Deficiency of the RIβ subunit of protein kinase A causes body tremor and impaired fear conditioning memory in rats

The RIβ subunit of cAMP-dependent protein kinase (PKA), encoded by Prkar1b, is a neuronal isoform of the type I regulatory subunit of PKA. Mice lacking the RIβ subunit exhibit normal long-term potentiation (LTP) in the Schaffer collateral pathway of the hippocampus and normal behavior in the open-field and fear conditioning tests. Here, we combined genetic, electrophysiological, and behavioral approaches to demonstrate that the RIβ subunit was involved in body tremor, LTP in the Schaffer collateral pathway, and fear conditioning memory in rats. Genetic analysis of WTC-furue, a mutant strain with spontaneous tremors, revealed a deletion in the Prkar1b gene of the WTC-furue genome. Prkar1b-deficient rats created by the CRISPR/Cas9 system exhibited body tremor. Hippocampal slices from mutant rats showed deficient LTP in the Schaffer collateral–CA1 synapse. Mutant rats also exhibited decreased freezing time following contextual and cued fear conditioning, as well as increased exploratory behavior in the open field. These findings indicate the roles of the RIβ subunit in tremor pathogenesis and contextual and cued fear memory, and suggest that the hippocampal and amygdala roles of this subunit differ between mice and rats and that rats are therefore beneficial for exploring RIβ function

Which Side-Bending X-ray Position is Better to Evaluate the Preoperative Curve Flexibility in Adolescent Idiopathic Scoliosis Patients, Supine or Prone?

Study Design Prospective cohort study. Purpose The present study aimed to evaluate the difference in the preoperative curve flexibility between the supine and prone positions in patients with adolescent idiopathic scoliosis (AIS). Overview of Literature In AIS, a side-bending view is necessary to differentiate a structural curve from a nonstructural curve using the Lenke classification system. However, there are no published studies about which position, supine or prone, is more effective when evaluating preoperative curve flexibility using side-bending X-ray images in AIS patients. Methods Radiographs were analyzed for 32 AIS patients (26 females, six males) who underwent posterior correction and fusion of their main thoracic (MT) curves. Cobb angles of MT, proximal thoracic (PT), and thoracolumbar/lumbar (TL/L) curves were measured preoperatively using upright, supine (anteroposterior and side-bending), and prone (posteroanterior and side-bending) X-rays. Results The average Cobb angles of PT, MT, and TL/L curves on preoperative upright/supine/prone X-rays were 29.1°/26.7°/26.6°, 60.7°/48.5°/48.2°, and 41.0°/32.6°/33.1°, respectively. The average Cobb angles of PT, MT, and TL/L curves on supine/prone sidebending X-rays were 19.2°/20.3°, 36.3°/36.4°, and 13.9°/15.7°, respectively. The flexibility rates of PT, MT, and TL/L curves in supine/prone positions were 35.3%/32.5%, 40.6%/40.2%, and 71.7%/68.2%, respectively. Comparing flexibility rates in the prone position with those in the supine position in each case, the average ratios of PT, MT, and TL/L curves were found to be 1.0, 1.0, and 0.9, respectively. There were no statistically significant differences between supine and prone side-bending X-ray measurements. However, the Lenke classification in six of 32 patients (18.8%) differed between supine and prone positions because the TL/L curve in the supine position was slightly more flexible than in the prone position. Conclusions Supine side-bending films may be suitable for the evaluation of preoperative curve flexibility in AIS, especially for lumbar modifier C

Hippocampus-related cognitive disorders develop in the absence of epilepsy and ataxia in the heterozygous Cacna1a mutant mice tottering

CACNA1A-associated epilepsy and ataxia frequently accompany cognitive impairments as devastating co-morbidities. However, it is unclear whether the cognitive deficits are consequences secondary to the neurological symptoms elicited by CACNA1A mutations. To address this issue, Cacna1a mutant mice tottering (tg), and in particular tg/+ heterozygotes, serve as a suitable model system, given that tg/+ heterozygotes fail to display spontaneous absence epilepsy and ataxia typically observed in tg/tg homozygotes. Here, we examined hippocampus-dependent behaviors and hippocampal learning-related synaptic plasticity in tg mice. In behavioral analyses of tg/+ and tg/tg, acquisition and retention of spatial reference memory were characteristically impaired in the Morris water maze task, while working memory was intact in the eight-arm radial maze and T-maze tasks. tg/+ heterozygotes showed normal motor function in contrast to tg/tg homozygotes. In electrophysiological analyses, Schaffer collateral–CA1 synapses showed a deficit in the maintenance of long-term potentiation in tg/+ and tg/tg mice and an increased paired-pulse facilitation induced by paired pulses with 100 ms in tg/tg mice. Our results indicate that the tg mutation causes a dominant disorder of the hippocampus-related memory and synaptic plasticity, raising the possibility that in CACNA1A-associated human diseases, functionally aberrant CaV2.1 Ca²⁺ channels actively induce the observed cognitive deficits independently of the neurological symptoms

Chemosensitivity of a Recurrent Desmoid Tumor with Increased Osteopontin Expression and a Novel Frame-Shift Mutation at Codon 1564 of the APC Gene

In this report, we describe a case of recurrent desmoid tumor that was characterized by a novel APC gene mutation and osteopontin (OPN) expression. A 20-year-old female patient with adenomatous polyposis underwent a right colectomy at 13 years of age. Five years later, she developed an abdominal desmoid tumor that was resected. After 2 more years, a recurrent desmoid tumor was found in the same region. This tumor grew rapidly and quickly became massive. The doubling time was estimated to be 122 days, based on the computed tomography findings. When we analyzed the APC gene in the recurrent desmoid tumor, we found a novel frame-shift mutation at codon 1564. This frame-shift mutation changed TTA to TAG, which is a stop codon. Northern blot analysis and immunohistochemical analysis for OPN, a GRGDS (glycine-arginine-glycine-aspartic acid-serine)- containing adhesive molecule, revealed abundant amounts of OPN mRNA and protein expression in this desmoid tumor. We postulated that the truncated APC protein and OPN expression might be involved in the invasive nature of this recurrent desmoid tumor. A primary cell culture derived from the desmoid tumor was assessed for chemosensitivity to 5-fluorouracil, cisplatin, doxorubicin, colchicine, docetaxel, and anti-OPN antibody. Docetaxel was found to have the strongest inhibitory effect on cell growth. As a result, docetaxel was administered to this patient (60 mg/m2/month) for 3 cycles. Over the next 2 years, no detectable recurrences occurred. Thus, docetaxel was clinically effective for the treatment of a recurrent desmoid tumor

Chemosensitivity of a Recurrent Desmoid Tumor with Increased Osteopontin Expression and a Novel Frame-Shift Mutation at Codon 1564 of the APC Gene

In this report, we describe a case of recurrent desmoid tumor that was characterized by a novel APC gene mutation and osteopontin (OPN) expression. A 20-year-old female patient with adenomatous polyposis underwent a right colectomy at 13 years of age. Five years later, she developed an abdominal desmoid tumor that was resected. After 2 more years, a recurrent desmoid tumor was found in the same region. This tumor grew rapidly and quickly became massive. The doubling time was estimated to be 122 days, based on the computed tomography findings. When we analyzed the APC gene in the recurrent desmoid tumor, we found a novel frame-shift mutation at codon 1564. This frame-shift mutation changed TTA to TAG, which is a stop codon. Northern blot analysis and immunohistochemical analysis for OPN, a GRGDS (glycine-arginine-glycine-aspartic acid-serine)- containing adhesive molecule, revealed abundant amounts of OPN mRNA and protein expression in this desmoid tumor. We postulated that the truncated APC protein and OPN expression might be involved in the invasive nature of this recurrent desmoid tumor. A primary cell culture derived from the desmoid tumor was assessed for chemosensitivity to 5-fluorouracil, cisplatin, doxorubicin, colchicine, docetaxel, and anti-OPN antibody. Docetaxel was found to have the strongest inhibitory effect on cell growth. As a result, docetaxel was administered to this patient (60 mg/m2/month) for 3 cycles. Over the next 2 years, no detectable recurrences occurred. Thus, docetaxel was clinically effective for the treatment of a recurrent desmoid tumor