-
Frontiers in Immunology 2024Icanbelimod (formerly CBP-307) is a next-generation S1PR modulator, targeting S1PR. In this first-in-human study, icanbelimod was investigated in healthy men in... (Randomized Controlled Trial)
Randomized Controlled Trial
Icanbelimod (CBP-307), a next-generation Sphingosine-1-phosphate receptor modulator, in healthy men: pharmacokinetics, pharmacodynamics, safety, and tolerability in a randomized trial in Australia.
BACKGROUND
Icanbelimod (formerly CBP-307) is a next-generation S1PR modulator, targeting S1PR. In this first-in-human study, icanbelimod was investigated in healthy men in Australia.
METHODS
Participants were randomized 3:1, double-blind, to icanbelimod or placebo in four single-dose cohorts (0.1 mg, 0.25 mg, 0.5 mg [n=8 per cohort], 2.5 mg [n=4]) or for 28-days once-daily treatment in two cohorts (0.15 mg, 0.25 mg [n=8 per cohort]). Participants in the 0.25-mg cohort received 0.1 mg on Day 1. Treatments were administered orally after fasting; following one-week washout, icanbelimod was administered after breakfast in the 0.5-mg cohort.
RESULTS
Icanbelimod exposure increased rapidly and dose-dependently with single and multiple dosing (T 4-7 hours). Lymphocyte counts decreased rapidly after single (-11%, 0.1 mg; -40%, 0.25 mg; -71%, 0.5 mg; -77%, 2.5 mg) and multiple doses (-49%, 0.15 mg; -75%, 0.25 mg), and recovered quickly, 7 days after dosing. After single-dose 0.5 mg, although a high-fat breakfast versus fasting did not affect maximal decrease, lymphocyte counts tended to be lower after breakfast across most timepoints up to 72 hours. Twenty-eight participants (63.6%) experienced mainly mild treatment-emergent adverse events (TEAEs). After single-dose icanbelimod, the most common TEAEs were headache (28.6%, n=6) and dizziness (19.0%, n=4). Three participants experienced transient bradycardia, with one serious, following single-dose 2.5 mg icanbelimod. After multiple-dose icanbelimod, the most common TEAEs were headache (50.0%, n=6) and lymphopenia (41.7%, n=5), and two participants withdrew due to non-serious TEAEs. Up-titration attenuated heart rate reductions.
CONCLUSION
Icanbelimod was well-tolerated up to 0.5 mg and effectively reduced lymphocyte counts.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, identifier NCT02280434.b.
Topics: Humans; Male; Adult; Australia; Double-Blind Method; Young Adult; Healthy Volunteers; Sphingosine 1 Phosphate Receptor Modulators; Middle Aged; Sphingosine-1-Phosphate Receptors; Lymphocyte Count; Adolescent
PubMed: 38953034
DOI: 10.3389/fimmu.2024.1380975 -
JPMA. the Journal of the Pakistan... Jun 2024Isolated Left Ventricular Non-compaction (LVNC) is a type of cardiomyopathy that usually has a genetic origin. Its diagnosis is based on finding such as deep...
Isolated Left Ventricular Non-compaction (LVNC) is a type of cardiomyopathy that usually has a genetic origin. Its diagnosis is based on finding such as deep intertrabecular recesses or sinusoids and ventricular trabeculations communicating with the left ventricular cavity. LVNC was first clinically recognised almost four decades ago, yet its diagnostic and management challenges persist. In this report, we present the case of an 18-year-old boy, who presented at the National Institute of Cardiovascular Diseases, Karachi, in March 2023, with complaints of dizziness, pedal oedema, and shortness of breath. Echocardiography revealed signs suggestive of LVNC, which were confirmed conclusively on Cardiovascular Magnetic Resonance (CMR) (NC/C ratio>2.4). The patient underwent implantable cardioverter defibrillator (ICD) placement, was discharged after a smooth post-procedure recovery, and is doing well on follow-ups. Hence, ICD and guideline-directed medical therapy as a combination have turned out to have satisfactory outcomes in decreasing morbidity and providing mortality benefits for such patients.
Topics: Humans; Male; Adolescent; Defibrillators, Implantable; Isolated Noncompaction of the Ventricular Myocardium; Echocardiography; Dyspnea; Dizziness
PubMed: 38948997
DOI: 10.47391/JPMA.10034 -
Frontiers in Neurology 2024Vestibular migraine (VM), an intricate subtype of migraine, amalgamates the dual attributes of migraine and vestibular disorders. In clinical settings, individuals with...
BACKGROUND
Vestibular migraine (VM), an intricate subtype of migraine, amalgamates the dual attributes of migraine and vestibular disorders. In clinical settings, individuals with VM frequently articulate concerns regarding the manifestation of subjective cognitive impairment. This cognitive dysfunction is intricately linked with diminished mobility, heightened susceptibility to falls, and increased absenteeism in afflicted patients. Consequently, comprehending the features of cognitive impairment in VM patients holds potential clinical significance. The pursuit of rapid and objective methods for detection and assessment is foundational and prerequisite for efficacious cognitive management of VM patients.
METHODS
The study encompassed 50 patients diagnosed with vestibular migraine and recruited 50 age-sex matched healthy controls. All participants underwent anti-saccade tasks, and cognitive evaluation was performed using the MMSE and MoCA to assess overall cognitive function. Additionally, RBANS scales were employed to measure specific cognitive domains.
RESULTS
The VM patients and normal controls demonstrated statistical parity in terms of age, gender, education, weight, and BMI, with no significant differences observed. Analysis of cognitive scores divulged a marked increase in the incidence of Mild Cognitive Impairment (MCI) in VM patients compared to Healthy Controls (HCs). Both MMSE and MoCA scores were notably lower in VM patients compared to their healthy counterparts. The RBANS cognitive test indicated significant impairment in immediate memory, visuospatial construction, language, attention, and delayed memory among VM patients. Notably, the Trail Making Test and Stroop Color-Word Test revealed compromised processing speed and executive function cognitive domains. The anti-saccadic task highlighted significantly elevated anti-saccadic latency and frequency of direction errors in vestibular migraine patients. Symptom severity, illness duration, and episode frequency in VM patients positively correlated with counter-scanning errors and negatively correlated with cognitive performance across diverse cognitive domains.
CONCLUSION
VM patients exhibit cognitive decline across multiple cognitive domains during the interictal period. This cognitive impairment may not be fully reversible, underscoring its potential clinical significance for cognitive management in VM patients. The sensitivity of anti-saccade tasks to the cognitive status of VM patients positions them as promising objective indicators for diagnosis, intervention, and evaluation of cognitive impairment effects in VM in future applications.
PubMed: 38948136
DOI: 10.3389/fneur.2024.1419372 -
Kidney Medicine Jul 2024Intradialytic hypotension significantly affects patient safety and clinical outcomes during hemodialysis. Despite various pharmacological and nonpharmacological...
Intradialytic hypotension significantly affects patient safety and clinical outcomes during hemodialysis. Despite various pharmacological and nonpharmacological interventions, effective management remains elusive. In this report, we detail a case of intradialytic hypotension in a male patient in his 40s, undergoing hemodialysis with a history of polycystic kidney disease. Eight years ago, the patient underwent bilateral nephrectomy because of a severe cystic infection, after which his systolic blood pressure (BP) persistently remained at 50-70 mm Hg during dialysis sessions. The initial treatment strategy for hypotension included fludrocortisone, midodrine, and prednisolone, leading to a slight temporary increase in BP, which subsequently declined. As the patient's condition deteriorated, the administration of norepinephrine or dopamine became necessary to sustain BP during dialysis. Given the patient's resistance to these treatments, a daily dose of 25 mg of atomoxetine was introduced. Following this treatment, there was a gradual improvement in the patient's vertigo, weakness, and BP. This case illustrates that low-dose atomoxetine can alleviate symptoms and elevate BP in patients experiencing severe intradialytic hypotension during hemodialysis.
PubMed: 38947771
DOI: 10.1016/j.xkme.2024.100840 -
Cureus May 2024Background The cerebellopontine angle (CPA) cistern houses vital neurovascular structures such as cranial nerves V, VII, and VIII and the anterior inferior cerebellar...
Prevalence of Anterior Inferior Cerebellar Artery Vascular Loop in Cerebellopontine Angle With Three-Dimensional Constructive Interference in Steady State (CISS) Sequence MRI.
Background The cerebellopontine angle (CPA) cistern houses vital neurovascular structures such as cranial nerves V, VII, and VIII and the anterior inferior cerebellar artery (AICA), often leading to neurovascular compression syndromes due to its complex anatomy. Although vascular compression is a recognized cause of certain neuralgias, its association with otologic symptoms such as tinnitus, hearing loss, and dizziness remains uncertain. Hence, this study aims to determine the prevalence of the AICA vascular loop in the CPA cistern on MRI in patients with asymptomatic audiovestibular symptoms. Methodology Adult patients who underwent MRI, including the posterior fossa's high-resolution volumetric T2 sequence (three-dimensional constructive interference in steady state (3D-CISS)), were assessed. Patients with a history of audiovestibular symptoms (tinnitus/dizziness/vertigo/sensorineural hearing loss), intracranial tumor, vascular lesions, intracranial surgery, brain radiation therapy, traumatic brain injury, poor image quality, and MRI scans without 3D-CISS sequences were excluded. Two radiologists independently reviewed 114 (228 sides) MRI studies for the vascular loop of AICA in the CPA cistern and the extension of the AICA loop into the ipsilateral internal acoustic meatus which was graded by Chavda's classification. Results The prevalence of vascular loop of AICA in the CPA cistern was as high as 47.6% in asymptomatic patients. Grade I Chavda vascular loop was the most common type followed by type II, with type III being the least common type. Conclusions Knowledge regarding the high prevalence of the AICA loop in the asymptomatic population and the lack of significant correlation between the presence of the AICA loop and otovestibular symptoms should be considered in preoperative planning for decompression procedures.
PubMed: 38947685
DOI: 10.7759/cureus.61393 -
MedRxiv : the Preprint Server For... Jun 2024Acute SARS-CoV-2 infection triggers the generation of diverse and functional autoantibodies (AABs), even after mild cases. Persistently elevated autoantibodies have been...
Acute SARS-CoV-2 infection triggers the generation of diverse and functional autoantibodies (AABs), even after mild cases. Persistently elevated autoantibodies have been found in some individuals with long COVID (LC). Using a >21,000 human protein array, we identified diverse AAB targets in LC patients that correlated with their symptoms. Elevated AABs to proteins in the nervous system were found in LC patients with neurocognitive and neurological symptoms. Purified Immunoglobulin G (IgG) samples from these individuals reacted with human pons tissue and were cross-reactive with mouse sciatic nerves, spinal cord, and meninges. Antibody reactivity to sciatic nerves and meninges correlated with patient-reported headache and disorientation. Passive transfer of IgG from patients to mice led to increased sensitivity and pain, mirroring patient-reported symptoms. Similarly, mice injected with IgG showed loss of balance and coordination, reflecting donor-reported dizziness. Our findings suggest that targeting AABs could benefit some LC patients.
PubMed: 38947091
DOI: 10.1101/2024.06.18.24309100 -
World Journal of Gastrointestinal... Jun 2024Duodenal Brunner's gland hyperplasia (BGH) is a therapeutic target when complications such as bleeding or gastrointestinal obstruction occur or when malignancy cannot be...
BACKGROUND
Duodenal Brunner's gland hyperplasia (BGH) is a therapeutic target when complications such as bleeding or gastrointestinal obstruction occur or when malignancy cannot be ruled out. Herein, we present a case of large BGH treated with endoscopic mucosal resection (EMR).
CASE SUMMARY
An 83-year-old woman presented at our hospital with dizziness. Blood tests revealed severe anemia, esophagogastroduodenoscopy showed a 6.5 cm lesion protruding from the anterior wall of the duodenal bulb, and biopsy revealed the presence of glandular epithelium. Endoscopic ultrasonography (EUS) demonstrated relatively high echogenicity with a cystic component. The muscularis propria was slightly elevated at the base of the lesion. EMR was performed without complications. The formalin-fixed lesion size was 6 cm × 3.5 cm × 3 cm, showing nodular proliferation of non-dysplastic Brunner's glands compartmentalized by fibrous septa, confirming the diagnosis of BGH. Reports of EMR or hot snare polypectomy are rare for duodenal BGH > 6 cm. In this case, the choice of EMR was made by obtaining information on the base of the lesion as well as on the internal characteristics through EUS.
CONCLUSION
Large duodenal lesions with good endoscopic maneuverability and no evident muscular layer involvement on EUS may be resectable EMR.
PubMed: 38946860
DOI: 10.4253/wjge.v16.i6.368 -
Journal of Audiology & Otology Jul 2024: Perception of verticality is clinically assessed using the subjective visual vertical (SVV), a test of the otolith system that consists of aligning a bar on the...
BACKGROUND AND OBJECTIVES
: Perception of verticality is clinically assessed using the subjective visual vertical (SVV), a test of the otolith system that consists of aligning a bar on the gravitational vertical in darkness. Patients with acute unilateral vestibulopathy (AUVP) show a systematic SVV bias toward the affected side, whichever the side of line orientation. Whether SVV estimates are symmetrical has not been investigated.
SUBJECTS AND METHODS
: This study included 10 patients with AUVP (vestibular neuritis) and 10 with BPPV (posterior semicircular canal). SVV measurements were made at two preset angles of line orientation (15° and 30°) toward the ipsilateral and contralateral sides, relative to the affected side.
RESULTS
: The results showed asymmetrical SVV estimates in the AUVP group, with significantly greater SVV errors for ipsilateral than contralateral line orientation, as well as for the preset angle of 30° compared to 15°. SVV estimates were significantly lower in patients with BPPV who also exhibited SVV asymmetry. SVV estimates remained unchanged just after the maneuver and were normalized some days later or after supplementary maneuvers.
CONCLUSIONS
: SVV asymmetry should be routinely considered in the clinic. We recommend individually assessing ipsilateral and contralateral SVV and using at least two preset angles. This allows for a better assessment and diagnosis of otolith organ imbalance that can trigger chronic instability and dizziness. The contribution of neck afferents related to head position in space seems to be the main source of SVV asymmetry.
PubMed: 38946330
DOI: 10.7874/jao.2023.00346 -
Journal of Audiology & Otology Jul 2024: Various materials are used to perform post-mastoidectomy mastoid obliteration (MO) to reduce the risk of recurrent infections, stasis of secretions, or caloric...
BACKGROUND AND OBJECTIVES
: Various materials are used to perform post-mastoidectomy mastoid obliteration (MO) to reduce the risk of recurrent infections, stasis of secretions, or caloric dizziness. Autologous materials used as fillers for MO tend to be insufficient owing to shrinkage over time or inadequate volume of these substances. Synthetic materials are unsatisfactory for MO because of the risk of rejection and extrusion. We investigated the safety and effectiveness of bone allografts for post-mastoidectomy MO.
SUBJECTS AND METHODS
: We reviewed the medical records of patients who underwent mastoidectomy with MO between January 2013 and January 2021. In the MO group, bone allografts were additionally used to fill the residual mastoid cavity. In the canal wall down (CWD) group, all patients underwent CWD mastoidectomy with use of additional inferiorly based mucoperiosteal flaps.
RESULTS
: The study included the MO group (23 ears) and the CWD group (53 ears). In the MO group, compared with the preoperative status, we observed a decrease in the tendency of the air-bone gap postoperatively. Compared with the CWD group, the total complication rate showed a decreasing tendency in the MO group.
CONCLUSIONS
: No patient showed post-MO shrinkage of the grafted bone allograft or otorrhea. Further large-scale studies are warranted to confirm the advantages of bone allografts for MO, including maintenance with time and sufficient amount.
PubMed: 38946329
DOI: 10.7874/jao.2023.00367 -
BMC Genomics Jun 2024Ménière's disease (MD) is a disorder of the inner ear that causes episodic bouts of severe dizziness, roaring tinnitus, and fluctuating hearing loss. To date, no...
BACKGROUND
Ménière's disease (MD) is a disorder of the inner ear that causes episodic bouts of severe dizziness, roaring tinnitus, and fluctuating hearing loss. To date, no targeted therapy exists. As such, we have undertaken a large whole genome sequencing study on carefully phenotyped unilateral MD patients with the goal of gene/pathway discovery and a move towards targeted intervention. This study was a retrospective review of patients with a history of Ménière's disease. Genomic DNA, acquired from saliva samples, was purified and subjected to whole genome sequencing.
RESULTS
Stringent variant calling, performed on 511 samples passing quality checks, followed by gene-based filtering by recurrence and proximity in molecular interaction networks, led to 481 high priority MD genes. These high priority genes, including MPHOSPH8, MYO18A, TRIOBP, OTOGL, TNC, and MYO6, were previously implicated in hearing loss, balance, and cochlear function, and were significantly enriched in common variant studies of hearing loss. Validation in an independent MD cohort confirmed 82 recurrent genes. Pathway analysis pointed to cell-cell adhesion, extracellular matrix, and cellular energy maintenance as key mediators of MD. Furthermore, the MD-prioritized genes were highly expressed in human inner ear hair cells and dark/vestibular cells, and were differentially expressed in a mouse model of hearing loss.
CONCLUSION
By enabling the development of model systems that may lead to targeted therapies and MD screening panels, the genes and variants identified in this study will inform diagnosis and treatment of MD.
Topics: Meniere Disease; Humans; Endolymphatic Hydrops; Animals; Mice; Genomics; Male; Female; Retrospective Studies; Whole Genome Sequencing; Middle Aged; Adult
PubMed: 38943082
DOI: 10.1186/s12864-024-10552-3