Proteomic profiling of bronchoalveolar lavage fluid uncovers protein clusters linked to survival in idiopathic forms of interstitial lung disease.

Background: Idiopathic interstitial pneumonias (IIPs) such as idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with autoimmune features (IPAF), present diagnostic and therapeutic challenges due to their heterogeneous nature. This study aimed to identify intrinsic molecular signatures within the lung microenvironment of these IIPs through proteomic analysis of bronchoalveolar lavage fluid (BALF). Methods: Patients with IIP (n=23) underwent comprehensive clinical evaluation including pre-treatment bronchoscopy and were compared to controls without lung disease (n=5). Proteomic profiling of BALF was conducted using label-free quantitative methods. Unsupervised cluster analyses identified protein expression profiles which were then analyzed to predict survival outcomes and investigate associated pathways. Results: Proteomic profiling successfully differentiated IIP from controls. k-means clustering, based on protein expression revealed three distinct IIP clusters, which were not associated with age, smoking history, or baseline pulmonary function. These clusters had unique survival trajectories and provided more accurate survival predictions than the Gender Age Physiology (GAP) index (C-index 0.794 vs. 0.709). The cluster with the worst prognosis featured decreased inflammatory signaling and complement activation, with pathway analysis highlighting altered immune response pathways related to immunoglobulin production and B cell-mediated immunity. Conclusions: The unsupervised clustering of BALF proteomics provided a novel stratification of IIP patients, with potential implications for prognostic and therapeutic targeting. The identified molecular phenotypes underscore the diversity within the IIP classification and the potential importance of personalized treatments for these conditions. Future validation in larger, multi-ethnic cohorts is essential to confirm these findings and to explore their utility in clinical decision-making for patients with IIP.

Long-term postoperative prognosis and associated risk factors of chronic subdural hematoma in the elderly.

Surgical treatment for chronic subdural hematoma（CSDH）has contributed to good outcome. However, several recent studies have revealed that surgical outcomes for elderly patients were not decisively good. In this study, prognosis of CSDH patients in elderly were analyzed. This study included 232 CSDH patients who were treated in our department and 2 affiliated hospitals, and poor prognosis was defined as aggravation of modified Rankin scale (mRS) at examination comparing with that at discharge, or mRS 3 and higher at examination. We collected data from medical records and questionnaires on the following clinical characteristics of patients: age, sex, findings at admission, medication of antiplatelets and anticoagulants, radiological findings on computed tomography, recurrence, place of discharge, perioperative systemic complications, and mRS at discharge and at examination. The cut-off value of age for poor prognosis of all CSDH patients was 74 years old in this study. In multivariate analysis of all cases, age was prognostic factor for poor outcome:75 years old or higher（p=0.0002）. In this group, mRS at discharge(p=0.0184) and postoperative medical diseases(p<0.0001) were the risk factors of poor prognosis. In this present study, high age and activities of daily life（ADL） at discharge were significant prognostic factors for poor outcome of CSDH. Improvement of ADL at discharge with care for postoperative systemic complications and careful rehabilitation can contribute to good prognosis for CSDH in elderly patients.

Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility.

We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute cellular stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. At the mechanistic levels, the microglial secretion of High-Mobility Group Box (HMGB), which is known to bind with and regulate the NMDA-type glutamate receptors, was elevated. Consequently, the hyperactivation of the prelimbic layer 5 excitatory neurons, a neural substrate for cognitive inflexibility, was also observed. The upregulation of the microglial HMGB signaling and neuronal hyperactivation were normalized by the pharmacological and microglia-specific genetic interventions. Taken together, we show a pivotal role of cortical microglia and microglia-neuron interaction in stress-induced cognitive inflexibility. We underscore the N-GAPDH cascade in microglia, which causally mediates stress-induced cognitive alteration.

Real-world epidemiology and treatment patterns of patients with locally advanced or metastatic urothelial carcinoma: Retrospective analysis of Diagnosis Procedure Combination claims data in Japan.

OBJECTIVES: Evaluate real-world epidemiologic trends and treatment patterns in newly diagnosed patients with locally advanced or metastatic urothelial carcinoma (la/mUC) in Japan. METHODS: This retrospective analysis included adults with newly diagnosed la/mUC in Japan (January 2015-December 2019) from a nationwide-linked electronic medical record Diagnostic Procedure Combination claims dataset. Outcomes included epidemiologic trends (incidence and prevalence), baseline demographics, clinical characteristics, and treatment patterns in newly diagnosed patients with la/mUC before (2015-2017) and after (2018-2019) approval of pembrolizumab in Japan. RESULTS: Of 975 patients included, 76.4% were men; 71.6% were aged 70 years or older. Most cases (70.5%) were of the bladder. Between 2015 and 2019, the annual age-adjusted incidence increased from 6.8 to 12.4 per 100 000; the annual age-adjusted period prevalence increased from 13.0 to 25.2 per 100 000; and 307 (31.5%) and 668 (68.5%) patients were diagnosed from 2015 to 2017 and 2018 to 2019, respectively. Overall, 731 (75%) patients received systemic anticancer therapy; all received 1 line and 50.2% received 2 lines of therapy; 78.3% of patients received gemcitabine plus platinum-based therapy and 2.2% received pembrolizumab as first-line treatment. First-line treatment rates increased from 69.4% to 77.5% after pembrolizumab approval. Of 367 patients who received second-line treatment, 22.3% received gemcitabine plus platinum-based therapy; 14.7% received pembrolizumab. CONCLUSIONS: In the Japanese regions considered, incidence and prevalence of newly diagnosed la/mUC increased over time and first-line treatment with pembrolizumab increased after approval.

Usefulness of pituitary high-resolution 3D MRI with deep-learning-based reconstruction for perioperative evaluation of pituitary adenomas.

PURPOSE: To evaluate the diagnostic value of T1-weighted 3D fast spin-echo sequence (CUBE) with deep learning-based reconstruction (DLR) for depiction of pituitary adenoma and parasellar regions on contrast-enhanced MRI. METHODS: We evaluated 24 patients with pituitary adenoma or residual tumor using CUBE with and without DLR, 1-mm slice thickness 2D T1WI (1-mm 2D T1WI) with DLR, and 3D spoiled gradient echo sequence (SPGR) as contrast-enhanced MRI. Depiction scores of pituitary adenoma and parasellar regions were assigned by two neuroradiologists, and contrast-to-noise ratio (CNR) was calculated. RESULTS: CUBE with DLR showed significantly higher scores for depicting pituitary adenoma or residual tumor compared to CUBE without DLR, 1-mm 2D T1WI with DLR, and SPGR (p < 0.01). The depiction score for delineation of the boundary between adenoma and the cavernous sinus was higher for CUBE with DLR than for 1-mm 2D T1WI with DLR (p = 0.01), but the difference was not significant when compared to SPGR (p = 0.20). CUBE with DLR had better interobserver agreement for evaluating adenomas than 1-mm 2D T1WI with DLR (Kappa values, 0.75 vs. 0.41). The CNR of the adenoma to the brain parenchyma increased to a ratio of 3.6 (obtained by dividing 13.7, CNR of CUBE with DLR, by 3.8, that without DLR, p < 0.01). CUBE with DLR had a significantly higher CNR than SPGR, but not 1-mm 2D T1WI with DLR. CONCLUSION: On the contrast-enhanced MRI, compared to CUBE without DLR, 1-mm 2D T1WI with DLR and SPGR, CUBE with DLR improves the depiction of pituitary adenoma and parasellar regions.

CREB3L1/OASIS: cell cycle regulator and tumor suppressor.

Cell cycle checkpoints detect DNA errors, eventually arresting the cell cycle to promote DNA repair. Failure of such cell cycle arrest causes aberrant cell proliferation, promoting the pathogenesis of multiple diseases, including cancer. Endoplasmic reticulum (ER) stress transducers activate the unfolded protein response, which not only deals with unfolded proteins in ER lumen but also orchestrates diverse physiological phenomena such as cell differentiation and lipid metabolism. Among ER stress transducers, cyclic AMP-responsive element-binding protein 3-like protein 1 (CREB3L1) [also known as old astrocyte specifically induced substance (OASIS)] is an ER-resident transmembrane transcription factor. This molecule is cleaved by regulated intramembrane proteolysis, followed by activation as a transcription factor. OASIS is preferentially expressed in specific cells, including astrocytes and osteoblasts, to regulate their differentiation. In accordance with its name, OASIS was originally identified as being upregulated in long-term-cultured astrocytes undergoing cell cycle arrest because of replicative stress. In the context of cell cycle regulation, previously unknown physiological roles of OASIS have been discovered. OASIS is activated as a transcription factor in response to DNA damage to induce p21-mediated cell cycle arrest. Although p21 is directly induced by the master regulator of the cell cycle, p53, no crosstalk occurs between p21 induction by OASIS or p53. Here, we summarize previously unknown cell cycle regulation by ER-resident transcription factor OASIS, particularly focusing on commonalities and differences in cell cycle arrest between OASIS and p53. This review also mentions tumorigenesis caused by OASIS dysfunctions, and OASIS's potential as a tumor suppressor and therapeutic target.

AIbZIP/CREB3L4 Promotes Cell Proliferation via the SKP2-p27 Axis in Luminal Androgen Receptor Subtype Triple-Negative Breast Cancer.

Breast cancer ranks first in incidence and fifth in cancer-related deaths among all types of cancer globally. Among breast cancer, triple-negative breast cancer (TNBC) has few known therapeutic targets and a poor prognosis. Therefore, new therapeutic targets and strategies against TNBC are required. We found that androgen-induced basic leucine zipper (AIbZIP), also known as cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4), which is encoded by Creb3l4, is highly upregulated in a particular subtype of TNBC, luminal androgen receptor (LAR) subtype. We analyzed the function of AIbZIP through depletion of AIbZIP by siRNA knockdown in LAR subtype TNBC cell lines, MFM223 and MDAMB453. In AIbZIP-depleted cells, the proliferation ratios of cells were greatly suppressed. Moreover, G1-S transition was inhibited in AIbZIP-depleted cells. We comprehensively analyzed the expression levels of proteins that regulate G1-S transition and found that p27 was specifically upregulated in AIbZIP-depleted cells. Furthermore, we identified that this p27 downregulation was caused by protein degradation modulated by the ubiquitin-proteasome system via F-box protein S-phase kinase-associated protein 2 (SKP2) upregulation. Our findings demonstrate that AIbZIP is a novel p27-SKP2 pathway-regulating factor and a potential molecule that contributes to LAR subtype TNBC progression. IMPLICATIONS: This research shows a new mechanism for the proliferation of LAR subtype TNBC regulated by AIbZIP, that may provide novel insight into the LAR subtype TNBC progression and the molecular mechanisms involved in cell proliferation.

The impact of respiratory reactance in oscillometry on survival in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. Pulmonary function tests (PFTs) aid in evaluating the disease status of IPF. The clinical significance of oscillometry measurements in interstitial lung diseases has recently been reported. Our previous study showed that respiratory reactance (Xrs) measured by oscillometry reflected disease severity and predicted subsequent lung capacity decline in patients with IPF. However, the direct impact of Xrs on survival needs to be determined, and there are currently no reference values in oscillometry to predict prognosis. Therefore, this study aimed to investigate the association between oscillometry measurements, particularly Xrs, and survival in patients with IPF and to determine the cutoff values of Xrs that predict 3-year survival. METHODS: We analyzed the relationship between the measured values of PFT and oscillometry derived from 178 patients with IPF. Univariate and multivariate Cox proportional hazards analyses were performed to investigate the relationships between clinical indices at the time of the first oscillometry and survival. We performed the time-dependent receiver operating characteristic (ROC) curve analysis to set the optimized cutoff values of Xrs for 3-year survival prediction. We examined the discriminating power of cutoff values of Xrs on survival using the Kaplan-Meier method and the log-rank test. RESULTS: Xrs components, especially in the inspiratory phase (In), significantly correlated with the PFT values. In the multivariate analyses, Xrs (all of reactance at 5 Hz [X5], resonant frequency [Fres], and low-frequency reactance area [ALX] in the inspiratory phase) had a significant impact on survival (X5, p = 0.003; Fres, p = 0.016; ALX, p = 0.003) independent of age, sex, and other prognostic factors derived from the univariate analysis. The area under the ROC curve was 0.765, 0.759, and 0.766 for X5 In, Fres In, and ALX In, with cutoff values determined at - 0.98, 10.67, and 5.32, respectively. We found significant differences in survival after dividing patients using each of the cutoff values of Xrs. CONCLUSIONS: In patients with IPF, Xrs measured by oscillometry significantly impacted survival. We also determined the cutoff values of Xrs to discriminate patients with poor prognoses.

Independent activation of CREB3L2 by glucose fills a regulatory gap in mouse ß-cells by co-ordinating insulin biosynthesis with secretory granule formation.

OBJECTIVE: Although individual steps have been characterized, there is little understanding of the overall process whereby glucose co-ordinates the biosynthesis of insulin with its export out of the endoplasmic reticulum (ER) and incorporation into insulin secretory granules (ISGs). Here we investigate a role for the transcription factor CREB3L2 in this context. METHODS: MIN6 cells and mouse islets were analysed by immunoblotting after treatment with glucose, fatty acids, thapsigargin and various inhibitors. Knockdown of CREB3L2 was achieved using si or sh constructs by transfection, or viral delivery. In vivo metabolic phenotyping was conducted after deletion of CREB3L2 in ß-cells of adult mice using Ins1-CreER+. Islets were isolated for RNAseq and assays of glucose-stimulated insulin secretion (GSIS). Trafficking was monitored in islet monolayers using a GFP-tagged proinsulin construct that allows for synchronised release from the ER. RESULTS: With a Km ≈3.5 mM, glucose rapidly (T1/2 0.9 h) increased full length (FL) CREB3L2 followed by a slower rise (T1/2 2.5 h) in its transcriptionally-active cleavage product, P60 CREB3L2. Glucose stimulation repressed the ER stress marker, CHOP, and this was partially reverted by knockdown of CREB3L2. Activation of CREB3L2 by glucose was not due to ER stress, however, but a combination of O-GlcNAcylation, which impaired proteasomal degradation of FL-CREB3L2, and mTORC1 stimulation, which enhanced its conversion to P60. cAMP generation also activated CREB3L2, but independently of glucose. Deletion of CREB3L2 inhibited GSIS ex vivo and, following a high-fat diet (HFD), impaired glucose tolerance and insulin secretion in vivo. RNAseq revealed that CREB3L2 regulated genes controlling trafficking to-and-from the Golgi, as well as a broader cohort associated with ß-cell compensation during a HFD. Although post-Golgi trafficking appeared intact, knockdown of CREB3L2 impaired the generation of both nascent ISGs and proinsulin condensates in the Golgi, implying a defect in ER export of proinsulin and/or its processing in the Golgi. CONCLUSION: The stimulation of CREB3L2 by glucose defines a novel, rapid and direct mechanism for co-ordinating the synthesis, packaging and storage of insulin, thereby minimizing ER overload and optimizing ß-cell function under conditions of high secretory demand. Upregulation of CREB3L2 also potentially contributes to the benefits of GLP1 agonism and might in itself constitute a novel means of treating ß-cell failure.

Periodontal Regenerative Therapy with Recombinant Human Fibroblast Growth Factor (rhFGF) -2 for Stage III Grade C Periodontitis: A Case Report with 6-month Follow-up.

This report describes a case of generalized chronic periodontitis requiring periodontal regenerative therapy. The patient was a 56-year-old woman visiting the Tokyo Dental College Suidobashi Hospital with the chief complaint of swelling in the maxillary right gingiva. An initial examination revealed 34.0% of sites with a probing depth (PD) of ≥4 mm. The prevalence of sites with bleeding on probing was 32.7%. The plaque control record (PCR) score was 65.7%. Radiographic examination revealed angular bone resorption at #18 and 48. Horizontal absorption was also observed in other areas. The percent bone loss/age at #48 was 1.07. A clinical diagnosis of generalized chronic periodontitis (Stage III, Grade C) was made. Based on the clinical diagnosis of severe chronic periodontitis, initial periodontal therapy was performed. An improvement was observed in periodontal conditions at re-evaluation. The PCR score was 16.7%. Periodontal surgery was performed for teeth with a residual PD of ≥4 mm. Periodontal regenerative therapy using rhFGF-2 were performed on intrabony defects in #18 and 48. Open flap debridement was performed on #16, 26, and 27. Following evaluation, oral function was restored using all-ceramic crowns (#46). At 6 months postoperatively, the patient was transitioned to supportive periodontal therapy (SPT). During the 6-month SPT, stable periodontal conditions that facilitated a favourable level of plaque control were maintained.

A Case Report of Periodontal Regenerative Therapy Using Recombinant Human Fibroblast Growth Factor 2 and Deproteinized Bovine Bone Mineral with Non-incised Papillae Surgical Approach (NIPSA) for Angular Bone Defect in Patient with Stage III Grade C Periodontitis.

This report describes a case of Stage III Grade C periodontitis requiring periodontal regenerative therapy. The patient was a 19-year-old woman who presented with the chief complaint of gingival recession in the incisor region. An initial examination revealed that 45.3% of sites had a probing depth of ≥4 mm and 45.8% bleeding on probing. Radiographic examination showed angular bone resorption in #25, 26, 31, 36, and 46 and horizontal resorption in other regions. Initial periodontal therapy was implemented based on a clinical diagnosis of Stage III Grade C periodontitis (generalized aggressive periodontitis). Occlusal adjustment was also performed at sites showing premature contact (#26 and 36) after suppression of inflammation. Periodontal regenerative therapy using recombinant human fibroblast growth factor (rhFGF) -2 was performed on #25, 26, and 46. Combination therapy with rhFGF-2 and deproteinized bovine bone mineral (DBBM) was performed on #31 and 36. A non-incised papillae surgical approach (NIPSA) was used on #31. Periodontal conditions were then re-evaluated and the patient placed on supportive periodontal therapy. Regenerative therapy using rhFGF-2 and DBBM with NIPSA yielded an improvement in clinical parameters and bone resorption. This improvement has been adequately maintained over a 12-month period. Continued care is needed to maintain stable periodontal conditions.

Treatment of Gingival Recession in Multiple Teeth Using Coronally Advanced Flap with Connective Tissue Graft: A Case Report.

This report describes a case of gingival recession in multiple teeth with severe dentin hypersensitivity (DH) in which treatment included periodontal plastic surgery. The patient was a 34-year-old woman presenting with the chief complaint of DH at gingivalrecession sites. The patient had undergone orthodontic treatment when she was 30 years old. An initial examination revealed that none of the sites showed a probing depth of ≥4 mm and 21% of sites bleeding on probing. The clinical diagnosis was plaque-induced gingivitis. Teeth #14, 16, 23, 25, 26, 34, 35, 45, and 46 showed gingival recession ranging from 1 to 4 mm. Gingival recession at #45 extended to the muco-gingival junction. No association with alveolar bone loss was observed in any of the interdental areas. Therefore, the sites presenting with gingival recession were classified as Miller Class I, except #45, which was classified as Class II. The periodontal phenotype was 'thin'. Based on the results of clinical examination and diagnosis, initial periodontal therapy (IP) consisting of oral hygiene instruction, supra-gingival scaling, application of a desensitizing agent, and composite resin restoration was performed. The Visual Analog Scale (VAS) score, which was used to assess degree of DH, showed only a minimal decrease, however, at post-IP. Subsequently, a modified coronally advanced tunnel (a modified technique for achieving a coronally advanced flap) using a connective tissue graft was performed in #14, 16, 23, 25, 26, 45, and 46. After re-evaluation, the patient was placed on maintenance care. The series of interventions resulted in a considerable improvement in the VAS and oral health-related quality of life scores. Furthermore, a change in the periodontal phenotype, from 'thin' to 'thick', was observed, which may contribute to the prevention of further gingival recession and DH. The present case suggests that periodontal plastic surgery is an effective treatment modality for the resolution of DH.

Spontaneous remission of skull Langerhans cell histiocytosis that had developed by repeated head injury: illustrative case.

BACKGROUND: Langerhans cell histiocytosis (LCH) was previously characterized as the proliferation of Langerhans-type histiocytes with a wide range of clinical presentations that arise mostly in children. The typical presentation is a gradually enlarging, painless skull mass. Rapid clinical deterioration is rare. OBSERVATIONS: A 3-year-old boy who had incurred a right frontal impact head injury demonstrated no apparent neurological deficits. He subsequently bruised the same region multiple times. The right frontal swelling gradually increased over the course of 6 days after the initial injury. Skull radiography showed no bony lesion. The same site enlarged markedly 12 days after the initial injury. Magnetic resonance imaging revealed a frontal bony tumorous lesion associated with multiple subcutaneous cystic mass lesions. The patient underwent open biopsy of the skull lesion and evacuation of the subcutaneous lesions. Histopathological examination confirmed the diagnosis of LCH. Immunohistochemical evaluation revealed positivity for CD1a and langerin and no immunopositivity for BRAF V600E. The skull lesion spontaneously disappeared 30 days after the biopsy without recurrence. LESSONS: Physicians should be aware of this rare clinical manifestation of LCH that developed by a repeat head injury.

Serum Testosterone Is Associated With the Severity of COVID-19.

BACKGROUND/AIM: Coronavirus disease 2019 (COVID-19) is more likely to be severe in men than in women. Its association with sex hormones as an aggravating factor for male patients has been attracting attention. This study aimed to investigate whether serum testosterone is associated with the aggravation of COVID-19. PATIENTS AND METHODS: Serum testosterone concentrations in 116 male patients with COVID-19 and residual serum were measured and examined upon their admission to Sapporo Medical University Hospital between February 1, 2020 and March 31, 2021. RESULTS: Blood samples collected from these patients with COVID-19 were analyzed. The serum testosterone levels were 2.19±1.35, 1.29±0.88, and 0.75±0.58 ng/ml in mild, moderate, and severe groups, respectively. Patients with severe COVID-19 on admission had lower testosterone levels (p<0.001). At a cutoff level of 1.31 ng/ml, the area under the curve for the comparison of severe with non-severe cases was 0.825. Furthermore, serum testosterone levels negatively correlated with C-reactive protein and serum amyloid A levels but positively correlated with calcium, zinc, C3, and C4. CONCLUSION: In male patients with COVID-19, low serum testosterone levels correlated with disease severity, accompanied by a strong inflammatory reaction and proportion of complement consumption.

R-loop landscapes in the developing human brain are linked to neural differentiation and cell-type specific transcription.

Here, we construct genome-scale maps for R-loops, three-stranded nucleic acid structures comprised of a DNA/RNA hybrid and a displaced single strand of DNA, in the proliferative and differentiated zones of the human prenatal brain. We show that R-loops are abundant in the progenitor-rich germinal matrix, with preferential formation at promoters slated for upregulated expression at later stages of differentiation, including numerous neurodevelopmental risk genes. RNase H1-mediated contraction of the genomic R-loop space in neural progenitors shifted differentiation toward the neuronal lineage and was associated with transcriptomic alterations and defective functional and structural neuronal connectivity in vivo and in vitro. Therefore, R-loops are important for fine-tuning differentiation-sensitive gene expression programs of neural progenitor cells.

Double-sided entire papilla preservation technique in the combination periodontal regenerative therapy: A case report.

BACKGROUND: With the entire papilla preservation (EPP) technique, it is possible to perform regenerative therapy without incisions in the interdental papilla and to reduce the risk of papillary rupture. However, one limitation of the EPP is the sole access from the buccal side. Here, we present a case of periodontitis treated by the combination regenerative therapy employing the Double-sided (buccal-palatal) EPP (DEPP) technique, which adds a palatal vertical incision to the EPP. METHODS: A patient with 1-2 wall intrabony defects received the regenerative therapy using recombinant human fibroblast growth factor (rhFGF)-2 and carbonate apatite (CO3 Ap). Using the DEPP technique, vertical incisions at buccal and palatal aspects were placed to gain adequate access to the 1-2 wall intrabony defects between #11 and #12 without incision in the interdental papilla. After debridement, rhFGF-2 and CO3 Ap were applied to the defect. Periodontal clinical parameters and radiographic images were evaluated at the first visit, following initial periodontal therapy (baseline), 6, 9, and 12 months postoperatively. RESULTS: Wound healing was uneventful. Scarring of the incision lines was minimal. At 12 months postoperatively, probing depth reduction was 4 mm, clinical attachment gain was 4 mm, and gingival recession was not observed. An improvement in radiopacity in the previous bone defect was observed. CONCLUSION: The DEPP is an innovative technique that allows approaching from both the buccal and palatal sides while ensuring flap extensibility without compromising the interdental papilla. This report suggests that the combination of regenerative therapy with the DEPP may be promising in the treatment of intrabony defects. KEY POINTS: Why is this case new information? The DEPP allows a direct visual approach to a 1-2 wall intrabony defect extending from the buccal to palatal sides, and increases flap extensibility, without compromising the papilla. What are the keys to the successful management of this case? Assessment of three-dimensional bone defect morphology is required. Computed tomography images are very useful. The flap elevation just under the interdental papilla should be carefully performed with a small excavator to avoid damage to the interdental papilla. What are the primary limitations to success in this case? Despite the addition of a palatal incision, it was not possible to obtain complete flexibility of the palatal gingiva. Caution must be taken in a case in which the distance between the interdental papilla is narrow. Even if the interdental papilla is ruptured during the operation, recovery is possible by continuing the operation and suturing the rupture at the end.

Impact of cell cycle on repair of ruptured nuclear envelope and sensitivity to nuclear envelope stress in glioblastoma.

The nuclear envelope (NE) is often challenged by various stresses (known as "NE stress"), leading to its dysfunction. Accumulating evidence has proven the pathological relevance of NE stress in numerous diseases ranging from cancer to neurodegenerative diseases. Although several proteins involved in the reassembly of the NE after mitosis have been identified as the NE repair factors, the regulatory mechanisms modulating the efficiency of NE repair remain unclear. Here, we showed that response to NE stress varied among different types of cancer cell lines. U251MG derived from glioblastoma exhibited severe nuclear deformation and massive DNA damage at the deformed nuclear region upon mechanical NE stress. In contrast, another cell line derived from glioblastoma, U87MG, only presented mild nuclear deformation without DNA damage. Time-lapse imaging demonstrated that repairing of ruptured NE often failed in U251MG, but not in U87MG. These differences were unlikely to have been due to weakened NE in U251MG because the expression levels of lamin A/C, determinants of the physical property of the NE, were comparable and loss of compartmentalization across the NE was observed just after laser ablation of the NE in both cell lines. U251MG proliferated more rapidly than U87MG concomitant with reduced expression of p21, a major inhibitor of cyclin-dependent kinases, suggesting a correlation between NE stress response and cell cycle progression. Indeed, visualization of cell cycle stages using fluorescent ubiquitination-based cell cycle indicator reporters revealed greater resistance of U251MG to NE stress at G1 phase than at S and G2 phases. Furthermore, attenuation of cell cycle progression by inducing p21 in U251MG counteracted the nuclear deformation and DNA damage upon NE stress. These findings imply that dysregulation of cell cycle progression in cancer cells causes loss of the NE integrity and its consequences such as DNA damage and cell death upon mechanical NE stress.

Protective effect of Bifidobacterium longum BB536 against nausea caused by pirfenidone in a mouse model of pellagra.

Pellagra is caused by abnormal intake and/or use of nicotinic acid and is known in part to be induced by the use of medications such as isoniazid or pirfenidone. We previously investigated atypical phenotypes of pellagra, such as nausea, using a mouse model of pellagra and found that gut microbiota play an important role in the development of these phenotypes. Here, we investigated the effect of Bifidobacterium longum BB536 on pellagra-related nausea caused by pirfenidone in our mouse model. Our pharmacological data indicated that pirfenidone (PFD) causes modulation of the gut microbiota profile, which appeared to play an important role in the development of pellagra-related nausea. A gut microbiota-mediated protective effect of B. longum BB536 against nausea caused by PFD was also identified. Finally, the urinary ratio of nicotinamide/N-methylnicotinamide was shown to be a biomarker of pellagra-like adverse effects induced by PFD, and it may contribute to the prevention of these effects in patients with idiopathic pulmonary fibrosis.

Usefulness of Transcranial Motor Evoked Potential in Clipping Surgery for Cerebral Aneurysms-Introduction of a New Protocol for Stable Monitoring.

The usefulness of transcranial motor evoked potentials (Tc-MEPs) in clipping surgery has been reported. However, numerous false positive and false negative cases were reported. We report the usefulness of a new protocol compared with direct cortical MEP (Dc-MEP).Materials were 351 patients who underwent aneurysmal clipping under simultaneous monitoring of Tc- and Dc-MEPs. A total of 337 patients without hemiparesis and 14 with hemiparesis were separately analyzed. Intraoperative changes of Tc-MEP thresholds were examined in the first 50 patients without hemiparesis. The stimulation strength of Tc-MEP was set at +20% of the stimulation threshold. As thresholds changed intraoperatively, thresholds were examined every 10 min and changed stimulation strength.Stimulation thresholds of Tc-MEP were significantly decreased after craniotomy and significantly increased after CSF aspiration. The recording ratios of Tc- and Dc-MEPs were 98.8% and 90.5%, respectively. Out of 304 patients without MEP change, 5 patients developed transient or mild hemiparesis with infarction of the territory of the perforating artery arising from the posterior communicating artery. Out of 31 patients whose MEP transiently disappeared, 3 patients developed transient or mild hemiparesis. The other two patients without MEP recovery manifested persistent hemiparesis. In 14 patients with preoperative hemiparesis, 3 patients whose healthy/affected ratio of Tc-MEP was large developed severe persistent hemiparesis.We clarified the intraoperative changes of Tc-MEP thresholds for the first time. A new protocol of Tc-MEP that followed thresholds and changed stimulation strength to +20% of thresholds is useful for stable monitoring. The usefulness of Tc-MEP is the same as that or better than that of Dc-MEP.