Lacosamide-induced sinus node dysfunction followed by severe agranulocytosis.

BACKGROUND: Lacosamide (LCM) is the antiepileptic drug approved by the U.S. Food and Drug Administration in 2008 that facilitates slow activation of the voltage-gated sodium channels. Neutropenia and cardiac events including sinus node dysfunction (SND) and atrioventricular block have been previously reported as adverse effects of LCM. To date, there have been no reports of severe agranulocytosis resulting in death associated with LCM. Additionally, there have been no reports of concomitant SND and agranulocytosis after LCM administration. Herein we report the first case of LCM-induced severe SND followed by agranulocytosis. CASE PRESENTATION: The patient with focal epilepsy was initiated on LCM 100 mg/day and the dose was increased to 200 mg/day on the 9th hospital day. Severe SND developed on the 10th hospital day and LCM was discontinued. Thereafter agranulocytosis appeared on the 11th hospital day, and the patient died from septic shock on the 15th hospital day. CONCLUSIONS: This case illustrates the need for careful follow-up of the electrocardiogram and the complete blood cell counts when initiating LCM. Moreover, it should be noticed that various side effects may occur simultaneously in the early period of LCM use, even for a short time and at low dosages.

Orally active ghrelin receptor inverse agonists and their actions on a rat obesity model.

A series of 2-alkylamino nicotinamide analogs was prepared as orally active ghrelin receptor (ghrelinR) inverse agonists. Starting from compound 1, oral bioavailability was improved by modifying metabolically unstable sites and reducing molecular weight. Brain-permeable compound 33 and compound 24 with low brain permeability were tested in rat models of obesity; 30 mg/kg of compound 33 suppressed weight gain. PK/PD analysis revealed that the anti-obesity effect of ghrelinR inverse agonists depends on their brain concentrations.

Structural Optimization of Ghrelin Receptor Inverse Agonists to Improve Lipophilicity and Avoid Mechanism-Based CYP3A4 Inactivation.

Structural optimization of 2-aminonicotinamide derivatives as ghrelin receptor inverse agonists is reported. So as to avoid mechanism-based inactivation (MBI) of CYP3A4, 1,3-benzodioxol ring of the lead compound was modified. Improvement of the main activity and lipophilicity was achieved simultaneously, leading to compound 18a, which showed high lipophilic ligand efficiency (LLE) and low MBI activity.

Role of complement activation and disruption of the blood-brain barrier in the pathogenesis of multiple system atrophy.

Multiple system atrophy (MSA) is a progressive and sporadic neurodegenerative disorder characterized by the histological appearance of glial cytoplasmic inclusions primarily composed of α-synuclein. Recently, complement-mediated neuroinflammation has been proposed as a key factor in the pathogenesis of numerous neurodegenerative disorders. We conducted immunohistochemical/immunofluorescent assays targeting a number of complements to explore the role of complements in MSA pathogenesis using brain samples from deceased patients and controls. Complement deposition was notably increased in the cerebral vasculature and myelin sheath in the MSA brains. Furthermore, fibrinogen leakage resulting from the disruption of the blood-brain barrier (BBB) was observed, along with the presence of C1q-positive microglia clusters surrounding the MSA brain vessels. These immunohistochemical/immunofluorescent findings suggest that complement activation and BBB disruption play critical roles in MSA progression.

Detection of foaling using a tail-attached device with a thermistor and tri-axial accelerometer in pregnant mares.

It is desirable to attend to the mare at the time of foaling in order to assist fetal delivery and prevent complications. The early detection of the onset of labor is an important issue for the equine industry. The purpose of this study was to examine the applicability of a sensor for foaling detection using the data of surface temperature (ST), roll angle (rotation about the y-axis) and y-axis (long axis of the tail) acceleration which were collected from a multimodal device attached to the ventral tail base of the mare. The data were collected every 3 minutes in 17 pregnant mares. Roll angle differences from the reference values and the mare's posture (standing or recumbent) confirmed by video were compared and associated. Cohen's kappa coefficient was 0.99 when the threshold was set as ± 0.3 radian in roll angle differences. This result clearly showed that the sensor data can accurately distinguish between standing and recumbent postures. The hourly sensor data with a lower ST (LST < 35.5°C), a recumbent posture determined by the roll angle, and tail-raising (TR, decline of 200 mg or more from the reference value in y-axis acceleration) was significantly higher during the last hour prepartum than 2-120 hours before parturition (P < 0.01). The accuracy of foaling detection within one hour was verified using the following three indicators: LST; lying down (LD, change from standing to recumbent posture); and TR. When LST, LD and TR were individually examined, even though all indicators showed that sensitivity was 100%, the precision was 13.1%, 8.1% and 2.8%, respectively. When the data were combined as LST+LD, LST+TR, LD+TR and LST+LD+TR, detection of foaling improved, with precisions of 100%, 32.1%, 56.7% and 100%, respectively. In conclusion, the tail-attached multimodal device examined in this present study is useful for detecting foaling.

Striatal dopamine transporter binding differs between dementia with Lewy bodies and Parkinson's disease with dementia.

123I-ioflupane single-photon emission computed tomography (SPECT) is a highly sensitive and established neuroimaging technique for parkinsonian syndromes (PS). However, differentiating PS by visual inspection or analysis of regions of interest is challenging. To date, image analysis has not been able to differentiate dementia with Lewy bodies (DLB) from Parkinson's disease with dementia (PDD). This study aimed to differentiate PS based on the characteristics of striatal dopamine transporter (DAT) binding using voxel-based analysis. We acquired 123I-ioflupane SPECT data from patients with DLB (n = 30), Parkinson's disease (PD; n = 122), PDD (n = 19), multiple system atrophy with predominant parkinsonism (MSA-P; n = 18), and progressive supranuclear palsy (PSP; n = 45). DAT binding was reduced in the posterior striatum of patients with PD and PDD, whereas it was similar in MSA-P, PSP, and DLB. Hippocampal atrophy, visually evaluated by cerebral magnetic resonance imaging, did not affect striatal DAT binding in DLB. DAT binding in the anterior striatum was inversely correlated with the severity of parkinsonism in PD and PDD but not in DLB. Thus, the appearance of striatal DAT binding might indicate different pathological processes in DLB and PDD.

Vanishing tumefactive ANCA-associated hypertrophic pachymeningitis: A case report.

We report a case of a 59-year-old man with hypertrophic pachymeningitis (HP), initially presenting as a tumefactive lesion that disappeared spontaneously. He developed headache and left abducens nerve palsy 2 years before admission, and cerebral magnetic resonance imaging (MRI) revealed a round mass lesion. Meningioma was initially considered, but the lesion disappeared spontaneously along with the symptoms. However, 6 months before admission, left abducens nerve palsy reappeared. Repeated MRI revealed multiple intracranial tumefactive lesions. HP was diagnosed based on the pathological analysis of the biopsied specimen. HP can appear as a vanishing tumor, and pathological evaluation is essential for a precise diagnosis. If spontaneous disappearance of tumefactive intracranial lesions is encountered, the possibility of HP should be considered.

Sibling Cases of Charcot-Marie-Tooth Disease Type 4H with a Homozygous FGD4 Mutation and Cauda Equina Thickening.

Charcot-Marie-Tooth disease type 4H (CMT4H) is an autosomal recessive inherited demyelinating neuropathy caused by an FYVE, RhoGEF, and a PH domain-containing protein 4 (FGD4) gene mutation. CMT4H is characterized by an early onset, slow progression, scoliosis, distal muscle atrophy, and foot deformities. We herein present sibling cases of CMT4H with a homozygous mutation in the FGD4 gene. Both patients exhibited cauda equina thickening on magnetic resonance imaging, which had not been reported among the previous CMT4H cases. This is the first report of CMT4H with a homozygous FGD4 c.1730G>A (p.Arg577Gln) mutation showing mild progression and cauda equina thickening.

Neurogenic calf amyotrophy with CK elevation by entrapment radiculopathy; clinical, radiological, and pathological analyses of 18 cases.

OBJECTIVE: To characterize the clinical, radiological, and pathological manifestations of 18 cases showing neurogenic calf amyotrophy with creatine kinase (CK) elevation by entrapment radiculopathy (NCACKEER). METHODS: We retrospectively reviewed and evaluated the medical records of patients who complained of weakness or atrophy of the calf muscles in our department between 2004 and 2019. We identified 18 cases fulfilling the proposed criteria of NCACKEER. We extracted neurological, laboratory, neurophysiological, and neuroradiological data from all cases. Moreover, we evaluated biopsy specimens from the gastrocnemius in four cases. RESULTS: Eighteen NCACKEER cases exhibited the characteristic findings that can discriminate previously known myopathies or polyneuropathies affecting distal legs. We noticed male predominance (72%) with an average age at diagnosis of 65.6 years. Muscle weakness or atrophy was localized in the distal legs, with Achilles tendon reflexes absent in all cases. We observed elevated serum CK levels with a range from 237 to 2294 IU/L. All electromyography (EMG) studies showed neurogenic changes in the affected muscles. Lumbar spinal MRI exhibited either spinal canal stenosis at various vertebral levels or intervertebral foraminal stenosis at L4/5 and L5/S1 in all cases with significant straightening spinal and sacral alignments. All muscle biopsy specimens showed findings of neurogenic muscular degeneration with no inflammatory infiltrations. Cases with higher CK elevation had more necrotic muscle fibers. CONCLUSION: We established the clinical characteristics of NCACKEER. Evaluations of serum CK level and skeletal muscle CT imaging are useful for screening, and lumbar spinal MRI, EMG and/or muscle biopsy are necessary for diagnostic confirmation.

Forest understories controlled the soil organic carbon stock during the fallow period in African tropical forest: a 13C analysis.

Soil organic carbon (SOC) dynamics after slash-burn agriculture are poorly understood in African tropical forest, though recent studies have revealed C4 grass invasion as a forest understory influences SOC dynamics after deforestation. This study aimed to quantify the relative SOC contribution of C4 and C3 plants separately through the sequential fallow periods of forest (cropland, or 4-7, 20-30, or >50 years of fallow forest) in the tropical forest of eastern Cameroon. We evaluated the SOC stock and natural 13C abundance for each layer. The SOC stock was largest in 4-7 years fallow forest (136.6 ± 8.8 Mg C ha-1; 100 cm depth, and C4:C3 = 58:42), and decreased with increasing fallow period. SOC from C4 plants was larger in the 4-7 and 20-30 years fallow forests (57.2-60.4 ± 5.8 Mg C ha-1; 100 cm depth), while it clearly decreased in >50 years fallow forest (35.0 ± 4.1 Mg C ha-1; 100 cm depth), resulting in the smallest SOC in this mature forest (106.4 ± 12.9 Mg C ha-1; 100 cm depth). These findings indicate that C4 grass understories contributed to the SOC restoration during early fallow succession in the tropical forest of eastern Cameroon.

[Charcot-Marie-Tooth disease showing transient central nervous system lesions after a large amount of alcohol intake: A case report].

A 23-year-old man experienced numbness in the perioral region and right arm, and right leg weakness on the second day after drinking a large amount of alcohol during foreign travel. His symptoms disappeared but then reappeared repetitively. Cerebral MRI performed on the third day after onset showed multiple white matter lesions; however, these lesions disappeared 26 days after onset. Neurological examination and nerve conduction studies revealed demyelinating polyneuropathy. Genetic testing for Charcot-Marie-Tooth disease, X-linked dominant 1 (CMTX1) due to GJB1 mutation was conducted based on the symptoms of transient central nervous system lesions and polyneuropathy exhibited by the patient and his mother. As a result, a c.530T>C (p.V177A) substitution in exon 2 of GJB1 was identified. CMTX1 patients should be advised to avoid excessive drinking because this could induce central nervous system lesions.

Royal jelly supplementation improves lipoprotein metabolism in humans.

Royal jelly (RJ) has several physiological effects and is widely used in commercial medical products and health foods. We examined the effects of RJ supplementation on serum lipoprotein metabolism in humans. Fifteen volunteers were divided into an RJ intake group (n=7) and a control group (n=8). The RJ group took 6 g per day for 4 wk. Their serum total cholesterol (TC) and serum low-density lipoprotein (LDL) decreased significantly compared with those of the control group (p<0.05). There were no significant differences in serum high-density lipoprotein (HDL) or triglyceride concentrations. Moreover, the relationship between the serum cholesterol and lipoprotein levels was investigated. Among the lipoprotein fractions, small very-low-density lipoprotein was decreased (p<0.05) after RJ intake. Our results suggest that dietary RJ decreases TC and LDL by lowering small VLDL levels.

Symbiotic N 2 -Fixation Estimated by the (15) N Tracer Technique and Growth of Pueraria phaseoloides (Roxb.) Benth. Inoculated with Bradyrhizobium Strain in Field Conditions.

This field experiment was established in Eastern Cameroon to examine the effect of selected rhizobial inoculation on N2-fixation and growth of Pueraria phaseoloides. Treatments consisted of noninoculated and Bradyrhizobium yuanmingense S3-4-inoculated Pueraria with three replications each. Ipomoea batatas as a non-N2-fixing reference was interspersed in each Pueraria plot. All the twelve plots received 2 gN/m(2) of (15)N ammonium sulfate 10% atom excess. At harvest, dry matter yields and the nitrogen derived from atmospheric N2-fixation (%Ndfa) of inoculated Pueraria were significantly (P < 0.05) higher (81% and 10.83%, resp.) than those of noninoculated Pueraria. The inoculation enhanced nodule dry weight 2.44-fold. Consequently, the harvested N significantly (P < 0.05) increased by 83% in inoculated Pueraria, resulting from the increase in N2-fixation and soil N uptake. A loss of 55 to 60% of the N fertilizer was reported, and 36 to 40% of it was immobilized in soil. Here, we demonstrated that both N2-fixing potential of P. phaseoloides and soil N uptake are improved through field inoculations using efficient bradyrhizobial species. In practice, the inoculation contributes to maximize N input in soils by the cover crop's biomass and represent a good strategy to improve soil fertility for subsequent cultivation.

Anti-Hu Antibody-associated Paraneoplastic Neurological Syndrome Showing Peripheral Neuropathy and Atypical Multifocal Brain Lesions.

A 64-year-old Japanese woman presented with a three-month history of progressive numbness and weakness of the lower extremities. A neurological examination and nerve conduction study indicated sensorimotor polyneuropathy. Since the serum anti-Hu antibody titer was remarkably elevated, paraneoplastic neurological syndrome was highly suspected. A thoracoscopic biopsy of the hilar lymph nodes, in which (18)F-fluorodeoxyglucose uptake was obviously increased, revealed pathological findings for small-cell lung cancer (SCLC). Subsequently, the patient presented with generalized tonic-clonic seizures, and cerebral MRI showed reversible multifocal brain lesions, considered to reflect paraneoplastic encephalopathy. After two courses of chemotherapy for SCLC, the brain lesions totally disappeared.

Anti-MuSK Antibody-positive Myasthenia Gravis Mimicking Amyotrophic Lateral Sclerosis.

We herein investigated the clinical features of three patients with anti-muscle-specific tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG), which was initially difficult to distinguish from amyotrophic lateral sclerosis (ALS). The patients exhibited dropped head syndrome or dysphagia as initial symptoms. Although their clinical findings were compatible with the revised El Escorial Criteria for ALS, their progression appeared to be more rapid than that of ALS. Both the edrophonium and repetitive nerve stimulation tests yielded negative results, and diurnal fluctuation was not confirmed. The patients were ultimately diagnosed with anti-MuSK antibody-positive MG. We therefore recommend the measurement of anti-MuSK antibodies when encountering such cases.

Synthesis, SAR studies, and evaluation of 1,4-benzoxazepine derivatives as selective 5-HT1A receptor agonists with neuroprotective effect: Discovery of Piclozotan.

A new series of 1,4-benzoxazepine derivatives was designed, synthesized, and evaluated for binding to 5-HT1A receptor and cerebral anti-ischemic effect. A lot of compounds exhibited nanomolar affinity for 5-HT1A receptor with good selectivity over both dopamine D2 and alpha1-adrenergic receptors. Among these compounds, 3-chloro-4-[4-[4-(2-pyridinyl)-1,2,3,6-tetrahydropyridin-1-yl]butyl]-1, 4-benzoxazepin-5(4H)-one (50: SUN N4057 (Piclozotan) as 2HCl salt) showed remarkable neuroprotective activity in a transient middle cerebral artery occlusion (t-MCAO) model.