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Background: The long-term effect of adipose-derived mesenchymal stromal cells (ASCs) to restore radiation-induced salivary gland hypofunction in previous head and neck cancer patients have not been validated in larger settings., Methods: The study was the 12-months follow-up of a randomised trial, including patients with hyposalivation. Patients were randomised to receive allogeneic ASCs or placebo in the submandibular glands. Primary endpoint was unstimulated whole saliva (UWS) followed by stimulated whole saliva, patient-reported outcomes (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Head and Neck Module and the Xerostomia Questionnaire) and safety., Results: Of the 120 enrolled patients, 117 (97.5%) were assessed at 12 months. Treatment with ASCs did not increase UWS compared to placebo: increase in UWS was 0.02 mL/min (95% CI 0.01 to 0.04) in the ASC group and 0.02 mL/min (95% CI 0 to 0.03) in the placebo group, p=0.56. ASCs reduced the symptom burden for dry mouth with -10.07 units (95% CI -13.39 to -6.75) compared to -4.15 units (95% CI -7.46 to -0.84) in the placebo group, p=0.01. Compared to placebo, ASCs did not improve sticky saliva (-9.27 vs. -4.55 units, p=0.13), swallowing (-4.50 vs. 3.49 units, p=0.5) or xerostomia -3.12 vs. -2.74 units, p=0.82). Treatment was safe and associated with a transient immune response., Conclusion: Intraglandular ACS therapy in the submandibular glands significantly relieved subjective dry mouth symptoms. Both ASCs and placebo increased UWS, but ASCs did not prove superior to placebo in restoring salivary gland function, based on salivary flow rate.

Background: Adipose-derived mesenchymal stem/stromal cells (ASCs) are proposed as a new xerostomia treatment. The study evaluated the long-term safety and effectiveness of allogeneic ASCs in radiation-induced xerostomia among patients with previous oropharyngeal cancer., Methods: This study constitutes 3-year follow-up on the original 10 patients who received allogeneic ASCs injections to the submandibular and parotid glands as part of the MESRIX-II trial. The MESRIX-II trial included the preliminary 4-month follow-up. The primary endpoint was long-term safety. Secondary endpoints were effectiveness evaluated by changes in salivary flow rate and patient-reported outcomes (PROs). Immune response was evaluated by assessing the development of donor-specific antibodies (DSA)., Findings: All 10 MESRIX-II patients completed the long-term follow-up (ie, no missing data). During the long-term follow-up, 2 patients encountered a significant adverse event, which was determined to be unrelated to the treatment. No DSAs were detectable at 3 years. The stimulated salivary flow rate increased significantly from an average of 0.66 mL/minute at baseline to 0.86 mL/minute at follow-up, corresponding to an increase of 0.20 [95% CI 0.08 to 0.30] mL/minute, or approximately 30%. Among the PROs, sticky saliva symptoms were reduced, with a -20.0 [95% CI -37.3 to -2.7] units., Interpretation: In conclusion, this study is the first to present long-term follow-up outcomes of allogeneic ASC treatment as a therapeutic option for radiation-induced xerostomia. The study found that ASC treatment appears safe, and there were no indications of adverse immune responses at the 3-year follow-up. Further studies are warranted to evaluate the findings in larger settings., (© The Author(s) 2024. Published by Oxford University Press.)

HLA-DRB1*03:201 differs from HLA-DRB1*03:01 in exon 3 at codon 178 resulting in a proline to serine substitution., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-DQA1*01:65 differs from HLA-DQA1*01:03 in exon 1 at amino acid -7 a valine to methionine substitution., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-DPA1*01:46 differs from HLA-DPA1*01:03 in exon 2 at amino acid 85; Aspartate to Asparagine substitution., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The importance of the human leukocyte antigen (HLA) system in kidney transplantation is well-known, but it remains unexplored if patient HLA antigens constitute independent risk factors in complications after transplantation. We hypothesized that specific HLA class II phenotypes associated with immune-mediated disease (HLA-IMD) predispose to immunological activity and/or complications after kidney transplantation. Based on the literature we defined HLA-DR2-DQ6; -DR3-DQ2 and -DR4-DQ8 as HLA-IMD phenotypes. We investigated associations between HLA-IMD phenotypes in patients, biomarkers of systemic chronic inflammation at the time of transplantation, and the outcome after kidney transplantation in a retrospective cohort study of 611 kidney transplanted patients. The HLA-IMD phenotypes were associated with higher levels of biomarkers of systemic inflammation. The HLA-DR4-DQ8 phenotype was associated with mortality after transplantation in Cox analyses with adjustments for confounders. Data support the hypothesis that specific HLA class II phenotypes affects immunological pathways that determine the midterm clinical outcome of kidney transplantation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Allogeneic haematopoietic stem cell transplantation is a clinical example of precision medicine, as one individual donor is selected for one individual patient based on genetic findings in the human leukocyte antigen (HLA) system. Unrelated donor search for Danish patients is based on an international collaboration between global registries hosting more than 37 million potential donors worldwide for patients in need. The implementation of next-generation sequencing technologies has been a revolution in donor registry typing due to more precise, detailed and cheaper HLA analyses, which is discussed in this review.

Background: In allogeneic hematopoietic stem cell (HSC) transplantation, collection of a sufficient number of HSCs at a fixed time point is crucial. For HSC mobilization into the peripheral blood, the standard regimen, that is, granulocyte-colony-stimulating factor (G-CSF), may be inadequate. Use of plerixafor as adjuvant to G-CSF is so far off-label in healthy donors., Study Design and Methods: We present six cases in which the "just-in-time" addition of plerixafor ensured proper CD34+ collection from healthy donors with insufficient G-CSF mobilization. In four of these cases a high number of CD34+ cells was needed due to subsequent CD34+ selection or haploidentical transplantation., Results: From all six donors a sufficient number of CD34+ cells was obtained by using plerixafor as an adjuvant to G-CSF. This treatment regimen resulted in only mild side effects for the donor., Conclusion: We have presented six cases with different causes leading to insufficient G-CSF mobilization in allogeneic donors and in which the administration of plerixafor just-in-time ensured a proper graft for transplantation., (© 2013 American Association of Blood Banks.)

Background and Purpose: Genetic factors contribute to the aetiology of the prevalent form of migraine without aura (MO) and migraine with typical aura (MTA). Due to the complex inheritance of MO and MTA, the genetic background is still not fully established. In a population-based genome-wide association study by Chasman et al. (Nat Genet 2011: 43: 695-698), three common variants were found to confer risk of migraine at a genome-wide significant level (P < 5 × 10(-8) ). We aimed to evaluate the top association single nucleotide polymorphisms (SNPs) from the discovery set by Chasman et al. in a primarily clinic-based Danish and Icelandic cohort., Methods: The top association SNPs were assessed in 2523 cases and 38,170 controls, and a meta-analysis was performed, combining the discovery set with all the follow-up studies. Finally the confirmed SNPs were assessed in a genotype-phenotype analysis., Results: Two out of three SNPs that showed genome-wide significant associations in the previous study: rs10166942 (near TRPM8) and rs11172113 (in LRP1) were significantly associated with migraine in the present study. The meta-analysis confirmed the previous three genome-wide significant associated SNPs (rs2651899, rs10166942 and rs11172113) to confer risk of migraine. In addition, the C-allele of rs2078371 (near TSPAN-2) also reached genome-wide significance for association with migraine [OR = 1.14; CI = (1.09-1.20); P = 2.55 × 10(-8) ]., Conclusion: TSPAN-2 encodes an integral membrane protein involved in oligodendrogenesis. This new finding supports the plausible implication of neuroglia in the pathophysiology of MO and MTA., (© 2013 The Author(s) European Journal of Neurology © 2013 EFNS.)

Background and aims NXN-188 is a combined neuronal nitric oxide synthase (nNOS) inhibitor and 5HT-1B/1D receptor agonist which has previously shown efficacy in the acute treatment of migraine. Nitric oxide (NO) is involved in the pathogenesis of migraine pain and is formed after cortical spreading depression. Therefore NXN-188 could perhaps prevent the development of the headache phase in migraine with aura if taken during the aura. The aims of the present study were to evaluate the efficacy and safety of 600mg NXN-188 in the acute treatment of migraine when dosed during the aura. Methods A single-centre, randomized, double-blind, placebo-controlled, two-way crossover trial. The study medication was taken during the aura and the patients kept a study diary for 48h post-dose. Results Of 615 patients screened, 50 patients were included in the study and randomized. Only 18 patients completed both treatments in compliance with the study procedures. 22% of patients reported freedom of headache at 2h after intake of NXN-188 compared with only 11% of patients after placebo. Conclusions The dual-action drug NXN-188 with 5HT-1B/1D agonism and nNOS inhibition, taken orally during the aura phase did not have a statistically substantial effect on migraine headache in this study. This study was limited by a high drop-out rate and small sample of included patients who were able to complete the cross-over protocol. Therefore, efficacy of the treatment cannot be refuted with certainty. Implications This study illustrates the difficulties of doing well controlled studies in migraine patients with aura. nNOS inhibition is expected to be effective mostly in the aura phase, i.e. the oral administration may have had too slow pharmacokinetics to have effect. Parenteral administration may overcome this obstacle. 5HT-1B/1D agonism is not effective when dosed during migraine aura. Repeated dosing of the NXN-188 during and immediately following the aura may have exploited more the dualaction. The high drop-out rate may be reduced in future studies by having the patients familiarize themselves with the study procedure by filling out the attack report form while treating one attack with their own medication before entering the trial. A parallel group comparison may be a more effective trial design for treatment during an aura.

Background and Purpose: Although the genetics of familial hemiplegic migraine are being unraveled, this is not the case for the prevalent types of migraine. However, a recent genome wide association study (GWAS) reported an association of the single nucleotide polymorphism (SNP) rs1835740 and migraine. The aim of this study is to evaluate the association of clinical characteristics in migraine with aura (MA) with the newly discovered minor allele A of rs1835740 at 8q22.1., Methods: Participants were recruited from the Danish Headache Center and from specialist practices during the periods 1999-2002 and 2005-2006, and diagnosed according to the International Classification of Headache Disorders (ICHD-II) using a validated physician-conducted semi-structured interview. A large number of clinical characteristics were systematically determined. Caucasians of Danish ancestry diagnosed with MA and successfully genotyped for the SNP rs1835740 were included. Patients with hemiplegic migraine were excluded. Blood samples were collected for extraction of genomic DNA and genotyped for the common susceptibility variant rs1835740., Results: Six hundred and ninety one successfully genotyped MA patients with substantial description of their clinical characteristics were included. Two hundred and fifty one were heterozygous and 40 were homozygote for the variant marker. Carriers of the rs1835740 variant showed a non-significant tendency towards having a higher frequency of aura symptoms and a non-significant tendency towards milder migraine headache characteristics and fewer accompanying symptoms. These tendencies were not increased in homozygote carriers., Conclusion: None of the clinical characteristics of MA were significantly influenced by the common susceptibility variant on 8q22.1., (© 2011 The Author(s). European Journal of Neurology © 2011 EFNS.)

Objective: The aim was to identify and describe migraine trigger factors in patients with familial hemiplegic migraine (FHM) from a population-based sample., Methods: 127 FHM patients were sent a questionnaire listing 16 trigger factors. Distinction was made between attacks of hemiplegic migraine (HM) and migraine with aura (MA) or without aura (MO) within each patient., Results: The response rate was 59% (75/127) of whom 57 (76%) had current HM attacks. Sixty-three per cent (47/75) reported at least one factor triggering HM, and 36% (27/75) reported at least one factor that often or always caused HM. Twenty per cent (15/75) reported only HM, whereas FHM in combinations with MA and MO were reported by 80% (60/75). Stress (with attacks either following or during the stress), bright light, intense emotional influences and sleeping too much or too little were the trigger factors mentioned by most., Conclusion: Many FHM patients report trigger factors and one-third reported at least one trigger factor often or always triggering FHM. The typical triggers are the same as for MA. Patients should be educated to avoid these factors. The role of trigger factors in the onset of new or first attacks of FHM remains unknown.

Objective: The aim of the present study was to characterize perceived consistent triggers of migraine with aura (MA)., Method: Questionnaires specifically designed to characterize various trigger factors were sent to 181 participants identified in an earlier study. All participants had formerly identified at least one factor that often or always triggered an MA attack. They only answered questions regarding this or these factor(s)., Results: The response rate to the questionnaire was 70% (126/179). A number of subtype triggers were mentioned by a high proportion of patients: too much work (under the stress category 54/64), reflected sunlight (under the light category 35/44), too little sleep (under the sleep category 19/24), red wine (under the alcohol category 20/22), passive smoking (under the smoke category 11/11), menstruation (under the menstruation or break from the pill category 12/14) and perfume (under the fumes/heavy scents category 12/15). Hormones, light and stress were reported to cause at least 50 % of MA attacks in 62%, 47% and 42% of participants, respectively. No participants reported alcohol to be the trigger of 50% or more of their attacks. In the groups of participants with "light", "fumes/heavy scents", "smoke" or "physical effort" as triggers, nearly all patients reported that an exposure time to the trigger of less than 3 hours (90-100% of patients) was necessary to trigger an attack and a latency to onset of attack of less than 3 hours (90-100% of patients)., Conclusion: Our study has provided new knowledge about factors that in particular patients consistently trigger MA. In daily routine practice this information should be helpful in identifying factors to avoid. Patients with trigger factors that always or usually trigger attacks of MA will be highly useful for imaging and other experimental studies.

Introduction: Calcitonin gene-related peptide (CGRP) is a key molecule in migraine pathogenesis. Intravenous CGRP infusion triggers delayed migraine-like attacks in patients with migraine without aura (MO). In contrast to patients with MO, in prior studies patients with familial hemiplegic migraine (FHM) did not report more migraine-like attacks compared to controls. Whether CGRP triggers migraine in patients with typical (non-hemiplegic) migraine with aura is (MA) unknown. In the present study we examined the migraine inducing effect of CGRP infusion in patients suffering from MA and healthy controls., Methods: Fourteen patients suffering exclusively from migraine with typical aura (MA) and 11 healthy volunteers received a continuous intravenous infusion of 1.5 µg/min CGRP over 20 minutes. Headache and other migraine symptoms were scored every 10 minutes for one hour and self recorded hourly thereafter and until 13 hours post-infusion., Results: CGRP infusion induced significantly more delayed headaches in MA patients (12 out of 14) than in controls (2 out of 11) (p = 0.001). Furthermore, significantly more MA patients (57%; 8 out of 14) fulfilled criteria for an experimentally induced migraine attack after CGRP than controls (0%; 0 out of 11) (P = 0.003). Four patients (28%) reported aura symptoms after CGRP infusion., Conclusion: CGRP triggered migraine-like attacks without aura in patients suffering exclusively from MA. It also triggered a typical aura in 28% of the patients. These data indicate similar neurobiological pathways responsible for triggering migraine headache in MA and MO patients, and suggest differences between MA/MO and FHM.

Introduction: Specific problems occur in clinical treatment trials for migraine with aura that differ from those encountered in treatment trials for migraine without aura., Discussion: Based on our experience with four such trials, we point to a number of possible solutions and outline areas for future inquiry. We make recommendations about subject selection; the choice, definition and assessment of outcome measures; optimal treatments in relation to aura and headache; and we provide samples of study report forms used to record occurrence of aura and headache in this population.

The aim of the present study was to identify trigger factors in migraine with aura (MA). A total of 629 MA patients representative of the Danish population were sent a questionnaire listing 16 trigger factors thought to be relevant as well as space for free text. Distinction was made between attacks with or without aura within each patient. The questionnaire was returned by 522 patients of whom 347 had current MA attacks. In total 80% with current attacks (278/347) indicated that at least one factor triggered their migraine, and 67% (187/278) in this group indicated that they were aware of at least one factor often or always giving rise to an attack of MA. Forty-one per cent (113/278) had co-occurring attacks of migraine without aura (MO). Stress (following stress), bright light, intense emotional influences, stress (during stress) and sleeping too much or too little were the trigger factors mentioned by most. Attack frequency had little impact on the number of trigger factors. Women reported more trigger factors than men. Patients having attacks of both MA and MO reported more trigger factors for MO attacks than for MA attacks. In conclusion, 80% of patients with MA reported trigger factors and two-thirds of these reported at least one trigger factor often or always triggering an attack of MA. Patients should be educated to avoid these factors.

The ability of tonabersat to relieve the symptoms of migraine attacks with or without aura was evaluated in a randomized, double-blind, placebo-controlled, multicentre, parallel-group study. Patients received 20 or 40 mg of tonabersat, or 50 mg of sumatriptan (positive control), or placebo at the onset of a moderate or severe attack. Headache intensity, relief and recurrence were recorded for 24 h after dosing. On the basis of primary or secondary efficacy measures, tonabersat did not provide a clinically or statistically significant advantage over placebo. Tonabersat generally was well tolerated and had no effect on vital signs, electrocardiogram recordings or laboratory values. The lack of efficacy may be a function of the slow absorption of tonabersat. As a consequence of slow absorption, daily administration of tonabersat as prophylaxis for migraine attacks is under investigation in ongoing studies.

Background: Migraine with aura is thought likely to be caused by cortical spreading depression (CSD). Tonabersat inhibits CSD, and we therefore investigated whether tonabersat has a preventive effect in migraine with aura., Methods: In this randomised, double-blind, placebo-controlled crossover trial, 40 mg tonabersat once daily was compared with matched placebo in patients who had at least one aura attack per month during the past 3 months. Randomisation was by computer-generated list. Patients kept a detailed diary to enable objective diagnosis of each attack as migraine with aura, migraine without aura, or other type of headache. Primary endpoints were a reduction in aura attacks with or without headache and a reduction in migraine headache days with or without an aura. Analysis was per protocol. This trial is registered, number NCT00332007., Findings: 39 patients were included in the study, of whom 31 were included in the statistical analysis of efficacy. Median (IQR) attacks of aura were reduced from 3.2 (1.0-5.0) per 12 weeks on placebo to 1.0 (0-3.0) on tonabersat (p=0.01), whereas the other primary outcome measure, median migraine headache days with or without aura, was not significantly different between placebo and tonabersat groups (3.0 days in each group; p=0.09). Tonabersat was well tolerated but overall had more side-effects than placebo., Interpretation: Tonabersat showed a preventive effect on attacks of migraine aura but no efficacy on non-aura attacks, in keeping with its known inhibitory effect on CSD. The results support the theory that auras are caused by CSD and that this phenomenon is not involved in attacks without aura., Funding: Minster Pharmaceuticals; Lundbeck Foundation.