Serotonin Receptors in Myocardial Infarction: Friend or Foe?

Acute myocardial infarction (AMI) is one of the leading causes of death worldwide and treatment costs pose a major burden on the global health care system. Despite the variety of treatment options, individual recovery can be still poor and the mortality rate, especially in the first few years after the event, remains high. Therefore, intense research is currently focused on identifying novel target molecules to improve the outcome following AMI. One of the potentially interesting targets is the serotonergic system (5-HT system), not at least because of its connection to mental disorders. It is known that patients suffering from AMI have an increased risk of developing depression and vice versa. This implicates that the 5-HT system can be affected in response to AMI and might thus represent a target structure for patients' treatment. This review aims to highlight the importance of the 5-HT system after AMI by describing the role of individual serotonin receptors (5-HTR) in the regulation of physiological and pathophysiological responses. It particularly focuses on the signaling pathways of the serotonin receptors 1, 2, 4, and 7, which are expressed in the cardiovascular system, during disease onset, and the following remodeling process. This overview also emphasizes the importance of the 5-HT system in AMI etiology and highlights 5-HTRs as potential treatment targets.

A Nation-Wide Survey of High School Baseball Coaches' Perceptions Indicates their Arm Care Programs Play a Role in Injury Prevention.

BACKGROUND: Arm care programs consisting of upper extremity strengthening and stretching have been recommended for injury prevention for pitchers of all ages. There has been no investigation into high school baseball coaches' usage and perceptions of arm care programs to mitigate physical impairments associated with injuries in baseball players. HYPOTHESIS/PURPOSE: The purpose of this study was to investigate the current usage of arm care programs by high school baseball coaches. The primary objective was to determine if coaches use group-based or individualized arm care programs. The secondary objective sought to determine if the use of arm care programs is influenced by coaches' age, education, and experience level. Finally, this study explored the potential barriers to arm care implementation and high school baseball coaches' current awareness and beliefs of injury prevention. STUDY DESIGN: Descriptive cross-sectional survey. METHODS: A 29-item online survey was emailed to 18,500 high school baseball coaches throughout the United States. Data were collected for three months, and the response rate was 3.7%. RESULTS: A total of 87.3% (n=571/654) of responding coaches use arm care programs with their players. Of coaches performing arm care, only 18.5% of 571 individualize their arm care exercises based on specific player needs. However, older and more experienced coaches are more likely to individualize their programs. Among the 12.7% (n=83/654) of coaches who do not use arm care programs, the two most commonly cited reasons for not implementing arm care were lack of observed benefit (41%) and insufficient staff (31%). Although 42% of 654 coaches recognized reduced shoulder mobility as a major contributor to injury, risk factors such as throwing with a fatigued arm, previous injury history, and throwing > 8 months per year were not consistently identified as primary risk factors. CONCLUSION: The results of this study suggest that the majority high school baseball coaches implement group-based arm care exercise programs to prevent injury. Lack of confidence in the effectiveness and staffing limitations were major barriers to implementation of arm care programming. However, the responding coaches exhibited inconsistent risk factor awareness and dated injury prevention beliefs. Therefore, better educational collaboration between rehabilitation professionals and high school coaches regarding injury risk factors and preventative strategies is warranted. LEVEL OF EVIDENCE: Level 3.

Simultaneous Multislice for Accelerating Diffusion MRI in Clinical Neuroradiology Protocols.

BACKGROUND AND PURPOSE: Diffusion MR imaging sequences essential for clinical neuroradiology imaging protocols may be accelerated with simultaneous multislice acquisitions. We tested whether simultaneous multislice-accelerated diffusion data were clinically equivalent to standard acquisitions. MATERIALS AND METHODS: In this retrospective study, clinical diffusion sequences obtained before and after implementation of 2-slice simultaneous multislice acceleration and an altered diffusion gradient sampling scheme using the same 3T MRI scanner and 20-channel coil (n = 25 per group) were independently and blindly evaluated by 2 neuroradiologists for perceived quality, artifacts, and overall diagnostic utility. Diffusion tractography was performed in 13 patients both with and without 2-slice simultaneous multislice acceleration (b = 0, 1000, 2000 s/mm2; 60 directions). The corticospinal tract and arcuate fasciculus ipsilateral to the lesion were generated using the same ROIs and then blindly assessed by a neurosurgeon for anatomic fidelity, perceived quality, and impact on surgical management. Tract volumes were compared for spatial overlap. RESULTS: Two-slice simultaneous multislice diffusion reduced acquisition times from 141 to 45 seconds for routine diffusion and from 7.5 to 5.9 minutes for diffusion tractography using 3T MR imaging. The simultaneous multislice-accelerated diffusion sequence was rated equivalent for diagnostic utility despite reductions to perceived image quality. Simultaneous multislice-accelerated diffusion tractography was rated clinically equivalent. Dice similarity coefficients between routine and simultaneous multislice-generated corticospinal tract and arcuate fasciculus tract volumes were 0.78 (SD, 0.03) and 0.71 (SD, 0.05), respectively. CONCLUSIONS: Two-slice simultaneous multislice diffusion appeared clinically equivalent for standard acquisitions and diffusion tractography. Simultaneous multislice makes it feasible to acquire higher angular and q-space-resolution diffusion acquisitions required for translating advanced diffusion models into clinical practice.

Sport-specific differences in dynamic visual acuity and gaze stabilization in division-I collegiate athletes.

BACKGROUND: The vestibular-ocular reflex (VOR) integrates the vestibular and ocular systems to maintain gaze during head motion. This reflex is often negatively affected following sport-related concussion. Objective measures of gaze stability, a function mediated by the VOR, such as the computerized dynamic visual acuity test (DVAT) and gaze stabilization test (GST), may have utility in concussion management. However, normative data specific to sport, sex, or concussion history have not been established in collegiate athletes. OBJECTIVE: The objective of this study was to establish normative values for the DVAT and GST in collegiate athletes and explore the effect of sport, sex, and concussion history on VOR assessments. METHODS: The DVAT and GST were completed by 124 collegiate athletes (72 male, 52 female, mean±SD, age: 19.71±1.74 years, height: 173.99±13.97 cm, weight: 80.06±26.52 kg) recruited from Division-I athletic teams (football, soccer and cheerleading). The DVAT and GST were performed in the rightward and leftward directions during a single session in a standardized environment. Normative values for DVAT and GST measures were expressed as percentiles. Non-parametric statistics were used to compare differences between groups based on sex, sport, and concussion history. Alpha was set a-priori at 0.05. RESULTS: Overall, the median LogMAR unit for 124 athletes completing the DVAT was 0 (IQR = 0.17) for both leftward and rightward. The median velocities achieved on the GST were 145 °/sec and 150 °/sec (IQR = 45 and 40) for the leftward and rightward directions respectively. Significant differences were observed between sports (p = 0.001-0.17) for the GST with cheerleading demonstrating higher velocities than the other sports. However, no significant differences were identified based on sex (p≥0.09) or history of concussion (p≥0.15). CONCLUSIONS: Normative estimates for the DVAT and GST may assist in the clinical interpretation of outcomes when used in post-concussion evaluation for collegiate athletes. Although sex and previous concussion history had no effect on the DVAT or GST, performance on these measures may be influenced by type of sport. Sport-related differences in the GST may reflect VOR adaptations based on individual sport-specific demands.

Direct In Vivo MRI Discrimination of Brain Stem Nuclei and Pathways.

BACKGROUND AND PURPOSE: The brain stem is a complex configuration of small nuclei and pathways for motor, sensory, and autonomic control that are essential for life, yet internal brain stem anatomy is difficult to characterize in living subjects. We hypothesized that the 3D fast gray matter acquisition T1 inversion recovery sequence, which uses a short inversion time to suppress signal from white matter, could improve contrast resolution of brain stem pathways and nuclei with 3T MR imaging. MATERIALS AND METHODS: After preliminary optimization for contrast resolution, the fast gray matter acquisition T1 inversion recovery sequence was performed in 10 healthy subjects (5 women; mean age, 28.8 ± 4.8 years) with the following parameters: TR/TE/TI = 3000/2.55/410 ms, flip angle = 4°, isotropic resolution = 0.8 mm, with 4 averages (acquired separately and averaged outside k-space to reduce motion; total scan time = 58 minutes). One subject returned for an additional 5-average study that was combined with a previous session to create a highest quality atlas for anatomic assignments. A 1-mm isotropic resolution, 12-minute version, proved successful in a patient with a prior infarct. RESULTS: The fast gray matter acquisition T1 inversion recovery sequence generated excellent contrast resolution of small brain stem pathways in all 3 planes for all 10 subjects. Several nuclei could be resolved directly by image contrast alone or indirectly located due to bordering visualized structures (eg, locus coeruleus and pedunculopontine nucleus). CONCLUSIONS: The fast gray matter acquisition T1 inversion recovery sequence has the potential to provide imaging correlates to clinical conditions that affect the brain stem, improve neurosurgical navigation, validate diffusion tractography of the brain stem, and generate a 3D atlas for automatic parcellation of specific brain stem structures.

The evalaution of the foot core system in individuals with plantar heel pain.

OBJECTIVE: To compare foot posture, plantar sensation, plantar fascia thickness, intrinsic foot muscle performance, and abductor hallucis morphology in individuals with and without plantar heel pain (PHP). DESIGN: Cross-Sectional. SETTING: Laboratory. PARTICIPANTS: Sixteen individuals with PHP and sixteen matched healthy participants. MAIN OUTCOME MEASURES: Static foot posture, plantar sensation, plantar fascia thickness, intrinsic foot muscle performance and abductor hallucis morphology were evaluated. Foot posture was assessed with the Foot Posture Index-6. Abductor hallucis morphology and plantar fascia thickness were measured utilizing diagnostic ultrasound. Plantar foot sensation was assessed at the head of the first metatarsal and medial longitudinal arch using Semmes-Weinstein Monofilaments. Intrinsic foot muscle performance was assessed using the intrinsic foot muscle test (IFMT). Mann-Whitney U and independent t-tests were used to examine between group differences. RESULTS: Individuals with PHP exhibited a more pronated foot posture and greater plantar fascia thickness at the proximal insertion compared to healthy controls. Plantar sensation thresholds were higher in the PHP compared to healthy controls at the head of the first metatarsal. There were no group differences in abductor hallucis morphology or IFMT performance. CONCLUSIONS: Individuals with PHP exhibited a more pronated foot posture, thicker plantar fascia, and diminished plantar tactile sensation.

3T MRI Whole-Brain Microscopy Discrimination of Subcortical Anatomy, Part 2: Basal Forebrain.

BACKGROUND AND PURPOSE: The basal forebrain contains multiple structures of great interest to emerging functional neurosurgery applications, yet many neuroradiologists are unfamiliar with this neuroanatomy because it is not resolved with current clinical MR imaging. MATERIALS AND METHODS: We applied an optimized TSE T2 sequence to washed whole postmortem brain samples (n = 13) to demonstrate and characterize the detailed anatomy of the basal forebrain using a clinical 3T MR imaging scanner. We measured the size of selected internal myelinated pathways and measured subthalamic nucleus size, oblique orientation, and position relative to the intercommissural point. RESULTS: We identified most basal ganglia and diencephalon structures using serial axial, coronal, and sagittal planes relative to the intercommissural plane. Specific oblique image orientations demonstrated the positions and anatomic relationships for selected structures of interest to functional neurosurgery. We observed only 0.2- to 0.3-mm right-left differences in the anteroposterior and superoinferior length of the subthalamic nucleus (P = .084 and .047, respectively). Individual variability for the subthalamic nucleus was greatest for angulation within the sagittal plane (range, 15°-37°), transverse dimension (range, 2-6.7 mm), and most inferior border (range, 4-7 mm below the intercommissural plane). CONCLUSIONS: Direct identification of basal forebrain structures in multiple planes using the TSE T2 sequence makes this challenging neuroanatomy more accessible to practicing neuroradiologists. This protocol can be used to better define individual variations relevant to functional neurosurgical targeting and validate/complement advanced MR imaging methods being developed for direct visualization of these structures in living patients.

3T MRI Whole-Brain Microscopy Discrimination of Subcortical Anatomy, Part 1: Brain Stem.

BACKGROUND AND PURPOSE: The brain stem is compactly organized with life-sustaining sensorimotor and autonomic structures that can be affected by numerous pathologies but can be difficult to resolve on conventional MR imaging. MATERIALS AND METHODS: We applied an optimized TSE T2 sequence to washed postmortem brain samples to reveal exquisite and reproducible brain stem anatomic MR imaging contrast comparable with histologic atlases. This resource-efficient approach can be performed across multiple whole-brain samples with relatively short acquisition times (2 hours per imaging plane) using clinical 3T MR imaging systems. RESULTS: We identified most brain stem structures at 7 canonical axial levels. Multiplanar or oblique planes illustrate the 3D course and spatial relationships of major brain stem white matter pathways. Measurements of the relative position, course, and cross-sectional area of these pathways across multiple samples allow estimation of pathway location in other samples or clinical subjects. Possible structure-function asymmetries in these pathways will require further study-that is, the cross-sectional area of the left corticospinal tract in the midpons appeared 20% larger (n = 13 brains, P < .10). CONCLUSIONS: Compared with traditional atlases, multiplanar MR imaging contrast has advantages for learning and retaining brain stem anatomy for clinicians and trainees. Direct TSE MR imaging sequence discrimination of brain stem anatomy can help validate other MR imaging contrasts, such as diffusion tractography, or serve as a structural template for extracting quantitative MR imaging data in future postmortem investigations.

Clinical pilot study of transcranial direct current stimulation combined with Cognitive Emotional Training for medication resistant depression.

BACKGROUND: While the clinical results from transcranial direct current stimulation (tDCS) for the treatment of depression have been promising, antidepressant effects in patients with medication resistance have been suboptimal. There is therefore a need to further optimise tDCS for medication resistant patients. In this clinical pilot study we examined the feasibility, safety, and clinical efficacy of combining tDCS with a psychological intervention which targets dysfunctional circuitry related to emotion regulation in depression, Cognitive Emotional Training (CET). METHODS: tDCS was administered during CET three times a week for a total of 18 sessions over 6 weeks. Mood, cognition and emotion processing outcomes were examined at baseline and after 3 and 6 weeks of treatment. RESULTS: Twenty patients with medication resistant depression participated, of whom 17 were study completers. tDCS combined with CET was found to be feasible, safe, and associated with significant antidepressant efficacy at 6 weeks, with 41% of study completers showing treatment response (≥ 50% improvement in depression score). There were no significant cognitive enhancing effects with the exception of improved emotion recognition. Responders demonstrated superior recognition for the emotions fear and surprise at pre-treatment compared to non-responders, suggesting that better pre-treatment emotion recognition may be associated with antidepressant efficacy. LIMITATIONS: This was an open label study. CONCLUSIONS: tDCS combined with CET has potential as a novel method for optimising the antidepressant efficacy of tDCS in medication resistant patients. Future controlled studies are required to determine whether tDCS combined with CET has greater antidepressant efficacy compared to either intervention alone.

Moisture content of root canal dentine affects detection of microcracks using micro-computed tomography.

AIM: To evaluate the effect of moisture content in root canal dentine on detection of microcracks using micro-computed tomography. METHODOLOGY: Ten roots with and without craze lines or cracks (each n = 5) were selected and scanned six times with different moisture conditions of root dentine using a micro-CT scanner at a high resolution of 10.5 µm. Scanning conditions were as follows: (i) after 30-day wet storage, (ii) after 2-h dry time, (iii) after 48-h wet storage, (iv) after 24-h dry time, (v) after 48-h wet storage, (vi) after 2-h dry time. From each scan, cross-sectional images were obtained at intervals of 1 mm (total n = 708) and evaluated for the presence of dentinal microcracks twice by five calibrated blinded observers. Statistical analysis was performed by nonparametric analysis of variance for longitudinal data (P < 0.05). RESULTS: Intra-rater percentage agreement ranged between 92% and 98%, whereas inter-rater percentage agreement was 81% and 83%, respectively. No significant differences between all wet groups as well as between both groups with 2-h dry time were detected (P > 0.05). Almost no cracks were observed after wet storage with a significant increase of cracks after 2-h dry time (P < 0.001). Significantly more microcracks were identified after 24 h than after 2-h dry time (P < 0.004). CONCLUSIONS: Moisture content of dentine influenced detection of microcracks when evaluated using micro-CT. Scanning should be performed on dried specimens to allow reliable identification of dentinal defects. Formation of new cracks during dry periods up to 24 h was disproved.

Head and Neck MRI Findings in CHARGE Syndrome.

Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, and Ear abnormalities and deafness (CHARGE) syndrome is a disorder with multiple congenital anomalies seen on imaging. A retrospective review of 10 patients with CHARGE syndrome who underwent MR imaging of the brain as part of a preoperative evaluation for cochlear implantation was conducted. Structural abnormalities of the entire MR imaging of the head were evaluated, including the auditory system, olfactory system, face, skull base, and central nervous system. The most frequent MR imaging findings included dysplasias of the semicircular canals and hypoplasia of the frontal lobe olfactory sulci. Less frequent findings included cleft lip/palate and coloboma. Our study uncovered new findings of a J-shaped sella, dorsal angulation of the clivus, and absent/atrophic parotid glands, not previously described in patients with CHARGE. Our results emphasize the utility of MR imaging in the diagnosis and management of patients with CHARGE syndrome.

Serological diagnostics in the detection of IgG autoantibodies against human collagen VII in epidermolysis bullosa acquisita: a multicentre analysis.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a rare, potentially devastating autoimmune disease of the skin. IgG autoantibodies directed against type VII collagen (Col7), the major component of anchoring fibrils, induce skin fragility leading to cutaneous and mucocutaneous blister formation, which is mostly of a scarring phenotype. Thus, powerful and reproducible diagnostic assays are critical to establish the diagnosis of EBA early to avoid irreversible sequelae. OBJECTIVES: The present international, retrospective multicentre study included a large cohort of patients with EBA and evaluated the diagnostic power of four different diagnostic assays for the detection of anti-Col7 IgG autoantibodies. METHODS: Overall, 95 EBA sera and 200 control sera consisting of 100 bullous pemphigoid sera, 50 pemphigus vulgaris sera and 50 sera of healthy controls were tested for anti-Col7 IgG autoantibodies using indirect immunofluorescence (IIF), two commercial enzyme-linked immunosorbent assay (ELISA) systems and Western blot (WB) analysis. EBA sera were taken from patients with positive direct immunofluorescence and IgG reactivity in at least one of the immunoserological assays (IIF, ELISA, WB). RESULTS: A Col7-NC1/NC2 ELISA (MBL, Nagoya, Japan) showed the highest sensitivity (97·9%), followed by a Col7-NC1 ELISA (Euroimmun, Lübeck, Germany) (89·5%), WB with Col7-NC1 (85·3%), and IIF on saline-split human skin (74·7%). The specificities of both ELISA systems were comparable (NC1 98·7%, NC1/NC2 99·3%). Furthermore, WB was more sensitive than IIF, which was more specific. CONCLUSIONS: The two commercially available ELISA systems allow for a highly sensitive and specific diagnosis of EBA. The sensitivity of the Col7-NC1/NC2 ELISA is significantly higher compared with the ELISA based on the Col7-NC1 domain only.

A cross-species approach to identify transcriptional regulators exemplified for Dnajc22 and Hnf4a.

There is an enormous need to make better use of the ever increasing wealth of publicly available genomic information and to utilize the tremendous progress in computational approaches in the life sciences. Transcriptional regulation of protein-coding genes is a major mechanism of controlling cellular functions. However, the myriad of transcription factors potentially controlling transcription of any given gene makes it often difficult to quickly identify the biological relevant transcription factors. Here, we report on the identification of Hnf4a as a major transcription factor of the so far unstudied DnaJ heat shock protein family (Hsp40) member C22 (Dnajc22). We propose an approach utilizing recent advances in computational biology and the wealth of publicly available genomic information guiding the identification of potential transcription factor candidates together with wet-lab experiments validating computational models. More specifically, the combined use of co-expression analyses based on self-organizing maps with sequence-based transcription factor binding prediction led to the identification of Hnf4a as the potential transcriptional regulator for Dnajc22 which was further corroborated using publicly available datasets on Hnf4a. Following this procedure, we determined its functional binding site in the murine Dnajc22 locus using ChIP-qPCR and luciferase assays and verified this regulatory loop in fruitfly, zebrafish, and humans.

Palliative CT-Guided Cordotomy for Medically Intractable Pain in Patients with Cancer.

Palliative cervical cordotomy can be performed via percutaneous radiofrequency ablation of the lateral C1-2 spinothalamic tract. This rare procedure can be safe, effective, and advantageous in mitigating medically intractable unilateral extremity pain for selected patients with end-stage cancer. This report reviews the indications, techniques, risks, and potential benefits of cordotomy. We describe our recent experience treating 3 patients with CT-guided C1-2 cordotomy and provide the first characterization of spinal cord diffusion MR imaging changes associated with successful cordotomy.

[Louse-borne-relapsing-fever in refugees from the Horn of Africa; a case series of 25 patients]. / 25 Fälle von Läuserückfallfieber bei Flüchtlingen aus Ostafrika.

Background | Relapsing fever is divided into tick borne relapsing fever (TBRF) and louse borne relapsing fever (LBRF). This report describes 25 refugees from East Africa who were diagnosed to suffer from LBRF within a period of 6 month only at a single hospital in Munich / Germany. Material & Methods | The aim was to point out common clinical features as well as laboratory findings and clinical symptoms before and after initiation of treatment in 25 patients with louse borne relapsing fever (LBRF) who were diagnosed and treated at Klinikum München Schwabing from August 2015 to January 2016. To the best of our knowledge this is the largest case series of LBRF in the western world for decades. Main focus of the investigation was put on clinical aspects. Results | All 25 patients suffered from acute onset of high fever with chills, headache and severe prostration. Laboratory analysis showed high CRP and a marked thrombocytopenia. A Giemsa blood stain was procured immediately in order to look for malaria. In the blood smear spirochetes with typical shape and aspect of borrelia species could be detected.The further PCR analysis confirmed infection with Borrelia recurrentis. Treatment with Doxycycline was started forthwith. The condition improved already on the second day after treatment was started and all were restored to health in less than a week. Apart from a mild to moderate Jarisch-Herxheimer-reaction we didn`t see any side effects of the therapy. Conclusion | LBRF has to be taken into account in feverish patients who come as refugees from East-Africa. It seems that our patients belong to a cluster which probably has its origin in Libya and more patients are to be expected in the near future. As LBRF might cause outbreaks in refugee camps it is pivotal to be aware of this emerging infectious disease in refugees from East-Africa.

New Clinically Feasible 3T MRI Protocol to Discriminate Internal Brain Stem Anatomy.

Two new 3T MR imaging contrast methods, track density imaging and echo modulation curve T2 mapping, were combined with simultaneous multisection acquisition to reveal exquisite anatomic detail at 7 canonical levels of the brain stem. Compared with conventional MR imaging contrasts, many individual brain stem tracts and nuclear groups were directly visualized for the first time at 3T. This new approach is clinically practical and feasible (total scan time = 20 minutes), allowing better brain stem anatomic localization and characterization.

Pulsed field magnetization in rare-earth kagome systems.

The rare-earth kagome systems R 3Ga5SiO14 (R = Nd or Pr) exhibit cooperative paramagnetism at low temperatures. Evidence for correlated spin clusters in these weakly frustrated systems has previously been obtained from neutron scattering and from ESR and NMR results. The present pulsed field (0-60 T, 25 ms) magnetization measurements made on single crystals of Nd3Ga5SiO14 (NGS) and Pr3Ga5SiO14 (PGS) at temperatures down to 450 mK have revealed striking differences in the magnetic responses of the two materials. For NGS the magnetization shows a low field plateau, saturation in high transient fields, and significant hysteresis while the PGS magnetization does not saturate in transient fields up to 60 T and shows no hysteresis or plateaus. Nd(3+) is a Kramers ion while Pr(3+) is a non-Kramers ion and the crystal field effects are quite different in the two systems. For the conditions used in the experiments the magnetization behavior is not in agreement with Heisenberg model predictions for kagome systems in which easy-axis anisotropy is much larger than the exchange coupling. The extremely slow spin dynamics found below 4 K in NGS is, however, consistent with the model for Kramers ions and provides a basis for explaining the pulsed field magnetization features.

Orbital lesions with low signal intensity on T2-weighted imaging.

The purpose of the present review is to discuss and display orbital lesions that demonstrate hypo-intense signal on T2-weighted images (T2WI). The physical basis for hypo-intense signal on T2WI produced by various substances is discussed. Orbital lesions that are hypo-intense on T2WI are subsequently reviewed, including a discussion on their composition as well as relevant clinical and imaging clues that may aid in their diagnosis.

Clinical pharmacology of ponesimod, a selective S1P1 receptor modulator, after uptitration to supratherapeutic doses in healthy subjects.

PURPOSE: The aim of this study was to assess in healthy subjects the safety, tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an oral selective sphingosine-1-phosphate receptor 1 (S1P1) modulator in development for multiple sclerosis, by using an uptitration scheme up to supratherapeutic doses. METHODS: This was a double-blind, placebo-controlled, randomised, parallel group, uptitration study. Male and female subjects received ascending oral doses of ponesimod (n=12) or placebo (n=4) once daily for 3 days at each dose level (10-20-40-60-80-100mg). RESULTS: The most frequent adverse events were chest discomfort, headache, dizziness, dyspnoea, abdominal pain, and night sweats. Chest discomfort and dyspnoea were considered dose-limiting. A transient decrease in heart rate was observed following the first 10-mg ponesimod dose (maximum mean decrease of 9 beats per minute (bpm) (placebo: 2 bpm)). After uptitration, effects on heart rate were indistinguishable from placebo. A dose-dependent effect on pulmonary function tests was observed and reached a plateau with 60-80 mg ponesimod (maximum mean decrease from baseline of 1.24l (-30.5%) in forced expiratory volume in 1s). A plateau in mean lymphocyte count reduction of approximately 70% from baseline was reached at the 40 mg dose level. Observed effects were fully reversible within 10days after treatment discontinuation. No relevant sex differences were observed. CONCLUSIONS: At supratherapeutic doses, symptoms of chest discomfort and dyspnoea were dose-limiting. An uptitration dosing scheme is to be preferred in clinical studies in patients in order to limit effects of ponesimod on heart rate and atrioventricular (AV) conduction.