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1.  Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk 
Rationale: Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far.
Objectives: To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci.
Methods: Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms.
Measurements and Main Results: Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3.
Conclusions: Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics
PMCID: PMC4595678  PMID: 26051272
Immunochip; HLA; IL23; BTNL2; association
2.  Effectiveness of Bicycle Safety Helmets in Preventing Facial Injuries in Road Accidents 
Archives of Trauma Research  2016;5(3):e30011.
The effectiveness of bicycle safety helmets in preventing head injuries is well- documented. Recent studies differ regarding the effectiveness of bicycle helmets in preventing facial injuries, especially those of the mid-face and the mandible.
The present study was conducted to determine the protective effect of a bicycle helmet in preventing mid-face and mandibular fractures.
Patients and Methods
Data from an accident research unit were analyzed to collect technical collision details (relative collision speed, type of collision, collision partner, and use of a helmet) and clinical data (type of fracture).
Between 1999 and 2011, 5,350 bicycle crashes were included in the study. Of these, 175 (3.3%) had fractures of the mid-face or mandible. In total, 228 mid-face or mandibular fractures were identified. A significant correlation was found between age and relative collision speed, and the incidence of a fracture. While no significant correlation was found between the use of a helmet and the incidence of mid-facial fractures, the use of a helmet was correlated with a significantly increased incidence of mandibular fractures.
Higher age of cyclists and increasing speed of the accident opponent significantly increase the likelihood of sustaining facial fractures. The use of bicycle helmets does not significantly reduce the incidence of mid-facial fractures, while being correlated with an even increased incidence of mandibular fractures.
PMCID: PMC5079115  PMID: 27800459
Bicyclist; Bicycle Helmet; Facial Injury; Mid-face Fracture; Mandibular Fracture
3.  Immunochip analysis identifies association of the RAD50/IL13 region with human longevity 
Aging Cell  2016;15(3):585-588.
Human longevity is characterized by a remarkable lack of confirmed genetic associations. Here, we report on the identification of a novel locus for longevity in the RAD50/IL13 region on chromosome 5q31.1 using a combined European sample of 3208 long‐lived individuals (LLI) and 8919 younger controls. First, we performed a large‐scale association study on 1458 German LLI (mean age 99.0 years) and 6368 controls (mean age 57.2 years) by targeting known immune‐associated loci covered by the Immunochip. The analysis of 142 136 autosomal single nucleotide polymorphisms (SNPs) revealed an Immunochip‐wide significant signal (PI mmunochip = 7.01 × 10–9) for the SNP rs2075650 in the TOMM40/APOE region, which has been previously described in the context of human longevity. To identify novel susceptibility loci, we selected 15 markers with PI mmunochip < 5 × 10–4 for replication in two samples from France (1257 LLI, mean age 102.4 years; 1811 controls, mean age 49.1 years) and Denmark (493 LLI, mean age 96.2 years; 740 controls, mean age 63.1 years). The association at SNP rs2706372 replicated in the French study collection and showed a similar trend in the Danish participants and was also significant in a meta‐analysis of the combined French and Danish data after adjusting for multiple testing. In a meta‐analysis of all three samples, rs2706372 reached a P‐value of PI mmunochip+Repl = 5.42 × 10−7 (OR = 1.20; 95% CI = 1.12–1.28). SNP rs2706372 is located in the extended RAD50/IL13 region. RAD50 seems a plausible longevity candidate due to its involvement in DNA repair and inflammation. Further studies are needed to identify the functional variant(s) that predispose(s) to a long and healthy life.
PMCID: PMC4854908  PMID: 27004735
5q31.1; genetic association; human longevity; IL13; Immunochip; RAD50
4.  Road Traffic Related Injury Severity in Truck Drivers: A Prospective Medical and Technical Analysis of 582 Truck Crashes 
Archives of Trauma Research  2016;5(2):e31380.
While cyclists and pedestrians are known to be at significant risk for severe injuries when exposed to road traffic accidents (RTA) involving trucks, little is known about RTA injury risk for truck drivers.
The aim of this study was to analyze the injury severity in truck drivers following RTAs.
Patients and Methods
Our local accident research unit prospectively documented 43000 RTAs involving 582 trucks between 2000 and 2011. Injury severity, including the abbreviated injury scale (AIS) and the maximum abbreviated injury scale (MAIS) were analyzed. Technical parameters (e.g. delta-v, direction of impact), the location of accident, and its dependency on the road type were also taken into consideration.
Thirteen percent (77/582) of truck drivers were injured. Extremities were found to be at highest risk of injury with the lower extremities (36x) being injured most severely (10x: AIS 2 and 3). Death occurred only after collisions with other trucks, and severity of injuries increased with an increased speed limit. The maximum abbreviated injury scale was higher in the crash opponents (56x MAIS ≥ 3) compared to the truck drivers (8x MAIS ≥ 3). Overall, 82% of the crash opponents were injured.
The safety of truck drivers is assured by their vehicles, the consequence being that the risk of becoming injured is likely to be low. However, the legs especially are at high risk for severe injuries during RTAs. This probability increases in the instance of a collision with another truck. Nevertheless, in RTAs involving trucks and regular passenger vehicles, the other party is in higher risk of injury.
PMCID: PMC5035669  PMID: 27679790
Trucks; Abbreviated Injury Scale; Trauma
5.  Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study 
Lancet (London, England)  2016;387(10014):156-167.
Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.
This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile.
After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10−78), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10−18). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10−4).
Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time.
International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
PMCID: PMC4714968  PMID: 26490195
6.  Open Repair Versus Thoracic Endovascular Aortic Repair in Multiple-Injured Patients: Observations From a Level-1 Trauma Center 
Archives of Trauma Research  2015;4(4):e27183.
Blunt trauma of the thoracic aorta is a rare but potentially life-threatening entity. Intimal tears are a domain of non-operative management, whereas all other types of lesions should be repaired urgently. There is now a clear trend favoring minimally invasive stent grafting over open surgical repair.
The aim of the present study was to retrospectively evaluate the mortality and morbidity with either treatment option. Therefore, a retrospective observational study was performed to compare two different treatment methods at two different time periods at one trauma center.
Patients and Methods:
Between 1977 and 2012, all severely injured patients referred to our level 1 trauma center were screened for blunt aortic injuries. We compared baseline characteristics, 30-day and overall mortality, morbidity, duration of intensive care treatment, procedure time, and transfusion of packed red blood between patients who underwent open surgical or stent repair.
During the observation period, 45 blunt aortic injuries were recorded. The average Injury Severity Score (ISS) was 41.8 (range 29 - 68). Twenty-five patients underwent Open Repair (OR), and another 20 patients were scheduled to emergency stent grafting. The 30-day mortality in the surgical and stent groups were 5/25 (20%) and 2/20 (10%), respectively. The average time for open surgery was 151 minutes; the mean time for stent grafting was 67 minutes (P = 0.001). Postoperative stay on the intensive care unit was between one and 59 days (median 10) in group one and between four and 50 days in group two (median 26)(P = 0.03). Patients undergoing OR required transfusion of 6.0 units of packed red cells in median; patients undergoing stent grafting required a median of 2.0 units of packed red cells (P < 0.001). In the stent grafting group, 30-day mortality was 10% (2/20).
Due to more sophisticated diagnostic tools and surgical approaches, mortality and morbidity of blunt aortic injuries were significantly reduced over the years compared to thoracic endovascular aortic repair and OR over two different time periods.
PMCID: PMC4733514  PMID: 26848470
Aortic Rupture; Traffic Accident; Injury Severity Score; In-Hospital Mortality; Multiple Injuries
7.  Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells 
Nature communications  2015;6:6804.
Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0×10−9) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P =4.8×10−16). Clec16a knock down (KD) mice showed reduced number of B cells and elevated IgM levels compared to controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition.
PMCID: PMC4444044  PMID: 25891430
8.  Current Concepts for Patellar Dislocation 
Archives of Trauma Research  2015;4(3):e29301.
Patellar dislocation usually occurs to the lateral side, leading to ruptures of the Medial Patellofemoral Ligament (MPFL) in about 90% of the cases. Even though several prognostic factors are identified for patellofemoral instability after patellar dislocation so far, the appropriate therapy remains a controversial issue.
Evidence Acquisition:
Authors searched the Medline library for studies on both surgical and conservative treatment for patellar dislocation and patellofemoral instability. Additionally, the reference list of each article was searched for additional studies.
A thorough analysis of the anatomical risk factors with a particular focus on patella alta, increased Tibial Tuberosity-Trochlear Groove (TT-TG) distance, trochlear dysplasia as well as torsional abnormalities should be performed early after the first dislocation to allow adequate patient counseling. Summarizing the results of all published randomized clinical trials and comparing surgical and conservative treatment after the first-time patellar dislocation until today indicated no significant evident difference for children, adolescents, and adults. Therefore, nonoperative treatment was indicated after a first-time patellar dislocation in the vast majority of patients.
Surgical treatment for patellar dislocation is indicated primarily in case of relevant concomitant injuries such as osteochondral fractures, and secondarily for recurrent dislocations.
PMCID: PMC4636822  PMID: 26566512
Knee; Patella; Patellar Dislocation; Evidence-Based Medicine; Medial Patellofemoral Ligament; Patellofemoral Instability
9.  Solid Organ Transplantation in Patients with Inflammatory Bowel Diseases (IBD): Analysis of Transplantation Outcome and IBD Activity in a Large Single Center Cohort 
PLoS ONE  2015;10(8):e0135807.
Currently, limited data of the outcome of inflammatory bowel disease (IBD) in patients after solid organ transplantation (SOT) are available. We aimed to analyze effects of SOT on the IBD course in a large IBD patient cohort.
Clinical data from 1537 IBD patients were analyzed for patients who underwent SOT (n = 31) between July 2002 and May 2014. Sub-analyses included SOT outcome parameters, IBD activity before and after SOT, and efficacy of IBD treatment.
4.74% of patients with ulcerative colitis (UC) and 0.84% of patients with Crohn’s disease (CD) underwent SOT (p = 2.69 x 10−6, UC vs. CD). 77.4% of patients with SOT underwent liver transplantation (LTx) with tacrolimus-based immunosuppressive therapy after SOT. All LTx were due to primary sclerosing cholangitis (PSC) or PSC overlap syndromes. Six patients (19.4%) required renal transplantation and one patient (3.2%) heart transplantation. A survival rate of 83.9% after a median follow-up period of 103 months was observed. Before SOT, 65.0% of patients were in clinical remission and 5 patients received immunosuppressive therapy (16.1%). After SOT, 61.0% of patients were in remission (p = 1.00 vs. before SOT) and 29.0% required IBD-specific immunosuppressive or anti-TNF therapy (p = 0.54 vs. before SOT). 42.9% of patients with worsening of IBD after SOT were at higher risk of needing steroid therapy for increased IBD activity (p = 0.03; relative risk (RR): 10.29; 95% CI 1.26–84.06). Four patients (13.0%) needed anti-TNF therapy after SOT (response rate 75%).
SOT was more common in UC patients due to the higher prevalence of PSC-related liver cirrhosis in UC. Despite mainly tacrolimus-based immunosuppressive regimens, outcome of SOT and IBD was excellent in this cohort. In this SOT cohort, concomitant immunosuppressive therapy due to IBD was well tolerated.
PMCID: PMC4545391  PMID: 26288187
10.  The NOD2 Single Nucleotide Polymorphism rs72796353 (IVS4+10 A>C) Is a Predictor for Perianal Fistulas in Patients with Crohn's Disease in the Absence of Other NOD2 Mutations 
PLoS ONE  2015;10(7):e0116044.
A previous study suggested an association of the single nucleotide polymorphism (SNP) rs72796353 (IVS4+10 A>C) in the NOD2 gene with susceptibility to Crohn’s disease (CD). However, this finding has not been confirmed. Given that NOD2 variants still represent the most important predictors for CD susceptibility and phenotype, we evaluated the association of rs72796353 with inflammatory bowel disease (IBD) susceptibility and the IBD phenotype.
Genomic DNA from 2256 Caucasians, including 1073 CD patients, 464 patients with ulcerative colitis (UC), and 719 healthy controls, was genotyped for the NOD2 SNP rs72796353 and the three main CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847. Subsequently, IBD association and genotype-phenotype analyses were conducted.
In contrast to the strong associations of the NOD2 SNPs rs2066844 (p=3.51 x 10-3), rs2066845 (p=1.54 x 10-2), and rs2066847 (p=1.61 x 10-20) with CD susceptibility, no significant association of rs72796353 with CD or UC susceptibility was found. However, in CD patients without the three main CD-associated NOD2 mutations, rs72796353 was significantly associated with the development of perianal fistulas (p=2.78 x 10-7, OR 5.27, [95% CI 2.75-10.12] vs. NOD2 wild-type carriers).
Currently, this study represents the largest genotype-phenotype analysis of the impact of the NOD2 variant rs72796353 on the disease phenotype in IBD. Our data demonstrate that in CD patients the IVS4+10 A>C variant is strongly associated with the development of perianal fistulas. This association is particularly pronounced in patients who are not carriers of the three main CD-associated NOD2 mutations, suggesting rs72796353 as additional genetic marker for the CD disease behaviour.
PMCID: PMC4493062  PMID: 26147989
11.  Protective mucosal immunity mediated by epithelial CD1d and IL-10 
Nature  2014;509(7501):497-502.
The mechanisms by which mucosal homeostasis is maintained are of central importance to inflammatory bowel disease. Critical to these processes is the intestinal epithelial cell (IEC), which regulates immune responses at the interface between the commensal microbiota and the host1,2. CD1d presents self and microbial lipid antigens to natural killer T (NKT) cells, which are involved in the pathogenesis of colitis in animal models and human inflammatory bowel disease3–8. As CD1d crosslinking on model IECs results in the production of the important regulatory cytokine interleukin (IL)-10 (ref.9), decreased epithelial CD1d expression—as observed in inflammatory bowel disease10,11—may contribute substantially to intestinal inflammation. Here we show in mice that whereas bone-marrow-derived CD1d signals contribute to NKT-cell-mediated intestinal inflammation, engagement of epithelial CD1d elicits protective effects through the activation of STAT3 and STAT3-dependent transcription of IL-10, heat shock protein 110 (HSP110; also known as HSP105), and CD1d itself. All of these epithelial elements are critically involved in controlling CD1d-mediated intestinal inflammation. This is demonstrated by severe NKT-cell-mediated colitis upon IEC-specific deletion of IL-10, CD1d, and its critical regulator microsomal triglyceride transfer protein (MTP)12,13, as well as deletion of HSP110 in the radioresistant compartment. Our studies thus uncover a novel pathway of IEC-dependent regulation of mucosal homeostasis and highlight a critical role of IL-10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.
PMCID: PMC4132962  PMID: 24717441
12.  Concepts and Potential Future Developments for Treatment of Periprosthetic Proximal Femoral Fractures 
Periprosthetic proximal femoral fractures are a major challenge for the orthopaedic surgeon, with a continuously increasing incidence due to aging populations and concordantly increasing numbers of total hip replacements. Surgical decision-making mainly depends on the stability of the arthroplasty, and the quality of bone stock. As patients final outcomes mainly depend on early mobilization, a high primary stability of the construct is of particular relevance. Osteosynthetic procedures are usually applied for fractures with a stable arthroplasty, while fractures with a loosened endoprosthesis commonly require revision arthroplasty. Osteoporotic bone with insufficient anchoring substance for screws poses one major concern for cases with well-fixed arthroplasties. Complication rates and perioperative mortality have remained unacceptably high, emphasizing the need for new innovations in the treatment of periprosthetic fractures. Transprosthetic drilling of screws through the hip stem as the most solid and reliable part in the patient might represent a promising future approach, with auspicious results in recent biomechanical studies.
PMCID: PMC4578140  PMID: 26401164
Intraprosthetic screw fixation; periprosthetic fracture; Vancouver classification
13.  The NOD2 p.Leu1007fsX1008 Mutation (rs2066847) Is a Stronger Predictor of the Clinical Course of Crohn's Disease than the FOXO3A Intron Variant rs12212067 
PLoS ONE  2014;9(11):e108503.
Very recently, a sub-analysis of genome-wide association scans revealed that the non-coding single nucleotide polymorphism (SNP) rs12212067 in the FOXO3A gene is associated with a milder course of Crohn's disease (CD) (Cell 2013;155:57–69). The aim of our study was to evaluate the clinical value of the SNP rs12212067 in predicting the severity of CD by correlating CD patient genotype status with the most relevant complications of CD such as stenoses, fistulas, and CD-related surgery.
Methodology/Principal Findings
We genotyped 550 CD patients for rs12212067 (FOXO3A) and the three common CD-associated NOD2 mutations rs2066844, rs2066847, and rs2066847 and performed genotype-phenotype analyses.
No significant phenotypic differences were found between the wild-type genotype TT of the FOXO3A SNP rs12212067 and the minor genotypes TG and GG independently from NOD2 variants. The allele frequency of the minor G allele was 12.7%. Age at diagnosis, disease duration, body mass index, surgery rate, stenoses, fistula, need for immunosuppressive therapy, and disease course were not significantly different. In contrast, the NOD2 mutant p.Leu1007fsX1008 (rs2066847) was highly associated with penetrating CD (p = 0.01), the development of fistulas (p = 0.01) and stenoses (p = 0.01), and ileal disease localization (p = 0.03). Importantly, the NOD2 SNP rs2066847 was a strong separator between an aggressive and a mild course of CD (p = 2.99×10−5), while the FOXO3A SNP rs12212067 did not separate between mild and aggressive CD behavior in our cohort (p = 0.35). 96.2% of the homozygous NOD2 p.Leu1007fsX1008 carriers had an aggressive disease behavior compared to 69.3% of the patients with the NOD2 wild-type genotype (p = 0.007).
In clinical practice, the NOD2 variant p.Leu1007fsX1008 (rs2066847), in particular in homozygous form, is a much stronger marker for a severe clinical phenotype than the FOXO3A rs12212067 SNP for a mild disease course on an individual patient level despite its important impact on the inflammatory response of monocytes.
PMCID: PMC4217717  PMID: 25365249
14.  Repair of segmental long-bone defects by stem cell concentrate augmented scaffolds: a clinical and positron emission tomography - computed tomography analysis 
International Orthopaedics  2013;37(11):2231-2237.
Treating segmental long-bone defects remains a major challenge. For defects >3 cm, segmental transport represents the gold standard, even though the method is time consuming and afflicted with several complications. The aim of this study was to evaluate healing of such defects after grafting an osteogenic scaffold previously seeded with stem cell concentrate.
We evaluated five patients with segmental long-bone defects (3–14 cm) treated with bone marrow aspirate concentrates (BMAC) seeded onto a bovine xenogenous scaffold. The healing process was monitored by X-rays and positron emission tomography–computed tomography (PET-CT) three months after surgery.
Centrifugation led to a concentration of leukocytes by factor 8.1 ± 7.5. Full weight bearing was achieved 11.3 ± 5.0 weeks after surgery. PET analysis showed an increased influx of fluoride by factor 8.3 ± 6.4 compared with the contralateral side (p < 0.01). Bone density in the cortical area was 75 ± 16 % of the contralateral side (p < 0.03). The patient with the largest defect sustained an implant failure in the distal femur and finally accomplished therapy by segmental transport. He also had the lowest uptake of fluoride of the patient collective (2.2-fold increase).
Stem cell concentrates can be an alternative to segmental bone transport. Further studies are needed to compare this method with autologous bone grafting and segmental transport.
PMCID: PMC3824887  PMID: 24013459
Segmental bone defect; Scaffold; Mesenchymal stem cells (MSC); Stem cell concentrate
15.  Different thermal conductivity in drilling of cemented compared with cementless hip prostheses in the treatment of periprosthetic fractures of the proximal femur—an experimental biomechanical analysis 
International Orthopaedics  2013;37(10):1885-1889.
The purpose of this study was to evaluate the different temperature levels whilst drilling cemented and cementless hip prostheses implanted in bovine femora, and to evaluate the insulating function of the cement layer.
Standard hip prostheses were implanted in bovine donor diaphyses, with or without a cement layer. Drilling was then performed using high-performance-cutting drills with a reinforced core, a drilling diameter of 5.5 mm and cooling channels through the tip of the drill for constantly applied internal cooling solution. An open type cooling model was used in this setup. Temperature was continuously measured by seven thermocouples placed around the borehole. Thermographic scans were also performed during drilling.
At the cemented implant surface, the temperature never surpassed 24.7 °C when constantly applied internal cooling was used. Without the insulating cement layer (i.e. during drilling of the cementless bone–prosthesis construct), the temperature increased to 47 °C.
Constantly applied internal cooling can avoid structural bone and soft tissue damage during drilling procedures. With a cement layer, the temperatures only increased to non-damaging levels. The results could be useful in the treatment of periprosthetic fractures with intraprosthetic implant fixation.
PMCID: PMC3779579  PMID: 23775453
16.  Association Between Variants of PRDM1 and NDP52 and Crohn’s Disease, Based on Exome Sequencing and Functional Studies 
Gastroenterology  2013;145(2):339-347.
Background & Aims
Genome-wide association studies (GWASs) have identified 140 Crohn’s disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.
We sequenced whole exomes of 42 unrelated subjects with Crohn’s disease (CD) and 5 healthy individuals (controls), and then filtered single-nucleotide variants by incorporating association results from meta-analyses of CD GWASs and in silico mutation effect prediction algorithms. We then genotyped 9348 patients with CD, 2868 with ulcerative colitis, and 14,567 controls, and associated variants analyzed in functional studies using materials from patients and controls and in vitro model systems.
We identified rare missense mutations in PR domain-containing1 (PRDM1) and associated these with CD. These increased proliferation of T cells and secretion of cytokines upon activation, and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWASs, correlated with reduced expression of PRDM1 in ileal biopsies and peripheral blood mononuclear cells (combined P=1.6×0−8). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P=4.83×10−9). We found that this variant impairs the regulatory functions of NDP52 to inhibit NFκB activation of genes that regulate inflammation and affect stability of proteins in toll-like receptor pathways.
We have extended GWAS results and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWASs and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role for autophagy in pathogenesis of CD.
PMCID: PMC3753067  PMID: 23624108
inflammatory bowel disease; whole-exome sequencing; complex disease
17.  Temperature control with internally applied cooling in solid material drilling: an experimental, biomechanical study 
International Orthopaedics  2013;37(7):1355-1361.
The purpose of this study was to evaluate the different temperature levels while drilling solid materials and to compare different cooling solutions for possible temperature control. An additional purpose was to develop an internal cooling device which can be connected to routinely used manual drilling devices in trauma surgery.
Drilling was performed on a straight hip stem implanted in bovine femora without cooling, with externally applied cooling and with a newly developed internal cooling device. Temperature changes were measured by seven thermocouples arranged near the borehole. Additionally, thermographic scans were performed during drilling.
Drilling without cooling leads to an immediate increase in temperature to levels of thermal osteonecrosis (over 200 °C). With externally applied cooling temperatures were decreased, but were still up to a tissue damaging 85 °C. Internally applied cooling led to a temperature decrease to tissue-preserving levels during the drilling procedure (24.7 °C).
Internal cooling with HPC-drillers lowered the measured temperatures to non-tissue damaging temperatures and should avoid structural tissue damage.
PMCID: PMC3685654  PMID: 23512602
18.  Rate and Predictors of Mucosal Healing in Patients with Inflammatory Bowel Disease Treated with Anti-TNF-Alpha Antibodies 
PLoS ONE  2014;9(6):e99293.
Mucosal healing (MH) is an important treatment goal in patients with inflammatory bowel disease (IBD), but factors predicting MH under medical therapy are largely unknown. In this study, we aimed to characterize predictive factors for MH in anti-TNF-alpha antibody-treated IBD patients.
We retrospectively analyzed 248 IBD patients (61.3% CD, 38.7% UC) treated with anti-TNF-alpha antibodies (infliximab and/or adalimumab) for MH, defined as macroscopic absence of inflammatory lesions (Mayo endoscopy score 0 or SES-CD score 0) in colonoscopies which were analyzed before and after initiation of an anti-TNF-alpha antibody treatment.
In patients treated with only one anti-TNF-alpha antibody (“TNF1 group”, n = 202), 56 patients (27.7%) achieved complete MH at follow-up colonoscopy (median overall follow-up time: 63 months). In a second cohort (n = 46), which comprised patients who were consecutively treated with two anti-TNF-alpha antibodies (“TNF2 group”), 13 patients (28.3%) achieved complete MH (median overall follow-up time: 64.5 months). Compared to patients without MH, CRP values at follow-up colonoscopy were significantly lower in patients with MH (TNF1 group: p = 8.35×10−5; TNF2 group: p = 0.002). Multivariate analyses confirmed CRP at follow-up colonoscopy as predictor for MH in the TNF1 group (p = 0.012). Overall need for surgery was lower in patients with MH (TNF1 group: p = 0.01; TNF2 group: p = 0.03).
We identified low serum CRP level at follow-up colonoscopy as predictor for MH, while MH was an excellent negative predictor for the need for surgery.
PMCID: PMC4059645  PMID: 24932476
19.  Oncostatin M Mediates STAT3-Dependent Intestinal Epithelial Restitution via Increased Cell Proliferation, Decreased Apoptosis and Upregulation of SERPIN Family Members 
PLoS ONE  2014;9(4):e93498.
Oncostatin M (OSM) is produced by activated T cells, monocytes, and dendritic cells and signals through two distinct receptor complexes consisting of gp130 and LIFR (I) or OSMR-β and gp130 (II), respectively. Aim of this study was to analyze the role of OSM in intestinal epithelial cells (IEC) and intestinal inflammation.
OSM expression and OSM receptor distribution was analyzed by PCR and immunohistochemistry experiments, signal transduction by immunoblotting. Gene expression studies were performed by microarray analysis and RT-PCR. Apoptosis was measured by caspases-3/7 activity. IEC migration and proliferation was studied in wounding and water soluble tetrazolium assays.
The IEC lines Caco-2, DLD-1, SW480, HCT116 and HT-29 express mRNA for the OSM receptor subunits gp130 and OSMR-β, while only HCT116, HT-29 and DLD-1 cells express LIFR mRNA. OSM binding to its receptor complex activates STAT1, STAT3, ERK-1/2, SAPK/JNK-1/2, and Akt. Microarray analysis revealed 79 genes that were significantly up-regulated (adj.-p≤0.05) by OSM in IEC. Most up-regulated genes belong to the functional categories “immunity and defense” (p = 2.1×10−7), “apoptosis” (p = 3.7×10−4) and “JAK/STAT cascade” (p = 3.4×10−6). Members of the SERPIN gene family were among the most strongly up-regulated genes. OSM significantly increased STAT3- and MEK1-dependent IEC cell proliferation (p<0.05) and wound healing (p = 3.9×10−5). OSM protein expression was increased in colonic biopsies of patients with active inflammatory bowel disease (IBD).
OSM promotes STAT3-dependent intestinal epithelial cell proliferation and wound healing in vitro. Considering the increased OSM expression in colonic biopsy specimens of patients with active IBD, OSM upregulation may modulate a barrier-protective host response in intestinal inflammation. Further in vivo studies are warranted to elucidate the exact role of OSM in intestinal inflammation and the potential of OSM as a drug target in IBD.
PMCID: PMC3977870  PMID: 24710357
21.  High density genotyping study identifies four new susceptibility loci for atopic dermatitis 
Nature genetics  2013;45(7):808-812.
Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds1, and recent data indicate a role for autoreactivity in at least a subgroup of patients2. With filaggrin (FLG) a major locus causing a skin barrier deficiency was identified3. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German cases and 5,449 controls using the Immunochip array, followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified 4 new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.
PMCID: PMC3797441  PMID: 23727859
22.  Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis 
Liu, Jimmy Z. | Hov, Johannes Roksund | Folseraas, Trine | Ellinghaus, Eva | Rushbrook, Simon M. | Doncheva, Nadezhda T. | Andreassen, Ole A. | Weersma, Rinse K. | Weismüller, Tobias J. | Eksteen, Bertus | Invernizzi, Pietro | Hirschfield, Gideon M. | Gotthardt, Daniel Nils | Pares, Albert | Ellinghaus, David | Shah, Tejas | Juran, Brian D. | Milkiewicz, Piotr | Rust, Christian | Schramm, Christoph | Müller, Tobias | Srivastava, Brijesh | Dalekos, Georgios | Nöthen, Markus M. | Herms, Stefan | Winkelmann, Juliane | Mitrovic, Mitja | Braun, Felix | Ponsioen, Cyriel Y. | Croucher, Peter J. P. | Sterneck, Martina | Teufel, Andreas | Mason, Andrew L. | Saarela, Janna | Leppa, Virpi | Dorfman, Ruslan | Alvaro, Domenico | Floreani, Annarosa | Onengut-Gumuscu, Suna | Rich, Stephen S. | Thompson, Wesley K. | Schork, Andrew J. | Næss, Sigrid | Thomsen, Ingo | Mayr, Gabriele | König, Inke R. | Hveem, Kristian | Cleynen, Isabelle | Gutierrez-Achury, Javier | Ricaño-Ponce, Isis | van Heel, David | Björnsson, Einar | Sandford, Richard N. | Durie, Peter R. | Melum, Espen | Vatn, Morten H | Silverberg, Mark S. | Duerr, Richard H. | Padyukov, Leonid | Brand, Stephan | Sans, Miquel | Annese, Vito | Achkar, Jean-Paul | Boberg, Kirsten Muri | Marschall, Hanns-Ulrich | Chazouillères, Olivier | Bowlus, Christopher L. | Wijmenga, Cisca | Schrumpf, Erik | Vermeire, Severine | Albrecht, Mario | Rioux, John D. | Alexander, Graeme | Bergquist, Annika | Cho, Judy | Schreiber, Stefan | Manns, Michael P. | Färkkilä, Martti | Dale, Anders M. | Chapman, Roger W. | Lazaridis, Konstantinos N. | Franke, Andre | Anderson, Carl A. | Karlsen, Tom H.
Nature genetics  2013;45(6):670-675.
PMCID: PMC3667736  PMID: 23603763
genetic association study; disease genetics; immunogenetics; liver
23.  Intestinal DMBT1 Expression Is Modulated by Crohn’s Disease-Associated IL23R Variants and by a DMBT1 Variant Which Influences Binding of the Transcription Factors CREB1 and ATF-2 
PLoS ONE  2013;8(11):e77773.
DMBT is an antibacterial pattern recognition and scavenger receptor. In this study, we analyzed the role of DMBT1 single nucleotide polymorphisms (SNPs) regarding inflammatory bowel disease (IBD) susceptibility and examined their functional impact on transcription factor binding and downstream gene expression.
Seven SNPs in the DMBT1 gene region were analyzed in 2073 individuals including 818 Crohn’s disease (CD) patients and 972 healthy controls in two independent case-control panels. Comprehensive epistasis analyses for the known CD susceptibility genes NOD2, IL23R and IL27 were performed. The influence of IL23R variants on DMBT1 expression was analyzed. Functional analysis included siRNA transfection, quantitative PCR, western blot, electrophoretic mobility shift and luciferase assays.
IL-22 induces DMBT1 protein expression in intestinal epithelial cells dependent on STAT3, ATF-2 and CREB1. IL-22 expression-modulating, CD risk-associated IL23R variants influence DMBT1 expression in CD patients and DMBT1 levels are increased in the inflamed intestinal mucosa of CD patients. Several DMBT1 SNPs were associated with CD susceptibility. SNP rs2981804 was most strongly associated with CD in the combined panel (p = 3.0×10−7, OR 1.42; 95% CI 1.24–1.63). All haplotype groups tested showed highly significant associations with CD (including omnibus P-values as low as 6.1×10−18). The most strongly CD risk-associated, non-coding DMBT1 SNP rs2981804 modifies the DNA binding sites for the transcription factors CREB1 and ATF-2 and the respective genomic region comprising rs2981804 is able to act as a transcriptional regulator in vitro. Intestinal DMBT1 expression is decreased in CD patients carrying the rs2981804 CD risk allele.
We identified novel associations of DMBT1 variants with CD susceptibility and discovered a novel functional role of rs2981804 in regulating DMBT1 expression. Our data suggest an important role of DMBT1 in CD pathogenesis.
PMCID: PMC3818382  PMID: 24223725
24.  Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease 
Jostins, Luke | Ripke, Stephan | Weersma, Rinse K | Duerr, Richard H | McGovern, Dermot P | Hui, Ken Y | Lee, James C | Schumm, L Philip | Sharma, Yashoda | Anderson, Carl A | Essers, Jonah | Mitrovic, Mitja | Ning, Kaida | Cleynen, Isabelle | Theatre, Emilie | Spain, Sarah L | Raychaudhuri, Soumya | Goyette, Philippe | Wei, Zhi | Abraham, Clara | Achkar, Jean-Paul | Ahmad, Tariq | Amininejad, Leila | Ananthakrishnan, Ashwin N | Andersen, Vibeke | Andrews, Jane M | Baidoo, Leonard | Balschun, Tobias | Bampton, Peter A | Bitton, Alain | Boucher, Gabrielle | Brand, Stephan | Büning, Carsten | Cohain, Ariella | Cichon, Sven | D’Amato, Mauro | De Jong, Dirk | Devaney, Kathy L | Dubinsky, Marla | Edwards, Cathryn | Ellinghaus, David | Ferguson, Lynnette R | Franchimont, Denis | Fransen, Karin | Gearry, Richard | Georges, Michel | Gieger, Christian | Glas, Jürgen | Haritunians, Talin | Hart, Ailsa | Hawkey, Chris | Hedl, Matija | Hu, Xinli | Karlsen, Tom H | Kupcinskas, Limas | Kugathasan, Subra | Latiano, Anna | Laukens, Debby | Lawrance, Ian C | Lees, Charlie W | Louis, Edouard | Mahy, Gillian | Mansfield, John | Morgan, Angharad R | Mowat, Craig | Newman, William | Palmieri, Orazio | Ponsioen, Cyriel Y | Potocnik, Uros | Prescott, Natalie J | Regueiro, Miguel | Rotter, Jerome I | Russell, Richard K | Sanderson, Jeremy D | Sans, Miquel | Satsangi, Jack | Schreiber, Stefan | Simms, Lisa A | Sventoraityte, Jurgita | Targan, Stephan R | Taylor, Kent D | Tremelling, Mark | Verspaget, Hein W | De Vos, Martine | Wijmenga, Cisca | Wilson, David C | Winkelmann, Juliane | Xavier, Ramnik J | Zeissig, Sebastian | Zhang, Bin | Zhang, Clarence K | Zhao, Hongyu | Silverberg, Mark S | Annese, Vito | Hakonarson, Hakon | Brant, Steven R | Radford-Smith, Graham | Mathew, Christopher G | Rioux, John D | Schadt, Eric E | Daly, Mark J | Franke, Andre | Parkes, Miles | Vermeire, Severine | Barrett, Jeffrey C | Cho, Judy H
Nature  2012;491(7422):119-124.
Crohn’s disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry with rising prevalence in other populations1. Genome-wide association studies (GWAS) and subsequent meta-analyses of CD and UC2,3 as separate phenotypes implicated previously unsuspected mechanisms, such as autophagy4, in pathogenesis and showed that some IBD loci are shared with other inflammatory diseases5. Here we expand knowledge of relevant pathways by undertaking a meta-analysis of CD and UC genome-wide association scans, with validation of significant findings in more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional and balancing selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe striking overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
PMCID: PMC3491803  PMID: 23128233
25.  IRGM Variants and Susceptibility to Inflammatory Bowel Disease in the German Population 
PLoS ONE  2013;8(1):e54338.
Background & Aims
Genome-wide association studies identified the autophagy gene IRGM to be strongly associated with Crohn's disease (CD) but its impact in ulcerative colitis (UC), its phenotypic effects and potential epistatic interactions with other IBD susceptibility genes are less clear which we therefore analyzed in this study.
Methodology/Principal Findings
Genomic DNA from 2060 individuals including 817 CD patients, 283 UC patients, and 961 healthy, unrelated controls (all of Caucasian origin) was analyzed for six IRGM single nucleotide polymorphisms (SNPs) (rs13371189, rs10065172 = p.Leu105Leu, rs4958847, rs1000113, rs11747270, rs931058). In all patients, a detailed genotype-phenotype analysis and testing for epistasis with the three major CD susceptibility genes NOD2, IL23R and ATG16L1 were performed.
Our analysis revealed an association of the IRGM SNPs rs13371189 (p = 0.02, OR 1.31 [95% CI 1.05–1.65]), rs10065172 = p.Leu105Leu (p = 0.016, OR 1.33 [95% CI 1.06–1.66]) and rs1000113 (p = 0.047, OR 1.27 [95% CI 1.01–1.61]) with CD susceptibility. There was linkage disequilibrium between these three IRGM SNPs. In UC, several IRGM haplotypes were weakly associated with UC susceptibility (p<0.05). Genotype-phenotype analysis revealed no significant associations with a specific IBD phenotype or ileal CD involvement. There was evidence for weak gene-gene-interaction between several SNPs of the autophagy genes IRGM and ATG16L1 (p<0.05), which, however, did not remain significant after Bonferroni correction.
Our results confirm IRGM as susceptibility gene for CD in the German population, supporting a role for the autophagy genes IRGM and ATG16L1 in the pathogenesis of CD.
PMCID: PMC3554777  PMID: 23365659

Results 1-25 (41)