, Xianshu | Olson, Janet E. | Vachon, Celine | Purrington, Kristen | Severi, Gianluca | Baglietto, Laura | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Czene, Kamila | Eriksson, Mikael | Humphreys, Keith | Darabi, Hatef | Ahmed, Shahana | Shah, Mitul | Pharoah, Paul D.P. | Hall, Per | Giles, Graham G. | Benítez, Javier | Dunning, Alison M. | Chenevix-Trench, Georgia | Easton, Douglas F. | Berchuck, Andrew | Eeles, Rosalind A. | Olama, Ali Amin Al | Kote-Jarai, Zsofia | Benlloch, Sara | Antoniou, Antonis | McGuffog, Lesley | Offit, Ken | Lee, Andrew | Dicks, Ed | Luccarini, Craig | Tessier, Daniel C. | Bacot, Francois | Vincent, Daniel | LaBoissière, Sylvie | Robidoux, Frederic | Nielsen, Sune F. | Cunningham, Julie M. | Windebank, Sharon A. | Hilker, Christopher A. | Meyer, Jeffrey | Angelakos, Maggie | Maskiell, Judi | van der Schoot, Ellen | Rutgers, Emiel | Verhoef, Senno | Hogervorst, Frans | Boonyawongviroj, Prat | Siriwanarungsan, Pornthep | Schrauder, Michael | Rübner, Matthias | Oeser, Sonja | Landrith, Silke | Williams, Eileen | Ryder-Mills, Elaine | Sargus, Kara | McInerney, Niall | Colleran, Gabrielle | Rowan, Andrew | Jones, Angela | Sohn, Christof | Schneeweiß, Andeas | Bugert, Peter | Álvarez, Núria | Lacey, James | Wang, Sophia | Ma, Huiyan | Lu, Yani | Deapen, Dennis | Pinder, Rich | Lee, Eunjung | Schumacher, Fred | Horn-Ross, Pam | Reynolds, Peggy | Nelson, David | Ziegler, Hartwig | Wolf, Sonja | Hermann, Volker | Lo, Wing-Yee | Justenhoven, Christina | Baisch, Christian | Fischer, Hans-Peter | Brüning, Thomas | Pesch, Beate | Rabstein, Sylvia | Lotz, Anne | Harth, Volker | Heikkinen, Tuomas | Erkkilä, Irja | Aaltonen, Kirsimari | von Smitten, Karl | Antonenkova, Natalia | Hillemanns, Peter | Christiansen, Hans | Myöhänen, Eija | Kemiläinen, Helena | Thorne, Heather | Niedermayr, Eveline | Bowtell, D | Chenevix-Trench, G | deFazio, A | Gertig, D | Green, A | Webb, P | Green, A. | Parsons, P. | Hayward, N. | Webb, P. | Whiteman, D. | Fung, Annie | Yashiki, June | Peuteman, Gilian | Smeets, Dominiek | Brussel, Thomas Van | Corthouts, Kathleen | Obi, Nadia | Heinz, Judith | Behrens, Sabine | Eilber, Ursula | Celik, Muhabbet | Olchers, Til | Manoukian, Siranoush | Peissel, Bernard | Scuvera, Giulietta | Zaffaroni, Daniela | Bonanni, Bernardo | Feroce, Irene | Maniscalco, Angela | Rossi, Alessandra | Bernard, Loris | Tranchant, Martine | Valois, Marie-France | Turgeon, Annie | Heguy, Lea | Sze Yee, Phuah | Kang, Peter | Nee, Kang In | Mariapun, Shivaani | Sook-Yee, Yoon | Lee, Daphne | Ching, Teh Yew | Taib, Nur Aishah Mohd | Otsukka, Meeri | Mononen, Kari | Selander, Teresa | Weerasooriya, Nayana | staff, OFBCR | Krol-Warmerdam, E. | Molenaar, J. | Blom, J. | Brinton, Louise | Szeszenia-Dabrowska, Neonila | Peplonska, Beata | Zatonski, Witold | Chao, Pei | Stagner, Michael | Bos, Petra | Blom, Jannet | Crepin, Ellen | Nieuwlaat, Anja | Heemskerk, Annette | Higham, Sue | Cross, Simon | Cramp, Helen | Connley, Dan | Balasubramanian, Sabapathy | Brock, Ian | Luccarini, Craig | Conroy, Don | Baynes, Caroline | Chua, Kimberley
Human Molecular Genetics  2014;23(22):6096-6111.
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04–1.10, P = 2.9 × 10−6], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03–1.07, P = 1.7 × 10−6) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07–1.12, P = 5.1 × 10−17). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05–1.10, P = 1.0 × 10−8); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04–1.07, P = 2.0 × 10−10). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
doi:10.1093/hmg/ddu311
PMCID: PMC4204770  PMID: 24943594
3.  The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes 
European Journal of Human Genetics  2010;18(9):999-1005.
Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000. The etiology of HPE is extremely heterogeneous and can be teratogenic or genetic. We screened four known HPE genes in a Dutch cohort of 86 non-syndromic HPE index cases, including 53 family members. We detected 21 mutations (24.4%), 3 in SHH, 9 in ZIC2 and 9 in SIX3. Eight mutations involved amino-acid substitutions, 7 ins/del mutations, 1 frame-shift, 3 identical poly-alanine tract expansions and 2 gene deletions. Pathogenicity of mutations was presumed based on de novo character, predicted non-functionality of mutated proteins, segregation of mutations with affected family-members or combinations of these features. Two mutations were reported previously. SNP array confirmed detected deletions; one spanning the ZIC2/ZIC5 genes (approx. 100 kb) the other a 1.45 Mb deletion including SIX2/SIX3 genes. The mutation percentage (24%) is comparable with previous reports, but we detected significantly less mutations in SHH: 3.5 vs 10.7% (P=0.043) and significantly more in SIX3: 10.5 vs 4.3% (P=0.018). For TGIF1 and ZIC2 mutation the rate was in conformity with earlier reports. About half of the mutations were de novo, one was a germ line mosaic. The familial mutations displayed extensive heterogeneity in clinical manifestation. Of seven familial index patients only two parental carriers showed minor HPE signs, five were completely asymptomatic. Therefore, each novel mutation should be considered as a risk factor for clinically manifest HPE, with the caveat of reduced clinical penetrance.
doi:10.1038/ejhg.2010.70
PMCID: PMC2987413  PMID: 20531442
Holoprosencephaly; SHH; SIX3; ZIC2; TGIF; genotype–phenotype
4.  Linkage analysis with chromosome 15q11-13 markers shows genomic imprinting in familial Angelman syndrome. 
Journal of Medical Genetics  1992;29(12):853-857.
Angelman syndrome (AS) and Prader-Willi syndrome (PWS) have become the classical examples of genomic imprinting in man, as completely different phenotypes are generated by the absence of maternal (AS) or paternal (PWS) contributions to the q11-13 region of chromosome 15 as a result of deletion or uniparental disomy. Apparently, most patients are sporadic cases. The genetic mechanism underlying familial AS has remained enigmatic for a long time. Recently, evidence has been emerging suggesting autosomal dominant inheritance of a detectable or undetectable defect in a gene or genes at 15q11-13, subject to genomic imprinting. The present report describes an unusually large pedigree with segregation of AS through maternal inheritance and apparent asymptomatic transmission through several male ancestors. Deletion and paternal disomy at 15q11-13 were excluded. However, the genetic defect is still located in this region, as we obtained a maximum lod score of 5.40 for linkage to the GABA receptor locus GABRB3 and the anonymous DNA marker D15S10, which have been mapped within or adjacent to the AS critical region at 15q11-13. The size of the pedigree allowed calculation of an odds ratio in favour of genomic imprinting of 9.25 x 10(5). This family illustrates the necessity of extensive pedigree analysis when considering recurrence risks for relatives of AS patients, those without detectable deletion or disomy in particular.
Images
PMCID: PMC1016200  PMID: 1362220
5.  The effects of stimulation of the autonomic nervous system via perioperative nutrition on postoperative ileus and anastomotic leakage following colorectal surgery (SANICS II trial): a study protocol for a double-blind randomized controlled trial 
Trials  2015;16:20.
Background
Postoperative ileus and anastomotic leakage are important complications following colorectal surgery associated with short-term morbidity and mortality. Previous experimental and preclinical studies have shown that a short intervention with enriched enteral nutrition dampens inflammation via stimulation of the autonomic nervous system and thereby reduces postoperative ileus. Furthermore, early administration of enteral nutrition reduced anastomotic leakage. This study will investigate the effect of nutritional stimulation of the autonomic nervous system just before, during and early after colorectal surgery on inflammation, postoperative ileus and anastomotic leakage.
Methods/Design
This multicenter, prospective, double-blind, randomized controlled trial will include 280 patients undergoing colorectal surgery. All patients will receive a selfmigrating nasojejunal tube that will be connected to a specially designed blinded tubing system. Patients will be allocated either to the intervention group, receiving perioperative nutrition, or to the control group, receiving no nutrition. The primary endpoint is postoperative ileus. Secondary endpoints include anastomotic leakage, local and systemic inflammation, (aspiration) pneumonia, surgical complications classified according to Clavien-Dindo, quality of life, gut barrier integrity and time until functional recovery. Furthermore, a cost-effectiveness analysis will be performed.
Discussion
Activation of the autonomic nervous system via perioperative enteral feeding is expected to dampen the local and systemic inflammatory response. Consequently, postoperative ileus will be reduced as well as anastomotic leakage. The present study is the first to investigate the effects of enriched nutrition given shortly before, during and after surgery in a clinical setting.
Trial registration
ClinicalTrials.gov: NCT02175979 - date of registration: 25 June 2014.
Dutch Trial Registry: NTR4670 - date of registration: 1 August 2014.
doi:10.1186/s13063-014-0532-x
PMCID: PMC4318130  PMID: 25623276
Perioperative nutrition; Colorectal surgery; Postoperative ileus; Anastomotic leakage; Autonomic nervous system; Inflammation
6.  Postoperative Bleeding Risk for Oral Surgery under Continued Clopidogrel Antiplatelet Therapy 
BioMed Research International  2015;2015:823651.
Object. To determine the incidence of postoperative bleeding for oral osteotomy carried out under continued monoantiplatelet therapy with clopidogrel and dual therapy with clopidogrel/aspirin. Design. Retrospective single center observatory study of two study groups and a control group. Methods. A total of 64 and 60 oral osteotomy procedures carried out under continued monoclopidogrel therapy and dual clopidogrel/aspirin therapy, respectively, were followed for two weeks for postoperative bleeding. Another 281 similar procedures were also followed as a control group. All oral osteotomy procedures were carried out on an outpatient basis. Results. We observed postoperative bleeding in 2/281 (0.7%) cases in the control group, in 1/64 (1.6%) cases in the clopidogrel group, and in 2/60 (3.3%) cases in the dual clopidogrel/aspirin group. The corresponding 95% confidence intervals are 0–1.7%, 0–4.7%, and 0–7.8%, respectively, and the incidences did not differ significantly among the three groups (P > 0.09). Postoperative hemorrhage was treated successfully in all cases with local measures. No changes of antiplatelet medication, transfusion, nor hospitalisation were necessary. No major cardiovascular events were recorded. Conclusions. Our results indicate that minor oral surgery can be performed safely under continued monoantiplatelet medication with clopidogrel or dual antiplatelet medication with clopidogrel/aspirin.
doi:10.1155/2015/823651
PMCID: PMC4303007  PMID: 25632402
7.  High prevalence of incomplete right bundle branch block in facioscapulohumeral muscular dystrophy without cardiac symptoms 
Functional Neurology  2014;29(3):159-165.
Summary
The exact prevalence and nature of cardiac involvement in facioscapulohumeral muscular dystrophy (FSHD) is unknown. Nevertheless, the current opinion is that symptomatic cardiac disease is rare.
We performed a cardiac screening [electrocardiogram (ECG) and echocardiography in the event of ECG abnormalities] in 75 genetically confirmed, ambulant FSHD patients without cardiac symptoms, with an eight-year follow-up of 57 patients, and compared the findings with results of previously performed cardiac screenings in the normal population. Baseline ECG demonstrated incomplete right bundle branch block (RBBB) in 33%, complete RBBB in 4%, and other minor abnormalities in 16%. Echocardiography showed no abnormalities. No significant changes were found after eight years of follow-up. Comparison with ECG abnormalities in the normal population showed a higher prevalence of incomplete RBBB (9.7 times higher) and of complete RBBB (4.8 times higher) in FSHD patients. This study in cardiac asymptomatic FSHD patients shows i) increased prevalence of incomplete RBBB in the absence of cardiomyopathy; ii) no progression of these abnormalities during eight years of follow-up. We conclude that FSHD patients without cardiac complaints do not need specific cardiac screening or surveillance. Furthermore, the increased prevalence of incomplete RBBB in the absence of cardiomyopathy suggests a selective involvement of the His-Purkinje system in FSHD.
PMCID: PMC4264782  PMID: 25473735
bundle branch block (BBB); facioscapulohumeral muscular dystrophy (FSHD); electrocardiography (ECG)
8.  γ-H2AX foci as in vivo effect biomarker in children emphasize the importance to minimize x-ray doses in paediatric CT imaging 
European Radiology  2014;25(3):800-811.
Objectives
Investigation of DNA damage induced by CT x-rays in paediatric patients versus patient dose in a multicentre setting.
Methods
From 51 paediatric patients (median age, 3.8 years) who underwent an abdomen or chest CT examination in one of the five participating radiology departments, blood samples were taken before and shortly after the examination. DNA damage was estimated by scoring γ-H2AX foci in peripheral blood T lymphocytes. Patient-specific organ and tissue doses were calculated with a validated Monte Carlo program. Individual lifetime attributable risks (LAR) for cancer incidence and mortality were estimated according to the BEIR VII risk models.
Results
Despite the low CT doses, a median increase of 0.13 γ-H2AX foci/cell was observed. Plotting the induced γ-H2AX foci versus blood dose indicated a low-dose hypersensitivity, supported also by an in vitro dose–response study. Differences in dose levels between radiology centres were reflected in differences in DNA damage. LAR of cancer mortality for the paediatric chest CT and abdomen CT cohort was 0.08 and 0.13 ‰ respectively.
Conclusion
CT x-rays induce DNA damage in paediatric patients even at low doses and the level of DNA damage is reduced by application of more effective CT dose reduction techniques and paediatric protocols.
Key Points
• CT induces a small, significant number of double-strand DNA breaks in children.
• More effective CT dose reduction results in less DNA damage.
• Risk estimates based on the LNT hypothesis may represent underestimates.
doi:10.1007/s00330-014-3463-8
PMCID: PMC4328121  PMID: 25354556
X-ray computed tomography; Double-strand DNA breaks; Radiobiology; gammaH2AX protein; Paediatrics
9.  Improving Work Functioning and Mental Health of Health Care Employees Using an E-Mental Health Approach to Workers' Health Surveillance: Pretest–Posttest Study 
Safety and Health at Work  2014;5(4):216-221.
Background
Mental health complaints are quite common in health care employees and can have adverse effects on work functioning. The aim of this study was to evaluate an e-mental health (EMH) approach to workers' health surveillance (WHS) for nurses and allied health professionals. Using the waiting-list group of a previous randomized controlled trial with high dropout and low compliance to the intervention, we studied the pre- and posteffects of the EMH approach in a larger group of participants.
Methods
We applied a pretest–posttest study design. The WHS consisted of online screening on impaired work functioning and mental health followed by online automatically generated personalized feedback, online tailored advice, and access to self-help EMH interventions. The effects on work functioning, stress, and work-related fatigue after 3 months were analyzed using paired t tests and effect sizes.
Results
One hundred and twenty-eight nurses and allied health professionals participated at pretest as well as posttest. Significant improvements were found on work functioning (p = 0.01) and work-related fatigue (p < 0.01). Work functioning had relevantly improved in 30% of participants. A small meaningful effect on stress was found (Cohen d = .23) in the participants who had logged onto an EMH intervention (20%, n = 26).
Conclusion
The EMH approach to WHS improves the work functioning and mental health of nurses and allied health professionals. However, because we found small effects and participation in the offered EMH interventions was low, there is ample room for improvement.
doi:10.1016/j.shaw.2014.08.002
PMCID: PMC4266797  PMID: 25516815
health personnel; internet self-help; mental health; occupational health; work functioning
10.  Definition, etiology, prevention and treatment of peri-implantitis – a review 
Head & Face Medicine  2014;10:34.
Peri-implant inflammations represent serious diseases after dental implant treatment, which affect both the surrounding hard and soft tissue. Due to prevalence rates up to 56%, peri-implantitis can lead to the loss of the implant without multilateral prevention and therapy concepts. Specific continuous check-ups with evaluation and elimination of risk factors (e.g. smoking, systemic diseases and periodontitis) are effective precautions. In addition to aspects of osseointegration, type and structure of the implant surface are of importance. For the treatment of peri-implant disease various conservative and surgical approaches are available. Mucositis and moderate forms of peri-implantitis can obviously be treated effectively using conservative methods. These include the utilization of different manual ablations, laser-supported systems as well as photodynamic therapy, which may be extended by local or systemic antibiotics. It is possible to regain osseointegration. In cases with advanced peri-implantitis surgical therapies are more effective than conservative approaches. Depending on the configuration of the defects, resective surgery can be carried out for elimination of peri-implant lesions, whereas regenerative therapies may be applicable for defect filling. The cumulative interceptive supportive therapy (CIST) protocol serves as guidance for the treatment of the peri-implantitis. The aim of this review is to provide an overview about current data and to give advices regarding diagnosis, prevention and treatment of peri-implant disease for practitioners.
doi:10.1186/1746-160X-10-34
PMCID: PMC4164121  PMID: 25185675
Peri-implantitis; Peri-implant disease; Review; Periodontal disease; Mucositis; Peri-implantitis therapy; Epidemiology; Etiology
11.  Media Reporting of Neuroscience Depends on Timing, Topic and Newspaper Type 
PLoS ONE  2014;9(8):e104780.
The rapid developments in neuroscientific techniques raise high expectations among the general public and therefore warrant close monitoring of the translation to the media and daily-life applications. The need of empirical research into neuroscience communication is emphasized by its susceptibility to evoke misconceptions and polarized beliefs. As the mass media are the main sources of information about (neuro-)science for a majority of the general public, the objective of the current research is to quantify how critically and accurately newspapers report on neuroscience as a function of the timing of publication (within or outside of periods of heightened media attention to neuroscience, termed “news waves”), the topic of the research (e.g. development, health, law) and the newspaper type (quality, popular, free newspapers). The results show that articles published during neuroscience news waves were less neutral and more optimistic, but not different in accuracy. Furthermore, the overall tone and accuracy of articles depended on the topic; for example, articles on development often had an optimistic tone whereas articles on law were often skeptical or balanced, and articles on health care had highest accuracy. Average accuracy was rather low, but articles in quality newspapers were relatively more accurate than in popular and free newspapers. Our results provide specific recommendations for researchers and science communicators, to improve the translation of neuroscience findings through the media: 1) Caution is warranted during periods of heightened attention (news waves), as reporting tends to be more optimistic; 2) Caution is also warranted not to follow topic-related biases in optimism (e.g., development) or skepticism (e.g., law); 3) Researchers should keep in mind that overall accuracy of reporting is low, and especially articles in popular and free newspapers provide a minimal amount of details. This indicates that researchers themselves may need to be more active in preventing misconceptions to arise.
doi:10.1371/journal.pone.0104780
PMCID: PMC4130600  PMID: 25117741
12.  Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks 
eLife  2014;3:e02725.
DNA replication errors that persist as mismatch mutations make up the molecular fingerprint of mismatch repair (MMR)-deficient tumors and convey them with resistance to standard therapy. Using whole-genome and whole-exome sequencing, we here confirm an MMR-deficient mutation signature that is distinct from other tumor genomes, but surprisingly similar to germ-line DNA, indicating that a substantial fraction of human genetic variation arises through mutations escaping MMR. Moreover, we identify a large set of recurrent indels that may serve to detect microsatellite instability (MSI). Indeed, using endometrial tumors with immunohistochemically proven MMR deficiency, we optimize a novel marker set capable of detecting MSI and show it to have greater specificity and selectivity than standard MSI tests. Additionally, we show that recurrent indels are enriched for the ‘DNA double-strand break repair by homologous recombination’ pathway. Consequently, DSB repair is reduced in MMR-deficient tumors, triggering a dose-dependent sensitivity of MMR-deficient tumor cultures to DSB inducers.
DOI: http://dx.doi.org/10.7554/eLife.02725.001
eLife digest
Before a cell divides, it must first copy all of its genetic material. Any mistakes that are made during this process are called mutations. Mutations can give rise to new traits but are mostly harmful to the cells, or cause cancer; therefore, cells have evolved tools that can efficiently spot these mistakes and repair them. One of the main tools is called mismatch repair (MMR).
Defects in the cell's mismatch repair tools can wreak havoc as this allows many mutations to accumulate. Zhao et al. looked at the genomes of tumors where mismatch repair was not working properly to see what makes these ‘MMR-deficient tumors’ different from other tumors. This revealed that MMR-deficient tumors have similar patterns of mutations to those seen in egg and sperm cells. This was unexpected and suggests that mutations that are not corrected by mismatch repair are an important source of the genetic differences found between different humans, and between humans and their ancestors.
Identifying cancerous tumors that are MMR-deficient is vital, as these tumors tend not to respond to commonly used cancer treatments. However, current clinical methods to identify MMR-deficient tumors often fail or produce results that are difficult to interpret. MMR-deficient tumors commonly contain mutations called indels, where short fragments of DNA are inserted or deleted into longer DNA sequences. Zhao et al. have found 59 indels that can be used to detect MMR-deficient tumors, where each indel had been identified in several tumors taken from different tissues. This new approach allowed MMR-deficiency to be identified in several types of tumor, including colon and ovarian cancers, with greater sensitivity and accuracy than the existing methods.
Zhao et al. also found that the indels in MMR-deficient tumors reduce the ability of the tumors to repair a type of DNA damage called double-strand breaks. In these, both strands of DNA that make up the double helix are broken and the DNA chain is severed. As this kind of damage is very harmful to a cell, making more double-strand breaks could therefore form part of a more effective treatment against MMR-deficient tumors; further research is needed to investigate this possibility.
DOI: http://dx.doi.org/10.7554/eLife.02725.002
doi:10.7554/eLife.02725
PMCID: PMC4141275  PMID: 25085081
whole-genome sequencing; mismatch repair deficiency; mutation pattern; MSI; DNA double-strand breaks; DSB inducers; human
13.  Does Pulsed Magnetic Field Therapy Influence Nerve Regeneration in the Median Nerve Model of the Rat? 
BioMed Research International  2014;2014:401760.
The aim of this study was to evaluate the impact of pulsed magnetic field therapy on peripheral nerve regeneration after median nerve injury and primary coaptation in the rat. Both median nerves were surgically exposed and denervated in 24 female Wistar rats. A microsurgical coaptation was performed on the right side, whereas on the left side a spontaneous healing was prevented. The study group underwent a daily pulsed magnetic field therapy; the other group served as a control group. The grasping force was recorded 2 weeks after the surgical intervention for a period of 12 weeks. The right median nerve was excised and histologically examined. The histomorphometric data and the functional assessments were analyzed by t-test statistics and one-way ANOVA. One-way ANOVA indicated a statistically significant influence of group affiliation and grasping force (P = 0.0078). Grasping strength was higher on a significant level in the experimental group compared to the control group permanently from the 9th week to the end of the study. T-test statistics revealed a significantly higher weight of the flexor digitorum sublimis muscle (P = 0.0385) in the experimental group. The histological evaluation did not reveal any statistically significant differences concerning the histomorphometric parameters. Our results suggest that the pulsed magnetic field therapy has a positive influence on the functional aspects of neural regeneration. More studies are needed to precisely evaluate and optimize the intensity and duration of the application.
doi:10.1155/2014/401760
PMCID: PMC4131097  PMID: 25143937
14.  Intensive care staff, the donation request and relatives’ satisfaction with the decision: a focus group study 
BMC Anesthesiology  2014;14:52.
Background
Effectiveness of the donation request is generally measured by consent rates, rather than by relatives’ satisfaction with their decision. Our aim was to elicit Dutch ICU staffs’ views and experiences with the donation request, to investigate their awareness of (dis)satisfaction with donation decisions by relatives, specifically in the case of refusal, and to collect advice that may leave more relatives satisfied with their decision.
Methods
Five focus groups with a total of 32 participants (IC physicians, IC nurses and transplant coordinators) from five university hospitals in the Netherlands. Transcripts were examined using standard qualitative methods.
Results
Four themes (donation request perceived by ICU staff from the perspective of relatives; donation request perceived by ICU staff from their own perspective; aftercare; donation in society) divided into 14 categories were identified.
According to ICU staff, relatives mentioned their own values more frequently than values of the potential donor as important for the decision. ICU staff observed this imbalance, but reacted empathically to the relatives’ point of view. ICU staff rarely suggested reconsideration of refusal and did not ask relatives for arguments.
ICU staff did not always feel comfortable with a request in the delicate context of brain death. Sometimes the interests of patient, relatives and those on the waiting list were irreconcilable.
ICU staff were mostly unaware of relatives’ regret following their decisions. Aftercare did not provide this type of information.
Donation request by IC physicians was influenced by the way organ donation has been regulated in society (law, donor register, education, media).
Conclusions
Our findings lead to the hypothesis that giving relatives more time and inviting them to reconsider their initial refusal will lead to a more stable decision and possibly more consent.
doi:10.1186/1471-2253-14-52
PMCID: PMC4107587  PMID: 25057260
Organ donation; Qualitative research; Health care professionals; Donation request; Regret
15.  Re-Thinking the Fear Avoidance Model: Toward a Multi-Dimensional Framework of Pain-Related Disability 
Pain  2013;154(11):2262-2265.
doi:10.1016/j.pain.2013.06.005
PMCID: PMC4078976  PMID: 23748115
Fear avoidance model; pain; disability; psychological risk factors
16.  The Rothmund-Thomson syndrome helicase RECQL4 is essential for hematopoiesis 
The Journal of Clinical Investigation  2014;124(8):3551-3565.
Mutations within the gene encoding the DNA helicase RECQL4 underlie the autosomal recessive cancer-predisposition disorder Rothmund-Thomson syndrome, though it is unclear how these mutations lead to disease. Here, we demonstrated that somatic deletion of Recql4 causes a rapid bone marrow failure in mice that involves cells from across the myeloid, lymphoid, and, most profoundly, erythroid lineages. Apoptosis was markedly elevated in multipotent progenitors lacking RECQL4 compared with WT cells. While the stem cell compartment was relatively spared in RECQL4-deficent mice, HSCs from these animals were not transplantable and even selected against. The requirement for RECQL4 was intrinsic in hematopoietic cells, and loss of RECQL4 in these cells was associated with increased replicative DNA damage and failed cell-cycle progression. Concurrent deletion of p53, which rescues loss of function in animals lacking the related helicase BLM, did not rescue BM phenotypes in RECQL4-deficient animals. In contrast, hematopoietic defects in cells from Recql4Δ/Δ mice were fully rescued by a RECQL4 variant without RecQ helicase activity, demonstrating that RECQL4 maintains hematopoiesis independently of helicase activity. Together, our data indicate that RECQL4 participates in DNA replication rather than genome stability and identify RECQL4 as a regulator of hematopoiesis with a nonredundant role compared with other RecQ helicases.
doi:10.1172/JCI75334
PMCID: PMC4109528  PMID: 24960165
17.  Face Transplantation: On the Verge of Becoming Clinical Routine? 
BioMed Research International  2014;2014:907272.
Introduction. Face transplantation (FT) is an innovative achievement of modern reconstructive surgery and is on the verge of becoming a common surgical opportunity. This review article was compiled to provide an update on this surgical field, especially regarding clinical outcomes, benefits, and complications implied. Methods. We performed an extensive research on all English-language Medline articles, case reports, and reviews published online until September 15, 2013. Used search terms were “face transplantation,” “face transplant,” “facial transplantation,” “facial transplant,” “face allograft,” and “facial allograft.” Results. To date 27 FTs have been performed worldwide. 19 of these cases have been published in the Medline database. Long-term follow-up reports of FT cases are rare. Three deaths associated with the procedure have occurred to date. The clinical outcomes of FT are satisfying. Reinnervation of sensation has been faster than motor recovery. Extensive functional improvements have been observed. Due to strict immunosuppression protocols, no case of hyperacute or chronic rejection and no graft-versus-host disease have occurred to date. Conclusions. As studies on long-term outcomes are missing, particularly regarding immunosuppression-related complications, FT will stay experimental for the next years. Nevertheless, for a small group of patients, FT already is a feasible reconstructive option.
doi:10.1155/2014/907272
PMCID: PMC4070394  PMID: 25009821
18.  Large scale mtDNA sequencing reveals sequence and functional conservation as major determinants of homoplasmic mtDNA variant distribution 
Mitochondrion  2011;11(6):964-972.
The mitochondrial DNA (mtDNA) is highly variable, containing large numbers of pathogenic mutations and neutral polymorphisms. The spectrum of homoplasmic mtDNA variation was characterized in 730 subjects and compared with known pathogenic sites. The frequency and distribution of variants in protein coding genes were inversely correlated with conservation at the amino acid level. Analysis of tRNA secondary structures indicated a preference of variants for the loops and some acceptor stem positions. This comprehensive overview of mtDNA variants distinguishes between regions and positions which are likely not critical, mainly conserved regions with pathogenic mutations and essential regions containing no mutations at all.
doi:10.1016/j.mito.2011.09.003
PMCID: PMC4038511  PMID: 21946566
MitoChip; mtDNA variants; Distribution; Pathogenicity
19.  TGF-β stimulation in human and murine cells reveals commonly affected biological processes and pathways at transcription level 
BMC Systems Biology  2014;8:55.
Background
The TGF-β signaling pathway is a fundamental pathway in the living cell, which plays a key role in many central cellular processes. The complex and sometimes contradicting mechanisms by which TGF-β yields phenotypic effects are not yet completely understood. In this study we investigated and compared the transcriptional response profile of TGF-β1 stimulation in different cell types. For this purpose, extensive experiments are performed and time-course microarray data are generated in human and mouse parenchymal liver cells, human mesenchymal stromal cells and mouse hematopoietic progenitor cells at different time points. We applied a panel of bioinformatics methods on our data to uncover common patterns in the dynamic gene expression response in respective cells.
Results
Our analysis revealed a quite variable and multifaceted transcriptional response profile of TGF-β1 stimulation, which goes far beyond the well-characterized classical TGF-β1 signaling pathway. Nonetheless, we could identify several commonly affected processes and signaling pathways across cell types and species. In addition our analysis suggested an important role of the transcription factor EGR1, which appeared to have a conserved influence across cell-types and species. Validation via an independent dataset on A549 lung adenocarcinoma cells largely confirmed our findings. Network analysis suggested explanations, how TGF-β1 stimulation could lead to the observed effects.
Conclusions
The analysis of dynamical transcriptional response to TGF-β treatment experiments in different human and murine cell systems revealed commonly affected biological processes and pathways, which could be linked to TGF-β1 via network analysis. This helps to gain insights about TGF-β pathway activities in these cell systems and its conserved interactions between the species and tissue types.
doi:10.1186/1752-0509-8-55
PMCID: PMC4049504  PMID: 24886091
TGF-β; Microarray; Time-course analysis; Gene set analysis; Clustering; Functional similarity
20.  Accelerometry Measuring the Outcome of Robot-Supported Upper Limb Training in Chronic Stroke: A Randomized Controlled Trial 
PLoS ONE  2014;9(5):e96414.
Purpose
This study aims to assess the extent to which accelerometers can be used to determine the effect of robot-supported task-oriented arm-hand training, relative to task-oriented arm-hand training alone, on the actual amount of arm-hand use of chronic stroke patients in their home situation.
Methods
This single-blind randomized controlled trial included 16 chronic stroke patients, randomly allocated using blocked randomization (n = 2) to receive task-oriented robot-supported arm-hand training or task-oriented (unsupported) arm-hand training. Training lasted 8 weeks, 4 times/week, 2×30 min/day using the (T-)TOAT ((Technology-supported)-Task-Oriented-Arm-Training) method. The actual amount of arm-hand use, was assessed at baseline, after 8 weeks training and 6 months after training cessation. Duration of use and intensity of use of the affected arm-hand during unimanual and bimanual activities were calculated.
Results
Duration and intensity of use of the affected arm-hand did not change significantly during and after training, with or without robot-support (i.e. duration of use of unimanual use of the affected arm-hand: median difference of −0.17% in the robot-group and −0.08% in the control group between baseline and after training cessation; intensity of the affected arm-hand: median difference of 3.95% in the robot-group and 3.32% in the control group between baseline and after training cessation). No significant between-group differences were found.
Conclusions
Accelerometer data did not show significant changes in actual amount of arm-hand use after task-oriented training, with or without robot-support. Next to the amount of use, discrimination between activities performed and information about quality of use of the affected arm-hand are essential to determine actual arm-hand performance.
Trial Registration
Controlled-trials.com ISRCTN82787126
doi:10.1371/journal.pone.0096414
PMCID: PMC4019639  PMID: 24823925
21.  Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci 
Background
A Xist RNA decorated Barr body is the structural hallmark of the compacted inactive X territory in female mammals. Using super-resolution three-dimensional structured illumination microscopy (3D-SIM) and quantitative image analysis, we compared its ultrastructure with active chromosome territories (CTs) in human and mouse somatic cells, and explored the spatio-temporal process of Barr body formation at onset of inactivation in early differentiating mouse embryonic stem cells (ESCs).
Results
We demonstrate that all CTs are composed of structurally linked chromatin domain clusters (CDCs). In active CTs the periphery of CDCs harbors low-density chromatin enriched with transcriptionally competent markers, called the perichromatin region (PR). The PR borders on a contiguous channel system, the interchromatin compartment (IC), which starts at nuclear pores and pervades CTs. We propose that the PR and macromolecular complexes in IC channels together form the transcriptionally permissive active nuclear compartment (ANC). The Barr body differs from active CTs by a partially collapsed ANC with CDCs coming significantly closer together, although a rudimentary IC channel system connected to nuclear pores is maintained. Distinct Xist RNA foci, closely adjacent to the nuclear matrix scaffold attachment factor-A (SAF-A) localize throughout Xi along the rudimentary ANC. In early differentiating ESCs initial Xist RNA spreading precedes Barr body formation, which occurs concurrent with the subsequent exclusion of RNA polymerase II (RNAP II). Induction of a transgenic autosomal Xist RNA in a male ESC triggers the formation of an ‘autosomal Barr body’ with less compacted chromatin and incomplete RNAP II exclusion.
Conclusions
3D-SIM provides experimental evidence for profound differences between the functional architecture of transcriptionally active CTs and the Barr body. Basic structural features of CT organization such as CDCs and IC channels are however still recognized, arguing against a uniform compaction of the Barr body at the nucleosome level. The localization of distinct Xist RNA foci at boundaries of the rudimentary ANC may be considered as snap-shots of a dynamic interaction with silenced genes. Enrichment of SAF-A within Xi territories and its close spatial association with Xist RNA suggests their cooperative function for structural organization of Xi.
doi:10.1186/1756-8935-7-8
PMCID: PMC4108088  PMID: 25057298
Super-resolution microscopy; X chromosome inactivation; Inactive X chromosome; Chromosome territory; CT; Xist RNA; Barr body; Chromatin domain; Interchromatin compartment; SAF-A
22.  Effects of task-oriented robot training on arm function, activity, and quality of life in chronic stroke patients: a randomized controlled trial 
Background
Over fifty percent of stroke patients experience chronic arm hand performance problems, compromising independence in daily life activities and quality of life. Task-oriented training may improve arm hand performance after stroke, whereby augmented therapy may lead to a better treatment outcome. Technology-supported training holds opportunities for increasing training intensity. However, the effects of robot-supported task-oriented training with real life objects in stroke patients are not known to date. The aim of the present study was to investigate the effectiveness and added value of the Haptic Master robot combined with task-oriented arm hand training in chronic stroke patients.
Methods
In a single-blind randomized controlled trial, 22 chronic stroke patients were randomly allocated to receive either task-oriented robot-assisted arm-hand training (experimental group) or task-oriented non-robotic arm-hand training (control group). For training, the T-TOAT (Technology-supported Task-Oriented Arm Training) method was applied. Training was provided during 8 weeks, 4 times/week, 2× 30 min/day.
Results
A significant improvement after training on the Action Research Arm Test (ARAT) was demonstrated in the experimental group (p = 0.008). Results were maintained until 6 months after cessation of the training. On the perceived performance measure (Motor Activity Log (MAL)), both, the experimental and control group improved significantly after training (control group p = 0.008; experimental group p = 0.013). The improvements on MAL in both groups were maintained until 6 months after cessation of the training. With regard to quality of life, only in the control group a significant improvement after training was found (EuroQol-5D p = 0.015, SF-36 physical p = 0.01). However, the improvement on SF-36 in the control group was not maintained (p = 0.012). No between-group differences could be demonstrated on any of the outcome measures.
Conclusion
Arm hand performance improved in chronic stroke patients, after eight weeks of task oriented training. The use of a Haptic Master robot in support of task-oriented arm training did not show additional value over the video-instructed task-oriented exercises in highly functional stroke patients.
Clinical trial registration information
Current Controlled Trials ISRCTN82787126
doi:10.1186/1743-0003-11-45
PMCID: PMC3973831  PMID: 24684808
Stroke; Hemiplegia; Robotics; Computer-assisted therapy; Rehabilitation; Upper extremity; Arm; Hand; Motor skills; Automation
23.  Arm hand skilled performance in cerebral palsy: activity preferences and their movement components 
BMC Neurology  2014;14:52.
Background
Assessment of arm-hand use is very important in children with cerebral palsy (CP) who encounter arm-hand problems. To determine validity and reliability of new instruments to assess actual performance, a set of standardized test situations including activities of daily living (ADL) is required. This study gives information with which such a set for upper extremity skill research may be fine-tuned, relative to a specific research question. Aim of this study is to a) identify upper extremity related ADL children with CP want to improve on, b) determine the 10 most preferred goals of children with CP, and c) identify movement components of all goals identified.
Method
The Canadian Occupational Performance Measure was used to identify upper extremity-related ADL preferences (goals) of 53 children with CP encountering arm-hand problems (mean age 9 ± 4.5 year). Goals were ranked based on importance attributed to each goal and the number of times a goal was mentioned, resulting in a gross list with goals. Additionally, two studies were performed, i.e. study A to determine the 10 most preferred goals for 3 age groups (2.5-5 years; 6-11 years, 12-19 years), based on the total preference score, and study B to identify movement components, like reaching and grasping, of all goals identified for both the leading and the assisting arm-hand.
Results
Seventy-two goals were identified. The 10 most preferred goals differed with age, changing from dressing and leisure-related goals in the youngest children to goals regarding personal care and eating for children aged 6-11 years. The oldest children preferred goals regarding eating, personal care and computer use. The movement components ‘positioning’, ‘reach’, ‘grasp’, and ‘hold’ were present in most tasks. ‘Manipulating’ was more important for the leading arm-hand, whereas ‘fixating’ was more important for the assisting arm-hand.
Conclusion
This study gave insight into the preferences regarding ADL children with CP would like to improve on, and the movement components characterizing these activities. This information can be used to create a set of standardized test situations, which can be used to assess the validity and reliability of new measurement instruments to gauge actual arm-hand skilled performance.
doi:10.1186/1471-2377-14-52
PMCID: PMC4000003  PMID: 24646071
Cerebral Palsy; Children; Adolescents; Activities of daily living; Upper extremity; Treatment goals; Training preferences; Canadian Occupational Performance Measure; Movement components; Rehabilitation
24.  Proximal tubular cells contain a phenotypically distinct, scattered cell population involved in tubular regeneration 
The Journal of pathology  2013;229(5):645-659.
Regeneration of injured tubular cells occurs after acute tubular necrosis primarily from intrinsic renal cells. This may occur from a pre-existing intratubular stem/progenitor cell population or from any surviving proximal tubular cell. In this study, we characterize a CD24-, CD133-, and vimentin-positive subpopulation of cells scattered throughout the proximal tubule in normal human kidney. Compared to adjacent ‘normal’ proximal tubular cells, these CD24-positive cells contained less cytoplasm, fewer mitochondria, and no brush border. In addition, 49 marker proteins are described that are expressed within the proximal tubules in a similar scattered pattern. For eight of these markers, we confirmed co-localization with CD24. In human biopsies of patients with acute tubular necrosis (ATN), the number of CD24-positive tubular cells was increased. In both normal human kidneys and the ATN biopsies, around 85% of proliferating cells were CD24-positive – indicating that this cell population participates in tubular regeneration. In healthy rat kidneys, the novel cell subpopulation was absent. However, upon unilateral ureteral obstruction (UUO), the novel cell population was detected in significant amounts in the injured kidney. In summary, in human renal biopsies, the CD24-positive cells represent tubular cells with a deviant phenotype, characterized by a distinct morphology and marker expression. After acute tubular injury, these cells become more numerous. In healthy rat kidneys, these cells are not detectable, whereas after UUO, they appeared de novo – arguing against the notion that these cells represent a pre-existing progenitor cell population. Our data indicate rather that these cells represent transiently dedifferentiated tubular cells involved in regeneration.
doi:10.1002/path.4125
PMCID: PMC3951144  PMID: 23124355
proximal tubules; progenitor cell; regeneration; acute tubular necrosis
25.  The Sum of Its Parts—Effects of Gastric Distention, Nutrient Content and Sensory Stimulation on Brain Activation 
PLoS ONE  2014;9(3):e90872.
During food consumption the brain integrates multiple interrelated neural and hormonal signals involved in the regulation of food intake. Factors influencing the decision to stop eating include the foods' sensory properties, macronutrient content, and volume, which in turn affect gastric distention and appetite hormone responses. So far, the contributions of gastric distention and oral stimulation by food on brain activation have not been studied. The primary objective of this study was to assess the effect of gastric distention with an intra-gastric load and the additional effect of oral stimulation on brain activity after food administration. Our secondary objective was to study the correlations between hormone responses and appetite-related ratings and brain activation. Fourteen men completed three functional magnetic resonance imaging sessions during which they either received a naso-gastric infusion of water (stomach distention), naso-gastric infusion of chocolate milk (stomach distention + nutrients), or ingested chocolate-milk (stomach distention + nutrients + oral exposure). Appetite ratings and blood parameters were measured at several time points. During gastric infusion, brain activation was observed in the midbrain, amygdala, hypothalamus, and hippocampus for both chocolate milk and water, i.e., irrespective of nutrient content. The thalamus, amygdala, putamen and precuneus were activated more after ingestion than after gastric infusion of chocolate milk, whereas infusion evoked greater activation in the hippocampus and anterior cingulate. Moreover, areas involved in gustation and reward were activated more after oral stimulation. Only insulin responses following naso-gastric infusion of chocolate milk correlated with brain activation, namely in the putamen and insula. In conclusion, we show that normal (oral) food ingestion evokes greater activation than gastric infusion in stomach distention and food intake-related brain areas. This provides neural evidence for the importance of sensory stimulation in the process of satiation.
Trial Registration
ClinicalTrials.gov NCT01644539.
doi:10.1371/journal.pone.0090872
PMCID: PMC3948722  PMID: 24614074

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