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ELife Apr 2020Transient Receptor Potential Melastatin 3 (TRPM3) is a Ca permeable non-selective cation channel activated by heat and chemical agonists such as pregnenolone sulfate and...
Transient Receptor Potential Melastatin 3 (TRPM3) is a Ca permeable non-selective cation channel activated by heat and chemical agonists such as pregnenolone sulfate and CIM0216. TRPM3 mutations in humans were recently reported to be associated with intellectual disability and epilepsy; the functional effects of those mutations, however, were not reported. Here, we show that both disease-associated mutations in the human TRPM3 render the channel overactive, but likely via different mechanisms. The Val to Met substitution in the S4-S5 loop induced a larger increase in basal activity and agonist sensitivity at room temperature than the Pro to Gln substitution in the extracellular segment of S6. In contrast, heat activation was increased more by the S6 mutant than by the S4-S5 segment mutant. Both mutants were inhibited by the TRPM3 antagonist primidone, suggesting a potential therapeutic intervention to treat this disease.
Topics: Calcium; Cells, Cultured; Ganglia, Spinal; HEK293 Cells; Humans; Mutation; Pregnenolone; TRPM Cation Channels
PubMed: 32343227
DOI: 10.7554/eLife.55634 -
Journal of Veterinary Internal Medicine Jan 2022Orthostatic tremor (OT) is a rare movement disorder characterized by high-frequency (>12 Hz) involuntary, rhythmic, sinusoidal movements affecting predominantly the...
BACKGROUND
Orthostatic tremor (OT) is a rare movement disorder characterized by high-frequency (>12 Hz) involuntary, rhythmic, sinusoidal movements affecting predominantly the limbs while standing.
OBJECTIVE
To describe the signalment, presenting complaints, phenotype, diagnostic findings, treatment, and outcome of a large sample of dogs with OT.
ANIMALS
Sixty dogs diagnosed with OT based on conscious electromyography.
METHODS
Multicenter retrospective case series study. Dogs were included if they had a conscious electromyography consistent with muscle discharge frequency >12 Hz while standing.
RESULTS
Fifty-three cases were diagnosed with primary OT (POT). Giant breed dogs represented most cases (83%; 44/53). Most dogs (79%; 42/53) were younger than 2 years of age at onset of signs, except for Retrievers which were all older than 3.5 years of age. The most common presenting complaints were pelvic limb tremors while standing (85%; 45/53) and difficulty when rising or sitting down (45%; 24/53). Improvement of clinical signs occurred in most dogs (85%; 45/53) treated medically with phenobarbital, primidone, gabapentin, pregabalin or clonazepam, but it was mostly partial rather than complete. Orthostatic tremor-plus was seen in 7 dogs that had concurrent neurological diseases.
CONCLUSIONS AND CLINICAL IMPORTANCE
Primary OT is a progressive disease of young, purebred, giant/large-breed dogs, which appears to begin later in life in Retrievers. Primary OT apparently responds partially to medications. Orthostatic tremor-plus exists in dogs and can be concomitant or associated with other neurological diseases.
Topics: Animals; Dizziness; Dog Diseases; Dogs; Electromyography; Retrospective Studies; Tremor
PubMed: 34897811
DOI: 10.1111/jvim.16328 -
Environmental Pollution (Barking, Essex... Oct 2022The presence of contaminants of emerging concern in the aquatic environment directly impacts water-living organisms and can alter their living functions. These compounds...
Prioritization based on risk assessment to study the bioconcentration and biotransformation of pharmaceuticals in glass eels (Anguilla anguilla) from the Adour estuary (Basque Country, France).
The presence of contaminants of emerging concern in the aquatic environment directly impacts water-living organisms and can alter their living functions. These compounds are often metabolized and excreted, but they can also be accumulated and spread through the food chain. The metabolized contaminants can also lead to the formation of new compounds with unknown toxicity and bioaccumulation potential. In this work, we have studied the occurrence, bioconcentration, and biotransformation of CECs in glass eels (Anguilla anguilla) using UHPLC-HRMS. To select the target CECs, we first carried out an environmental risk assessment of the WWTP effluent that releases directly into the Adour estuary (Bayonne, Basque Country, France). The risk quotients of every detected contaminant were calculated and three ecotoxicologically relevant contaminants were chosen to perform the exposure experiment: propranolol, diazepam, and irbesartan. An experiment of 14 days consisting of 7 days of exposure and 7 days of depuration was carried out to measure the bioconcentration of the chosen compounds. The quantitative results of the concentrations in glass eel showed that diazepam and irbesartan reached BCF ≈10 on day 7, but both compounds were eliminated after 7 days of depuration. On the other hand, propranolol's concentration remains constant all along with the experiment, and its presence can be detected even in the non-exposed control group, which might suggest environmental contamination. Two additional suspect screening strategies were used to identify metabolization products of the target compounds and other xenobiotics already present in wild glass eels. Only one metabolite was identified, nordiazepam, a well-known diazepam metabolite, probably due to the low metabolic rate of glass eels at this stage. The xenobiotic screening confirmed the presence of more xenobiotics in wild glass eels, prominent among them, the pharmaceuticals exemestane, primidone, iloprost, and norethandrolone.
Topics: Anguilla; Animals; Bioaccumulation; Biotransformation; Diazepam; Eels; Estuaries; Irbesartan; Pharmaceutical Preparations; Propranolol; Risk Assessment; Spain; Water Pollutants, Chemical
PubMed: 36007789
DOI: 10.1016/j.envpol.2022.120016 -
Clinical Epidemiology 2021To determine the risk of hip fracture in persons with Alzheimer´s disease (AD) who initiated antiepileptic drugs (AEDs).
OBJECTIVE
To determine the risk of hip fracture in persons with Alzheimer´s disease (AD) who initiated antiepileptic drugs (AEDs).
METHODS
In the Medication use and AD (MEDALZ) cohort of 70,719 Finnish community dwellers with clinically verified incident AD diagnosis in 2005-2011, we identified all incident users of AEDs using national Prescription register. AEDs were classified as older (valproate, carbamazepine, clonazepam, phenytoin, levetiracetam, primidone) or newer (pregabalin, gabapentin, oxcarbazepine, lamotrigine, topiramate). We matched each user to 2 non-users. Incident hip fractures until 2015 were identified from the Care register for health care. We calculated inverse probability of treatment weighted hazard ratios (HR), with 95% confidence intervals, using Cox regression.
RESULTS
Altogether 5522 incident users were identified and matched to 11,044 non-users (in both groups, women: 65%; median age: 81 years). Altogether 53.3% of users initiated with newer AEDs (pregabalin 79.8%, gabapentin 10.2%) while 46.7% initiated with older AEDs (valproate 67.6%, carbamazepine 13.0%). Age- and sex-adjusted IR of hip fracture per 100 person-years was 1.8 (95% CI 1.6-1.9) in non-users and 2.0 (95% CI 1.8-2.2) in users. Increased risk of hip fracture was observed in users (HR 1.17, 95% CI 1.05-1.30) compared with non-users. The risk was higher for short duration of use (<14 weeks, HR 3.64, 95% CI 2.90-4.58) than for medium duration (14 to <64 weeks, HR 1.74, 95% CI 1.48-2.05) or ≥64 weeks' use (HR 1.23, 95% CI 1.08-1.40), compared to non-users with same follow-up time. Older AEDs had HR of 1.46 (1.03-2.08) compared with newer AEDs.
CONCLUSION
Our results imply that AED use is associated with an increased risk of hip fracture in people with AD. These findings prompt careful consideration before prescribing AEDs to persons with AD. Persons with AD treated with antiepileptics should be carefully monitored due to their increased risk of falling and fractures.
PubMed: 33911901
DOI: 10.2147/CLEP.S278306 -
Molecules (Basel, Switzerland) Nov 2023The objective of the present report was to develop and validate a simple, selective, and reproducible high-performance liquid chromatography method with UV detection...
The objective of the present report was to develop and validate a simple, selective, and reproducible high-performance liquid chromatography method with UV detection suitable for routine therapeutic drug monitoring of the most commonly used antiepileptic drugs and some of their metabolites. Simple precipitation of plasma proteins with acetonitrile was used for sample preparation. 10,11-dihydrocarbamazepine was used as an internal standard. Chromatographic separation of the analytes was achieved by gradient elution on a Phenyl-Hexyl column at 40 °C, using methanol and potassium phosphate buffer (25 mM; pH 5.1) as a mobile phase. The method was validated according to the FDA guidelines for bioanalytical method validation. It showed to be selective, accurate, precise, and linear over the concentration ranges of 1-50 mg/L for phenobarbital, phenytoin, levetiracetam, rufinamide, zonisamide, and lacosamide; 0.5-50 mg/L for lamotrigine, primidone, carbamazepine and 10-monohydroxycarbazepine; 0.2-10 mg/L for carbamazepine metabolites: 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine and carbamazepine-10,11-epoxide; 0.1-10 mg/L for oxcarbazepine; 2-100 mg/L for felbamate and 3-150 mg/L for ethosuximide. The suitability of the validated method for routine therapeutic drug monitoring was confirmed by quantification of the analytes in plasma samples from patients with epilepsy on combination antiepileptic therapy.
Topics: Humans; Anticonvulsants; Chromatography, High Pressure Liquid; Drug Monitoring; Carbamazepine; Oxcarbazepine
PubMed: 38067559
DOI: 10.3390/molecules28237830 -
SAGE Open Medical Case Reports 2023Canavan disease is a rare fetal inherited leukodystrophy, caused by accumulation of N-acetyl-aspartate in the brain. Here, we report a child presented with frequent...
Canavan disease is a rare fetal inherited leukodystrophy, caused by accumulation of N-acetyl-aspartate in the brain. Here, we report a child presented with frequent intractable seizures and visual impairment. A 14-month-old female infant with a complaint of the absence of neck holding and generalized tonic-clonic seizures was referred to our hospital. Macrocephaly, setting sun eyes, tremor, and hypotonia were observed. Funduscopy showed optic atrophy. Our patient's flash visual evoked potential showed blindness. Her brain magnetic resonance imaging showed diffuse white matter in subcortical, basal ganglia, and dorsal pons. Electroencephalography showed diffuse slow and sharp waves. The genetic study detected a hemizygous mutation in the aspartoacylase gene. Our patient was diagnosed with Canavan disease and began anticonvulsant treatment. However, seizures were not under control. Then, her medications were discontinued, and clobazam and primidone were administered. In conclusion, starting clobazam and primidone may help prevent frequently intractable seizures in Canavan disease patients.
PubMed: 36968992
DOI: 10.1177/2050313X231160885 -
Neurology Jun 2023A 66-year-old man with seizures that started at 61 years eventually developed drug-resistant epilepsy and was managed with medications and vagal nerve stimulation. The...
A 66-year-old man with seizures that started at 61 years eventually developed drug-resistant epilepsy and was managed with medications and vagal nerve stimulation. The patient had a convulsive event at 61 years, followed by recurrent events of confusion and speech arrest lasting 30-120 seconds. He underwent gadolinium-enhanced brain MRI and angiogram, which revealed pial enhancement in the right occipital, parietal, and posterior temporal regions with subcortical atrophy. CSF findings were unremarkable. Continuous video EEG showed electroclinical correlation for his episodes of confusion and speech arrest with recurrent brief runs of rhythmic delta from the right temporal region with evolution and spread to the entire right hemisphere. The patient tried multiple antiseizure medications including valproic acid, topiramate, phenytoin, carbamazepine, levetiracetam, brivaracetam, and lamotrigine without success. He was eventually put on a combination of lacosamide, zonisamide, clonazepam, and primidone, which helped to a certain extent, but the patient continued to have daily episodes and 10-12 electroclinical seizures noted on a follow-up 24-hour ambulatory EEG. Follow-up brain MRI with contrast confirmed the diagnosis. Phase II intracranial monitoring for surgical management was offered to the patient, which he deferred because of risks. Vagal nerve stimulator (VNS) was also offered as a palliative therapy to which the patient agreed. Gradual titration in VNS settings over 1 year helped to achieve seizure freedom. Presentation of focal seizure with this type of atypical etiology is rare. Typically, surgical management is used to achieve seizure freedom in this condition; successful management with VNS has not been reported so often.
Topics: Male; Humans; Middle Aged; Aged; Drug Resistant Epilepsy; Seizures; Vagus Nerve Stimulation; Brain; Clinical Reasoning; Treatment Outcome
PubMed: 36792377
DOI: 10.1212/WNL.0000000000206890 -
Scientific Reports Feb 2021Trace organic compounds (TrOCs) enter rivers with discharge of treated wastewater. These effluents can contain high loads of dissolved organic matter (DOM). In a 48 h...
Trace organic compounds (TrOCs) enter rivers with discharge of treated wastewater. These effluents can contain high loads of dissolved organic matter (DOM). In a 48 h field study, we investigated changes in molecular composition of seven DOM compound classes (FTICR-MS) and attenuation of 17 polar TrOCs in a small urban stream receiving treated wastewater. Correlations between TrOCs and DOM were used to identify simultaneous changes in surface water and the hyporheic zone. Changes in TrOC concentrations in surface water ranged between a decrease of 29.2% for methylbenzotriazole and an increase of 152.2% for the transformation product gabapentin-lactam. In the hyporheic zone, only decreasing TrOC concentrations were observed, ranging from 4.9% for primidone to 93.8% for venlafaxine . TrOC attenuation coincided with a decline of molecular diversity of easily biodegradable DOM compound classes while molecular diversity of poorly biodegradable DOM compound classes increased. This concurrence indicates similar or linked attenuation pathways for biodegradable DOM and TrOCs. Strong correlations between TrOCs and DOM compound classes as well as high attenuation of TrOCs primarily occurred in the hyporheic zone. This suggests high potential for DOM turnover and TrOC mitigation in rivers if hyporheic exchange is sufficient.
PubMed: 33603043
DOI: 10.1038/s41598-021-83750-8 -
Cureus Apr 2024Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder that presents with acute to subacute onset of unilateral progressive optic neuropathy, with...
Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder that presents with acute to subacute onset of unilateral progressive optic neuropathy, with sequential involvement of the fellow eye months to years later. The condition may be accompanied by neurological symptoms, including tremors, dystonia, seizures, or psychosis, in which case, it is termed LHON-plus. Here, we present the case of a 53-year-old man who was initially diagnosed with essential tremor but was later found to have LHON-plus after the onset of bilateral visual loss and a genetic panel. His essential tremor was refractory to standard pharmacological therapies, including propranolol, primidone, and topiramate. As a result, he elected to undergo bilateral deep brain stimulation (DBS) of the bilateral ventral intermediate nucleus of the thalamus with a dramatic improvement in symptoms. To our knowledge, this is the first case of essential tremor presenting in the context of LHON-plus to be treated successfully with DBS. While DBS has been applied in LHON-plus presenting with dystonia with limited success, our outcome suggests that there is promise in this approach and that more research is needed to evaluate it.
PubMed: 38756271
DOI: 10.7759/cureus.58255 -
Therapie 2020Pitch perception modifications are among the little-known adverse effects observed with antiepileptics, mainly affecting patients treated with carbamazepine (CBZ). Here,...
Pitch perception modifications are among the little-known adverse effects observed with antiepileptics, mainly affecting patients treated with carbamazepine (CBZ). Here, we describe an original French case of pitch perception modification due to CBZ resulting in perfect pitch loss. We also reviewed the literature as well as French and world health organisation global pharmacovigilance database. The case report concerns a 22-year-old patient with perfect pitch with untreated left temporal partial epilepsy. Following a generalized seizure, the introduction of CBZ prolonged release (200mg twice a day) is decided. As soon as CBZ is introduced, the patient notices a change in pitch perception, about a semitone lower. This adverse effect persisted despite a gradual decrease in doses. The patient reported a total recovery of his perfect pitch when CBZ stopped completely 11 years later. In the French pharmacovigilance database, only one other case of pitch perception modification under CBZ was recorded (no cases were found with oxcarbazepine, lacosamide, sodium valproate, lamotrigine, levetiracetam, phenobarbital, phenytoin, primidone, ethosuximide, vigabatrine, felbamate, gabapentin, tiagabine and topiramate). In the literature, 27 cases of pitch perception modification have been published with CBZ, 1 case with oxcarbazepine and 1 case with lacosamide. Pitch perception modification is a very rare adverse effect of CBZ, oxcarbazepine and lacosamide, identified in the literature mainly in the Japanese population, in experienced musicians. A rapid onset after the introduction of treatment, a complete resolution of symptoms, in most cases upon discontinuation of treatment, is observed, with no sequelae reported. Due to the impact on quality of life, especially in patients whose profession is related to music, knowledge of this adverse event seems important to evoke this diagnosis.
Topics: Adult; Anticonvulsants; Epilepsy; Humans; Pharmacovigilance; Pitch Perception; Quality of Life; Young Adult
PubMed: 32204934
DOI: 10.1016/j.therap.2020.02.017