Pharmacodynamic, pharmacokinetic and rat brain receptor occupancy profile of NLX-112, a highly selective 5-HT1A receptor biased agonist.

NLX-112 (i.e., F13640, befiradol) exhibits nanomolar affinity, exceptional selectivity and full agonist efficacy at serotonin 5-HT1A receptors. NLX-112 shows efficacy in rat, marmoset and macaque models of L-DOPA induced dyskinesia (LID) in Parkinson's disease and has shown clinical efficacy in a Phase 2a proof-of-concept study for this indication. Here we investigated, in rats, its pharmacodynamic, pharmacokinetic (PK) and brain 5-HT1A receptor occupancy profiles, and its PK properties in the absence and presence of L-DOPA. Total and free NLX-112 exposure in plasma, CSF and striatal ECF was dose-proportional over the range tested (0.04, 0.16 and 0.63 mg/kg i.p.). NLX-112 exposure increased rapidly (Tmax 0.25-0.5h) and exhibited approximately threefold longer half-life in brain than in plasma (1.1 and 3.6h, respectively). At a pharmacologically relevant dose of 0.16 mg/kg i.p., previously shown to elicit anti-LID activity in parkinsonian rats, brain concentration of NLX-112 was 51-63 ng/g from 0.15 to 1h. In microPET imaging experiments, NLX-112 showed dose-dependent reduction of 18F-F13640 (i.e., 18F-NLX-112) brain 5-HT1A receptor labeling in cingulate cortex and striatum, regions associated with motor control and mood, with almost complete inhibition of labeling at the dose of 0.63 mg/kg i.p.. Co-administration of L-DOPA (6 mg/kg s.c., a dose used to elicit LID in parkinsonian rats) together with NLX-112 (0.16 mg/kg i.p.) did not modify PK parameters in rat plasma and brain of either NLX-112 or L-DOPA. Here, we demonstrate that NLX-112's profile is compatible with 'druggable' parameters for CNS indications, and the results provide measures of brain concentrations and 5-HT1A receptor binding parameters relevant to the anti-dyskinetic activity of the compound.

Ear Dyskinesia in the Absence of Neuroleptics: A Case Report.

Ear dyskinesia, also known as "moving ear syndrome," is a rare movement disorder characterized by involuntary, rhythmic, or semi-rhythmic contractions of the external ear muscles. The condition is not well-documented in the medical literature, with only a few case reports available. We present the case of a 37-year-old teacher from Saudi Arabia who developed a history of sudden, progressive involuntary movement of the posterior head region, provoking movement of the external ears, over the course of one year. The movements were non-rhythmical, more prominent on the right side, and associated with occasional involvement of the face and anterior neck muscles. The patient had no history of neuroleptic use or other relevant medical conditions. Examination confirmed the presence of palpable muscle contractions originating mainly from the posterior region, with the movements not synchronized across the two sides. Investigations, including blood tests and brain MRI, did not reveal any underlying pathology. A diagnosis of ear dyskinesia was made, and botulinum toxin treatment was recommended; however, the treatment showed no results, and then the patient was subsequently lost to follow-up. This case adds to the limited literature on the rare phenomenon of ear dyskinesia, highlighting the clinical presentation and the challenges in the management of this unusual movement disorder. Further research is needed to better understand the underlying mechanisms and optimal treatment approaches for this condition.

Transcriptional regulation of CCNO during the formation of multiple motile cilia.

Primary ciliary dyskinesia (PCD) is a group of genetically heterogeneous disorders characterized by clinical manifestations resulting from abnormal ciliary motility. Mutations in critical genes, such as Cyclin O (CCNO), have been associated with severe respiratory disease, though limited data are currently available. Here we show that CCNO deficient ciliated cells can only form a reduced number of fully functional centrioles that can mature into ciliated basal bodies, and their transport and anchoring to the top of the plasma membrane are abnormal. Furthermore, we observed that CCNO localizes not only in the cytoplasm but also in the nucleus during the early stages of ciliogenesis, and this dual localization persists into adulthood. Transcriptome analysis revealed downregulation of genes involved in cilia assembly and movement, along with altered transcription factors associated with ciliation upon CCNO depletion. These findings indicate that CCNO may serve as a key regulator in the transcriptional regulation of multiciliogenesis.

Childhood gratification syndrome: Demystifying the clinical conundrum with a narrative literature review of the past 5 decades.

Background: Childhood gratification syndrome (CGS) refers to self-stimulatory or masturbatory behaviors in children, which may have an onset as early as in infancy (IGS). Aim: The aim of this review is to understand the various clinical manifestations of CGS/IGS and their clinical differentiation from commonly misdiagnosed neurological and physical illnesses and to formulate a preliminary approach to their diagnosis and management. Methods: This narrative review is based on a search of literature over the past 50 years (1972-2022) in three online databases (PubMed/Medline, Embase, and Google Scholar). Results: The behaviors are episodic, occurring for brief periods, involving posturing, stereotypical limb movements, pubic pressure with autonomic hyperactivity, and postepisodic lethargy. They mimic seizures, movement disorders, abdominal pain, and tics. The paper also highlights the gap in the current knowledge to guide future research in the area. CGS usually represents nonpathological "pleasure-seeking" habits of childhood, but at times, it may become problematic for the child and his family. A careful history and videotape analysis of the events confirms the diagnosis and behavioral therapy with parental reassurance as the mainstay of treatment. Conclusion: A better understanding and clinical awareness of the CGS are necessary to prevent misdiagnosis and delay in appropriate intervention.

The neuroprotective potential of magnesium in Parkinson's disease.

Pathogenic mechanisms implicated in the development of Parkinson disease (PD) are multifaceted and include alpha synuclein aggregation, oxidative stress due to generation of reactive oxygen species (ROS), mitochondrial dysfunction, apoptosis, imbalance of trace elements as well as endoplasmic reticulum stress, and inflammation. Alteration in the homeostasis of bivalent cations, such as iron, magnesium and calcium, has been implicated in the pathogenesis of PD. Low levels of magnesium have been associated with accelerated dopaminergic cell loss in animal PD models, and magnesium has been shown to have a neuroprotective effect in PD models. Evidence of a low magnesium level in the brain of PD individuals, with a low magnesium level in the diet, increasing the risk of PD, further strengthens the role of magnesium deficiency in the pathogenesis of PD. The presence of low-level magnesium in brain tissue and high level in CSF and serum support the possibility of dysfunctional magnesium transporters in PD. Indeed, variants in magnesium transport channels, such as TRPM7 and SLC41A1, have been recently detected in PD individuals. Magnesium, being an NMDA antagonist, could also have a therapeutic role in levodopa-induced dyskinesia. There are no clinical studies indicating a neuroprotective role of magnesium in PD, however, the Mediterranean diet and variants of the diet have been associated with a lower risk of PD, which may be due to the magnesium-rich constituents of the diet. Further clinical trials encompassing therapeutic models to optimize channel function, coupled with a high magnesium diet, may pave the way for promising neuroprotective intervention for PD.

An Unexpected Phenomenon: A Case of Citalopram-Induced Dyskinesia.

Dyskinetic movements are characterized as hyperkinetic, repetitive movements of the extremities, facial, and oral musculature, most associated with prolonged dopamine D2 receptor blockade. In rare instances, dyskinetic movements can be brought on by selective serotonin reuptake inhibitor (SSRI) usage via an indirect D2 blockade mechanism, mimicking the D2 blockade observed with dopamine receptor blocking agents (DRBAs), such as in first-generation antipsychotics. This mimicked D2 blockade by SSRIs is said to be due to increased tonic inhibition by serotonin on dopaminergic neurons in the dopaminergic pathways of the brain, specifically the nigrostriatal pathway. In this case report, we look at a patient with a history of cerebral palsy who developed acute dyskinetic movements after short-term citalopram usage. The objective is to bring attention to the possible extrapyramidal side effects (EPS) of SSRI usage.

Pontocerebellar Hypoplasia Type 9: A Case Study Highlighting Distinctive Magnetic Resonance Imaging Features.

Pontocerebellar hypoplasia type 9 (PCH9) is a rare, autosomal, recessive, neurodevelopmental disorder caused by a mutation in the AMPD2 gene. Despite its rarity, it presents distinctive clinical and neuroradiological features. Diagnosing it is challenging yet crucial for appropriate management. We describe a 21-month-old boy with clinical and neuroradiological manifestations of the diagnosis, including characteristic signs such as an eight-configured midbrain and hypoplasia of the brainstem and cerebellar structures. Genetic evaluation confirmed homozygous missense mutations in the AMPD2 gene. This case highlights the pathognomonic neuroradiological features of pontocerebellar hypoplasia type 9 that point toward diagnosis.

Primary Ciliary Dyskinesia Due to Compound Heterozygous Variants in CFAP221 with Obstructive Azoospermia: Young's Syndrome May Be a Phenotype of Primary Ciliary Dyskinesia.

We report the case of a 42-year-old man with bronchiectasis who had a history of infertility treatment for obstructive azoospermia. Young's syndrome was suspected based on the triad of obstructive azoospermia, sinusitis, and bronchiectasis. He had normal electron microscopy findings, normal nasal nitric oxide levels (116 nL/min), and no situs inversus. However, we found compound heterozygous variants in CFAP221. This led to a diagnosis of primary ciliary dyskinesia (PCD). Distinguishing PCD from Young's syndrome in patients with the triad of obstructive azoospermia, sinusitis, and bronchiectasis is challenging. Young's syndrome may be a phenotype of PCD.

Infertility and pregnancy outcomes among adults with primary ciliary dyskinesia.

STUDY QUESTION: What is the prevalence of infertility and ectopic pregnancies among individuals with primary ciliary dyskinesia (PCD)? SUMMARY ANSWER: We found that 39 of 50 men (78%) and 72 of 118 women (61%) with PCD were infertile and that women with PCD had an increased risk of ectopic pregnancies (7.6 per 100 pregnancies, 95% CI 4.7-12.2). WHAT IS KNOWN ALREADY: PCD is a heterogeneous multiorgan disease caused by mutations in genes required for the function and structure of motile cilia. Previous studies identified a link between PCD and infertility, but original data on prevalence of infertility and risk of ectopic pregnancies, the use and efficacy of medically assisted reproduction (MAR), and the association of fertility with PCD genotype are extremely limited. STUDY DESIGN SIZE DURATION: We performed a cross-sectional survey about fertility within the Living with PCD study (formerly COVID-PCD). Living with PCD is an international, online, participatory study that collects information directly from people with PCD. People with PCD of any age from anywhere in the world can participate in the study. At the time of the survey, 482 adults with PCD were registered within the Living with PCD study. PARTICIPANTS/MATERIALS SETTING METHODS: We sent a questionnaire on fertility on 12 July 2022, to all participants older than 18 years enrolled in the Living with PCD study. Responses were collected until 8 March 2023. The fertility questionnaire covered topics related to pregnancy attempts, use of MAR, and pregnancy outcomes. Data were collected via the Research Electronic Data Capture (REDCap) platform. We defined infertility as failure to achieve a clinical pregnancy after 12 months or use of MAR for at least one pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 265 of 482 adult participants (55%) completed the fertility questionnaire. Among 168 adults who had tried to conceive, 39 of 50 men (78%) and 72 of 118 women (61%) were infertile. Of the infertile men, 28 had tried MAR, and 17 of them (61%) fathered a child with the help of MAR. Among infertile women, 59 had used MAR, and 41 of them (69%) became pregnant with the help of MAR. In our population, women with PCD showed a relatively high risk of ectopic pregnancies: 1 in 10 women who became pregnant had at least one ectopic pregnancy and 7.6% of pregnancies were ectopic (95% CI 4.7-12.2). We evaluated the association between fertility and affected PCD genes in 46 individuals (11 men, 35 women) with available genetic and fertility information, and found differences between genotypes, e.g. all five women with a mutation in CCDC40 were infertile and all five with DNAH11 were fertile. LIMITATIONS REASONS FOR CAUTION: The study has limitations, including potential selection bias as people experiencing problems with fertility might be more likely to fill in the questionnaire, which may have influenced our prevalence estimates. We were unable to validate clinical data obtained from participant self-reports owing to the anonymous study design, which is likely to lead to recall bias. WIDER IMPLICATIONS OF THE FINDINGS: The study underlines the need for addressing infertility in routine PCD care, with a focus on informing individuals with PCD about their increased risk. It emphasizes the utility and efficacy of MAR in PCD-related infertility. Additionally, women attempting conception should be made aware of the increased risk of ectopic pregnancies and seek systematic early consultation to confirm an intrauterine pregnancy. Fertility, efficacy of MAR, and risk for adverse pregnancy outcomes differ between people with PCD-depending on genotypes-and close monitoring and support might be needed from fertility specialists to increase chances of successful conception. STUDY FUNDING/COMPETING INTERESTS: Our research was funded by the Swiss National Science Foundation, Switzerland (SNSF 320030B_192804), the Swiss Lung Association, Switzerland (2021-08_Pedersen), and we also received support from the PCD Foundation, USA; the Verein Kartagener Syndrom und Primäre Ciliäre Dyskinesie, Germany; the PCD Support UK, UK; and PCD Australia, Australia. M. Goutaki received funding from the Swiss National Science Foundation, Switzerland (PZ00P3_185923). B. Maitre participates in the RaDiCo-DCP funded by INSERM France. The study authors participate in the BEAT-PCD Clinical Research Collaboration supported by the European Respiratory Society. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID NCT04602481.

Hyperkinetic Biliary Dyskinesia: An Underrecognized Problem With Good Surgical Outcomes After Cholecystectomy.

Introduction While surgical indications for symptomatic cholelithiasis and biliary hypokinesia are clear, hyperkinetic biliary dyskinesia (HBD) is an underrecognized condition with poorly defined symptomology and management guidelines. HBD is typically defined as a gallbladder ejection fraction (EF) ≥ 80% on a hepatobiliary iminodiacetic acid (HIDA) scan. We aimed to identify the prevalence and radiographic reporting of HBD, physician referral patterns, and clinical outcomes following cholecystectomy. Methods  A retrospective cohort study of patients with HIDA scans completed over 21 years at our tertiary care hospital was performed. Demographics, symptomatology, referral patterns, and operative data were collected. HBD was defined as HIDA EF ≥80%. Patients with HBD who underwent cholecystectomy were analyzed. ANOVA and chi-square tests were used to compare variables among patients with or without symptom improvement using Statistical Product and Service Solutions (SPSS; IBM SPSS Statistics for Windows, Armonk, NY). Results Of 1,997 patients (73% female, mean age 51.7 years) who had HIDA scans with reported EF, 730 (36.6%) had an EF≥80%. Only 13.7% of HIDA scans with EF≥80% were reported as hyperkinetic, and the rest are "normal". Cholecystectomy was performed in 57 (7.8%) patients with EF≥80%, most being elective (89.5%) and all minimally invasive. Primary care physicians (PCPs) referred most elective cases to surgery (61.4%). The median time from HIDA to cholecystectomy was 146 days. Chronic cholecystitis was common in pathology (82.5%), while 38.6% had cholelithiasis. Overall, 53 patients (93.0%) reported symptom improvement at a median follow-up of 17.0 days. Patients without improvement had a higher prevalence of chronic gastrointestinal conditions (p<0.05), but not significantly more cholelithiasis, cholecystitis, time to surgery, or elective surgery status. Conclusions HBD is common but often underdiagnosed and thus likely underrecognized by treating physicians. Most HBD patients benefit from cholecystectomy, regardless of cholelithiasis. Patients with persistent symptoms after cholecystectomy may have confounding gastrointestinal diagnoses. Increased awareness among radiologists, referring PCPs, gastroenterologists, and surgeons about HBD and postoperative outcomes is needed to ensure that HBD is adequately treated.

Respiratory Aspects of Primary Ciliary Dyskinesia.

This review article explores the respiratory aspects of primary ciliary dyskinesia (PCD), a rare, heterogenous, genetic disorder characterized by impaired motile ciliary function. It discusses the clinical diagnosis and management strategies for PCD-related respiratory disease, including chronic sinusitis, otitis media with effusion, recurrent pneumonia, and bronchiectasis. The review emphasizes the need for a multidisciplinary approach to optimize care and clinical trials to improve outcomes in individuals with PCD, highlighting the importance of accurate diagnosis.

Validation of Polish-Language Questionnaires for Assessing the Quality of Life of Patients with Primary Ciliary Dyskinesia (PCD-QOL).

In recent years, questionnaires were published in English to assess the quality of life of patients with PCD (Primary Ciliary Diskinesia) for adults, adolescents aged 13-17 years, and children aged 6-12 years and their caregivers. This study aimed to prepare Polish versions of the questionnaires and validate them in specific age groups with the participation of Polish patients with PCD. The individual questionnaires were translated and discussed with the involvement of the creator of the original questionnaire in English. Patients completed the questionnaires according to their affiliation with one of the groups. Validation was based on internal consistency analysis (Cronbach's alpha coefficient and split-half reliability) and test-retest reliability (intraclass correlation coefficient-ICC). The internal consistency of all questionnaires was from moderate to very good (Cronbach's alpha 0.67-0.91, split-half reliability 0.53-0.95). The consistency of the measurements showed excellent repeatability (ICC 0.67-0.91). The surveyed Polish PCD patients rated their quality of life quite well (63-77%). QOL questionnaires for patients with PCD can be used routinely during each medical check-up as a simple tool to provide the doctor with an indication of the effectiveness of treatment and the impact of the disease on the patient's quality of life.

Novel pathogenic variants of DNAH5 associated with clinical and genetic spectra of primary ciliary dyskinesia in an Arab population.

Introduction: Primary ciliary dyskinesia (PCD) is caused by the dysfunction of motile cilia resulting in insufficient mucociliary clearance of the lungs. This study aimed to map novel PCD variants and determine their pathogenicity in PCD patients in Kuwait. Methods: Herein, we present five PCD individuals belonging to a cohort of 105 PCD individuals recruited from different hospitals in Kuwait. Genomic DNAs from the family members were analysed to screen for pathogenic PCD variants. Transmission electron microscopy (TEM) and immunofluorescence (IF) analyses were performed on the nasal biopsies to detect specific structural abnormalities within the ciliated cells. Results: Genetic screening and functional analyses confirmed that the five PCD individuals carried novel pathogenic variants of DNAH5 causing PCD in three Arabic families. Of these, one multiplex family with two affected individuals showed two novel homozygous missense variants in DNAH5 causing PCD with situs inversus; another multiplex family with two affected individuals showed two newly identified compound heterozygous variants in DNAH5 causing PCD with situs solitus. In addition, novel heterozygous variants were identified in a child with PCD and situs solitus from a singleton family with unrelated parents. TEM analysis demonstrated the lack of outer dynein arms (ODAs) in all analysed samples, and IF analysis confirmed the absence of the dynein arm component of DNAH5 from the ciliary axoneme. Conclusion: The newly identified pathogenic variants of DNAH5 are associated with PCD as well as variable pulmonary clinical manifestations in Arabic families.

Genetics of 67 patients of suspected primary ciliary dyskinesia from India.

Data are limited on the genetic profile of primary ciliary dyskinesia (PCD) from developing countries. Here, we report one of the first study on genetic profile of patients with suspected PCD from India. In this prospective cross-sectional study, we enrolled 162 children with suspected PCD. We recorded clinical features, relevant laboratory tests for PCD and performed whole exome sequencing (WES). We are reporting 67 patients here who had positive variant/s on WES. We had 117 variants in 40 genes among 67 patients. Among the 108 unique variants, 33 were categorized as pathogenic or likely pathogenic (P/LP). We had nine novel variants in out cohort. The 29 definite PCD cases, diagnosed by composite reference standards, had variants in 16 genes namely LRRC6/DNAAF11 (5), DNAH5 (3), CCDC39 (3), HYDIN (3), DNAH11 (2), CCDC40 (2), CCDC65 (2) and one each DNAAF3, DNAAF2, CFAP300, RPGR, CCDC103, CCDC114, SPAG1, DNAI1, and DNAH14. To conclude, we identified 108 unique variants in 40 genes among 67 patients. The common genes involved in definite cases of PCD in Indian patients were LRRC6, DNAH5, CCDC39, and HYDIN. Our findings suggest a need to develop a separate genetic panel for PCD in the Indian population.

Efficacy and safety of different pharmacological interventions in the treatment of tardive dyskinesia: a systematic review and network meta-analysis.

OBJECTIVES: The aim of this study is to indirectly compare and rank the different drugs that have been studied in randomized clinical trials (RCTs) in patients with tardive dyskinesia (TD) in terms of their efficacy in ameliorating the symptoms of TD and safety. DESIGN: A network meta-analysis and a systematic review were registered prospectively on PROSPERO under the ID: CRD42023407823 and were conducted in accordance with the PRISMA-NMA guidelines. DATA SOURCES: PubMed, Scopus, The Cochrane Central Register of Controlled Trials (CENTRAL), Web of Sciences, and Clinicaltrials.gov were searched to identify relevant records. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Any parallel randomized blinded controlled clinical trials that studied the use of any medications in treating TD and assessed the symptoms using a functional scale that has been previously validated. DATA EXTRACTION: The standardized mean difference of improvement along with the reported adverse events for each drug was extracted from each trial, and a network meta-analysis was conducted using a random-effects model. RESULTS: One thousand eight hundred seventeen patients in 33 RCTs were included in the analysis. Twenty-three different drugs were compared to placebo in terms of reduction in TD symptoms. Among these, valbenazine 80 mg (SMD = - 1.66, 95%CI = [- 2.55; - 0.78]), valbenazine 40 mg (- 1.00, [- 1.89; - 0.11]), and vitamin E (- 0.77, [- 1.45; - 0.1]) significantly reduced TD symptoms in comparison to placebo, while deutetrabenazine 36 mg (- 1.00, [- 2.12; 0.11]) and reserpine (- 0.54, [- 1.09; 0.02]) did not significantly reduce symptoms. Some serious adverse events were reported for valbenazine and deutetrabenazine, which included mainly psychiatric symptoms such as depression, worsening of schizophrenia, and suicidal ideation, while mild adverse events were reported for other drugs, and their incidence in the treatment arms was comparable to those in the placebo arm. CONCLUSIONS: Valbenazine (80 and 40 mg) and vitamin E demonstrated efficacy in treating tardive dyskinesia. However, the significant side effects of valbenazine should prompt further investigation of alternative treatment modalities.

Prenatal genetic diagnosis of fetuses with dextrocardia using whole exome sequencing in a tertiary center.

To evaluate the genetic etiology of fetal dextrocardia, associated ultrasound anomalies, and perinatal outcomes, we investigated the utility of whole exome sequencing (WES) for prenatal diagnosis of dextrocardia. Fetuses with dextrocardia were prospectively collected between January 2016 and December 2022. Trio-WES was performed on fetuses with dextrocardia, following normal karyotyping and/or chromosomal microarray analysis (CMA) results. A total of 29 fetuses with dextrocardia were collected, including 27 (93.1%) diagnosed with situs inversus totalis and 2 (6.9%) with situs inversus partialis. Cardiac malformations were present in nine cases, extra-cardiac anomalies were found in seven cases, and both cardiac and extra-cardiac malformations were identified in one case. The fetal karyotypes and CMA results of 29 cases were normal. Of the 29 cases with dextrocardia, 15 underwent WES, and the other 14 cases refused. Of the 15 cases that underwent WES, clinically relevant variants were identified in 5/15 (33.3%) cases, including the diagnostic variants DNAH5, DNAH11, LRRC56, PEX10, and ZIC3, which were verified by Sanger sequencing. Of the 10 cases with non-diagnostic results via WES, eight (80%) chose to continue the pregnancies. Of the 29 fetuses with dextrocardia, 10 were terminated during pregnancy, and 19 were live born. Fetal dextrocardia is often accompanied by cardiac and extra-cardiac anomalies, and fetal dextrocardia accompanied by situs inversus is associated with a high risk of primary ciliary dyskinesia. Trio-WES is recommended following normal karyotyping and CMA results because it can improve the diagnostic utility of genetic variants of fetal dextrocardia, accurately predict fetal prognosis, and guide perinatal management and the reproductive decisions of affected families.

Gastroparesis treatment options metoclopramide and prucalopride: analysis of the FDA Adverse Event Reporting System (FAERS) database.

BACKGROUND: We aimed to examine the common adverse drug reactions (ADRs) of metoclopramide, FDA-approved for treating many gastrointestinal conditions including gastroparesis, and prucalopride, FDA-approved for treating chronic idiopathic constipation but used off-label for other gastrointestinal conditions including gastroparesis. RESEARCH DESIGN AND METHODS: The FDA Adverse Event Reporting System (FAERS) was analyzed from January 2013 to December 2023. ADR reports regarding use of only metoclopramide or prucalopride were analyzed following exclusion of reports indicating use for treatment of non-gastrointestinal conditions. RESULTS: Analysis of 1,085 reports on metoclopramide revealed tardive dyskinesia (n = 393, 36.2%) and dystonia (n = 170, 15.7%) among the most reported ADRs in addition to QTc prolongation (n = 16, 1.5%) with progression to Torsade de pointes (n = 5, 0.5%) and triggering of pheochromocytoma crisis (n = 24, 2.2%). Analysis of 865 reports on prucalopride revealed headache (n = 120, 13.9%), diarrhea (n = 116, 13.4%), and abdominal pain (n = 100, 11.6%) as the most common ADRs with 22 reports (2.5%) of dystonia with the use of prucalopride. CONCLUSIONS: This FAERS database analysis shows post-marketing reports of ADRs from metoclopramide most frequently include tardive dyskinesia, dystonia, and tremor in addition to potentially fatal arrhythmias such as Torsade de pointes. Consumers of prucalopride may also be at risk of dystonia and other ADRs.

Excessive firing of dyskinesia-associated striatal direct pathway neurons is gated by dopamine and excitatory synaptic input.

The striatum integrates dopaminergic and glutamatergic inputs to select preferred versus alternative actions. However, the precise mechanisms underlying this process remain unclear. One way to study action selection is to understand how it breaks down in pathological states. Here, we explored the cellular and synaptic mechanisms of levodopa-induced dyskinesia (LID), a complication of Parkinson's disease therapy characterized by involuntary movements. We used an activity-dependent tool (FosTRAP) in conjunction with a mouse model of LID to investigate functionally distinct subsets of striatal direct pathway medium spiny neurons (dMSNs). In vivo, levodopa differentially activates dyskinesia-associated (TRAPed) dMSNs compared to other dMSNs. We found this differential activation of TRAPed dMSNs is likely to be driven by higher dopamine receptor expression, dopamine-dependent excitability, and excitatory input from the motor cortex and thalamus. Together, these findings suggest how the intrinsic and synaptic properties of heterogeneous dMSN subpopulations integrate to support action selection.

The relationship between lung function, exercise capacity, oxidant and antioxidant response in primary ciliary dyskinesia and cystic fibrosis.

BACKGROUND: There is a need to identify the complex interplay between various physiological mechanisms in primary ciliary dyskinesia (PCD) and cystic fibrosis (CF). The study investigated the interaction between respiratory function, exercise capacity, muscle strength, and inflammatory and oxidant/antioxidant responses in patients with PCD and CF. METHODS: The study included 30 PCD patients, 30 CF patients, and 29 age and sex-matched healthy subjects. Exercise capacity was assessed using the modified shuttle walk test (MSWT). Handgrip strength (HGS) was used to evaluate general muscle strength. Oxidative stress-inflammatory parameters were also assessed. Pulmonary function test was performed by spirometry. Regarding the forced expiratory volume in 1 second (FEV1) z-score, patients with PCD and CF were subdivided into normal, mild, and severe/moderate groups. RESULTS: Forced vital capacity (FVC) z-scores were lower in PCD and CF patients than controls. FEV1, FEV1/FVC, peak expiratory flow (PEF), and forced mid expiratory flow (FEF25-75%) z-scores were lower in PCD than in the other groups. HGS was lower in both mild PCD and normal CF patients relative to the controls. MSWT distance was lower in severe/moderate PCD patients than controls. Catalase (CAT), glutathione S-transferase (GST), glutathione peroxidase (GPx), and malondialdehyde (MDA) levels did not differ significantly among the study groups, but superoxide dismutase (SOD) level in severe/moderate PCD, and glutathione (GSH) level in normal CF were higher than in controls. Interleukin-6 (IL-6) level was higher in patients with normal PCD and CF compared to the controls. IL-1ß level was higher in PCD compared to controls. Additionally, correlations among these parameters were also determined in some patient groups. CONCLUSION: Homeostasis related to respiratory function, aerobic performance, muscle strength, inflammatory response, and oxidant/antioxidant balance were affected in PCD and CF. Evaluating these mechanisms together may contribute to elucidating the pathophysiology of these rare diseases.

Levodopa-induced dyskinesia in Parkinson's disease: Insights from cross-cohort prognostic analysis using machine learning.

BACKGROUND: Prolonged levodopa treatment in Parkinson's disease (PD) often leads to motor complications, including levodopa-induced dyskinesia (LID). Despite continuous levodopa treatment, some patients do not develop LID symptoms, even in later stages of the disease. OBJECTIVE: This study explores machine learning (ML) methods using baseline clinical characteristics to predict the development of LID in PD patients over four years, across multiple cohorts. METHODS: Using interpretable ML approaches, we analyzed clinical data from three independent longitudinal PD cohorts (LuxPARK, n = 356; PPMI, n = 484; ICEBERG, n = 113) to develop cross-cohort prognostic models and identify potential predictors for the development of LID. We examined cohort-specific and shared predictive factors, assessing model performance and stability through cross-validation analyses. RESULTS: Consistent cross-validation results for single and multiple cohort analyses highlighted the effectiveness of the ML models and identified baseline clinical characteristics with significant predictive value for the LID prognosis in PD. Predictors positively correlated with LID include axial symptoms, freezing of gait, and rigidity in the lower extremities. Conversely, the risk of developing LID was inversely associated with the occurrence of resting tremors, higher body weight, later onset of PD, and visuospatial abilities. CONCLUSIONS: This study presents interpretable ML models for dyskinesia prognosis with significant predictive power in cross-cohort analyses. The models may pave the way for proactive interventions against dyskinesia in PD by optimizing levodopa dosing regimens and adjunct treatments with dopamine agonists or MAO-B inhibitors, and by employing non-pharmacological interventions such as dietary adjustments affecting levodopa absorption for high-risk LID patients.