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Contains fulltext : 193372.pdf (publisher's version ) (Open Access), GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by approximately 9720 regulatory modules, of which approximately 3000 operate in multiple tissues and approximately 970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that >/=10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.

Item does not contain fulltext, Background and Aims: Crohn's disease [CD] is a chronic inflammatory disease with unpredictable behaviour. More than half of CD patients eventually develop complications such as stenosis, for which they then require endoscopic dilatation or surgery, as no anti-fibrotic drugs are currently available. We aim to identify disease-modifying genes associated with fibrostenotic CD. Methods: We performed a within-case analysis comparing 'extreme phenotypes' using the Immunochip and replication of the top single nucleotide polymorphisms [SNPs] with Agena Bioscience in two independent case-control cohorts totalling 322 cases with fibrostenotis [recurrent after surgery] and 619 cases with purely inflammatory CD. Results: Combined meta-analysis resulted in a genome-wide significant signal for SNP rs11861007 [p = 6.0910-11], located on chromosome 16, in lncRNA RP11-679B19.1, an lncRNA of unknown function, and close to exon 9 of the WWOX gene, which codes for WW domain-containing oxidoreductase. We analysed mRNA expression of TGF-beta and downstream genes in ileocecal resection material from ten patients with and without the WWOX risk allele. Patients carrying the risk allele [A] showed enhanced colonic expression of TGF-beta compared to patients homozygous for the wild-type [G] allele [p = 0.0079]. Conclusion: We have identified a variant in WWOX and in lncRNA RP11-679B19.1 as a disease-modifying genetic variant associated with recurrent fibrostenotic CD and replicated this association in an independent cohort. WWOX can potentially play a crucial role in fibrostenosis in CD, being positioned at the crossroads of inflammation and fibrosis.

Contains fulltext : 193372.pdf (publisher's version ) (Open Access), GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by approximately 9720 regulatory modules, of which approximately 3000 operate in multiple tissues and approximately 970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that >/=10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.

Item does not contain fulltext, Background and Aims: Crohn's disease [CD] is a chronic inflammatory disease with unpredictable behaviour. More than half of CD patients eventually develop complications such as stenosis, for which they then require endoscopic dilatation or surgery, as no anti-fibrotic drugs are currently available. We aim to identify disease-modifying genes associated with fibrostenotic CD. Methods: We performed a within-case analysis comparing 'extreme phenotypes' using the Immunochip and replication of the top single nucleotide polymorphisms [SNPs] with Agena Bioscience in two independent case-control cohorts totalling 322 cases with fibrostenotis [recurrent after surgery] and 619 cases with purely inflammatory CD. Results: Combined meta-analysis resulted in a genome-wide significant signal for SNP rs11861007 [p = 6.0910-11], located on chromosome 16, in lncRNA RP11-679B19.1, an lncRNA of unknown function, and close to exon 9 of the WWOX gene, which codes for WW domain-containing oxidoreductase. We analysed mRNA expression of TGF-beta and downstream genes in ileocecal resection material from ten patients with and without the WWOX risk allele. Patients carrying the risk allele [A] showed enhanced colonic expression of TGF-beta compared to patients homozygous for the wild-type [G] allele [p = 0.0079]. Conclusion: We have identified a variant in WWOX and in lncRNA RP11-679B19.1 as a disease-modifying genetic variant associated with recurrent fibrostenotic CD and replicated this association in an independent cohort. WWOX can potentially play a crucial role in fibrostenosis in CD, being positioned at the crossroads of inflammation and fibrosis.

Contains fulltext : 193372.pdf (publisher's version ) (Open Access), GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by approximately 9720 regulatory modules, of which approximately 3000 operate in multiple tissues and approximately 970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that >/=10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.

Item does not contain fulltext, Background and Aims: Crohn's disease [CD] is a chronic inflammatory disease with unpredictable behaviour. More than half of CD patients eventually develop complications such as stenosis, for which they then require endoscopic dilatation or surgery, as no anti-fibrotic drugs are currently available. We aim to identify disease-modifying genes associated with fibrostenotic CD. Methods: We performed a within-case analysis comparing 'extreme phenotypes' using the Immunochip and replication of the top single nucleotide polymorphisms [SNPs] with Agena Bioscience in two independent case-control cohorts totalling 322 cases with fibrostenotis [recurrent after surgery] and 619 cases with purely inflammatory CD. Results: Combined meta-analysis resulted in a genome-wide significant signal for SNP rs11861007 [p = 6.0910-11], located on chromosome 16, in lncRNA RP11-679B19.1, an lncRNA of unknown function, and close to exon 9 of the WWOX gene, which codes for WW domain-containing oxidoreductase. We analysed mRNA expression of TGF-beta and downstream genes in ileocecal resection material from ten patients with and without the WWOX risk allele. Patients carrying the risk allele [A] showed enhanced colonic expression of TGF-beta compared to patients homozygous for the wild-type [G] allele [p = 0.0079]. Conclusion: We have identified a variant in WWOX and in lncRNA RP11-679B19.1 as a disease-modifying genetic variant associated with recurrent fibrostenotic CD and replicated this association in an independent cohort. WWOX can potentially play a crucial role in fibrostenosis in CD, being positioned at the crossroads of inflammation and fibrosis.

Item does not contain fulltext, BACKGROUND AND AIM: Vulval Crohn's disease (VCD) is a rare extraintestinal cutaneous manifestation of Crohn's disease. No consensus on the diagnostic workup and therapeutic management of this condition has been provided in the current literature. PATIENTS AND METHODS: Retrospective, multicentre descriptive case series of female patients diagnosed and treated with VCD. By chart review, data on initial symptoms, clinical courses, histologic findings and therapeutic management were collected. RESULTS: Fifteen female patients with a median age of 28 years (interquartile range: 28-44 years) suffering from Crohn's disease of the ileum (27%), colon (33%) and ileocolon (40%) were included. VCD manifested most frequently with vulval swelling (93%), pain (80%) and erythema (73%). Histologic analysis demonstrated granulomatous inflammation in 78% and a mixed inflammatory cell infiltrate in 67% of cases. In eight (53%) cases, topical therapy resulted in temporary reduction of vulval symptoms. Combotreatment with immunosuppressive agents and tumour necrosis factor alpha inhibitors was the most effective second-line therapy: five (33%) patients achieved sustained clinical remission with this therapeutic strategy. CONCLUSION: The diagnostic workup of VCD is challenging and should be approached in a multidisciplinary manner. Histopathologic analysis of the vulva supports the diagnosis. Topical therapy and systemic treatment with immunosuppressive agents and tumour necrosis factor alpha inhibitors are advised to treat this condition.

Contains fulltext : 182718.pdf (publisher's version ) (Open Access), PURPOSE: The Dutch IBD Biobank aims to facilitate the discovery of predictors for individual disease course and treatment response in patients with inflammatory bowel disease (IBD). In this paper, we aim to describe the establishment of the Dutch IBD Biobank, including the facilitators and barriers to establishment. Moreover, we aim to provide a complete overview of the content of the Dutch IBD Biobank. PARTICIPANTS: Since 2007, every patient with IBD treated in one of the eight Dutch university medical centres is asked to participate in the Dutch IBD Biobank in which 225 standardised IBD-related data items and biomaterials, such as serum, DNA, biopsies and a stool sample, are collected. FINDINGS TO DATE: As of June 2014, the Dutch IBD Biobank had enrolled 3388 patients with IBD: 2118 Crohn's disease (62.5%), 1190 ulcerative colitis (35.1%), 74 IBD-unclassified (2.2%) and 6 IBD-indeterminate (0.2%). The inclusion of patients with IBD is ongoing. The quality of the biomaterials is good and serum, DNA and biopsies have been used in newly published studies. FUTURE PLANS: The genotyping (750 000 genetic variants) of all participants of the Dutch IBD Biobank is currently ongoing, enabling more genetic research. In addition, all participants will start reporting disease activity and outcome measures using an online platform and mobile app.

Item does not contain fulltext, BACKGROUND AND AIM: Vulval Crohn's disease (VCD) is a rare extraintestinal cutaneous manifestation of Crohn's disease. No consensus on the diagnostic workup and therapeutic management of this condition has been provided in the current literature. PATIENTS AND METHODS: Retrospective, multicentre descriptive case series of female patients diagnosed and treated with VCD. By chart review, data on initial symptoms, clinical courses, histologic findings and therapeutic management were collected. RESULTS: Fifteen female patients with a median age of 28 years (interquartile range: 28-44 years) suffering from Crohn's disease of the ileum (27%), colon (33%) and ileocolon (40%) were included. VCD manifested most frequently with vulval swelling (93%), pain (80%) and erythema (73%). Histologic analysis demonstrated granulomatous inflammation in 78% and a mixed inflammatory cell infiltrate in 67% of cases. In eight (53%) cases, topical therapy resulted in temporary reduction of vulval symptoms. Combotreatment with immunosuppressive agents and tumour necrosis factor alpha inhibitors was the most effective second-line therapy: five (33%) patients achieved sustained clinical remission with this therapeutic strategy. CONCLUSION: The diagnostic workup of VCD is challenging and should be approached in a multidisciplinary manner. Histopathologic analysis of the vulva supports the diagnosis. Topical therapy and systemic treatment with immunosuppressive agents and tumour necrosis factor alpha inhibitors are advised to treat this condition.

Contains fulltext : 182718.pdf (publisher's version ) (Open Access), PURPOSE: The Dutch IBD Biobank aims to facilitate the discovery of predictors for individual disease course and treatment response in patients with inflammatory bowel disease (IBD). In this paper, we aim to describe the establishment of the Dutch IBD Biobank, including the facilitators and barriers to establishment. Moreover, we aim to provide a complete overview of the content of the Dutch IBD Biobank. PARTICIPANTS: Since 2007, every patient with IBD treated in one of the eight Dutch university medical centres is asked to participate in the Dutch IBD Biobank in which 225 standardised IBD-related data items and biomaterials, such as serum, DNA, biopsies and a stool sample, are collected. FINDINGS TO DATE: As of June 2014, the Dutch IBD Biobank had enrolled 3388 patients with IBD: 2118 Crohn's disease (62.5%), 1190 ulcerative colitis (35.1%), 74 IBD-unclassified (2.2%) and 6 IBD-indeterminate (0.2%). The inclusion of patients with IBD is ongoing. The quality of the biomaterials is good and serum, DNA and biopsies have been used in newly published studies. FUTURE PLANS: The genotyping (750 000 genetic variants) of all participants of the Dutch IBD Biobank is currently ongoing, enabling more genetic research. In addition, all participants will start reporting disease activity and outcome measures using an online platform and mobile app.

Contains fulltext : 171211.PDF (publisher's version ) (Open Access), Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.

Contains fulltext : 171211.PDF (publisher's version ) (Open Access), Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.

Contains fulltext : 171211.PDF (publisher's version ) (Open Access), Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.

Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.

Contains fulltext : 138124.pdf (publisher's version ) (Open Access), The introduction of therapeutic antibodies against tumor necrosis factor (TNF) had a major impact on the treatment of ulcerative colitis (UC). Infliximab and adalimumab are powerful agents that are used for remission induction and maintenance therapy in UC and have an acceptable safety profile. However, a proportion of UC patients for whom therapy with anti-TNF agents is indicated fail or become intolerant to treatment with infliximab or adalimumab. Hence, there remains an unmet need for novel anti-TNF agents. Golimumab (Simponi(R)), a human anti-TNF antibody that is administered by monthly subcutaneous injections, is the most recently introduced TNF blocker for the treatment of UC. Here, we will discuss recent literature on clinical efficacy and safety of golimumab induction and maintenance treatment in patients with UC. Furthermore, we will discuss the positioning of golimumab for UC in current treatment algorithms.

Contains fulltext : 137403.pdf (publisher's version ) (Open Access), Anti-tumor necrosis factor therapy with adalimumab is an effective therapy for the induction and maintenance of remission in moderate to severe Crohn's disease. Although a large proportion of patients show a favorable clinical response to adalimumab, therapy failure is common. In this review, we provide a practical overview of adalimumab therapy in patients with Crohn's disease, with a specific focus on the clinical management of adalimumab failure. In the case of inadequate efficacy, a thorough assessment is required to confirm inflammatory disease activity and rule out noninflammatory causes. Evaluation may include biomarkers (fecal calprotectin and serum C-reactive protein), colonoscopy, and/or magnetic resonance enterography/enteroclysis. Furthermore, adalimumab trough levels and antibodies to adalimumab are informational after the confirmation of active inflammation. In the case of low or undetectable adalimumab trough levels, dose escalation to 40 mg weekly is recommended, whereas high antibody titers or adverse events frequently require switching to an alternative anti-TNF agent such as infliximab. Active inflammation despite therapeutic adalimumab trough levels requires alternative strategies such as switching to drugs with a different mode of action or surgical intervention.

Contains fulltext : 138124.pdf (publisher's version ) (Open Access), The introduction of therapeutic antibodies against tumor necrosis factor (TNF) had a major impact on the treatment of ulcerative colitis (UC). Infliximab and adalimumab are powerful agents that are used for remission induction and maintenance therapy in UC and have an acceptable safety profile. However, a proportion of UC patients for whom therapy with anti-TNF agents is indicated fail or become intolerant to treatment with infliximab or adalimumab. Hence, there remains an unmet need for novel anti-TNF agents. Golimumab (Simponi(R)), a human anti-TNF antibody that is administered by monthly subcutaneous injections, is the most recently introduced TNF blocker for the treatment of UC. Here, we will discuss recent literature on clinical efficacy and safety of golimumab induction and maintenance treatment in patients with UC. Furthermore, we will discuss the positioning of golimumab for UC in current treatment algorithms.

Contains fulltext : 137403.pdf (publisher's version ) (Open Access), Anti-tumor necrosis factor therapy with adalimumab is an effective therapy for the induction and maintenance of remission in moderate to severe Crohn's disease. Although a large proportion of patients show a favorable clinical response to adalimumab, therapy failure is common. In this review, we provide a practical overview of adalimumab therapy in patients with Crohn's disease, with a specific focus on the clinical management of adalimumab failure. In the case of inadequate efficacy, a thorough assessment is required to confirm inflammatory disease activity and rule out noninflammatory causes. Evaluation may include biomarkers (fecal calprotectin and serum C-reactive protein), colonoscopy, and/or magnetic resonance enterography/enteroclysis. Furthermore, adalimumab trough levels and antibodies to adalimumab are informational after the confirmation of active inflammation. In the case of low or undetectable adalimumab trough levels, dose escalation to 40 mg weekly is recommended, whereas high antibody titers or adverse events frequently require switching to an alternative anti-TNF agent such as infliximab. Active inflammation despite therapeutic adalimumab trough levels requires alternative strategies such as switching to drugs with a different mode of action or surgical intervention.

Contains fulltext : 138124.pdf (publisher's version ) (Open Access), The introduction of therapeutic antibodies against tumor necrosis factor (TNF) had a major impact on the treatment of ulcerative colitis (UC). Infliximab and adalimumab are powerful agents that are used for remission induction and maintenance therapy in UC and have an acceptable safety profile. However, a proportion of UC patients for whom therapy with anti-TNF agents is indicated fail or become intolerant to treatment with infliximab or adalimumab. Hence, there remains an unmet need for novel anti-TNF agents. Golimumab (Simponi(R)), a human anti-TNF antibody that is administered by monthly subcutaneous injections, is the most recently introduced TNF blocker for the treatment of UC. Here, we will discuss recent literature on clinical efficacy and safety of golimumab induction and maintenance treatment in patients with UC. Furthermore, we will discuss the positioning of golimumab for UC in current treatment algorithms.

Item does not contain fulltext, Cyclosporine and infliximab are so-called 'rescue-therapies' as last resort for the treatment of patients with severe glucocorticoid-refractory ulcerative colitis.- A recent study found that cyclosporine and infliximab are similar in terms of efficacy in the treatment of patients with severe ulcerative colitis.- Cyclosporine may be prescribed as a bridge to treatment with thiopurines; infliximab may be prescribed when a patient is intolerant or refractory to thiopurines.- Preoperative treatment with cyclosporine or infliximab does not affect the number of postoperative complications.

Item does not contain fulltext, Cyclosporine and infliximab are so-called 'rescue-therapies' as last resort for the treatment of patients with severe glucocorticoid-refractory ulcerative colitis.- A recent study found that cyclosporine and infliximab are similar in terms of efficacy in the treatment of patients with severe ulcerative colitis.- Cyclosporine may be prescribed as a bridge to treatment with thiopurines; infliximab may be prescribed when a patient is intolerant or refractory to thiopurines.- Preoperative treatment with cyclosporine or infliximab does not affect the number of postoperative complications.

Item does not contain fulltext, Cyclosporine and infliximab are so-called 'rescue-therapies' as last resort for the treatment of patients with severe glucocorticoid-refractory ulcerative colitis.- A recent study found that cyclosporine and infliximab are similar in terms of efficacy in the treatment of patients with severe ulcerative colitis.- Cyclosporine may be prescribed as a bridge to treatment with thiopurines; infliximab may be prescribed when a patient is intolerant or refractory to thiopurines.- Preoperative treatment with cyclosporine or infliximab does not affect the number of postoperative complications.

In this paper we consider the onset of shimmy oscillations of an aircraft nose landing gear. To this end we develop and study a mathematical model with torsional and lateral bending modes that are coupled through a wheel-mounted elastic tyre. The geometric effects of a positive rake angle are fully incorporated into the resulting five-dimensional ordinary differential equation model. A bifurcation analysis in terms of the forward velocity and the vertical force on the gear reveals routes to different types of shimmy oscillations. In particular, we find regions of stable torsional and stable lateral shimmy oscillations, as well as transient quasiperiodic shimmy where both modes are excited.

In this paper we consider the onset of shimmy oscillations of an aircraft nose landing gear. To this end we develop and study a mathematical model with torsional and lateral bending modes that are coupled through a wheel-mounted elastic tyre. The geometric effects of a positive rake angle are fully incorporated into the resulting five-dimensional ordinary differential equation model. A bifurcation analysis in terms of the forward velocity and the vertical force on the gear reveals routes to different types of shimmy oscillations. In particular, we find regions of stable torsional and stable lateral shimmy oscillations, as well as transient quasiperiodic shimmy where both modes are excited.