Laparoscopic cholecystectomy for patients with accessory liver lobe attached to the wall of the gallbladder: case reports.

BACKGROUND: Laparoscopic cholecystectomy (LC) is one of the most commonly undertaken procedures worldwide for cholecystolithiasis and cholecystitis. Accessory liver lobe (ALL) is a developmental anomaly defined as an excessive liver lobe composed of a normal liver parenchyma. Some ALL exist on the serosal side of the gallbladder. We herein present two cases of ALL incidentally detected during LC. CASE PRESENTATION: The first case was a 69-year-old woman diagnosed with chronic cholecystitis. LC was performed. ALL was observed anterior to the wall of the gallbladder and resected after clipping. Pathological findings revealed liver tissue with Glisson's capsule and a lobular structure in ALL. However, communication between the bile ducts of ALL and the main liver was unclear due to surgical heat degeneration. The second case was a 56-year-old woman diagnosed with acute cholecystitis. LC was performed approximately one month after the attack, and ALL attached to the wall of gallbladder. ALL was clipped and completely resected. Pathological findings showed that the bile ducts of ALL might be connected within the wall of gallbladder. CONCLUSIONS: We presented two cases of ALL attached to the gallbladder encountered during LC. Since ALL contains a normal liver parenchyma, postoperative bleeding or bile leakage may occur if it is inefficiently resected. Therefore, the complete resection of ALL is important to prevent these postoperative complications.

Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment.

Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer's disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.

Effects and risk factors of TAS-102 in real-world patients with metastatic colorectal cancer, EROTAS-R study.

BACKGROUND: Trifluridine/tipiracil (TAS-102) is an anticancer drug for metastatic colorectal cancer (CRC). This study aimed to analyze the effects and risk factors about effects of TAS-102 in real-world patients with metastatic CRC (the EROTAS-R study). METHODS: This study retrospectively analyzed 271 patients aged ≥ 20 years who underwent TAS-102 for metastatic CRC at nine related institutions from 2014 to 2021. Therapeutic results of TAS-102 + bevacizumab (Bev) and TAS-102, effect predictors, adverse events (AE), and AE predictors were examined. RESULTS: The backgrounds of all cases were as follows: average age, 66.7 ± 10.9 years; male ratio, 59.5%; performance status (PS) 0/1/2, 43.5%/50.6%/5.9%; and tumor site right/left, 25.5%/74.5%. The therapeutic results of 109 cases receiving TAS-102 + Bev and 162 cases receiving TAS-102 were as follows: disease control rate, 53.2% vs. 28.0% (p < 0.01); progressive free survival (PFS), 6.2 vs. 4.2 months (p < 0.01); and overall survival (S), 11.8 vs. 9.3 months (p = 0.03). Multivariate analysis for effect-related factors (odds ratio (OR), 95%confidence interval (CI)) showed the following: PS1 + 2 (0.257, 0.134-0.494, p < 0.01) and a combination of Bev (3.052, 1.598-5.827, p < 0.01). The rates of grade 3 AE for TAS-102 + Bev and TAS-102 were 53.2% and 48.8%, respectively (p = 0.47). Various AE predictors were as follows: male sex (p = 0.69), age ≥ 75 years (p = 0.59), PS1 + 2 (p = 0.20), body surface area < 1.53 m2 (p = 0.26), eGFR < 50 ml/min (p = 0.02), and AST ≥ 50 IU/L (p = 0.64). CONCLUSION: A better OS and PFS comparing TAS-102 + Bev to TAS-102 for CRC was achieved in a large number of real-world patients.

Endothelial Zeb2 preserves the hepatic angioarchitecture and protects against liver fibrosis.

AIMS: Hepatic capillaries are lined with specialized liver sinusoidal endothelial cells (LSECs) which support macromolecule passage to hepatocytes and prevent fibrosis by keeping hepatic stellate cells (HSCs) quiescent. LSEC specialization is co-determined by transcription factors. The zinc-finger E-box-binding homeobox (Zeb)2 transcription factor is enriched in LSECs. Here, we aimed to elucidate the endothelium-specific role of Zeb2 during maintenance of the liver and in liver fibrosis. METHODS AND RESULTS: To study the role of Zeb2 in liver endothelium we generated EC-specific Zeb2 knock-out (ECKO) mice. Sequencing of liver EC RNA revealed that deficiency of Zeb2 results in prominent expression changes in angiogenesis-related genes. Accordingly, the vascular area was expanded and the presence of pillars inside ECKO liver vessels indicated that this was likely due to increased intussusceptive angiogenesis. LSEC marker expression was not profoundly affected and fenestrations were preserved upon Zeb2 deficiency. However, an increase in continuous EC markers suggested that Zeb2-deficient LSECs are more prone to dedifferentiation, a process called 'capillarization'. Changes in the endothelial expression of ligands that may be involved in HSC quiescence together with significant changes in the expression profile of HSCs showed that Zeb2 regulates LSEC-HSC communication and HSC activation. Accordingly, upon exposure to the hepatotoxin carbon tetrachloride (CCl4), livers of ECKO mice showed increased capillarization, HSC activation, and fibrosis compared to livers from wild-type littermates. The vascular maintenance and anti-fibrotic role of endothelial Zeb2 was confirmed in mice with EC-specific overexpression of Zeb2, as the latter resulted in reduced vascularity and attenuated CCl4-induced liver fibrosis. CONCLUSION: Endothelial Zeb2 preserves liver angioarchitecture and protects against liver fibrosis. Zeb2 and Zeb2-dependent genes in liver ECs may be exploited to design novel therapeutic strategies to attenuate hepatic fibrosis.

HIVEP1 Is a Negative Regulator of NF-κB That Inhibits Systemic Inflammation in Sepsis.

Our previous work identified human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1) as a putative driver of LPS-induced NF-κB signaling in humans in vivo. While HIVEP1 is known to interact with NF-ĸB binding DNA motifs, its function in mammalian cells is unknown. We report increased HIVEP1 mRNA expression in monocytes from patients with sepsis and monocytes stimulated by Toll-like receptor agonists and bacteria. In complementary overexpression and gene deletion experiments HIVEP1 was shown to inhibit NF-ĸB activity and induction of NF-ĸB responsive genes. RNA sequencing demonstrated profound transcriptomic changes in HIVEP1 deficient monocytic cells and transcription factor binding site analysis showed enrichment for κB site regions. HIVEP1 bound to the promoter regions of NF-ĸB responsive genes. Inhibition of cytokine production by HIVEP1 was confirmed in LPS-stimulated murine Hivep1-/- macrophages and HIVEP1 knockdown zebrafish exposed to the common sepsis pathogen Streptococcus pneumoniae. These results identify HIVEP1 as a negative regulator of NF-κB in monocytes/macrophages that inhibits proinflammatory reactions in response to bacterial agonists in vitro and in vivo.

Introduction of a de novo Creb-binding protein gene mutation in sperm to produce a Rubinstein-Taybi syndrome model using inbred C57BL/6 mice.

Neurodevelopmental disorders, including intellectual disability and autism spectrum disorder, are often caused by de novo autosomal dominant mutations. While mouse models are frequently used to investigate these disorders, the genetic background sometimes affects the appearance or severity of mutant phenotypes. In a previous report, we developed a system to produce de novo heterozygous mutant mice using the Cre-LoxP system without the need to maintain the heterozygous mutant line itself (Takagi et al. 2015). To further verify the applicability of the de novo mutation system in sperm, we used this system to produce a mouse model for Rubinstein-Taybi syndrome, using a Cbp heterozygous mutant, which has been reported to be difficult to maintain on a C57BL/6 background. Here, we show that de novo Cbp- loss-of-function heterozygous mutant mice with a C57BL/6 background, present with a clear craniofacial phenotype and reduced locomotor activity in the open field test, which was not observed in the loss-of-function of Cbp heterozygous mutant line mice with a mixed genetic background, but was observed in the dominant negative Cbp heterozygous mutant line with a mixed genetic background. Meanwhile, the de novo heterozygous Cbp mutant mice still showed great variability in survival rates despite their inbred background. These results further confirmed that the de novo mutation system used in germ cells is effective for stable production and analysis of an autosomal dominant disorder mouse model, which is often difficult to maintain as a mutant mouse line.

Attenuated bidirectional short-term synaptic plasticity in the dentate gyrus of Schnurri-2 knockout mice, a model of schizophrenia.

The dentate gyrus of the hippocampus has been implicated in the pathophysiological basis of neuropsychiatric disorders including schizophrenia. We have identified several mouse models of neuropsychiatric disorders with robust molecular and functional defects in the dentate gyrus. Among them, mice lacking Schnurri-2 (Shn2 or HIVEP2) have been proposed as a model of schizophrenia and intellectual disability. Shn2 knockout mice exhibit behavioral abnormalities resembling symptoms of schizophrenia and HIVEP2-related intellectual disability as well as marked functional alterations in the soma and output synapse of the dentate granule cells (GCs). Although robust abnormalities were also observed in the dendritic spine morphology in the GCs, their functional correlates remain unknown. In the present study, we performed electrophysiological analyses of synaptic transmission at the medial perforant path (MPP) input onto the GCs in Shn2 knockout mice. While the basal synaptic efficacy was preserved, short-term synaptic depression induced by paired-pulse or low-frequency stimulation was reduced in the mutant mice. High-frequency tetanic stimulation induced lasting synaptic potentiation in both wild-type and mutant mice. However, the decaying synaptic potentiation shortly after the tetanic stimulation was significantly reduced in the mutant mice. These results indicate that the Shn2 deficiency attenuates bidirectional short-term synaptic plasticity at the MPP-GC synapse, thereby rendering the synapse more static. Our finding further supports a possible role of the dentate gyrus dysfunction in pathophysiology of schizophrenia and may also provide important information in interpreting morphology changes of the brain synapses in neuropsychiatric disorders.

Use of Anti-phospho-girdin Antibodies to Visualize Intestinal Tuft Cells in Free-Floating Mouse Jejunum Cryosections.

The actin binding protein girdin is a cytosolic protein that is required for actin remodeling to trigger cell migration in various tissues. Girdin is phosphorylated by both receptor and non-receptor tyrosine kinases at tyrosine 1798. Omori et al. developed site- and phosphorylation status-specific antibodies against human girdin at tyrosine-1798 (pY1798), which specifically bind to phosphorylated tyrosine-1798, but not to unphosphorylated tyrosine-1798. pY1798 antibodies have been used to specifically label tuft cells (TCs) that are present in mammalian gastrointestinal tissues, but the function of these cells is unclear. This protocol allows the robust visualization of TCs in the jejunum using pY1798 antibodies and immunofluorescence. To ensure successful and simple TC visualization, this protocol includes two histological techniques: production of free-floating cryosections from gelatin-filled jejunum tissue, and low-temperature antigen retrieval at 50 °C for 3 h. Filling the jejunum with gelatin maintains the shape of free-floating sections throughout the staining procedure, whereas low-temperature antigen retrieval ensures robust signals from TCs. Successful use of this protocol results in pY1798 staining of TCs distributed from villus tip to crypt. Stained TCs have a spool-shaped soma and fluorescent signals condense at the lumenal tip, which corresponds to the protruding 'tuft.' Phalloidin staining colocalized with pY1798-positive TCs at the thickened brush border, and corresponds to a rootlet mass extending from the TC tuft. This protocol could be used to examine TCs in human biopsy samples collected with gastrointestinal endoscopes. Furthermore, TCs were recently reported to accumulate following parasite infection in mice, suggesting that this protocol could have applications for diagnosis of parasite infections in the human gut.

[An Elderly Case of Recurrent Neuroendocrine Carcinoma of the Stomach Treated with Ramucirumab].

An 84-years-old man underwent total gastrectomy with D1 plus lymph node dissection in December 2015, and diagnosed as Stage III B neuroendocrine carcinoma of the stomach. An abdominal computed tomography revealed swollen paraaortic lymph nodes and left adrenal grand in May 2016. Since his serum level of CA19-9 was elevated, he was thus diagnosed as having recurrence, and was started chemotherapy with ramucirumab(RAM). After introduction of the chemotherapy, his serum level of CA19-9 was decreased gradually and metastatic foci were also decreased in size. Although the patient required relatively longer administration interval according to the severity of general fatigue, he continued the chemotherapy without severe adverse effects until he rejected further treatment in January 2017, and satisfactory therapeutic result was acquired. While the prognosis of gastric neuroendocrine carcinoma is reported to be very poor, no definitive therapeutic guideline is available at present. Especially in elderly patients, we should pay considerable attention to the selection of chemotherapeutic agents because of their own adverse effects. In the present case, RAM could be administered safely, and it seemed that RAM might become a useful therapeutic option for gastric neuroendocrine carcinoma even in elderly patients.

Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders.

Although the brains of patients with schizophrenia and bipolar disorder exhibit decreased brain pH relative to those of healthy controls upon postmortem examination, it remains controversial whether this finding reflects a primary feature of the diseases or is a result of confounding factors such as medication and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models that can be studied without confounds inherent in human studies. In the present study, we first reevaluated the pH of the postmortem brains of patients with schizophrenia and bipolar disorder by conducting a meta-analysis of existing data sets from 10 studies. We then measured pH, lactate levels, and related metabolite levels in brain homogenates from five neurodevelopmental mouse models of psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. All mice were drug naive with the same agonal state, postmortem interval, and age within each strain. Our meta-analysis revealed that brain pH was significantly lower in patients with schizophrenia and bipolar disorder than in control participants, even when a few potential confounding factors (postmortem interval, age, and history of antipsychotic use) were considered. In animal experiments, we observed significantly lower pH and higher lactate levels in the brains of model mice relative to controls, as well as a significant negative correlation between pH and lactate levels. Our findings suggest that lower pH associated with increased lactate levels is not a mere artifact, but rather implicated in the underlying pathophysiology of schizophrenia and bipolar disorder.

Immature morphological properties in subcellular-scale structures in the dentate gyrus of Schnurri-2 knockout mice: a model for schizophrenia and intellectual disability.

Accumulating evidence suggests that subcellular-scale structures such as dendritic spine and mitochondria may be involved in the pathogenesis/pathophysiology of schizophrenia and intellectual disability. Previously, we proposed mice lacking Schnurri-2 (Shn2; also called major histocompatibility complex [MHC]-binding protein 2 [MBP-2], or human immunodeficiency virus type I enhancer binding protein 2 [HIVEP2]) as a schizophrenia and intellectual disability model with mild chronic inflammation. In the mutants' brains, there are increases in C4b and C1q genes, which are considered to mediate synapse elimination during postnatal development. However, morphological properties of subcellular-scale structures such as dendritic spine in Shn2 knockout (KO) mice remain unknown. In this study, we conducted three-dimensional morphological analyses in subcellular-scale structures in dentate gyrus granule cells of Shn2 KO mice by serial block-face scanning electron microscopy. Shn2 KO mice showed immature dendritic spine morphology characterized by increases in spine length and decreases in spine diameter. There was a non-significant tendency toward decrease in spine density of Shn2 KO mice over wild-type mice, and spine volume was indistinguishable between genotypes. Shn2 KO mice exhibited a significant reduction in GluR1 expression and a nominally significant decrease in SV2 expression, while PSD95 expression had a non-significant tendency to decrease in Shn2 KO mice. There were significant decreases in dendrite diameter, nuclear volume, and the number of constricted mitochondria in the mutants. Additionally, neuronal density was elevated in Shn2 KO mice. These results suggest that Shn2 KO mice serve as a unique tool for investigating morphological abnormalities of subcellular-scale structures in schizophrenia, intellectual disability, and its related disorders.

Is Single-incision Laparoscopic Cholecystectomy Feasible for Acute Cholecystitis? A Consecutive Study of 60 Cases.

The feasibility of single-incision laparoscopic cholecystectomy (SIL-C) for patients with acute cholecystitis were evaluated based on the timing of operation after onset of symptoms. Sixty patients with acute cholecystitis who underwent SIL-C were divided into 2 groups according to the timing of operation: group E included 23 patients who underwent SIL-C within 72 hours, and group O included 37 patients who underwent SIL-C later. There were no statistical differences between group E and group O in clinicopathologic characteristics. Group E demonstrated significantly shorter operating time and less blood loss than group O. Although the incidences of additional port(s) requirements were not significantly different, 8 patients in group O required open conversion, indicating significantly higher rate. As group E demonstrated favorable surgical outcomes compared with group O, SIL-C for acute cholecystitis seems to be a feasible therapeutic procedure when performed within 72 hours as updated Tokyo Guidelines recommended.

[Two Cases of Single-Incision Laparoscopic Ileocecal Resection for Patients over 90 with Colon Cancer].

Single-incision laparoscopic surgery(SILS)is superior to multiport laparoscopic surgery in terms ofcosmetics, but in other terms it is still disputable and needs further investigation. The treatment of SILS for colon cancer has increased, however, the feasibility of single-incision laparoscopic colectomy(SILC)for patients over 90 with colon cancer has not been well examined. We report 2 cases ofsingle -incision laparoscopic ileocecal resection without complications. Case 1: A 104-year-old woman who had been diagnosed with pStage III a obstructive ascending colon cancer. There were no perioperative complications. She was discharged 15 days after the operation. During the 26 months of follow-up, there was no evidence oflocal recurrence or distant metastasis. Case 2: A 90-year-old woman who had been diagnosed with pStage I cecal cancer. There were no perioperative complications. She was discharged 10 days after the operation. Single-incision laparoscopic ileocecal resection for the aged patients is feasible when performed on patients selected by surgeons with extensive SILC experience.

[A Case of Gastrointestinal Stromal Tumor of the Small Intestine Complicated by Hemorrhagic Shock Due to Gastrointestinal and Intraperitoneal Bleedings].

A 44-years-old man presented to our hospital with bloody stool. CT of the abdomen revealed a 90mm mass adjacent to small intestine and high density ascites in lower abdomen. On the day of the admission, he lapsed into hemorrhagic shock caused by gastrointestinal bleedings. So emergency operation was performed. Operative findings showed a solid tumor of small intestine that were 95mm in diameter and a small amount of bloody ascites(100mL). Another tumor was also found in analis small intestine from primary lesion. Small bowel resections were performed for each lesion. Resected specimen showed the solid tumor, 95×70×50mm in size, in the small intestine. Histopathological findings showed outgrowth of spindle cells from the proper muscular layer to the subserosal layer. Immunohistochemical findings revealed positive staining for c-kit and CD34. c-kit positive GIST was thus diagnosed. Chemotherapy with imatinib was administered after surgery and the patient has been free from recurrent disease for 6 months after surgery.

Onset of Spinal Cord Astrocyte Precursor Emigration from the Ventricular Zone Involves the Zeb1 Transcription Factor.

During spinal cord development, astrocyte precursors arise from neuroepithelial progenitors, delaminate from the ventricular zone, and migrate toward their final locations where they differentiate. Although the mechanisms underlying their early specification and late differentiation are being deciphered, less is known about the temporal control of their migration. Here, we show that the epithelial-mesenchymal transition regulator Zeb1 is expressed in glial precursors and report that loss of Zeb1 function specifically delays the onset of astrocyte precursor delamination from the ventricular zone, correlating with transient deregulation of the adhesion protein Cadherin-1. Consequently, astrocyte precursor invasion into the Zeb1-/- mutant white matter is delayed, and induction of their differentiation is postponed. These findings illustrate how fine regulation of adhesive properties influences the onset of neural precursor migration and further support the notion that duration of exposure of migrating astrocyte precursors to environmental cues and/or their correct positioning influence the timing of their differentiation.

[A Case of Peritoneal Dissemination of Hilar Cholangiocarcinoma Presenting with Hematuria Six Years after Radical Surgery].

A 76-year-old man underwent radical surgery for Stage IV a hilar cholangiocarcinoma in July 2009, and had been followed at an outpatient clinic. Although no apparent recurrent lesion was detected by PET/CT examination, an elevated CA19-9 level was found in January 2014. He was then started on the oral anticancer drug S-1. However, his CA19-9 level increased gradually. The patient presented to a urological department with a complaint of macrohematuria in May 2015. Detailed examination revealed a mass lesion at the top of the urinary bladder, which was suspected to be peritoneal dissemination of the known hilar cholangiocarcinoma invading the urinary bladder wall. Thus, he underwent partial resection of the urinary bladder in July 2015. A histopathological examination of the resected specimen confirmed the diagnosis of recurrence. The patient is nowreceiving chemotherapy with gemcitabine and cisplatin. Detection of recurrences of cholangiocarcinoma is often difficult since the recurrence pattern of cholangiocarcinoma varies widely. However, early detection might enable longterm survival by adequate treatment including chemotherapy. Therefore, thorough multidisciplinary examinations are required when recurrence of cholangiocarcinoma is suspected. In addition, long-term follow-up after radical surgery is required since cholangiocarcinoma sometimes shows slow progression.

[Usefulness of Transumbilical Laparoscopic-Assisted Appendectomy for a Suspected Case of Hydrops Processus Vermiformis].

A-77-year-old man presented to our hospital with high fever and lower abdominal pain. Enhanced CT of the abdomen revealed swelling of the appendix with wall thickening and fluid collection. We diagnosed appendicitis with abscess formation and performed transumbilical laparoscopic-assisted appendectomy after the inflammation improved in response to antibiotics. Operative findings revealed a cystic lesion ofthe appendix and strong adhesion ofthe appendix to the terminal ileum. Based on these operative findings, we changed the operative procedure to a single-incision laparoscopic assisted ileocecal resection because ofthe possibility ofhydrops processus vermiformis. Histopathological findings revealed hyperplasia ofthe glandular epithelium with nuclear enlargement. Mucinous cystadenocarcinoma ofthe appendix was diagnosed. Additional surgery was not performed due to the patient's request. The patient has been free from recurrent disease for approximately 6 months after the surgery. Transumbilical laparoscopic-assisted appendectomy is useful for preventing pseudomyxoma peritonei and easing changes in extended operations for suspected cases of hydrops processus vermiformis.

Combined behavioral studies and in vivo imaging of inflammatory response and expression of mGlu5 receptors in schnurri-2 knockout mice.

Schnurri-2 (Shn-2) knockout (KO) mice have been proposed as a preclinical neuroinflammatory schizophrenia model. We used behavioral studies and imaging markers that can be readily translated to human populations to explore brain effects of inflammation. Shn-2 KO mice and their littermate control mice were imaged with two novel PET ligands; an inflammation marker [(11)C]PBR28 and the mGluR5 ligand [(18)F]FPEB. Locomotor activity was measured using open field exploration with saline, methamphetamine or amphetamine challenge. A significantly increased accumulation of [(11)C]PBR28 was found in the cortex, striatum, hippocampus and olfactory bulb of Shn-2 KO mice. Increased mGluR5 binding was also observed in the cortex and hippocampus of the Shn-2 KO mice. Open field locomotor testing revealed a large increase in novelty-induced hyperlocomotion in Shn-2 KO mice with abnormal (decreased) responses to either methamphetamine or amphetamine. These data provide additional support to demonstrate that the Shn-2 KO mouse model exhibits several behavioral and pathological markers resembling human schizophrenia making it an attractive translational model for the disease.

De novo inbred heterozygous Zeb2/Sip1 mutant mice uniquely generated by germ-line conditional knockout exhibit craniofacial, callosal and behavioral defects associated with Mowat-Wilson syndrome.

Mowat-Wilson syndrome (MOWS) is caused by de novo heterozygous mutation at ZEB2 (SIP1, ZFHX1B) gene, and exhibit moderate to severe intellectual disability (ID), a characteristic facial appearance, epilepsy and other congenital anomalies. Establishing a murine MOWS model is important, not only for investigating the pathogenesis of this disease, but also for identifying compounds that may improve the symptoms. However, because the heterozygous Zeb2 knockout mouse could not be maintained as a mouse line with the inbred C57BL/6 background, it was difficult to use those mice for the study of MOWS. Here, we systematically generated de novo Zeb2 Δex7/+ mice by inducing the Zeb2 mutation in the germ cells using conditional recombination system. The de novo Zeb2 Δex7/+ mice with C57BL/6 background developed multiple defects relevant to MOWS, including craniofacial abnormalities, defective corpus callosum formation and the decreased number of parvalbumin interneurons in the cortex. In behavioral analyses, these mice showed reduced motor activity, increased anxiety and impaired sociability. Notably, during the Barnes maze test, immobile Zeb2 mutant mice were observed over repeated trials. In contrast, neither the mouse line nor the de novo Zeb2 Δex7/+ mice with the closed colony ICR background showed cranial abnormalities or reduced motor activities. These results demonstrate the advantages of using de novo Zeb2 Δex7/+ mice with the C57BL/6 background as the MOWS model. To our knowledge, this is the first time an inducible de novo mutation system has been applied to murine germline cells to produce an animal model of a human congenital disease.

Single-Incision Laparoscopic Surgery for Undiagnosed Small Bowel Obstruction in a Patient without a History of Abdominal Surgery.

We herein report a 66-year-old female patient who developed an undiagnosed small bowel obstruction without a history of prior abdominal surgery and was successfully treated by single-incision laparoscopic surgery. A small bowel obstruction with unknown cause typically requires some sort of surgical treatment in parallel with a definitive diagnosis. Although open abdominal surgery has been generally performed for the treatment of small bowel obstructions, laparoscopic surgery for small bowel obstructions has been increasing in popularity due to its less invasiveness, including fewer postoperative complications and a shorter hospital stay. As a much less invasive therapeutic strategy, we have performed single-incision laparoscopic surgery for the treatment of an undiagnosed small bowel obstruction. We were able to make a definitive diagnosis after sufficient intra-abdominal inspection and to perform enterotomy through a small umbilical incision. Single-incision laparoscopic surgery appears to be comparable to conventional laparoscopic surgery and provides improved cosmesis, although it is an optional strategy only applicable to selected patients.