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We report a rare 16-year-old male case of Klippel-Feil anomaly associated with fetal alcohol syndrome exhibiting complex congenital vascular anomalies. The congenital vascular anomalies observed were the absence of a left internal carotid artery, a left vertebral artery arising from the subclavian artery in a very high cervical location and a bovine arch. The vascular and vertebral anomalies were evaluated using CT and MRI before cervical surgery.

Abstract Background Both mutation induction and clonal expansion of mutated cells cause cancer. The probability of cancer development depends on mutations, clonal growth rates, and carcinogenic mechanisms. A recent study showed cases of occupational cholangiocarcinomas that originate multifocally, with higher mutation burden levels than those in common cholangiocarcinomas. This study aimed to identify the effect of clonal expansion on and estimate the risk of occupational and common intrahepatic cholangiocarcinomas (ICCs) using a multistage model modified to include the effect of cell expansion at any carcinogenic stage. Methods The age-specific incidence of common ICC estimated from the Vital Statistics in Japan and the prognosis of ICC, and mutation frequencies of occupational and common ICC available from the previous report, were applied to a multistage model modified with cell proliferation effects. From the fittest model, the risk after exposure was estimated. Results The required number of stages for carcinogenesis was estimated to be three based on the incidences and mutation frequencies of occupational and common ICCs. Based on this estimation, the predicted incidence curve under the model was similar to that estimated from the ICC mortality rate, except for older adults. The model indicated a minor effect of clonal expansion on the observed occupational ICC risk. It predicted a rapid decrease in ICC risk after the cessation of occupational exposure, although the time of clinical detection of cancer after the exposure was affected by latency. The model predicted an increase in cancer risk in older adults caused by cell expansion and common background mutations. However, the risk in older adults was overestimated in the case of common ICC; this divergence could influence occupational ICC cases. Conclusions Three-stage ICC carcinogenesis has been proposed. The high mutation burden levels caused by occupational exposure led to an immediate incidence of cancer. After a long period of relatively low cancer risk, an increased risk in older adults was also predicted.

Abstract Voltage-sensing phosphatase (VSP) exhibits voltage-dependent phosphatase activity toward phosphoinositides. VSP generates a specialized phosphoinositide environment in mammalian sperm flagellum. However, the voltage-sensing mechanism of VSP in spermatozoa is not yet characterized. Here, we found that VSP is activated during sperm maturation, indicating that electric signals in immature spermatozoa are essential. Using a heterologous expression system, we show the voltage-sensing property of mouse VSP (mVSP). The voltage-sensing threshold of mVSP is approximately −30 mV, which is sensitive enough to activate mVSP in immature spermatozoa. We also report several knock-in mice in which we manipulate the voltage-sensitivity or electrochemical coupling of mVSP. Notably, the V312R mutant, with a minor voltage-sensitivity change, exhibits abnormal sperm motility after, but not before, capacitation. Additionally, the V312R mutant shows a significant change in the acyl-chain profile of phosphoinositide. Our findings suggest that electrical signals during sperm maturation are crucial for establishing the optimal phosphoinositide environment in spermatozoa.

Glutamate and GABA co-transmitting neurons exist in several brain regions; however, the mechanism by which these two neurotransmitters are co-released from the same synaptic terminals remains unclear. Here, we show that the supramammillary nucleus (SuM) to dentate granule cell synapses, which co-release glutamate and GABA, exhibit differences between glutamate and GABA release properties in paired-pulse ratio, Ca2+-sensitivity, presynaptic receptor modulation, and Ca2+ channel-vesicle coupling configuration. Moreover, uniquantal synaptic responses show independent glutamatergic and GABAergic responses. Morphological analysis reveals that most SuM terminals form distinct glutamatergic and GABAergic synapses in proximity, each characterized by GluN1 and GABAAα1 labeling, respectively. Notably, glutamate/GABA co-transmission exhibits distinct short-term plasticities, with frequency-dependent depression of glutamate and frequency-independent stable depression of GABA. Our findings suggest that glutamate and GABA are co-released from different synaptic vesicles within the SuM terminals, and reveal that distinct transmission modes of glutamate/GABA co-release serve as frequency-dependent filters of SuM inputs.

Abstract Developmental synapse elimination is crucial for shaping mature neural circuits. In the neonatal mouse cerebellum, Purkinje cells (PCs) receive excitatory synaptic inputs from multiple climbing fibers (CFs) and synapses from all but one CF are eliminated by around postnatal day 20. Heterosynaptic interaction between CFs and parallel fibers (PFs), the axons of cerebellar granule cells (GCs) forming excitatory synapses onto PCs and molecular layer interneurons (MLIs), is crucial for CF synapse elimination. However, mechanisms for this heterosynaptic interaction are largely unknown. Here we show that deletion of AMPA-type glutamate receptor functions in GCs impairs CF synapse elimination mediated by metabotropic glutamate receptor 1 (mGlu1) signaling in PCs. Furthermore, CF synapse elimination is impaired by deleting NMDA-type glutamate receptors from MLIs. We propose that PF activity is crucial for CF synapse elimination by directly activating mGlu1 in PCs and indirectly enhancing the inhibition of PCs through activating NMDA receptors in MLIs.

Abstract Nicotinic acetylcholine receptors (nAChRs) in the medial habenula (MHb)–interpeduncular nucleus (IPN) pathway play critical roles in nicotine-related behaviors. This pathway is particularly enriched in nAChR α3 and β4 subunits, both of which are genetically linked to nicotine dependence. However, the cellular and subcellular expression of endogenous α3β4-containing nAChRs remains largely unknown because specific antibodies and appropriate detection methods were unavailable. Here, we successfully uncovered the expression of endogenous nAChRs containing α3 and β4 subunits in the MHb–IPN pathway using novel specific antibodies and a fixative glyoxal that enables simultaneous detection of synaptic and extrasynaptic molecules. Immunofluorescence and immunoelectron microscopy revealed that both subunits were predominantly localized to the extrasynaptic cell surface of somatodendritic and axonal compartments of MHb neurons but not at their synaptic junctions. Immunolabeling for α3 and β4 subunits disappeared in α5β4-knockout brains, which we used as negative controls. The enriched and diffuse extrasynaptic expression along the MHb–IPN pathway suggests that α3β4-containing nAChRs may enhance the excitability of MHb neurons and neurotransmitter release from their presynaptic terminals in the IPN. The revealed distribution pattern provides a molecular and anatomical basis for understanding the functional role of α3β4-containing nAChRs in the crucial pathway of nicotine dependence.

Abstract Postsynaptic proteins play crucial roles in synaptic function and plasticity. During brain development, alterations in synaptic number, shape, and stability occur, known as synapse maturation. However, the postsynaptic protein composition changes during development are not fully understood. Here, we show the trajectory of the postsynaptic proteome in developing male mice and common marmosets. Proteomic analysis of mice at 2, 3, 6, and 12 weeks of age shows that proteins involved in synaptogenesis are differentially expressed during this period. Analysis of published transcriptome datasets shows that the changes in postsynaptic protein composition in the mouse brain after 2 weeks of age correlate with gene expression changes. Proteomic analysis of marmosets at 0, 2, 3, 6, and 24 months of age show that the changes in the marmoset brain can be categorized into two parts: the first 2 months and after that. The changes observed in the first 2 months are similar to those in the mouse brain between 2 and 12 weeks of age. The changes observed in marmoset after 2 months old include differential expression of synaptogenesis-related molecules, which hardly overlap with that in mice. Our results provide a comprehensive proteomic resource that underlies developmental synapse maturation in rodents and primates.

Abstract Kainate receptors (KARs) are one of the ionotropic glutamate receptors in the central nervous system (CNS) comprised of five subunits, GluK1-GluK5. There is a growing interest in the association between KARs and psychiatric disorders, and there have been several studies investigating the behavioral phenotypes of KAR deficient mice, however, the difference in the genetic background has been found to affect phenotype in multiple mouse models of human diseases. Here, we examined GluK1-5 single KO mice in a pure C57BL/6N background and identified that GluK3 KO mice specifically express anxiolytic-like behavior with an alteration in dopamine D2 receptor (D2R)-induced anxiety, and reduced D2R expression in the striatum. Biochemical studies in the mouse cortex confirmed that GluK3 subunits do not assemble with GluK4 and GluK5 subunits, that can be activated by lower concentration of agonists. Overall, we found that GluK3-containing KARs function to express anxiety, which may represent promising anti-anxiety medication targets.

Abstract In the central nervous system, astrocytes enable appropriate synapse function through glutamate clearance from the synaptic cleft; however, it remains unclear how astrocytic glutamate transporters function at peri-synaptic contact. Here, we report that Down syndrome cell adhesion molecule (DSCAM) in Purkinje cells controls synapse formation and function in the developing cerebellum. Dscam-mutant mice show defects in CF synapse translocation as is observed in loss of function mutations in the astrocytic glutamate transporter GLAST expressed in Bergmann glia. These mice show impaired glutamate clearance and the delocalization of GLAST away from the cleft of parallel fibre (PF) synapse. GLAST complexes with the extracellular domain of DSCAM. Riluzole, as an activator of GLAST-mediated uptake, rescues the proximal impairment in CF synapse formation in Purkinje cell-selective Dscam-deficient mice. DSCAM is required for motor learning, but not gross motor coordination. In conclusion, the intercellular association of synaptic and astrocyte proteins is important for synapse formation and function in neural transmission.

Intervertebral disc degeneration is a leading cause of chronic low back pain, affecting millions globally. Regenerative medicine, particularly cell-based therapies, presents a promising therapeutic strategy. This study evaluates the comparative efficacy of two biomaterials—hyaluronic acid (HA) and alginate—as carriers for nucleus pulposus (NP) cell transplantation in a beagle model of induced disc degeneration. NP cells were isolated, cultured, and injected with either HA or alginate into degenerated discs, with saline and non-cell-loaded carriers used as controls. Disc height index, T2-weighted MRI, and histological analyses were conducted over a 12-week follow-up period to assess reparative outcomes. Imaging revealed that both carrier and cell-loaded treatments improved outcomes compared to degenerative controls, with cell-loaded carriers consistently outperforming carrier-only treated discs. Histological assessments supported these findings, showing trends toward extracellular matrix restoration in both treatment groups. While both biomaterials demonstrated reparative potential, HA showed greater consistency in supporting NP cells in promoting disc regeneration. These results underscore HA’s potential as a superior carrier for NP cell-based therapies in addressing disc degeneration.

Low back pain (LBP) is a pervasive global health concern, primarily associated with intervertebral disc (IVD) degeneration. Although oxidative stress has been shown to contribute to IVD degeneration, the underlying mechanisms remain undetermined. This study aimed to unravel the role of superoxide dismutase 2 (SOD2) in IVD pathogenesis and target oxidative stress to limit IVD degeneration. SOD2 demonstrated a dynamic regulation in surgically excised human IVD tissues, with initial upregulation in moderate degeneration and downregulation in severely degenerated IVDs. Through a comprehensive set of in vitro and in vivo experiments, we found a suggestive association between excessive mitochondrial superoxide, cellular senescence, and matrix degradation in human and mouse IVD cells. We confirmed that aging and mechanical stress, established triggers for IVD degeneration, escalated mitochondrial superoxide levels in mouse models. Critically, chondrocyte-specific Sod2 deficiency accelerated age-related and mechanical stress-induced disc degeneration in mice, and could be attenuated by β-nicotinamide mononucleotide treatment. These revelations underscore the central role of SOD2 in IVD redox balance and unveil potential therapeutic avenues, making SOD2 and mitochondrial superoxide promising targets for effective LBP interventions.

After spinal cord injury (SCI), endoplasmic reticulum (ER) stress has been reported to be an integral part of the secondary injury process that causes apoptosis of glial cells, leading to remyelination failure. This report focuses on exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist widely used to treat diabetes, as a potential agent to improve functional outcome after SCI by improving the ER stress response. Exenatide administered subcutaneously immediately after injury and 7 days later in a rat model of moderate contusive SCI revealed significant improvement in hindlimb function without any hypoglycemia. Changes in the expression of glucose regulatory protein 78 (GRP78), an endoplasmic reticulum chaperone that protects against ER stress, and C/EBP homologous transcription factor protein (CHOP), a pro-apoptotic transcription factor in the apoptosis pathway were examined as indices of ER stress. We found that administration of exenatide after SCI suppressed CHOP while increasing GRP78 in the injured spinal cord, leading to a significant decrease in tissue damage and a significant increase in oligodendrocyte progenitor cell survival. This study suggests that administration of exenatide after SCI decreases ER stress and improves functional recovery without any apparent side-effects.

Abstract Brain-enriched guanylate kinase-associated protein (BEGAIN) is highly enriched in the post-synaptic density (PSD) fraction and was identified in our previous study as a protein associated with neuropathic pain in the spinal dorsal horn. PSD protein complexes containing N-methyl-d-aspartate receptors are known to be involved in neuropathic pain. Since these PSD proteins also participate in learning and memory, BEGAIN is also expected to play a crucial role in this behavior. To verify this, we first examined the distribution of BEGAIN in the brain. We found that BEGAIN was widely distributed in the brain and highly expressed in the dendritic regions of the hippocampus. Moreover, we found that BEGAIN was concentrated in the PSD fraction of the hippocampus. Furthermore, immunoelectron microscopy confirmed that BEGAIN was localized at the asymmetric synapses. Behavioral tests were performed using BEGAIN-knockout (KO) mice to determine the contribution of BEGAIN toward learning and memory. Spatial reference memory and reversal learning in the Barns circular maze test along with contextual fear and cued fear memory in the contextual and cued fear conditioning test were significantly impaired in BEGAIN-KO mice compared to with those in wild-type mice. Thus, this study reveals that BEGAIN is a component of the post-synaptic compartment of excitatory synapses involved in learning and memory.

Introduction: Osteoarthritis (OA) is the most common form of arthritis. OA results from the breakdown of cartilage, which leads to deterioration of the entire joint and the connective tissue that holds the joint together, and gradually and irreversibly worsens over time. Adipose-derived stem/stromal cells (ADSCs) have been used in the treatment of knee OA. However, the safety and efficacy of ADSC treatment of OA remain unclear. In this study, we investigated the pathophysiology of severe knee arthritis that occurred after ADSC treatment by screening for autoantibodies in synovial fluid from patients who received ADSC treatment. Methods: Adult Japanese patients with OA who received ADSC treatment at Saitama Cooperative Hospital between June 2018 and October 2021 were enrolled. Antibodies (Abs) were screened using immunoprecipitation (IPP) with [35S]-methionine-labeled HeLa cell extracts. The detected protein was identified by liquid chromatography coupled with time-of-flight mass spectrometry (MS) and ion trap MS, and the corresponding proteins were confirmed as autoantigens using immunoblotting. Ab titers were measured using an enzyme-linked immunosorbent assay. Results: A total of 113 patients received ADSC treatment, and 75% (85/113) received ADSC injection at least twice with a 6-month interval between. No obvious abnormalities were observed in any patient after their first treatment; by contrast, 53% (45/85) of patients who received their second or third ADSC injection showed severe knee arthritis. IPP detected a common anti-15 kDa Ab in synovial fluid of 62% (8/13) of the samples analyzed from patients who showed severe arthritis. This Ab was not detected in synovial fluid obtained from the same joints before treatment. The corresponding autoantigen was identified as histone H2B. All available synovial samples from patients who tested positive for anti-histone H2B Ab were newly positive after the treatment; that is, none had been positive for anti-histone H2B Ab before treatment. Conclusions: Multiple ADSC injections for OA induced severe arthritis in a high percentage of patients, particularly after the second injection. Synovial fluid from some patients with knee arthritis contained Ab to histone H2B that appeared only after ADSC treatment. These findings provide new insights into the pathogenesis of ADSC treatment-induced severe arthritis.

Abstract Background We report two cases of biceps brachii and brachialis paralysis due to musculocutaneous nerve injury in which elbow joint flexion was reconstructed using rotational transfer of the latissimus dorsi muscle with sutures to the radial and ulnar tuberosities, thereby enabling flexion by simultaneous activation of the humeroradial and humeroulnar joints. In cases of associated brachialis paralysis, weaker flexion strength can be expected when the forearm is in a pronated position than when it is in a supinated state. To the best of our knowledge, no previous study has reported the rotational position of the forearm during elbow joint flexion reconstruction. Case presentation Case 1 involved a 30-year-old Asian male who presented with a rupture of the musculocutaneous, median, radial, and ulnar nerves. Reconstruction was performed by rotational transfer of the latissimus dorsi muscle. In this case, the supination and pronation flexion forces were equal. Case 2 involved a 50-year-old Asian man who presented with partial loss of the musculocutaneous nerve, biceps brachii, and pectoralis major due to debridement. Reconstruction was performed by rotational transfer of the latissimus dorsi muscle. In this case, supination and pronation flexion strengths were demonstrated to be equal. Our reconstruction method used the rotational transfer of the latissimus dorsi muscle; the distal muscle flap was divided into radial and ulnar sides to allow elbow joint flexion by simultaneously activating the humeroradial and humeroulnar joints. These sides were then fixed to the anchors at the radial and ulnar tuberosities. Finally, they were wrapped around the myotendinous junction of the biceps brachii or brachialis and secured using sutures. Conclusions Although larger studies are required to verify these methods, this case study successfully demonstrates the following: (1) the flexion strength in the supinated position was equal to that in the pronated position; (2) the stability of the humeroradial and humeroulnar joints was unaffected by the forearm's rotational position; and (3) a satisfactory range of motion of the elbow joint was obtained, with no complications.

Abstract Background Evaluation of body composition after total hip arthroplasty (THA) is essential because it can be used to evaluate muscle and functional recovery. Muscle volume and degeneration are evaluated using computed tomography (CT). However, CT evaluation of muscle volume has several limitations, such as radiation exposure and high medical cost. Bioelectrical impedance analysis (BIA) has gained attention for resolving these limitations of CT. BIA takes advantage of the microelectric current; thus, metal implants may affect the results. Therefore, this study aimed to elucidate the effects of metal implants on BIA after THA. Methods Two groups of patients were assessed (Group 1: 70 patients who underwent unilateral THA and BIA; Group 2: 35 patients who underwent THA and BIA before and after THA). Electric impedance (resistance and reactance) of the operated and non-operated lower limbs was compared in Group 1. The pre- and post-operative impedances of the torso and operated ipsilateral limbs were compared in Group 2. Results Regarding electric impedance in Group 1, no significant differences were observed in electrical resistance and reactance between the operated and non-operated lower limbs. Concerning electric impedance in Group 2, postoperative electric resistance of the torso was significantly lower than that preoperatively. However, no significant difference was seen in electric resistance and reactance of the operated ipsilateral limbs preoperatively and postoperatively. Conclusions Electrical resistance and reactance of the limbs did not change significantly after THA. BIA is useful for measuring body composition after THA.

Abstract Background Laparoscopic surgery is reported to be useful in obese or elderly patients with colon cancer, who are at increased risk of postoperative complications because of comorbidities and physical decline. However, its usefulness is less clear in patients who are both elderly and obese and may be at high risk of complications. Methods Data for obese patients (body mass index ≥25) who underwent laparoscopic or open surgery for stage II or III colon cancer between January 2009 and December 2013 were collected by the Japan Society of Laparoscopic Colorectal Surgery. Surgical outcomes, postoperative complications, and relapse‐free survival (RFS) were compared between patients who underwent open surgery and those who underwent laparoscopic surgery according to whether they were elderly (≥70 y) or nonelderly (

Objective:. To investigate the oncological outcomes after transanal total mesorectal excision (TaTME) for rectal cancer and risk factors for local recurrence (LR). Background:. A high LR rate with a multifocal pattern early after TaTME has been reported in Norway and the Netherlands, causing controversy over the oncological safety of this technique. Methods:. Twenty-six member institutions of the Japan Society of Laparoscopic Colorectal Surgery participated in this retrospective cohort study. A total of 706 patients with primary rectal cancer who underwent TaTME between January 2012 and December 2019 were included for analysis. The primary endpoint was the cumulative 3-year LR rate. Results:. A total of 253 patients had clinical stage III disease (35.8%) and 91 (12.9%) had stage IV. Intersphincteric resection was performed in 318 patients (45.0%) and abdominoperineal resection in 193 (27.3%). There was 1 urethral injury (0.1%). A positive resection margin (R1) was seen in 42 patients (5.9%). Median follow-up was 3.42 years, and the 2- and 3-year cumulative LR rates were 4.95% (95% confidence interval: 3.50–6.75) and 6.82% (95% confidence interval: 5.08–8.89), respectively. A multifocal pattern was observed in 14 (25%) of 56 patients with LR. Tumor height from the anal verge, pathological T4 disease, pathological stage III/IV, positive perineural invasion, and R1 resection were significant risk factors for LR in multivariable analysis. Conclusions:. In this selected cohort in which intersphincteric resection or abdominoperineal resection was performed in more than half of cases, oncological outcomes were acceptable during a median follow-up of more than 3 years.

Although a wide variety of mechanisms take part in the secondary injury phase of spinal cord injury (SCI), inflammation is the most important factor implicated in the sequelae after SCI. Being central to the inflammation reaction, macrophages and their polarization are a topic that has garnered wide interest in the studies of SCI secondary injury. The glucagon-like peptide 1 (GLP-1) receptor agonist exenatide has been shown to enhance the endoplasmic reticulum stress response and improve motor function recovery after spinal cord injury (SCI). Since exenatide has also been reported to induce the production of M2 cells in models of cerebral infarction and neurodegenerative diseases, this study was conducted to examine the effects of exenatide administration on the inflammation process that ensues after spinal cord injury. In a rat contusion model of spinal cord injury, the exenatide group received a subcutaneous injection of 10 μg exenatide immediately after injury while those in the control group received 1 mL of phosphate-buffered saline. Quantitative RT-PCR and immunohistochemical staining were used to evaluate the effects of exenatide administration on the macrophages infiltrating the injured spinal cord, especially with regard to macrophage M1 and M2 profiles. The changes in hind limb motor function were assessed based on Basso, Beattie, Bresnahan locomotor rating scale (BBB scale) scores. The improvement in BBB scale scores was significantly higher in the exenatide group from day 7 after injury and onwards. Quantitative RT-PCR revealed an increase in the expression of M2 markers and anti-inflammatory interleukins in the exenatide group that was accompanied by a decrease in the expression of M1 markers and inflammatory cytokines. Immunohistochemical staining showed no significant difference in M1 macrophage numbers between the two groups, but a significantly higher number of M2 macrophages was observed in the exenatide group on day 3 after injury. Our findings suggest that exenatide administration promoted the number of M2-phenotype macrophages after SCI, which may have led to the observed improvement in hind limb motor function in a rat model of SCI.

Abstract Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1–3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.

Objective Fluoroscopy is often used in the surgery of unstable pelvic ring fractures, and improved safety in implant placement is an issue. An anterior subcutaneous pelvic fixator (INFIX) combined with a percutaneous screw has been reported to be a minimally invasive and effective surgical technique for unstable pelvic ring injuries. However, although percutaneous screw fixation is minimally invasive, its indications for fracture fixation and fractures with large fragment displacements in the vertical plane remain controversial. Therefore, this technical note aims to describe a new technique for unstable pelvic ring fractures. Methods We describe a 360° fusion of the pelvic ring to treat unstable pelvic ring fractures, including vertical shear pelvic ring fractures, using an intraoperative CT navigation system. Seven patients were treated with 360° fusion for type C pelvic ring fractures. In surgery, after reducing the fracture with external fixation, intraoperative CT navigation is used to perform a 360° fusion with INFIX and minimally invasive surgical spinopelvic fixation (MIS‐SPF). We will introduce a typical case and explain the procedure. Results A 360° fixation was performed, and no perioperative complications were noted. The mean blood loss was 253.2 ± 141.0 mL, and the mean operative time was 224.3 ± 67.4 min. In a typical case, bone union was obtained 1 year after surgery, and we removed all implants. Conclusions MIS‐SPF has a strong fixation force and helps reduce fractures' horizontal and vertical planes. In addition, 360° fusion with intraoperative CT navigation may help treat unstable pelvic ring fractures.

This study developed and validated a surgical instrument motion measurement system for skill evaluation during practical laparoscopic surgery training. Owing to the various advantages of laparoscopic surgery including minimal invasiveness, this technique has been widely used. However, expert surgeons have insufficient time for providing training to beginners due to the shortage of surgeons and limited working hours. Skill transfer efficiency has to be improved for which there is an urgent need to develop objective surgical skill evaluation methods. Therefore, a simple motion capture-based surgical instrument motion measurement system that could be easily installed in an operating room for skill assessment during practical surgical training was developed. The tip positions and orientations of the instruments were calculated based on the marker positions attached to the root of the instrument. Because the patterns of these markers are individual, this system can track multiple instruments simultaneously and detect exchanges. However due to the many obstacles in the operating room, the measurement data included noise and outliers. In this study, the effect of this decrease in measurement accuracy on feature calculation was determined. Accuracy verification experiments were conducted during wet-lab training to demonstrate the capability of this system to measure the motion of surgical instruments with practical accuracy. A surgical training experiment on a cadaver was conducted, and the motions of six surgical instruments were measured in 36 cases of laparoscopic radical nephrectomy. Outlier removal and smoothing methods were also developed and applied to remove the noise and outliers in the obtained data. The questionnaire survey conducted during the experiment confirmed that the measurement system did not interfere with the surgical operation. Thus, the proposed system was capable of making reliable measurements with minimal impact on surgery. The system will facilitate surgical education by enabling the evaluation of skill transfer of surgical skills.

The superficial dorsal horn (SDH) of the spinal cord contains a diverse array of neurons. The vast majority of these are interneurons, most of which are glutamatergic. These can be assigned to several populations, one of which is defined by expression of gastrin-releasing peptide receptor (GRPR). The GRPR cells are thought to be “tertiary pruritoceptors,” conveying itch information to lamina I projection neurons of the anterolateral system (ALS). Surprisingly, we recently found that GRPR-expressing neurons belong to a morphological class known as vertical cells, which are believed to transmit nociceptive information to lamina I ALS cells. Little is currently known about synaptic circuits engaged by the GRPR cells. Here we combine viral-mediated expression of PSD95-tagRFP fusion protein with super-resolution microscopy to reveal sources of excitatory input to GRPR cells. We find that they receive a relatively sparse input from peptidergic and non-peptidergic nociceptors in SDH, and a limited input from A- and C-low threshold mechanoreceptors on their ventral dendrites. They receive synapses from several excitatory interneuron populations, including those defined by expression of substance P, neuropeptide FF, cholecystokinin, neurokinin B, and neurotensin. We investigated downstream targets of GRPR cells by chemogenetically exciting them and identifying Fos-positive (activated) cells. In addition to lamina I projection neurons, many ALS cells in lateral lamina V and the lateral spinal nucleus were Fos-positive, suggesting that GRPR-expressing cells target a broader population of projection neurons than was previously recognised. Our findings indicate that GRPR cells receive a diverse synaptic input from various types of primary afferent and excitatory interneuron, and that they can activate ALS cells in both superficial and deep regions of the dorsal horn.

Abstract Excitatory interneurons in the superficial dorsal horn (SDH) are heterogeneous, and include a class known as vertical cells, which convey information to lamina I projection neurons. We recently used pro-NPFF antibody to reveal a discrete population of excitatory interneurons that express neuropeptide FF (NPFF). Here, we generated a new mouse line (NPFFCre) in which Cre is knocked into the Npff locus, and used Cre-dependent viruses and reporter mice to characterise NPFF cell properties. Both viral and reporter strategies labelled many cells in the SDH, and captured most pro-NPFF-immunoreactive neurons (75–80%). However, the majority of labelled cells lacked pro-NPFF, and we found considerable overlap with a population of neurons that express the gastrin-releasing peptide receptor (GRPR). Morphological reconstruction revealed that most pro-NPFF-containing neurons were vertical cells, but these differed from GRPR neurons (which are also vertical cells) in having a far higher dendritic spine density. Electrophysiological recording showed that NPFF cells also differed from GRPR cells in having a higher frequency of miniature EPSCs, being more electrically excitable and responding to a NPY Y1 receptor agonist. Together, these findings indicate that there are at least two distinct classes of vertical cells, which may have differing roles in somatosensory processing.

Abstract Background Lumbar fusion corrects spinal deformities and improves spinal complications. Hip osteoarthritis (OA) is strongly correlated with spinal mobility, and joint space narrowing of the hip after spinal fusion has gained attention. This study aimed to elucidate the effect of spinal fusion on hip joint space narrowing. Materials and methods We retrospectively examined 530 hips of 270 patients who underwent spinal surgery. All the patients underwent whole-spine radiography before and at the final follow-up. Patients were divided into three groups (N group: non-spinal fusion, S group: up to three interbody fusions, and L group: more than four interbody fusions). The rates of joint space narrowing, spinal parameters (sagittal vertical axis, thoracic kyphosis, lumbar lordosis, sacral slope, pelvic tilt, and pelvic incidence), and limb length discrepancy at the final follow-up were compared. A multilinear regression analysis was performed to identify the risk factors for the rate of joint space narrowing. Results The rate of joint space narrowing was significantly higher in the L group than in the N and S groups (P

Abstract Aim Whether a laparoscopic procedure can contribute to the improvement of clinical outcomes in obese patients with stage II/III rectal cancer compared to an open procedure remains unclear. Objective This study evaluated the technical and oncological safety of laparoscopic surgery versus open surgery in obese patients (body mass index [BMI] ≥25 kg/m2) with rectal cancer. Patients and Methods Data were collected from patients with pathological stage II/III rectal cancer and analyzed. Operations were performed via laparoscopic or open surgery from 2009 to 2013. A comparative analysis was performed after applying propensity score matching to the two cohorts (laparoscopic group and open group). The primary endpoint was 3‐y relapse‐free survival (RFS). Results Overall, 524 eligible cases were collected from 51 institutions. Equal numbers of propensity score‐matched patients were included in the laparoscopic (n = 193) group and open (n = 193) group. Although the rate of D3 lymph node dissection did not differ between the laparoscopic group (87.0%) and the open group (88.6%), the median number of harvested lymph nodes was significantly lower in the laparoscopic group versus open group (17.5 vs 21, P = 0.0047). The median postoperative hospital stay was also significantly shorter in the laparoscopic group (14 d) vs the open group (17 d) (P = 0.0014). Three‐y RFS was not significantly different between the two groups (hazard ratio 1.2454, 95% confidence interval 0.9201–1.6884, P = 0.4689). Conclusion The short‐ and long‐term results of this large cohort study (UMIN ID: UMIN000033529) indicated that laparoscopic surgery in obese rectal cancer patients has advantageous short‐term outcomes and no disadvantageous long‐term outcomes.

Abstract Allogeneic cell therapies are not fully effective in treating osteoarthritis of the knee (OAK). We recently reported that transplantation of autologous chondrocyte cell-sheets along with open-wedge high tibial osteotomy promoted hyaline cartilage repair in humans. Here we describe our regenerative therapy for OAK using polydactyly-derived allogeneic chondrocyte cell-sheets (PD sheets) and temperature-responsive culture inserts. Ten patients with OAK and cartilage defects categorized arthroscopically as Outerbridge grade III or IV received the therapy. Cartilage viscoelasticity and thickness were assessed before and after transplantation. Arthroscopic biopsies obtained 12 months after transplantation were analyzed histologically. Gene expression was analyzed to evaluate the PD sheets. In this small initial longitudinal series, PD sheet transplantation was effective in treating OAK, as indicated by changes in cartilage properties. Gene marker sets in PD sheets may predict outcomes after therapy and provide markers for the selection of donor cells. This combined surgery may be an ideal regenerative therapy with disease-modifying effects in OAK patients.

Abstract Aim In Japan, we have not been able to validate the results of laparoscopic surgery for locally advanced rectal cancer using the universal index “circumferential resection margin (CRM).” Previously, we established a semi‐opened circular specimen processing method and validated its feasibility. In the PRODUCT trial, we aimed to assess CRM in patients with locally advanced rectal cancer who underwent laparoscopic rectal resection. Methods This was a multicenter, prospective, observational study. Eligible patients had histologically confirmed rectal adenocarcinoma located at or below 12 cm above the anal verge with clinical stage II or III and were scheduled for laparoscopic or robotic surgery. The primary endpoint was pathological CRM. CRM ≤1 mm was defined as positive. Results A total of 303 patients operated on between August 2018 and January 2020 were included in the primary analysis. The number of patients with clinical stage II and III was 139 and 164, respectively. Upfront surgery was performed for 213 patients and neoadjuvant therapy for 90 patients. The median CRM was 4.0 mm (IQR, 2.1‐8.0 mm), and CRM was positive in 26 cases (8.6%). Univariate and multivariate analyses demonstrated that a predicted CRM from the mesorectal fascia of ≤1 mm on MRI was the significant factor for positive CRM (P = .0012 and P = .0045, respectively). Conclusion This study showed the quality of laparoscopic rectal resection based on the CRM in Japan. Preoperative MRI is recommended for locally advanced rectal cancer to prevent CRM positivity.

Background: The artificial bone grafts are performed on the defect after reduction of the calcaneal fracture. Generally, it is an artificial bone graft with an implant, and there are a few reports of an artificial bone graft without an implant. Cases: We report three cases (42-year-old male, 67-year-old male, 21-year-old female) of a tongue-shaped calcaneal fracture treated using a cylindrical unidirectional porous β-tricalcium phosphate artificial bone (Affinos®, Kurare co Ltd., Hyougo, Japan) to surgically repair bone defects after reduction. The bone defect is often observed when fracture is reduced in calcaneal fracture. There were significant bone defects, which were then fixed using Affinos® (forming a cylindrical shape block; diameter 10 mm x height 20 mm) to support the bone fragment, an artificial β-tricalcium phosphate bone with a porosity of 57 % (pore size 25–300 μm), characterized by a novel unidirectional porous structure. Postoperative early rehabilitation started with partial load from 5 weeks after surgery and was full weight bearing at 9 weeks after surgery. There was no correction loss and good bone fusion was obtained. By 12 months postoperatively, patients were able to be walking without pain and absorption and bone fusion around the artificial bone were observed maintaining the morphology immediately after reduction. The result was a good clinical result of one excellent (92 points) and two good (81 and 84 points) 1 year after surgery in the postoperative AOFAS Ankle-Hindfoot Scale. Conclusion: Affinos® has a frost-like structure, which endows it with good tissue invasive properties because of the capillary effect. Moreover, it has excellent osteoconduction capability. In these 3 cases, Affinos® showed good strength, affinity, absorption, and bone substitution in a tongue-shaped calcaneal fracture. Further prospective studies are required to confirm our findings.

Background: Vessel injuries during total knee arthroplasty or high tibial osteotomy are rare but have serious complications. This study aimed to analyze the running position of the popliteal artery (PA) and branching level of the anterior tibial artery (ATA), using magnetic resonance imaging (MRI). This analysis might be helpful in avoiding unnecessary vessel injury. Methods: In total, 105 patients (41 men and 64 women), whose running position of the PA and branching level of the ATA could be detected by preoperative MRI, were included in this study. We configured zones A, B, C, and D to be 5–10, 15–20, 25–30 and 35–40 mm distal from the lateral tibial plateau in the axial view, respectively. First, the distance between the posterior cortex of the tibia and anterior border of the PA was measured. Second, the PA position from the medial border of the tibia was measured. This measured value was divided by the transverse diameter of the tibia, and multiplied by 100 to obtain the PA position from the medial border of the tibia. Third, the branching level of ATA was measured from the joint line. Subsequently, each value was compared between men (the M group) and women (the W group). Results: The distance between the posterior cortex of the tibia and the anterior border of the PA was 5.5 ± 1.9, 10.4 ± 2.4, 12.5 ± 2.3 and 12.5 ± 2.3 (mm; mean ± SD) in zones A, B, C, and D, respectively. Comparing both groups, this distance was significantly larger (more separated posteriorly) in zones C and D in the M group. The PA position from the medial border of the tibia was 51.7 ± 6.5, 52.7 ± 8.2, 56.7 ± 10.5 and 66.8 ± 14 (%; mean ± SD) in zones A, B, C, and D, respectively. On comparing the two groups, this position was significantly larger (more laterally shifted) in zone D in the W group. The branching level of the ATA was not detected within 40 mm distal to the joint line in 92 patients (87.6%). However, it was detected within 40 mm (mean 32.5 mm; range 20–38) in 12 patients (11.4%). Among them, 11 were women. Only one woman had an aberrant branching pattern: the ATA bifurcated at the joint level. Conclusion: The PA positioned closest at the joint level, gradually separated and shifted laterally towards the distal side. The distance between the posterior cortex of the tibia and the anterior border of the PA was closer in women than in men in zones C and D. Although a difference of 2 mm is small, the risk of PA injury can be considered to be higher in women than in men. Furthermore, ATA injury is also a concern during retraction of the tibialis anterior muscle posteriorly, and the descending cut of the tibial tuberosity, particularly in women.

Abstract Tyramide signal amplification (TSA) is a highly sensitive method for histochemical analysis. Previously, we reported a TSA system, biotinyl tyramine-glucose oxidase (BT-GO), for bright-filed imaging. Here, we develop fluorochromized tyramide-glucose oxidase (FT-GO) as a multiplex fluorescent TSA system. FT-GO involves peroxidase-catalyzed deposition of fluorochromized tyramide (FT) with hydrogen peroxide produced by enzymatic reaction between glucose and glucose oxidase. We showed that FT-GO enhanced immunofluorescence signals while maintaining low background signals. Compared with indirect immunofluorescence detections, FT-GO demonstrated a more widespread distribution of monoaminergic projection systems in mouse and marmoset brains. For multiplex labeling with FT-GO, we quenched antibody-conjugated peroxidase using sodium azide. We applied FT-GO to multiplex fluorescent in situ hybridization, and succeeded in labeling neocortical interneuron subtypes by coupling with immunofluorescence. FT-GO immunofluorescence further increased the detectability of an adeno-associated virus tracer. Given its simplicity and a staining with a high signal-to-noise ratio, FT-GO would provide a versatile platform for histochemical analysis.

Abstract Age-related changes in the posterior extensor muscles of the cervical and lumbar spine have been reported in some studies; however, longitudinal changes in the thoracic spine of healthy subjects are rarely reported. Therefore, this study aimed to evaluate changes in the cross-sectional areas (CSAs) of posterior extensor muscles in the thoracic spine over 10 years and identify related factors. The subjects of this study were 85 volunteers (mean age: 44.7 ± 11.5) and the average follow-up period was about 10 years. The CSAs of the transversospinalis muscles, erector spinae muscles, and total CSAs of the extensor muscles from T1/2 to T11/12 were measured on magnetic resonance imaging. The extent of muscle fat infiltration was assessed by the signal intensity (luminance) of the extensor muscles’ total cross-section compared to a section of pure muscle. We applied a Poisson regression model, which is included in the generalized linear model, and first examined the univariate (crude) association between each relevant factor (age, sex, body mass index, lifestyle, back pain, neck pain, neck stiffness, and intervertebral disc degeneration) and CSA changes. Then, we constructed a multivariate model, which included age, sex, and related factors in the univariate analysis. The mean CSAs of the transversospinalis muscles, erector spinae muscles, and total CSAs of the extensor muscles significantly increased over 10 years. Exercise habit was associated with increased CSAs of the erector spinae muscles and the total area of the extensor muscles. The cross-section mean luminance significantly increased from baseline, indicating a significant increase of fat infiltration in the posterior extensor muscles. Progression of disc degeneration was inversely associated with increased fat infiltration in the total extensor muscles.

Somatosensory information is processed by a complex network of interneurons in the spinal dorsal horn. It has been reported that inhibitory interneurons that express neuropeptide Y (NPY), either permanently or during development, suppress mechanical itch, with no effect on pain. Here, we investigate the role of interneurons that continue to express NPY (NPY-INs) in the adult mouse spinal cord. We find that chemogenetic activation of NPY-INs reduces behaviours associated with acute pain and pruritogen-evoked itch, whereas silencing them causes exaggerated itch responses that depend on cells expressing the gastrin-releasing peptide receptor. As predicted by our previous studies, silencing of another population of inhibitory interneurons (those expressing dynorphin) also increases itch, but to a lesser extent. Importantly, NPY-IN activation also reduces behavioural signs of inflammatory and neuropathic pain. These results demonstrate that NPY-INs gate pain and itch transmission at the spinal level, and therefore represent a potential treatment target for pathological pain and itch.

Abstract Background Previous studies have reported that specific pro‐inflammatory cytokines or chemokines are more highly expressed in painful than in nonpainful intervertebral discs (IVDs). However, few studies have investigated their correlation with postsurgical outcomes or the relationship between postoperative pain and inflammatory cytokines in IVDs. Thus, the present study examined the correlation among the gene expression levels of pro‐inflammatory cytokines and chemokines in IVD tissues removed during surgery and low back pain (LBP), leg pain (LP), and leg numbness (LN) at one year after spinal fusion surgery in patients with a lumbar degenerative disease (LDD). Methods Chemokine and cytokine gene expression levels were measured in IVD samples from 48 patients with LDD. The associations between chemokine and cytokine gene expression levels and pain intensity (numeric rating scale [NRS]) were also analyzed. A correlation analysis was performed between gene expression in each IVD and preoperative and postoperative pain intensity. Results In the preoperative analysis, CCR6 was associated with NRSLBP (r = −0.291, P = 0.045). Postoperative pain analysis revealed correlations between postoperative NRSLBP and CCR6 (r = −0.328, P = 0.023) and between postoperative NRSLBP and IL‐6 (r = −0.382, P = 0.007). Furthermore, patients with high postoperative LBP intensity (NRSLBP ≥ 7) also had high LBP intensity (NRSLBP ≥ 6) before surgery, and a correlation was observed (r = 0.418, P = 0.003). None of the gene mRNAs correlated with NRSLP or NRSLN, respectively. Conclusions CCR6 and IL‐6 gene expression in the IVD was associated with postoperative LBP intensity and may indicate a need for postoperative pain management.

Functionally mature neural circuits are shaped during postnatal development by eliminating redundant synapses formed during the perinatal period. In the cerebellum of neonatal rodents, each Purkinje cell (PC) receives synaptic inputs from multiple (more than 4) climbing fibers (CFs). During the first 3 postnatal weeks, synaptic inputs from a single CF become markedly larger and those from the other CFs are eliminated in each PC, leading to mono-innervation of each PC by a strong CF in adulthood. While molecules involved in the strengthening and elimination of CF synapses during postnatal development are being elucidated, much less is known about the molecular mechanisms underlying CF synapse formation during the early postnatal period. Here, we show experimental evidence that suggests that a synapse organizer, PTPδ, is required for early postnatal CF synapse formation and the subsequent establishment of CF to PC synaptic wiring. We showed that PTPδ was localized at CF-PC synapses from postnatal day 0 (P0) irrespective of the expression of Aldolase C (Aldoc), a major marker of PC that distinguishes the cerebellar compartments. We found that the extension of a single strong CF along PC dendrites (CF translocation) was impaired in global PTPδ knockout (KO) mice from P12 to P29-31 predominantly in PCs that did not express Aldoc [Aldoc (–) PCs]. We also demonstrated via morphological and electrophysiological analyses that the number of CFs innervating individual PCs in PTPδ KO mice were fewer than in wild-type (WT) mice from P3 to P13 with a significant decrease in the strength of CF synaptic inputs in cerebellar anterior lobules where most PCs are Aldoc (–). Furthermore, CF-specific PTPδ-knockdown (KD) caused a reduction in the number of CFs innervating PCs with decreased CF synaptic inputs at P10-13 in anterior lobules. We found a mild impairment of motor performance in adult PTPδ KO mice. These results indicate that PTPδ acts as a presynaptic organizer for CF-PC formation and is required for normal CF-PC synaptic transmission, CF translocation, and presumably CF synapse maintenance predominantly in Aldoc (–) PCs. Furthermore, this study suggests that the impaired CF-PC synapse formation and development by the lack of PTPδ causes mild impairment of motor performance.

Abstract Aim The aim of this study was to compare the outcomes of GM142, a newly developed gelatin film with a concave and convex structure to a commercially available conventional film, hyaluronate‐carboxymethylcellulose. Methods Patients with primary rectal cancer who were scheduled for diverting ileostomy during laparoscopic surgery were eligible for this study. Patients were randomized before surgery and an antiadhesion film was applied under the umbilical incision. The primary outcome was the incidence of adhesion under the midline incision confirmed by second‐look surgery for diverting ileostomy closure. The secondary outcomes were the adhesion severity score, the extent of adhesion score, the presence of intestinal obstruction, and the success of all patching. Results A total of 146 patients were enrolled. A total of 123 patients were included in the full analysis set. The primary outcome of “no adhesion” was observed in 66.1% in the GM142 group and 55.7% in the conventional film group. The noninferiority of GM142 to conventional film was confirmed (P = .0005). The secondary outcomes were similar between the groups. For the safety evaluation, there were no safety concerns regarding allergic reactions to gelatin or increased gelatin‐specific IgE antibody titers. Conclusions The noninferiority of GM142 to conventional film was shown. GM142 showed no major safety issues. The clinical safety profiles of GM142 suggested certain physiological benefits of the gelatin film as an adhesion barrier.

Abstract Biological tissues and their networks frequently change dynamically across large volumes. Understanding network operations requires monitoring their activities in three dimensions (3D) with single-cell resolution. Several researchers have proposed various volumetric imaging technologies. However, most technologies require large-scale and complicated optical setups, as well as deep expertise for microscopic technologies, resulting in a high threshold for biologists. In this study, we propose an easy-to-use light-needle creating device for conventional two-photon microscopy systems. By only installing the device in one position for a filter cube that conventional fluorescent microscopes have, single scanning of the excitation laser light beam excited fluorophores throughout over 200 μm thickness specimens simultaneously. Furthermore, the developed microscopy system successfully demonstrated single-scan visualization of the 3D structure of transparent YFP-expressing brain slices. Finally, in acute mouse cortical slices with a thickness of approximately 250 μm, we detected calcium activities with 7.5 Hz temporal resolution in the neuronal population.

Abstract While self‐driving cars have already been widely investigated and achieved spectacular progress, a major obstacle in applications is the great difficulty in providing formal guarantees about their behaviors. Since the environment of the self‐driving is usually not known beforehand and highly uncertain, classical verification approaches cannot be applied to guarantee safety. To cope with any traffic situation, a novel online verification framework is presented for verifying behavioral safety of self‐driving cars. The framework is based on the proposed five safety considerations: new longitudinal and lateral safe distances, lane changes, overtaking and how to face new traffic participants. Different from the previous verification considerations, this verification framework allows actual behaviors of self‐driving cars to be temporarily inconsistent with the popular strict safe distance. As long as the self‐driving car respects the minimum safe distance calculated by our technique and executes improvement behaviors to restore the safe distance, it is still believed that the predictive behavior is safe. The framework can easily be integrated to existing self‐driving systems and evaluate different indicators involving the steering angle, acceleration and braking. The benefits of the framework in different urban scenarios of the CARLA simulator and real traffic data provided by the NGSIM project are demonstrated. Results show that the technology can successfully detect unsafe behaviors and provide effective measures to avoid potential collisions.

Background/purpose: Surgical orthodontic treatment is recommended for patients with severe dentoskeletal discrepancies, while camouflage orthodontic treatment is recommended for patients with mild to moderate discrepancies. However, the decision as to which treatment should be chosen is complicated. The purpose of this study was to determine differences in masticatory function in patients who underwent camouflage and surgical orthodontic treatment for skeletal Class III malocclusion, as well as the usefulness of Wits appraisal in treatment decision based on masticatory functional analysis. Materials and methods: The study subjects were 45 patients with skeletal Class III malocclusion (15 cases with camouflage orthodontics and 30 cases with orthognatic surgery) and 12 individuals with normal occlusion. We analyzed the pre-treatment records of electromyographic activities of masseter and temporalis muscles and jaw movements. Results: There were no significant differences in various functional measurements between the camouflage and surgery groups. However, there were significant but not strong correlations between ANB and both masseter muscle activity (r = 0.36, p

Abstract Major psychiatric disorders such as attention-deficit/hyperactivity disorder and schizophrenia are often accompanied by elevated impulsivity. However, anti-impulsive drug treatments are still limited. To explore a novel molecular target, we examined the role of dopamine D5 receptors in impulse control using mice that completely lack D5 receptors (D5KO mice). We also measured spontaneous activity and learning/memory ability because these deficits could confound the assessment of impulsivity. We found small but significant effects of D5 receptor knockout on home cage activity only at specific times of the day. In addition, an analysis using the q-learning model revealed that D5KO mice displayed lower behavioral adjustment after impulsive actions. However, our results also showed that baseline impulsive actions and the effects of an anti-impulsive drug in D5KO mice were comparable to those in wild-type littermates. Moreover, unlike previous studies that used other D5 receptor-deficient mouse lines, we did not observe reductions in locomotor activity, working memory deficits, or severe learning deficits in our line of D5KO mice. These findings demonstrate that D5 receptors are dispensable for impulse control. Our results also indicate that time series analysis and detailed analysis of the learning process are necessary to clarify the behavioral functions of D5 receptors.

Abstract Aim Much attention has been paid to conversion therapy for stage IV gastric cancer, however, its operative comorbidities and survival benefit have not yet been clarified. CONVO‐GC‐1, an international retrospective cohort study, was designed to investigate the role of conversion surgery in Japan, Korea, and China. Methods The rate of operative complications was the primary endpoint and the overall survival (OS), according to the four‐category criteria previously published (Gastric Cancer:19; 2016), was analyzed as the secondary endpoint. Results A total of 1206 patients underwent surgery after chemotherapy with curative intent. Operative complications were observed in 290 (24.0%) patients in all grades, including pancreatic fistula and surgical site infection. The median survival time (MST) of all resected patients was 36.7 mo (M) and those of R0, R1, and R2 resection were 56.6 M, 25.8 M, and 21.7 M, respectively. Moreover, the MST of R0 patients were 47.8 M, 116.7 M, 44.8 M in categories 1, 2, and 3, respectively, and not reached in category 4. Interestingly, the MST of P1 patients was as favorable as that of P0CY1 patients if R0 resection was achieved. The MST of patients with liver metastasis was also favorable regardless of the number of lesions, and the MST of patients with para‐aortic lymph node (LN) No 16a1/b2 metastasis was not inferior to that of patients with para‐aortic LN No 16a2/b1 metastasis. Conclusion Conversion therapy for stage IV gastric cancer is safe and could be a new therapeutic strategy to improve the survival of patients, especially those with R0 resection.

Abstract Calsyntenins (CLSTNs) are important synaptic molecules whose molecular functions are not fully understood. Although mutations in calsyntenin (CLSTN) genes have been associated with psychiatric disorders in humans, their function is still unclear. One of the reasons why the function of CLSTNs in the nervous system has not been clarified is the functional redundancy among the three paralogs. Therefore, to investigate the functions of mammalian CLSTNs, we generated triple knockout (TKO) mice lacking all CLSTN paralogs and examined their behavior. The mutant mice tended to freeze in novel environments and exhibited hypersensitivity to stress. Consistent with this, glucose levels under stress were significantly higher in the mutant mice than in the wild-type controls. In particular, phenotypes such as decreased motivation, which had not been reported in single Clstn KO mice, were newly discovered. The TKO mice generated in this study represent an important mouse model for clarifying the function of CLSTN in the future.

Abstract Background Lateral femoral cutaneous nerve (LFCN) injury after total hip arthroplasty causes patient dissatisfaction. This cadaveric study aimed to assess the risk for LFCN injury after the direct anterior approach (DAA) and anterolateral supine approach (ALS) with a focus on the anatomical variations of the LFCN. Methods Thirty-seven hemipelves from 20 formalin-preserved cadavers (10 males and 10 females) were dissected to identify the LFCN, evaluate variations, and measure the distance from the LFCN to each approach. The LFCN was classified as classical, late, multi trunk, or primary femoral. Results There were no significant variations in the LFCN between the sexes. The distance from the LFCN to DAA incision (10 [0–17.8] mm) was significantly less than that from the LFCN to ALS incision (27 [0–40] mm); moreover, 64.9% of DAA incisions crossed the LFCN. The classical type LFCN was closest to the DAA incision. The DAA incision most frequently crossed the LFCN at the proximal third, and the frequency of intersection of the LFCN and DAA incisions decreased by 25% by a 10-mm shortening of the DAA proximal incision. In contrast, 27% of ALS incisions crossed the LFCN. Multi trunk type LFCN was closest to the ALS incision. There were no significant differences between each approach and LFCN variations, and the frequency of intersection of the LFCN and ALS incisions decreased by 20% by a 10-mm shortening of the ALS proximal incision. Conclusions The intersection rates between the LFCN and the DAA and between the LFCN and the ALS were approximately 65 and 30%, respectively. Approximately 20–25% of these injuries may be avoidable by a 10-mm shortening of the proximal incision.

Study Design Retrospective study. Purpose The purpose of this study was to compare the accuracy of percutaneous pedicle screw (PPS) placement between prone and lateral decubitus positions during lateral lumbar interbody fusion (LLIF) and to evaluate the tendency of PPS positioning based on simple computed tomography measurements with patients in the lateral decubitus position. Overview of Literature There is insufficient information in the literature regarding the accuracy of inserting a PPS using fluoroscopy in patients in the lateral decubitus position. Methods We included 62 patients who underwent combined LLIF surgery and PPS fixation for degenerative lumbar spondylolisthesis with spinal canal stenosis. We compared the patient demographics and the accuracy of fluoroscopy-guided PPS placement between two groups: patients who remained in the lateral decubitus position for the pedicle screw fixation (single-position surgery [SPS] group) and those who were turned to the prone position (dual-position surgery [DPS] group). Results There were 40 patients in the DPS group and 22 in the SPS group. Of the 292 PPSs, only 12 were misplaced. In other words, 280/292 screws (95.9%) were placed correctly in the pedicle’s cortical shell (grade 0). PPS insertion did not cause neurological, vascular, or visceral injuries in either group. The breach rates for the DPS and SPS groups were 4.1% (grade 1, 5 screws; grade 2, 3 screws; grade 3, 0 screw) and 4.1% (grade 1, 2 screws; grade 2, 2 screws; grade 3, 0 screw), respectively. Although there were no statistically significant differences, the downside PPS had more screw malpositioning than the upside PPS. Conclusions We found that PPS insertion with the patient in the decubitus position under fluoroscopic guidance might be as safe and reliable a technique as PPS insertion in the prone position, with a misplacement rate similar to that previously published.

Abstract Sagittal misalignment has been associated with negative quality of life (QOL). However, there is no report on whether differences in preoperative sagittal misalignment in patients with lumbar degenerative diseases affect postoperative results after lateral lumbar interbody fusion (LLIF). We investigated whether preoperative sagittal alignment influences the correction of alignment after surgery and whether the preoperative sagittal alignment affects the rating of low back pain, leg pain, and leg numbness. The subjects were 81 patients (48 male, 33 females, average age at surgery 70.2 years) who underwent anterior–posterior combined surgery with LLIF and percutaneous pedicle screws from May 2018 to July 2020. Cluster analysis was performed using the preoperative sagittal vertical axis (SVA) value, and patients were classified into two groups (group 1; n = 30, SVA = 129.0 ± 53.4 mm, group 2; n = 51, SVA = 30.8 ± 23.5 mm). Baseline demographics and treatment data were compared between groups. Sagittal and pelvic parameters and pain scores, such as low back pain, leg pain, and leg numbness, were also compared. Operative time, blood loss, and length of hospital stay did not differ significantly between groups. The changes (Δ) in SVA and lumbar lordosis (LL) for all patients from before to after surgery were not significant (ΔSVA; p = 0.218, ΔLL; p = 0.189, respectively). The SVA, LL, and PI − LL changed significantly after the surgery in group 1, but no marked improvement in sagittal imbalance was obtained after LLIF surgery. The improvement in each pain score from before to after the surgery did not differ significantly between groups. LLIF surgery has a limited chance of recovering sagittal imbalance. However, postoperative low back pain, leg pain, and leg numbness may be improved by LLIF surgery, regardless of the preoperative sagittal alignment.

Abstract Background The subcutaneous screw rod system, commonly known as the internal pelvic fixator (INFIX), is useful in managing unstable pelvic ring fractures. Conventional INFIX and transiliac–transsacral (TITS) screw techniques are performed using C-arm fluoroscopy. There have been problems with medical exposure and screw insertion accuracy with these techniques. This work describes new INFIX and TITS techniques using intraoperative computed tomography (CT) navigation and C-arm fluoroscopy for pelvic ring fracture. Methods A typical case is presented in this study. An 86-year-old woman suffered from an unstable pelvic ring fracture due to a fall from a height. INFIX and TITS screw fixation with intraoperative CT navigation were selected to optimize surgical invasiveness and proper implant placement. Results The patient was placed in a supine position on a Jackson table. An intraoperative CT navigation was imaged, and screws were inserted under the navigation. Postoperative X-rays and CT confirmed that the screw was inserted correctly. This technique was less invasive to the patient and had little radiation exposure to the surgeon. Rehabilitation of walking practice was started early after the surgery, and she was able to walk with the assistance of a walker by the time of transfer. Conclusions The technique employed in our case study has the cumulative advantages of safety, accuracy, and reduced radiation exposure, together with the inherent advantages of functional outcomes of previously reported INFIX and TITS screw techniques. Further experience with this approach will refine this technique to overcome its limitations and facilitate its wider use.

Abstract Background Although nutritional status is crucial in gait recovery after femoral neck fracture surgery, the relationship between preoperative nutritional status and postoperative outcomes remains unknown. This study examined the effects of preoperative nutritional status on postoperative outcomes in patients undergoing femoral neck fracture surgery. Methods Data regarding the joints of 137 patients (29 men, 108 women) who underwent bipolar hemiarthroplasty for femoral neck fractures at our hospital from January 2015 to December 2019 were retrospectively examined. The Geriatric Nutritional Risk Index (GNRI), an index of nutritional status, was used to classify patients into two groups: a normal group (GNRI ≥92; n = 62) and an undernourished group (GNRI

Abstract Background Institutional variation in outcomes is a key factor to ascertain the generalizability of results and reliability of the clinical trial. This study evaluated institutional variation in survival and postoperative complications using data from JCOG0404 comparing laparoscopic colectomy (LAP) with open colectomy (OP). Methods Institutions with fewer than 10 registered patients were excluded from this analysis. Institutional variation was evaluated in terms of early postoperative complications, overall survival, and relapse‐free survival and estimated using a mixed‐effect model with institution as a random effect after adjusting for background factors. Results This analysis included 1028 patients in the safety analysis and 1040 patients in the efficacy analysis from 26 institutions. In the safety analysis, there was no variation in grades 3–4 early postoperative complications (in OP, median 6.3% [range 6.3%–6.3%]; in LAP, median 2.6% [range 2.6%–2.6%]), but some variation in grades 1–4 early postoperative complications was observed (in OP, median 20.8% [range 13.2%–31.8%]; in LAP, median 11.9% [range 7.2%–28.7%]), and that in grades 2–4 was observed only in LAP (median 8.8% [range 4.7%–24.0%]; in OP, median 12.7% [range 12.7%–12.7%]). Two specific institutions showed especially high incidences of postoperative complications in LAP. In the efficacy analysis, there was no institutional variation in OP, although a certain variation was observed in LAP. Conclusions Some institutional variations in safety and efficacy were observed, although only in LAP. We conclude that a qualification system, including training and education, is needed when new surgical techniques such as laparoscopic surgery are introduced in clinical practice.