Search

Background Achondroplasia (ACH), the most common form of short‐limbed skeletal dysplasia, is caused by gain‐of‐function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. More than 97% of patients result from a heterozygous p.G380R mutation in the FGFR3 gene. We present here a child who had two de novo variants in the FGFR3 on the same allele, a common p.G380R mutation and a novel p.S378N variant. Methods A 3‐year‐old Japanese girl born from non‐consanguineous healthy parents showed more severe clinical and radiological phenotypes than classic ACH, including severe short‐limbed short stature with marked ossification defects in the metaphysis and epiphysis, hydrocephalus and cervicomedullary compression due to foramen magnum stenosis, prolonged pulmonary hypoplasia, and significant delay in the gross motor development. Genomic DNA was extracted from the proband and whole‐exome sequencing was performed. The variants were subsequently confirmed by Sanger sequencing. Results Mutation analysis demonstrated that the proband had p.S378N (c.1133G>A) and p.G380R (c.1138G>A) variants in the FGFR3 gene. Both variants were not detected in her parents and therefore considered de novo. An allele‐specific PCR was developed in order to determine whether these mutations were on the same allele (cis) or on different alleles (trans). The c.1138G>A mutation was found in the PCR product generated with the primer for the mutant 1133A, but it was not detected in the product with the wild‐type 1133G, confirming that p.S378N and p.G380R variants were located on the same allele (cis). Conclusion This is the second case who had two FGFR3 variants in the transmembrane domain on the same allele. The p.S378N variant may provide an additive effect on the activating receptor with the p.G380R mutation and alter the protein function, which could be responsible for the severe phenotype of the present case., We present a case who had two de novo variants in the FGFR3 on the same allele, a common p.G380R mutation and a novel p.S378N variant. The p.S378N variant may provide an additive effect on the activating receptor with the p.G380R mutation and alter the protein function, which could be responsible for severe phenotype of the present case.

Background Achondroplasia (ACH) and hypochondroplasia (HCH) are the most common form of short-limb skeletal dysplasias caused by activated fibroblast growth factor receptor 3 (FGFR3) signaling. Although decreased bone mass was reported in gain-of-function mutation in Fgfr3 mice, both disorders have never been described as osteoporotic. In the present study, we evaluated bone mineral density (BMD) in ACH and HCH patients. Methods We measured spinal BMD (L1-L4) in 18 ACH and four HCH patients with an average age of 19.8 ± 7.5 years (range, 10-33 years). BMD Z-score in each individual was calculated for normalizing age and gender. Correlation between body mass index (BMI) and BMD was analyzed. Moreover, BMD and Z-score were compared between ACH patients and HCH patients. Results The average BMD of ACH/HCH patients was 0.805 ± 0.141 g/cm(2) (range, 0.554-1.056 g/cm(2) ), resulting in an average Z-score of -1.1 ± 0.8 (range, -2.4 to 0.6) of the standard value. A slightly positive correlation was observed between BMI and BMD (r = 0.45; P = 0.13). There was no significant difference in BMD and Z-score between ACH and HCH patients. Conclusion Spinal BMD was reduced in ACH/HCH patients, and was mildly correlated with individual BMI. We should carefully monitor BMD and examine osteoporosis-related symptoms in adolescent and adult ACH/HCH patients. © 2016 Japan Pediatric Society.

Aim: Symptoms of dementia are classified into cognitive dysfunction and behavioral and psychological symptoms of dementia, including sleep disturbance. Yokukansan (YKS) is effective for sleep disturbance in patients with dementia, but the mechanisms are still unclear. In this study, we evaluated sleep disturbance in rats with cerebral ischemia. We investigated the effect of YKS on sleep disturbance in cerebral ischemia-treated rats. Methods: Cerebral ischemia was induced by twice occluding both of the common carotid arteries. Wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep were classified using electroencephalography and electromyography. mRNA expression of sleep–wakefulness signals were quantified using reverse transcription–polymerase chain reaction. Results: Rats with cerebral ischemia had a higher total wakefulness time and lower total NREM sleep time during the light phase. These changes were ameliorated with 1000 mg/kg YKS for 14 days, but not 3 mg/kg donepezil for 7 days. mRNA expression of the prefrontal cortical prostaglandin (PG) E2 (EP4) receptor and of the PGD2 (DP) receptor was increased by cerebral ischemia. Elevated prefrontal cortical EP4 and DP receptor mRNA expression was reduced by YKS treatment. Conclusion: Rats with cerebral ischemia had NREM sleep disturbance. YKS might reduce this sleep disturbance by preventing neuroinflammation, and this was mediated by the EP4 and DP receptors in the prefrontal cortex.

The purpose of this study is to investigate the morphometric changes of the subchondral bone during the development of osteoarthritis (OA) in transgenic mice with achondroplasia (Fgfr3ach ) carrying a heterozygous gain-of-function mutation in Fgfr3. Two OA models (spontaneously developed with age: The aging model, and surgically induced by destabilization of the medial meniscus: The DMM model) were established. Articular cartilage, epiphysis, and metaphysis of the knee joint were histologically and morphometrically compared between wild-type mice, and Fgfr3ach mice in both OA models. Articular cartilage degeneration was scored according to the Osteoarthritis Research Society International (OARSI) scoring system. Several morphometric parameters including bone mineral density (BMD), bone volume/tissue volume (BV/TV), trabecular bone thickness (Tb.Th), and subchondral bone thickness in the medial tibial plateau (MTP) (Sb.Th med) were quantified by micro-computed tomography (CT). In the aging model, although there were no significant differences in the OARSI score between wild-type mice and Fgfr3ach mice, Sb.Th med and Tb.Th in the epiphysis significantly increased in wild-type mice. In the DMM model, the OARSI score of the medial compartment was significantly lower in Fgfr3ach mice than in wild-type mice. BMD, BV/TV, and Tb.Th in the epiphysis increased in wild-type mice and unchanged in Fgfr3ach mice, and the Sb.Th med was significantly larger in wild-type mice after surgery. Subchondral sclerosis, which preceded the cartilage degeneration, was inhibited in Fgfr3ach mice. Activated FGFR3 signaling prevented sclerotic changes of the subchondral bone and subsequent cartilage degeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:300-308, 2018.

Background: Bifid rib is usually asymptomatic but sometimes occurs associated with other pathological conditions. The aim of this study was to investigate clinical and radiological characteristics in children with bifid rib. Methods: Nine children with the diagnosis of bifid rib between 2005 and 2010 were reviewed. Chest radiography and computed tomography (CT) were performed in all patients, and 3-D images were additionally reconstructed in six patients. Results: Five girls and four boys with a mean age at presentation of 4.2 years had various types of unilateral bifid rib. Seven patients complained of a chest wall mass, whereas two patients whose costal abnormalities were incidentally detected on chest radiography were asymptomatic. Bifid ribs were confirmed on plain radiographs in six patients, while the other three patients were finally diagnosed on reconstruction 3D-CT. One patient with a flared rib on a radiograph showed bifurcation of the costal cartilage on 3D-CT. The other two patients with upper rib abnormalities on radiography had downward extension of the cervical or first rib articulating with the upper branch of the bifid first or second rib, respectively. Conclusion: Reconstruction 3D-CT can demonstrate complicated thoracic abnormalities in patients with atypical appearance of the rib on plain radiographs. An isolated bifid rib may require no further intervention.

BACKGROUND: Antihistamines with strong sedative-hypnotic properties are frequently prescribed for insomnia secondary to allergy, but the potential risks of such administration have not been fully elucidated. SUBJECTS AND METHODS: This randomized, double-blind, placebo-controlled crossover study was conducted to evaluate next-day sleepiness and psychomotor performance following the administration of antihistamines. Twenty-two healthy male participants participated in four drug administration sessions with more than a 1-week interval between the sessions. Either zolpidem 10 mg, or diphenhydramine 50 mg, or ketotifen 1 mg, or a placebo was administered before sleep, and polysomnography was conducted to evaluate sleep. In the morning and afternoon of the day after administration, the participants were evaluated for subjective sleepiness, objective sleepiness, and psychomotor performance. RESULTS: The antihistamines with high blood-brain barrier-crossing efficiency were significantly associated with sleepiness and psychomotor performance decline the next day. Ketotifen showed the strongest carryover effect, followed by diphenhydramine. Compared with the placebo, no significant carryover effect was observed with zolpidem. CONCLUSION: The results suggest that the risk-benefit balance should be considered in the ready use of antihistamines that easily cross the blood-brain barrier for alleviating secondary insomnia associated with allergies. Copyright © 2012 John Wiley & Sons, Ltd. Language: en

We examined the neuroprotective mechanism of cannabidiol, non-psychoactive component of marijuana, on the infarction in a 4 h mouse middle cerebral artery (MCA) occlusion model in comparison with Delta(9)-tetrahydrocannabinol (Delta(9)-THC). Release of glutamate in the cortex was measured at 2 h after MCA occlusion. Myeloperoxidase (MPO) and cerebral blood flow were measured at 1 h after reperfusion. In addition, infarct size and MPO were determined at 24 and 72 h after MCA occlusion. The neuroprotective effect of cannabidiol was not inhibited by either SR141716 or AM630. Both pre- and post-ischemic treatment with cannabidiol resulted in potent and long-lasting neuroprotection, whereas only pre-ischemic treatment with Delta(9)-THC reduced the infarction. Unlike Delta(9)-THC, cannabidiol did not affect the excess release of glutamate in the cortex after occlusion. Cannabidiol suppressed the decrease in cerebral blood flow by the failure of cerebral microcirculation after reperfusion and inhibited MPO activity in neutrophils. Furthermore, the number of MPO-immunopositive cells was reduced in the ipsilateral hemisphere in cannabidiol-treated group. Cannabidiol provides potent and long-lasting neuroprotection through an anti-inflammatory CB(1) receptor-independent mechanism, suggesting that cannabidiol will have a palliative action and open new therapeutic possibilities for treating cerebrovascular disorders.

The aim of the present study was to clarify whether subjective sleepiness accurately reflects benzodiazepine-related decline in psychomotor function after taking benzodiazepines (BZPs) in aged people. Subjects were eight healthy, young (mean age, 19.8 years) and seven healthy, older (mean age, 60.9 years) men. Placebo and diazepam (DZP) were administered orally in a single-blind crossover manner to the young subjects (placebo, 5 mg DZP and 10 mg DZP) and to the older subjects (placebo and 5 mg DZP). Plasma drug concentration, choice reaction time (CRT) as an objective measure of psychomotor function, and the Stanford Sleepiness Scale (SSS) as a measure of subjective sleepiness were monitored every 20 min from 1000 until 1600 h, being the drug administered at 1200 h. Pharmacokinetic variables did not differ significantly between the two age groups. DZP at 10 mg in young subjects induced significant increases in both the CRT and SSS score. DZP at 5 mg induced no significant increase in SSS score in either age group but did induce a significant increase in CRT only in the older subjects that matched that in young subjects given 10 mg DZP. The older subjects suffered from dissociation between subjective sleepiness and objective psychomotor impairment under DZP treatment. Such individuals may underestimate the detrimental effects on brain function. Copyright © 2007 John Wiley & Sons, Ltd.

The present study investigated the effect of schizandrin, a component of the fruit of Schizandra chinesis Baill (Fructus Schizandrae), on memory impairment in rats. Scopolamine (0.5 mg/kg, i.p.), a non-selective muscarinic receptor antagonist, markedly impaired spatial memory in an eight-arm radial maze. A higher dose of scopolamine (3 mg/kg, i.p.) also impaired the passive avoidance response. Schizandrin (1 and 10 mg/kg, p.o.) significantly reversed the scopolamine-induced impairment of spatial memory. Similarly, schizandrin (1 mg/kg, p.o.) significantly reversed the scopolamine-induced impairment of the passive avoidance response. Moreover, in mice, schizandrin (1 and 10 mg/kg, p.o.) enhanced tremors induced by oxotremorine, a muscarinic M(1) receptor agonist. Taken together these findings suggest that schizandrin reverses scopolamine-induced memory impairment, in part, by enhancing cholinergic function, and that schizandrin might be useful for treating memory deficits.

The present study investigated the effects of Kamikihi-to (KKT), a Kampo medicine, on impairment of spatial memory in rats using an eight-arm radial maze task. Scopolamine (0.5 mg/kg, i.p.), a non-selective muscarinic receptor antagonist, and Delta(9)-tetrahydrocannabinol (THC; 6 mg/kg, i.p.), a principal psychoactive component of marihuana, each markedly impaired the spatial memory. KKT (1 and 3 mg/kg, p.o.) significantly improved the scopolamine-induced impairment of spatial memory. KKT (30 mg/kg, p.o.) also improved significantly the THC-induced impairment of spatial memory. Moreover, KKT (3 and 30 mg/kg, p.o.) enhanced tremors induced by oxotremorine, a muscarinic M(1) receptor agonist. Taken together these findings suggest that KKT is a useful drug for treating memory deficits.

Zanapezil (TAK-147 (3-[1benzylpiperdin-4-yl]-1-(2,3,4,5-tetrahydro-1 H-1-benzazepin-8-yl) propan-1-one fumarate)) is a selective acetylcholine (ACh) esterase inhibitor under investigation as a drug for Alzheimer's disease (AD) treatment. In this study, the effects of TAK-147 at 2 mg kg(-1) p.o. for 21 days, compared to donepezil (E2020), on the levels of ACh, catecolamines and indoleamines were investigated in the ventral hippocampus (VH) of freely moving rats by microdialysis-high-performance liquid chromatography. The results revealed that the VH contains 92.05+/-21.97 fmol 20 microl(-1) ACh and the following monoamines levels (pg 30 microl(-1)), norepinephrine (NE) 1.92+/-0.39, epinephrine (Epi) 1.91+/-0.183, 3-methoxy-4-hydroxyphenylglycol (MHPG) 11.53+/-3.22, normetanephrine 3.26+/-0.61, dopamine (DA) 0.77+/-0.23, 3,4-dihydroxyphenylacetic acid (DOPAC) 3.37+/-1.01, homovanillic acid (4-hydroxy-3-methoxyphenylacetic acid; HVA) 4.04+/-0.93, 3-methoxytyramine 0.64+/-0.13, serotonin (5-HT) 0.73+/-0.16 and 5-hydroxyindoleacetic acid (5-HIAA) 313.15+/-18.42. On the 21st day and prior to the last dose, TAK-147 increased ACh, Epi, DA and 5-HT, whereas E2020 increased MHPG, Epi and DA. Following the last dose, TAK-147 increased NE, whereas E2020 increased NE, ACh and 5-HT in addition to their effects prior to the last dose. TAK-147 decreased HVA : DA ratio, but only marginally decreased DOPAC : DA and 5-HIAA : 5-HT ratios. On the other hand, E2020 decreased ratios of HVA : DA, DOPAC : DA (prior to the last dose), and 5-HIAA : 5-HT (90-180 min after the last dose). Both drugs decreased MHPG : NE only at 180 min after the last dose. The results also showed that TAK-147 increased Epi : NE ratio prior to and for 120 min following the last dose, whereas E2020 increased the ratio only before the last dose. The present results show that TAK-147 at a subthreshold dose could differentially increase ACh and 5-HT, compared to MHPG increased by E2020. The last dose of each drug could extend their effects to other monoamines. The increase of the monoamines levels, in addition to that on the ACh, and decrease of their oxidation could be of value in the treatment of the AD, other dementic diseases and the cohort neurological disorders depending on the type of the monoamine underlying the disorder.

Brief focal ischemia leading to temporary neurological deficits induces delayed hyperintensity on T1-weighted magnetic resonance imaging (MRI) in the striatum of humans and rats. The T1 hyperintensity may stem from biochemical alterations including manganese (Mn) accumulation after ischemia. To clarify the significance of this MRI modification, we investigated the changes in the dorsolateral striatum of rats from 4 hours through 16 weeks after a 15-minute period of middle cerebral artery occlusion (MCAO), for MRI changes, Mn concentration, neuronal number, reactivities of astrocytes and microglia/macrophages, mitochondrial Mn-superoxide dismutase (Mn-SOD), glutamine synthetase (GS), and amyloid precursor protein. The cognitive and behavioral studies were performed in patients and rats and compared with striatal T1 hyperintensity to show whether alteration in brain function correlated with MRI and histological changes. The T1-weighted MRI signal intensity of the dorsolateral striatum increased from 5 days to 4 weeks after 15-minute MCAO, and subsequently decreased until 16 weeks. The Mn concentration of the dorsolateral striatum increased after ischemia in concert with induction of Mn-SOD and GS in reactive astrocytes. The neuronal survival ratio in the dorsolateral striatum decreased significantly from 4 hours through 16 weeks, accompanied by extracellular amyloid precursor protein accumulation and chronic glial/inflammatory responses. The patients and rats with neuroradiological striatal degeneration had late-onset cognitive and/or behavioral declines after brief focal ischemia. This study suggests that (1) the hyperintensity on T1-weighted MRI after mild ischemia may involve tissue Mn accumulation accompanied by Mn-SOD and GS induction in reactive astrocytes, (2) the MRI changes correspond to striatal neurodegeneration with a chronic inflammatory response and signs of oxidative stress, and (3) the subjects with these MRI changes are at risk for showing a late impairment of brain function even though the transient ischemia is followed by total neurological recovery.