Differences in circulating alpha-calcitonin gene-related peptide levels in inflammatory bowel disease and its relation to migraine comorbidity: a cross-sectional study

Objective: To analyze the specificity of calcitonin gene-related peptide (CGRP) levels, we measured alpha-CGRP circulating levels in a large series of patients with a recent diagnosis of inflammatory bowel disease (IBD) who were interviewed regarding comorbid headache. Background: Several studies have found an association between migraine and IBD. Methods: In this cross-sectional study performed in an IBD clinic, morning serum alpha-CGRP levels were measured by enzyme-linked immunosorbent assay in 96 patients who were recently diagnosed with IBD and compared to those from 50 similar patients with chronic migraine (CM) and 50 healthy controls (HC). Results: Alpha-CGRP levels were higher in patients with IBD (median [interquartile range] 56.9 [35.6-73.9] pg/mL) and patients with CM (53.0 [36.7-73.9] pg/mL) compared to HC (37.2 [30.0-51.8] pg/mL; p=0.003; p=0.019, respectively). Regarding IBD diagnostic subtypes, alpha-CGRP levels for ulcerative colitis (67.2±49.3pg/mL; 57.0 [35.6-73.4] pg/mL) and Crohn's disease (54.9±27.5pg/mL; 57.7 [29.1-76.1] pg/mL) were significantly higher than those of HC (p=0.013, p=0.040, respectively). Alpha-CGRP levels were further different in patients with IBD with migraine (70.9 [51.8-88.7] pg/mL) compared to HC (p<0.001), patients with IBD without headache (57.5 [33.3-73.8] pg/mL; p=0.049), and patients with IBD with tension-type headache but without migraine (41.7 [28.5-66.9] pg/mL; p=0.004), though alpha-CGRP levels in patients with IBD without migraine (53.7 [32.9-73.5] pg/mL) remained different over HC (p=0.028). Conclusion: Together with CM, circulating alpha-CGRP levels are different in patients with IBD, perhaps reflecting a chronic inflammatory state. IBD is an example of how alpha-CGRP levels are not a totally specific migraine biomarker. However, alpha-CGRP levels were further increased in patients with IBD who have a history of migraine, which reinforces its role as a biomarker in migraine patients, always bearing in mind their comorbidities.FUNDING INFORMATION: This study was funded by Instituto de Salud Carlos III (ISCIII) through the project PI20/01358 and co-funded by Fondos Europeos de Desarrollo Regional (FEDER), “Una manera de hacer Europa.” ACKNOWLEDGMENTS: We are grateful to the nurse of our IBD Unit, María Soledad Serrano, for her continuous support

Increased prevalence of migraine in women with inflammatory bowel disease: a cross-sectional study

Background: Some studies have suggested an association between migraine and inflammatory bowel disease. We determined migraine prevalence in a cohort of patients with inflammatory bowel disease. Methods: Patients with inflammatory bowel disease aged 18-65 years were interviewed using an ad hoc headache questionnaire. Those who admitted a history of headache in the last year answered the three questions of the ID-Migraine questionnaire. Those who answered "yes" to the three of them were classified as "definite" and those who answered "yes" to two were classified as "probable" migraine. Results: We interviewed 283 patients with inflammatory bowel disease. Of these, 176 (62.2%) had headache. Fifty-nine (20.8%; 95% CI 16.3-26.0%) met migraine criteria either definite (n=33; 11.7%; 95% CI 8.2-16.0%) or probable (n=26; 9.2%; 95% CI 6.1-13.2). When divided by gender, 12 men (9.6%; 95% CI 5.1-16.2%) and 47 women (29.8%; 95% CI 22.8-37.5%) met migraine criteria. The prevalence of migraine was increased in inflammatory bowel disease patients from the current cohort (20.8%) versus that reported for our general population for the same age group (12.6%; p<0.0001). These differences remained significant in female inflammatory bowel disease patients (29.8% versus 17.2% in our general population; p<0.0001), but not in males (9.6% in inflammatory bowel disease vs 8.0%; p=0.30). Seventeen patients with inflammatory bowel disease (6.0%; 95% CI 3.54-9.44%) fulfilled chronic migraine criteria. There were no differences in migraine prevalence by inflammatory bowel disease subtypes. Conclusion: Migraine prevalence, including chronic migraine, seems to be increased in patients with inflammatory bowel disease. The fact that this association was stronger for women suggests an influence of sex-related factors.Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study has been founded by Instituto de Salud Carlos III (ISCII) through the project PI20/01358 and cofunded by Fondos Europeos de Desarrollo Regional (FEDER), “Una manera de hacer Europa”. Acknowledgments: We are very grateful to our IBD nurse Marıa Soledad Serrano for her continuous support

Efficacy of bosentan in patients with refractory thromboangiitis obliterans (Buerger disease): A case series and review of the literature

The cornerstone of therapy in thromboangiitis obliterans (TAO) is complete abstinence from tobacco. In addition to discontinuation of cigarette smoking, very few pharmacological and surgical options of controversial efficacy are available to date. New therapeutic options with greater efficacy are clearly needed to properly manage these patients. In this preliminary study, we assessed the effectiveness and safety of bosentan in a case series of 8 adults with TAO and severe ischemic ulceronecrotic lesions who were treated with bosentan after inadequate response to platelet inhibitors, vasodilators, and intravenous alprostadil. Additionally, we reviewed 18 well-documented patients with refractory TAO treated with bosentan, which was previously reported (PubMed 1965-2015). These 26 patients formed the basis of our present analysis. All were current smokers. The median duration of bosentan treatment (SD) was 4.5 +/- 4 months (range 3-16). Eleven patients (42%) were unable to completely abstain from smoking during their follow-up. With bosentan treatment, no new ischemic lesions were observed in the target extremities. A complete therapeutic response was achieved in 80% of patients, whereas a partial response was observed in 12%. Two patients (8%) ultimately required amputation despite treatment. After discontinuation of bosentan, patients were followed for a median of 20 +/- 14 months (range 3-60). Two patients whose trophic lesions had healed relapsed. When comparing patients who gave up smoking with those who were unable to completely abstain from smoking during follow-up, no significant differences were found in efficacy outcomes. Four patients (15%) developed adverse events, requiring bosentan discontinuation in 1 case. These preliminary data suggest that bosentan may be considered a therapeutic option for treatment of cases of severe TAO refractory to conventional treatment, and merit further evaluation in larger controlled, randomized clinical studies

Antibacterial polypropylene mesh fixation with a cyanoacrylate adhesive improves its response to infection

22 p.Background: Antibacterial meshes for hernia repair seek to avoid infection in the patient. As thesebiomaterials are especially prone to bacteria settling at their sutured borders, this study examines whether the use of a cyanoacrylate tissue adhesive could improve mesh behavior at the fixation zones. Methods: First, antibacterial polypropylene meshes were prepared by soaking in 0.05% chlorhexidine, and the response of n-hexyl cyanoacrylate to contamination with Staphylococcus aureus ATCC25923 was assessed in vitro. Then, in a preclinical model, partial defects (5 x 3 cm) were created in the abdominal wall of 18 New Zealand White rabbits and repaired with mesh to establish the following 3 study groups: (1) mesh without chlorhexidine fixed with cyanoacrylate, (2) antibacterial mesh fixed with sutures, and (3) antibacterial mesh fixed with cyanoacrylate (n = 6 each). The implants were inoculated with 106 CFU/ mL of S aureus. At 14 days after surgery, bacterial adhesion to the implant and its integration within host tissue were determined through microbiological, histological and immunohistochemical procedures. Results: As observed in vitro, the cyanoacrylate gave rise to a 1.5-cm bacteria-free margin around the prosthetic mesh. In vivo, the tissue adhesive prevented bacterial adhesion to the fixation zones, reducing infection of chlorhexidine-free meshes and optimizing the efficacy of the antibacterial meshes compared with those fixed with sutures. Conclusion: These findings indicated that cyanoacrylate fixation does not affect mesh integration into the host tissue. Likewise, the antibacterial behavior and tissue response of a chlorhexidine-treated polypropylene mesh is improved when cyanoacrylate is used for its fixation.Ministerio de Ciencia, Innovación y Universidade

Antibacterial biopolymer gel coating on meshes used for abdominal hernia repair promotes effective wound repair in the presence of infection

14 p.Prosthetic mesh infection is a devastating complication of abdominal hernia repair which impairs natural healing in the implant area, leading to increased rates of patient morbidity, mortality, and prolonged hospitalization. This preclinical study was designed to assess the effects on abdominal wall tissue repair of coating meshes with a chlorhexidine or rifampicin-carboxymethylcellulose biopolymer gel in a Staphylococcus aureus (S. aureus) infection model. Partial abdominal wall defects were created in New Zealand white rabbits (n = 20). Four study groups were established according to whether the meshes were coated or not with each of the antibacterial gels. Three groups were inoculated with S. aureus and finally repaired with lightweight polypropylene mesh. Fourteen days after surgery, implanted meshes were recovered for analysis of the gene and protein expression of collagens, macrophage phenotypes, and mRNA expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Compared to uncoated meshes, those coated with either biopolymer gel showed higher collagen 1/3 messenger RNA and collagen I protein expression, relatively increased VEGF mRNA expression, a significantly reduced macrophage response, and lower relative amounts of MMPs mRNAs. Our findings suggest that following mesh implant these coatings may help improving abdominal wall tissue repair in the presence of infectionMinisterio de Ciencia e Innovació

Neuroanatomic-based detection algorithm for automatic labeling of brain structures in brain injury

The number and grade of injured neuroanatomic structures and the type of injury determine the degree of impairment after a brain injury event and the recovery options of the patient. However, the body of knowledge and clinical intervention guides are basically focused on functional disorder and they still do not take into account the location of injuries. The prognostic value of location information is not known in detail either. This paper proposes a feature-based detection algorithm, named Neuroanatomic-Based Detection Algorithm (NBDA), based on SURF (Speeded Up Robust Feature) to label anatomical brain structures on cortical and sub-cortical areas. Themain goal is to register injured neuroanatomic structures to generate a database containing patient?s structural impairment profile. This kind of information permits to establish a relation with functional disorders and the prognostic evolution during neurorehabilitation procedures

MIF/CXCR4 signaling axis contributes to survival, invasion, and drug resistance of metastatic neuroblastoma cells in the bone marrow microenvironment

Background: The bone marrow (BM) is the most common site of dissemination in patients with aggressive, metastatic neuroblastoma (NB). However, the molecular mechanisms underlying the aggressive behavior of NB cells in the BM niche are still greatly unknown. In the present study, we explored biological mechanisms that play a critical role in NB cell survival and progression in the BM and investigated potential therapeutic targets. Methods: Patient-derived bone marrow (BM) primary cultures were generated using fresh BM aspirates obtained from NB patients. NB cell lines were cultured in the presence of BM conditioned media containing cell-secreted factors, and under low oxygen levels (1% O2) to mimic specific features of the BM microenvironment of high-risk NB patients. The BM niche was explored using cytokine profiling assays, cell migration-invasion and viability assays, flow cytometry and analysis of RNA-sequencing data. Selective pharmacological inhibition of factors identified as potential mediators of NB progression within the BM niche was performed in vitro and in vivo. Results: We identified macrophage migration inhibitory factor (MIF) as a key inflammatory cytokine involved in BM infiltration. Cytokine profiling and RNA-sequencing data analysis revealed NB cells as the main source of MIF in the BM, suggesting a potential role of MIF in tumor invasion. Exposure of NB cells to BM-conditions increased NB cell-surface expression of the MIF receptor CXCR4, which was associated with increased cell viability, enhanced migration-invasion, and activation of PI3K/AKT and MAPK/ERK signaling pathways. Moreover, subcutaneous co-injection of NB and BM cells enhanced tumor engraftment in mice. MIF inhibition with 4-IPP impaired in vitro NB aggressiveness, and improved drug response while delayed NB growth, improving survival of the NB xenograft model. Conclusions: Our findings suggest that BM infiltration by NB cells may be mediated, in part, by MIF-CXCR4 signaling. We demonstrate the antitumor efficacy of MIF targeting in vitro and in vivo that could represent a novel therapeutic target for patients with disseminated high-risk NB

Antibodies against the flotillin-1/2 complex in patients with multiple sclerosis

Lleixa and Caballero-avila et al. report that antibodies targeting the flotillin-1/2 complex are present in a subgroup of patients with multiple sclerosis. Further studies are needed to understand the clinical and pathological relevance of anti-flotillin-1/2 autoantibodies in multiple sclerosis. Multiple sclerosis is a tissue-specific autoimmune disease of the central nervous system in which the antigen(s) remains elusive. Antibodies targeting the flotillin-1/2 complex have been described in 1-2% of the patients in a recent study. Other candidate antigens as anoctamin-2 or neurofascin-155 have been previously described in multiple sclerosis patients, although their clinical relevance remains uncertain. Our study aims to analyse the frequency and clinical relevance of antibodies against neurofascin-155, anoctamin-2 and flotillin-1/2 complex in multiple sclerosis. Serum (n = 252) and CSF (n = 50) samples from 282 multiple sclerosis patients were included in the study. The control group was composed of 260 serum samples (71 healthy donors and 189 with other neuroinflammatory disorders). Anti-flotillin-1/2, anti-anoctamin-2 and anti-neurofascin-155 antibodies were tested by cell-based assays using transfected cells. We identified six multiple sclerosis patients with antibodies against the flotillin-1/2 complex (2.1%) and one multiple sclerosis patient with antibodies against anoctamin-2 (0.35%). All multiple sclerosis patients were negative for anti-neurofascin-155 antibodies. Three of the anti-flotillin-1/2 positive patients showed anti-flotillin-1/2 positivity in other serum samples extracted at different moments of their disease. Immunoglobulin G subclasses of anti-flotillin-1/2 antibodies were predominantly one and three. We confirm that antibodies targeting the flotillin-1/2 complex are present in a subgroup of patients with multiple sclerosis. Further studies are needed to understand the clinical and pathological relevance of anti-flotillin-1/2 autoantibodies in multiple sclerosis

Real-world effectiveness of caplacizumab vs the standard of care in immune thrombotic thrombocytopenic purpura

Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy caused by anti-ADAMTS13 antibodies. Caplacizumab is approved for adults with an acute episode of iTTP in conjunction with plasma exchange (PEX) and immunosuppression. The objective of this study was to analyze and compare the safety and efficacy of caplacizumab vs the standard of care and assess the effect of the concomitant use of rituximab. A retrospective study from the Spanish TTP Registry of patients treated with caplacizumab vs those who did not receive it was conducted. A total of 155 patients with iTTP (77 caplacizumab, 78 no caplacizumab) were included. Patients initially treated with caplacizumab had fewer exacerbations (4.5% vs 20.5%; P <.05) and less refractoriness (4.5% vs 14.1%; P <.05) than those who were not treated. Time to clinical response was shorter when caplacizumab was used as initial treatment vs caplacizumab used after refractoriness or exacerbation. The multivariate analysis showed that its use in the first 3 days after PEX was associated with a lower number of PEX (odds ratio, 7.5; CI, 2.3-12.7; P <.05) and days of hospitalization (odds ratio, 11.2; CI, 5.6-16.9; P <.001) compared with standard therapy. There was no difference in time to clinical remission in patients treated with caplacizumab compared with the use of rituximab. No severe adverse event was described in the caplacizumab group. In summary, caplacizumab reduced exacerbations and refractoriness compared with standard of care regimens. When administered within the first 3 days after PEX, it also provided a faster clinical response, reducing hospitalization time and the need for PEX