Unilateral hypoglossal nerve palsy following orthognathic surgery: A case report and literature review.

INTRODUCTION: Hypoglossal nerve palsy (HNP) can be caused by nerve damage from the central nerve to a peripheral nerve, and individuals with multiple factors could be predisposed to HNP. We report a case of isolated unilateral HNP after orthognathic surgery. CASE PRESENTATION: A 56-year-old Japanese woman complained of jaw distortion and malocclusion. She had undergone a Le Fort I osteotomy and bilateral sagittal split ramus osteotomy (BSSRO) under general anesthesia in August 2021. On postoperative day 3, she experienced tongue motility, and when the tongue protruded forward, the tongue tip shifted to the right, and swelling of the right lateral pharyngeal wall was observed. An additional blood test revealed increased antibody titer levels (40×), cytomegalovirus IgG EIA titer (16.9 U/mL), HSV-IgG EIA titer (40 U/mL), and EBV-viral capsid antigen (VCA) IgG EIA titer (1.4 U/mL). We administered valacyclovir hydrochloride 1000 mg/day for 7 days, prednisolone (PSL) 60 mg/day, mecobalamin 1500 µg/day, and adenosine triphosphate (ATP) disodium hydrate 300 mg/day. A neurological examination revealed no central lesions, and we continued the patient's tongue-function training and oral hygiene guidance. The tongue apex deviation was resolved approx. 3 months postoperatively. DISCUSSION: There are no major reports on the etiology of HNP after orthognathic surgery. The possibility of HNP triggered by endotracheal intubation or through packing gauze under general anesthesia and viral infection cannot be ruled out. CONCLUSION: Clinicians should be aware of the possibility of unilateral HNP following orthognathic surgery.

Identification of a new gibberellin receptor agonist, diphegaractin, by a cell-free chemical screening system.

Gibberellin (GA) is a phytohormone that regulates various developmental processes during the plant life cycle. In this study, we identify a new GA agonist, diphegaractin, using a wheat cell-free based drug screening system with grape GA receptor. A GA-dependent interaction assay system using GA receptors and DELLA proteins from Vitis vinifera was constructed using AlphaScreen technology and cell-free produced proteins. From the chemical compound library, diphegaractin was found to enhance the interactions between GA receptors and DELLA proteins from grape in vitro. In grapes, we found that diphegaractin induces elongation of the bunch and increases the sugar concentration of grape berries. Furthermore, diphegaractin shows GA-like activity, including promotion of root elongation in lettuce and Arabidopsis, as well as reducing peel pigmentation and suppressing peel puffing in citrus fruit. To the best of our knowledge, this study is the first to successfully identify a GA receptor agonist showing GA-like activity in agricultural plants using an in vitro molecular-targeted drug screening system.

Efficacy and safety of mycophenolate mofetil in treating immune-related hepatitis induced by immune checkpoint inhibitor use: A retrospective study.

Background and Aim: To investigate the outcomes in eight Japanese patients with cancer treated with mycophenolate mofetil (MMF) and corticosteroids for immune checkpoint inhibitor treatment-induced severe immune-related hepatitis (ir-hepatitis) and the efficacy and safety of MMF. Methods: We retrospectively examined patient background, treatment course, as well as examination and imaging data using electronic medical records. Results: The ratio of male to female patients was 7:1, and the median age was 60 years (27-72 years). There were five and two cases of kidney cancer and malignant melanoma, respectively, and one case of lung cancer. The median number of days until MMF administration in addition to systemic corticosteroid therapy after the onset of ir-hepatitis was 14.5 (2-42). The patients were categorized as four "good responders" who showed an improvement in the liver function tests following MMF treatment and four "poor responders" who did not. Furthermore, the time from the onset of ir-hepatitis to initial MMF administration was significantly shorter in good responders (median 3 days, range 2-15 days) than in poor responders (median 25.5 days, range 14-42 days) (P = 0.042). No significant intergroup difference was observed in other clinical factors. No serious adverse events caused by MMF were observed in any case. Conclusions: According to these findings, early recognition of corticosteroid refractoriness and the use of MMF may be beneficial in patients with ir-hepatitis.

Association between impaired healing after orthognathic surgery and irritable bowel syndrome: A case report and literature review.

INTRODUCTION: In the disease irritable bowel syndrome (IBS), gastrointestinal function is worsened even though no organic abnormalities are observed in the gastrointestinal mucosa. We report the case of an orthognathic surgery patient with suspected irritable bowel syndrome. CASE: In September 2017, a 15-year-old Japanese female was referred to us with dental crowding, malocclusion, and mandibular protrusion. In June 2019, a disagreement with classmates led to abdominal pain, diarrhea, and hemorrhage; in August 2019, a preoperative blood test showed sudden anemia, and her surgery was thus postponed. Subsequent upper and lower gastrointestinal endoscopy revealed no organic abnormality, and no definitive diagnosis was made. In March 2020, after an improvement in anemia was observed, a segmental Le Fort I osteotomy and bilateral sagittal split ramus osteotomy (BSSRO) were performed under general anesthesia. On the third post-operative day, due to the mucosal dehiscence adjacent to the suture part, the titanium plate was exposed, and irrigation of the wound with normal saline solution and oral hygiene instruction was continued daily for 2 weeks. Two years and eight months have passed since the surgery, and the healing of the oral mucosa and bone has been uneventful. DISCUSSION: The relationship between IBS and post-operative impaired healing associated with the fragility of the oral mucosa is unknown. However, psychological stress has been reported as a cause of IBS and to be related to oral microorganisms. CONCLUSION: Reducing risk factors for IBS and maintaining proper perioperative oral hygiene is essential in managing similar cases.

Efficacy and safety of Infliximab for steroid-resistant immune-related adverse events: A retrospective study.

The present study investigated outcomes of infliximab (IFX) treatment among 8 Japanese patients with various types of cancer (4 with malignant melanoma, 3 with lung cancer and 1 with renal cancer) who developed severe steroid-resistant immune-related adverse events (irAEs) in association with immune checkpoint inhibitors (ICIs) to determine its efficacy and safety. Information, including patient background, treatment progress, examination data and imaging data, was collected retrospectively from electronic medical records. Adverse reactions were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Specific ICIs used were anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibody preparations in 7, 2 and 5 patients, respectively. Specific irAEs included grade 3 diarrhea/colitis in 7 patients and disseminated intravascular coagulation and myocarditis attributed to autoimmune activation in 1 patient. The median duration between systemic steroid and IFX treatments was 9 (range, 2-39) days. A total of 3 patients responded to IFX, 1 of whom responded after one dose and 2 responded after two doses. Respective diseases improved to grade 0 after a median of 18 (range, 9-32) days. No AEs were attributable to IFX. Additionally, anti-cytomegalovirus (CMV) and antibacterial agents were administered in parallel given the presence of CMV and Clostridium difficile (CD) infections in all patients, except in 1 exhibiting a marked IFX response after one dose. The combination of highly immunosuppressive IFX and high-dose systemic steroid administration over a long period presumably predisposed the patients to opportunistic enteric infections. Accordingly, early initiation of IFX treatment in conjunction with systemic steroid therapy should be considered for severe diarrhea/colitis and other irAEs. However, the possibility for CMV and CD infections should be recognized, and for these the treatment strategy may need to be modified at an early stage.

[Effect of Relative Dose Intensity(RDI)-Guided Dose Adjustments of Palbociclib on Duration of Treatment in Patients with Severe Neutropenia].

The study subjects consisted of 54 patients with inoperable or recurrent breast cancer who were administered a combination of palbociclib plus endocrine therapy. We examined the onset of neutropenia during the first course of treatment and evaluated the influence that various risk factors had on treatment continuity. Patients with neutropenia Grade≥3 had significantly lower relative dose intensity(RDI) values during the first course of treatment than did patients with neutropenia Grade ≤2. Patients with neutropenia Grade≥3 showed significantly longer treatment to failure than did patients with neutropenia Grade≤2. These results suggest that the degree of neutropenia during the first course of treatment might contribute to treatment continuity and that it is important to improve the curative effect by maintaining appropriate RDI and by continuously administering palbociclib in patients with neutropenia Grade≥3.

Two middle-aged cases of deep overbite without molar support treated by orthognathic surgery.

INTRODUCTION: Patients with severe overbite in middle age often undergo prosthetic treatment without a diagnosis of dentofacial deformity, but soft tissue trauma can occur in such patients due to the lack of inter-occlusal space. Comprehensive surgical orthodontic treatment and prosthetic treatment are indicated to correct the overbite and soft tissue injury for such patients. PRESENTATION OF CASE: We report the cases of two middle-aged patients with dentofacial deformity and severe overbite without molar support. In both cases, prosthetic treatment had been performed for many years without any improvement of the occlusion. Case 1: A 47-year-old Japanese man had a maxillary incisor protrusion and reduced lower anterior facial height profile with the left mandibular molars lost due to periodontal disease. After preoperative orthodontic treatment and occlusal elevation in the molar teeth using an implant prosthesis, a sagittal split ramus osteotomy (SSRO) was performed. Case 2: A 57-year-old Japanese woman had mandibular retrognathia with maxilla and mandibular-arch length discrepancy. The left mandibular molars needed to be extracted due to periodontal disease. After preoperative orthodontic treatment and reconstruction of the molar occlusion using an implant prosthesis, three-segment Le Fort I osteotomy and SSRO were performed. DISCUSSION: Malocclusion with dentofacial deformity is a risk factor for severe deep overbite or other occlusion collapse. CONCLUSION: In middle-aged patients with deep overbite with missing molar teeth, we should consider both prosthodontic treatment and comprehensive dental therapy, including orthognathic surgery.

Antidiabetic effects of novel cell culture established from grapevine, Vitis vinifera cv. Koshu.

Vitis vinifera cv. Koshu is an indigenous cultivar in Japan and has several characteristics that distinguish it from European V. vinifera. In Japan, Koshu is the most popular cultivar for wine making. We report herein a cell culture established from Koshu for use as a system for the production of resveratrol and its derivatives. Grape cell culture YU-1 was developed from the apex tissues of Koshu. YU-1 growth was favorably compared with BY-2 growth, a standard cell line in plant cell biology. Stilbene production and stilbene synthesis gene expression in YU-1 were upregulated by UV-C irradiation. YU-1 irradiated with UV-C decreased hemolymph sugar levels in model animals. Taken together, this study suggests that YU-1 may be used as a source of valuable medicinal components in plant cell bioreactor systems.

Tendencies of Woman Doctors Registered in Japan during the Taisho Era.

The Taisho-Era (1912 to 1926) was a period during which Japanese women increasingly took part in various social activities and employment. The author surveyed the registered woman-doctors listed in the official gazette and the journal of the Japanese Society of Woman Doctors from the first to the 10th years of the Taisho-Era (1912 to 1921) and investigated their medical life-times, including with regard to their husbands and family surroundings, hobbies, and so on. According to the author, there were 467 woman doctors during the first 10 years of the Taisho-Era, far more than the 239 during the Meiji-Era (1886 to 1912). Immediately after medical registration they had a tendency to choose employment in large cities such as Tokyo because there were many medical facilities suitable' for clinical training there. After several years of this training, some of them moved their activities to the countryside. The 1923 Great Kanto Earthquake caused tremendous damagp,to people, including the woman doctors, who were affected by the collapse of buildings and fires (this subject is developed in a separate paper).

Peptidoglycan from fermentation by-product triggers defense responses in grapevine.

Plants are constantly under attack from a variety of microorganisms, and rely on a series of complex detection and response systems to protect themselves from infection. Here, we found that a by-product of glutamate fermentation triggered defense responses in grapevine, increasing the expression of defense response genes in cultured cells, foliar chitinase activity, and resistance to infection by downy mildew in leaf explants. To identify the molecule that triggered this innate immunity, we fractionated and purified candidates extracted from Corynebacterium glutamicum, a bacterium used in the production of amino acids by fermentation. Using hydrolysis by lysozyme, a silkworm larva plasma detection system, and gel filtration analysis, we identified peptidoglycan as inducing the defense responses. Peptidoglycans of Escherichia coli, Bacillus subtilis, and Staphylococcus aureus also generated similar defensive responses.

Partial characterization of proapoptotic action of biliary deteriorated lipids on biliary epithelial cells in pancreaticobiliary diseases.

BACKGROUND: Lysophosphatidylcholine (LPC), a derivative of phosphatidylcholine (PC) hydrolyzed by phospholipase A2 (PLA2), is reported to be increased in bile of the patients with pancreaticobiliary maljunction or intrahepatic cholelithiasis, both of which are major risk factors for biliary tract cancers with undefined etiology. METHODS: To investigate the influence of LPC on biliary epithelial cells (BECs), a human cholangiocarcinoma cell line HuCCT-1 and an immortalized human BECs line MMNK-1 were treated by LPC in vitro. RESULTS: The treatment of LPC exhibited cytotoxicity with significant induction of apoptosis. In addition to upregulation of Fas receptor mRNA, the activities of caspase-8 and -3 were significantly increased by LPC treatment. We also observed upregulation of Bax mRNA and significant activation of caspase-9. Interestingly, LPC significantly upregulated G2A, a member of transmembrane G protein-coupled receptor family at mRNA and protein levels, and 9-hydroxyoctadecaduenoic acid (9HODE), an oxidized free fatty acid that functions as a ligand for G2A dramatically reduced cell viability when treated together with LPC. CONCLUSIONS: These data suggest that PLA2, which catalyzes the hydrolysis of PC to yield LPC and free fatty acid, is supposed to be an important etiological factor in BECs injury in pancreaticobiliary maljunction or intrahepatic cholelithiasis.

Effect of a dienogest for an experimental three-dimensional endometrial culture model for endometriosis.

The pathogenesis of endometriosis remains poorly understood at least in part because early stages of the disease process are difficult to investigate. Previous studies have proposed a three-dimensional fibrin matrix culture model to study human endometriosis. We examined the ultrastructural features of the endometriosis in this model and assessed the effect of a progestin on endometrial outgrowth and apoptosis in this culture system. Endometrial explants were placed in three-dimensional fibrin matrix culture and treated with and without various concentrations of the progestin dienogest. By the second week, endometrial gland-like formation was established in outgrowths both attached to and at a distance from the explants. These cells formed a combination of clumps and tubular monolayers surrounding a central cavity. Electron microscopy demonstrated that these cells are polarized with microvilli on the apical surface, desmosome-like structures, and basement membrane; features consistent with glandular epithelial cells. Outgrowth of endometrial stromal cells and glandular formation was impaired in response to dienogest in a dose-dependent manner. Our study shows that the human endometrial explants cultured in three-dimensional fibrin matrix establish outgrowths that ultrastructurally resemble ectopic endometrial implants. This model may provide insight into the cellular processes leading to endometriosis formation and enables screening of therapeutic compounds.

Detection of the Hematopoietic Stem and Progenitor Cell Marker CD133 during Angiogenesis in Three-Dimensional Collagen Gel Culture.

We detected the hematopoietic stem and progenitor cell marker CD133 using immunogold labeling during angiogenesis in a three-dimensional collagen gel culture. CD133-positive cells were present in capillary tubes newly formed from aortic explants in vitro. The CD133-positive cell population had the capacity to form capillary tubes. Lovastatin strongly inhibited cell migration from aortic explants and caused the degradation of the capillary tubes. The present study provides insight into the function of CD133 during angiogenesis as well as an explanation for the antiangiogenic effect of statins.

Detection of CD133 (prominin-1) in a human hepatoblastoma cell line (HuH-6 clone 5).

We examined CD133 distribution in a human hepatoblastoma cell line (HuH-6 clone 5). We directly observed the cultured cells on a pressure-resistant thin film (silicon nitride thin film) in a buffer solution by using the newly developed atmospheric scanning electron microscope (ASEM), which features an open sample dish with a silicon nitride thin film window at its base, through which the scanning electron microscope beam scans samples in solution, from below. The ASEM enabled observation of the ventral cell surface, which could not be observed using standard SEM. However, observation of the dorsal cell surface was difficult with the ASEM. Therefore, we developed a new method to observe the dorsal side of cells by using Aclar® plastic film. In this method, cells are cultured on Aclar plastic film and the dorsal side of cells is in contact with the thin silicon nitride film of the ASEM dish. A preliminary study using the ASEM showed that CD133 was mainly localized in membrane ruffles in the peripheral regions of the cell. Standard transmission electron microscopy and scanning electron microscopy revealed that CD133 was preferentially concentrated in a complex structure comprising filopodia and the leading edge of lamellipodia. We also observed co-localization of CD133 with F-actin. An antibody against CD133 decreased cell migration. Methyl-ß-cyclodextrin treatment decreased cell adhesion as well as lamellipodium and filopodium formation. A decrease in the cholesterol level may perturb CD133 membrane localization. The results suggest that CD133 membrane localization plays a role in tumor cell adhesion and migration.

Auxin-responsive grape Aux/IAA9 regulates transgenic Arabidopsis plant growth.

We report the characterization of VvIAA9, an auxin/indole-3-acetic acid (Aux/IAA) protein, in grapevine (Vitis vinifera L.). VvIAA9 was expressed abundantly in leaves and berries. VvIAA9 transcription was drastically upregulated from anthesis to onset of ripening (termed véraison), in which berry diameter rapidly increased. Treatment with exogenous IAA induced VvIAA9 expression in grape leaves, suggesting that VvIAA9 is an auxin-responsive Aux/IAA protein. The overexpression of VvIAA9 in Arabidopsis thaliana promoted plant growth, including rapid floral transition. However, no morphological differences were observed between the control plant and the VvIAA9-overexpressing plant. The overexpression of VvIAA9 in Arabidopsis plants rendered the plants hyposensitive to exogenous IAA. The exogenous IAA treatment did not induce VvIAA9-overexpressing Arabidopsis plant growth and expression of IAA-responsive HAT2. Taken together, we conclude that grape Aux/IAA9 protein is likely to play a crucial role as a plant growth regulator.

Characterization of grape C-repeat-binding factor 2 and B-box-type zinc finger protein in transgenic Arabidopsis plants under stress conditions.

Simultaneous induction of multiple stress tolerance by single-gene transfer is a powerful strategy to engineer crop plants to improve tolerance to environmental stress under field condition. The possibility of enhancement of multiple stress tolerance by four grape transcription factors that enhance low-temperature tolerance (VvCBF2, VvCBF4, VvCBFL, and VvZFPL) were analyzed using the Arabidopsis plants overexpressing these factors. Consequently, two of the four proteins, VvCBF2 and VvZFPL, were found to confer tolerance to cold, drought, and salinity stresses in Arabidopsis plants, but not to heat stress. Photosynthesis-related genes were down-regulated in both CBF2- and ZFPL-overexpressing plants, resulting in plant growth retardation. On the other hand, the overexpression of VvCBF2 activated the transcription of CBL-interacting protein kinase 7, a serine/threonine kinase involved in cold response, in Arabidopsis plants. Our study provides that one of grape CBF family, VvCBF2, and one of B-box ZFP family, VvZFPL, confer multiple stress tolerance to plants.

Auxin-nonresponsive grape Aux/IAA19 is a positive regulator of plant growth.

We report the characterization of VvIAA19, an auxin/indole-3-acetic acid (Aux/IAA) protein, in grapevine (Vitis vinifera L.). VvIAA19 was expressed abundantly in berries. VvIAA19 transcription was rapidly increased at pre-anthesis and then decreased during fruit set. Before véraison, however, VvIAA19 gene expression was upregulated again and maximum expression was maintained until the end of ripening. Exogenous IAA did not induce VvIAA19 expression in grape leaves, suggesting that VvIAA19 might be auxin-nonresponsive. The overexpression of VvIAA19 in Arabidopsis thaliana had a notable effect on plant growth. Although no morphological changes were observed, transgenic Arabidopsis plants overexpressing VvIAA19 exhibited faster growth, including root elongation and floral transition, than the control plant, suggesting that the constitutive expression of VvIAA19 protein resulted in increased growth rates without any detectable harm. Taken together, we conclude that grape Aux/IAA19 protein is likely to play a crucial role as a plant growth regulator.

Spontaneously hypertensive rats develop pronounced hepatic steatosis induced by choline-deficient diet: Evidence for hypertension as a potential enhancer in non-alcoholic steatohepatitis.

AIM: Patients with non-alcoholic steatohepatitis (NASH) frequently have many co-morbidities including essential hypertension, which is reported to increase vascular production of reactive oxygen species (ROS) and alter the hepatic anti-oxidant defense system. Since ROS play a role in the pathogenesis of NASH, it is hypothesized that hypertension modulates the hepatic oxidative status and influences the development of NASH. The aim of this study was to investigate the potential effects of hypertension on the progression of NASH. METHODS: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats as normotensive controls were fed choline-deficient (CD) diet for 5 weeks. Histological changes, messenger RNA (mRNA) expression and thiobarbituric acid reactive substances (TBARS) levels in the liver were assessed in each group. RESULTS: Choline-deficient diet led to pronounced hepatic steatosis in SHR with an 8-fold increase of the hepatic triglyceride content, while there was no significant increase in WKY. These changes in SHR were associated with significant reduction in the expression of mRNA for peroxisome proliferator activated receptor α, acyl-CoA oxidase, microsomal triglyceride transfer protein, and apolipoprotein B100. Consistent with the significant reduction of hepatic superoxide dismutase activity and marked downregulation of the gene expression of hepatic antioxidant enzymes, the hepatic TBARS level and the plasma level of alanine aminotransferase were only increased in SHR on CD diet. CONCLUSIONS: Spontaneously hypertensive rats receiving CD diet showed severe hepatic steatosis associated with reduction of hepatic anti-oxidant capacity, leading to increased hepatic oxidative stress and tissue damage. Accordingly, hypertension might have a potential effect on the progression of NASH.

HSG1, a grape Bcl-2-associated athanogene, promotes floral transition by activating CONSTANS expression in transgenic Arabidopsis plant.

HSG1 (Heat shock-induced gene 1) is one of the high-temperature-induced proteins in grapevine. Sequence analysis has demonstrated that HSG1 is a grape Bcl-2-associated athanogene (BAG) that contains IQ and BAG domains in its sequence. HSG1 expression was not detected in leaves without heat treatment, while tendrils, stems, flowers, and berries expressed HSG1 even without heat treatment. By heat treatment at 45°C for 60 min, HSG1 expression was upregulated in both leaves and berries. HSG1-overexpressing Arabidopsis plant remained viable even after exposure to extremely high temperatures. Although no morphological changes were observed, the HSG1-overexpressing Arabidopsis plant exhibited faster floral transition than the control plant. Analysis of the transcription profile of HSG1-overexpressing seedling by cDNA microarray and quantitative RT-PCR demonstrated that the gene expression of the flowering promoter, CONSTANS (CO), in the photoperiod pathway was up-regulated in the seedling. Importantly, the overexpression of HSG1 increased CO expression by ~400% compared with the control seedling. Meanwhile, heat treatment upregulated grape CO expression in grape leaves. Our study provides the possibility that plant BAG protein may be related to the regulation of floral transition by activating CO expression in the photoperiod pathway.

Pink-colored grape berry is the result of short insertion in intron of color regulatory gene.

We report here that pink grape berries were obtained by a short insertion in the intron of the MybA1 gene, a gene that regulates grape berry color. Genetic variation was detected among the MybA1 genes from grapes cultivated worldwide. PCR analysis of the MybA1 gene demonstrated that the size of the MybA1 gene in the red allele differs among grapes. Oriental V. vinifera bearing pink berries has the longest MybA1 gene among grapes, whereas the shortest MybA1 gene was detected in occidental V. vinifera grapes. The nucleotide sequences of the MybA1 genes demonstrated that oriental V. vinifera has two additional gene fragments (44 bp and 111 bp) in the promoter region of the MybA1 gene in the red allele and another 33 bp fragment in the second intron of the MybA1 gene in the red allele. The short insertion in the intron decreased the transcription activity in the model system and retained MybA1 transcripts with unspliced intron in the total RNA. From the experiments using deletion mutants of the 33 bp short insertion, 16 bp of the 3' end in the insertion is a key structure for a defect in splicing of MybA1 transcripts. Thus, a weakly colored grape berry might be a result of the short insertion in the intron of a color regulatory gene. This is new evidence concerning the molecular mechanism of the fate of grape berry color. These findings are expected to contribute to the further understanding of the color variation in grape berries, which is correlated with the evolutional events occurring in the MybA1 gene of grapes.