Deletion of p38 MAPK in macrophages ameliorates peritoneal fibrosis and inflammation in peritoneal dialysis.

One of the most common causes of peritoneal dialysis withdrawal is ultrafiltration failure which is characterized by peritoneal membrane thickening and fibrosis. Although previous studies have demonstrated the inhibitory effect of p38 MAPK inhibitors on peritoneal fibrosis in mice, it was unclear which specific cells contribute to peritoneal fibrosis. To investigate the role of p38 MAPK in peritoneal fibrosis more precisely, we examined the expression of p38 MAPK in human peritoneum and generated systemic inducible p38 MAPK knockout mice and macrophage-specific p38 MAPK knockout mice. Furthermore, the response to lipopolysaccharide (LPS) was assessed in p38 MAPK-knocked down RAW 264.7 cells to further explore the role of p38 MAPK in macrophages. We found that phosphorylated p38 MAPK levels were increased in the thickened peritoneum of both human and mice. Both chlorhexidine gluconate (CG)-treated systemic inducible and macrophage-specific p38 MAPK knockout mice ameliorated peritoneal thickening, mRNA expression related to inflammation and fibrosis, and the number of αSMA- and MAC-2-positive cells in the peritoneum compared to CG control mice. Reduction of p38 MAPK in RAW 264.7 cells suppressed inflammatory mRNA expression induced by LPS. These findings suggest that p38 MAPK in macrophages plays a critical role in peritoneal inflammation and thickening.

Biocompatibility Evaluation of an Artificial Metallic Bone with Lattice Structure for Reconstruction of Bone Defect.

Mandibular reconstruction for large bone defects is performed with consideration of patients' specific morphology and sufficient strength. Metal additive manufacturing techniques have been used to develop biomaterials for mandibular reconstruction. Titanium artificial mandibles with a lattice structure have been proposed, and the optimal conditions for their strength to withstand mechanical stress around the mandible have been reported. This study investigated the biocompatibility of a titanium artificial bone with a lattice structure fabricated under optimal conditions. The samples were fabricated using metal additive manufacturing. Body diagonals with nodes (BDN) were selected as suitable lattice structures. Dode medium (DM) was selected for comparison. The samples were implanted into rabbit tibial defects and resected with the surrounding bone at two and four weeks. Specimens were evaluated radiographically, histologically, and histomorphometrically. Radiopacity in each lattice structure was observed at two and four weeks. Histological evaluation showed trabecular bone-like tissue inside the BDN compared to the DM at four weeks. No significant differences were noted in the bone volume inside the structures. This study demonstrated the in vivo compatibility of artificial metallic bones with a BDN structure under mechanical stress conditions.

GALAD score for the diagnosis of Hepatocellular Carcinoma in sub-Saharan Africa; a validation study in Ghanaian patients.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide including sub-Saharan Africa. The GALAD score, derived from Gender, Age, Lens culinaris agglutinin-reactive fraction of alpha fetoprotein (AFP-L3%), AFP and Des-carboxy-prothrombin (DCP) has high accuracy in diagnosing HCC in Asia, Europe, and North America, however, it has not been validated in an African cohort. The aim of this study was to assess the performance of the GALAD score in the diagnosis of HCC in sub-Saharan Africa. Clinical data from patients with cirrhosis (n=93) or HCC (n=78) from outpatient hepatology clinics at three teaching hospitals in Ghana were abstracted, and serum samples were analyzed. A logistic regression model predicting HCC status based on GALAD score was constructed to obtain the Receiver Operating Characteristics (ROC) curve for GALAD. The area under the curve (AUC) with 95% confidence interval (CI) was calculated. The median GALAD score was higher among HCC patients vs. cirrhosis controls (8.0 vs. -4.1, p<0.01). The AUC of the GALAD score for HCC detection was 0.86 (95% CI 0.79 - 0.92). At a cut-off value of -0.37, the GALAD score had a sensitivity of 0.81 and a specificity of 0.86. The AUC (95% CI) was 0.87 (0.80 - 0.95) and 0.81 (0.67 - 0.94) in HBV positive and HBV negative patients, respectively. The GALAD score has a high accuracy for HCC detection. It has great potential to improve HCC surveillance in sub-Saharan Africa where imaging resources are limited.

Comparison of survivals between sublobar resection and lobar resection for patients with clinical stage I non-small cell lung cancer and interstitial lung disease: a propensity score matching analysis.

BACKGROUND: Patients with early-stage lung cancer and interstitial lung disease have a poorer prognosis than those without interstitial lung disease. This study aimed to compare the long-term outcomes of lobar and sublobar resections in these patients. METHODS: We retrospectively analyzed 138 consecutive patients with clinical stage I non-small cell lung cancer and interstitial lung disease who underwent surgical treatment at two institutions between January 2010 and December 2020. Propensity score matching analysis was performed to adjust for baseline characteristics. RESULTS: Thirty-six patients underwent sublobar resection and 102 underwent lobar resection. The median follow-up was 45.7 months. In all patients, 5-year overall survival (OS) rates were 33.2% and 73.2%, and 5-year recurrence-free survival (RFS) rates were 24.2% and 60.1% in the sublobar and lobar resection groups, respectively (p < 0.01, <0.01). Death due to lung cancer and locoregional recurrence were significantly more frequent in the sublobar resection group than in the lobar resection group (p = 0.034, <0.01, respectively). On propensity score matching analysis, the 5-year OS rates of the 19 matched pairs were 46.3% and 73.2%, and the RFS rates were 31.6% and 67.6% in the sublobar and lobar resection groups, respectively (p = 0.036, <0.01). The Cox proportional hazards model demonstrated a significant association between lobar resection and improved survival (p = 0.047). CONCLUSION: The patients in the lobar resection group had better survival rates than those in the sublobar resection group. In terms of long-term prognosis, deliberately limited surgery may not be necessary for patients who tolerate lobectomy.

Spatial sorting caused by downstream dispersal: implication for morphological evolution in isolated populations of fat minnow inhabiting small streams flowing through terraced rice paddies.

The evolutionary forces arising from differential dispersal are known as "spatial sorting," distinguishing them from natural selection arising from differential survival or differential reproductive success. Spatial sorting is often considered to be transient, because it is offset by the return of dispersers in many cases. However, in riverine systems, spatial sorting by downstream dispersal can be cumulative in habitats upstream of migration barriers such as weirs or falls, which can block the return of the dispersers. Terraced rice paddies are often found on steep mountain slopes in Japan and often incorporate small streams with numerous migration barriers. This study investigated the morphological features of fat minnow, Rhynchocypris oxycephalus jouyi (Cyprinidae), inhabiting above-barrier habitats of the small streams flowing through flood-prone terraced rice paddies and examined their function via a mark-recapture experiment. Although this study did not reveal a consistent pattern across all local populations, some above-barrier populations were characterised by individuals with a thinner caudal peduncle, thinner body, and longer ventral caudal fin lobes than those in neighbouring mainstream populations. A mark-recapture experiment during flooding showed that a thinner caudal peduncle and deeper body helped fat minnow avoid downstream dispersal and ascend a small step, and suggested that a longer ventral caudal fin lobe was important for ascending. These results suggest that the caudal morphologies of some above-barrier populations avoid or reduce the risk of downstream dispersal, supporting the idea that spatial sorting shapes functional traits, enhancing the spatial persistence of individuals in upstream habitats.

PLAG1 overexpression in salivary gland duct-acinar units results in epithelial tumors with acinar-like features: Tumorization of luminal stem/progenitor cells may result in the development of salivary gland tumors consisting of only luminal cells.

OBJECTIVES: Details about salivary gland tumor histogenesis remain unknown. Here, we established a newly generated murine salivary gland tumor model that could overexpress pleomorphic adenoma gene 1 (PLAG1) and attempted to clarify the events that occur during the early phase of salivary gland tumor histogenesis. METHODS: Salivary gland tumors were generated using murine models (Sox9IRES-CreERT2; ROSA26-PLAG1). Lineage tracing of Sox9-expressing cells was performed using Sox9IRES-CreERT2; ROSA26-tdTomato mice, which were generated by crossing Sox9CreERT2/- and ROSA26-tdTomato mice (expressing the tdTomato fluorescent protein). Organ-cultured embryonic salivary glands from the murine model were morphologically analyzed, and mRNA sequencing was conducted two days after tumor induction for gene enrichment and functional annotation analysis. RESULTS: Salivary gland tumors exhibited epithelial features with acinar-like structures because of gene rearrangements in the luminal cells. Structural disturbances in the duct-acinar unit of the salivary gland were observed and cancer-related pathways were enriched among the differentially upregulated genes in the early phase of tumor induction in an organ-cultured embryonic salivary gland tumor model. CONCLUSIONS: The newly generated murine salivary gland tumor model may show that the tumorization of luminal stem/progenitor cells can result in the development of salivary gland tumors comprising only luminal cells.

Interpopulation variation in dispersal behavior of fat minnow Rhynchocypris oxycephalus jouyi juveniles inhabiting fragmented habitats.

In many organisms, including fishes, downstream dispersal is often phenotype-dependent. Phenotype-dependent downstream dispersal can generate evolutionary pressure via spatial sorting, which non-randomly removes phenotypes enhancing downstream dispersal from upstream populations. Spatial sorting due to downstream dispersal could accumulate in fish populations in above-barrier habitats to which dispersed individuals cannot return, resulting in functional traits that reduce downstream dispersal. This evolutionary mechanism may be more important in smaller above-barrier habitats where downstream emigration occurs over shorter dispersal distances. This study observed the dispersal behavior of fat minnow Rhynchocypris oxycephalus jouyi juveniles in an experimental tank to examine whether juveniles from small above-barrier habitats show more behaviors favorable for reducing downstream dispersal than those from large above-barrier habitats. Juveniles from small above-barrier habitats avoided downstream dispersal for longer durations than those from large above-barrier habitats, but there was no difference in the frequency of ascending attempts. These results support the notion that behavioral traits of juveniles in small above-barrier populations have been refined by spatial sorting to reduce downstream dispersal. The finding that interpopulation variation in dispersal behavior occurred only for certain dispersal directions implies that the behavioral consequences of habitat fragmentation are more complex than previously assumed.

Bilirubin oxidase expression and activity enhancement from Myrothecium verrucaria in Aspergillus species.

We constructed a new Aspergillus expression vector (pSENSU2512nid) under the control of the enolase promoter with 12 tandem repeats of cis-acting elements (region III) and the heat shock protein 12 (Hsp12) 5' untranslated region (UTR). Bilirubin oxidase (EC: 1.3.3.5) from Myrothecium verrucaria, which catalyzes the oxidation of bilirubin to biliverdin, was overexpressed in Aspergillus oryzae and A. niger. The productivity was estimated to be approximately 1.2 g/L in the culture broth, which was approximately 6-fold higher than that of recombinant bilirubin oxidase (BOD) expressed in Pichia pastoris (Komagataella phaffii). BOD was purified using hydrophobic interaction chromatography, followed by ion exchange chromatography. The specific activity of the purified BOD against 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) substrate was 57.6 U/mg and 66.4 U/mg for A. oryzae and A. niger, respectively. l-Ascorbic acid (4 mM) addition and storage under deoxygenated conditions for 3-7 d increased the specific activity of these Aspergillus-expressed BODs approximately 2.3-fold (154.1 U/mg). The BOD specific activity was enhanced by incubation at higher temperature (30-50 °C). Further characterization of the enzyme catalytic efficiency revealed that the Km value remained unchanged, whereas the kcat value improved 3-fold. In conclusion, this high-level of BOD expression meets the requirements for industrial-level production. Additionally, we identified an effective method to enhance the low specific activity during expression, making it advantageous for industrial applications.

Primary Ciliary Dyskinesia Due to Compound Heterozygous Variants in CFAP221 with Obstructive Azoospermia: Young's Syndrome May Be a Phenotype of Primary Ciliary Dyskinesia.

We report the case of a 42-year-old man with bronchiectasis who had a history of infertility treatment for obstructive azoospermia. Young's syndrome was suspected based on the triad of obstructive azoospermia, sinusitis, and bronchiectasis. He had normal electron microscopy findings, normal nasal nitric oxide levels (116 nL/min), and no situs inversus. However, we found compound heterozygous variants in CFAP221. This led to a diagnosis of primary ciliary dyskinesia (PCD). Distinguishing PCD from Young's syndrome in patients with the triad of obstructive azoospermia, sinusitis, and bronchiectasis is challenging. Young's syndrome may be a phenotype of PCD.

Investigation of the Mechanical Strength of Artificial Metallic Mandibles with Lattice Structure for Mandibular Reconstruction.

Mandibular reconstructive surgery is necessary for large bone defects. Although various reconstruction methods have been performed clinically, there is no mandibular reconstruction method that meets both sufficient strength criteria and the patient's specific morphology. In this study, the material strength of the cylindrical lattice structures formed by electron-beam melting additive manufacturing using titanium alloy powder was investigated for mandibular reconstruction. The virtual strengths of 28 lattice structures were compared using numerical material tests with finite element method software. Subsequently, to compare the material properties of the selected structures from the preliminary tests, compression test, static bending test and fatigue test were conducted. The results showed that there were correlations with relative density and significant differences among the various structures when comparing internal stress with deformation, although there was a possibility of localized stress concentration and non-uniform stress distribution based on the lattice structure characteristics. These results suggest that the lattice structure of body diagonals with nodes and a cell size of 3.0 mm is a potential candidate for metallic artificial mandibles in mandibular reconstruction surgery.

Rare-Earth-Metal-Free Solid-State Fluorescent Carbonized-Polymer Microspheres for Unclonable Anti-Counterfeit Whispering-Gallery Emissions from Red to Near-Infrared Wavelengths.

Colloidal carbon dots (CDs) have garnered much attention as metal-free photoluminescent nanomaterials, yet creation of solid-state fluorescent (SSF) materials emitting in the deep red (DR) to near-infrared (NIR) range poses a significant challenge with practical implications. To address this challenge and to engineer photonic functionalities, a micro-resonator architecture is developed using carbonized polymer microspheres (CPMs), evolved from conventional colloidal nanodots. Gram-scale production of CPMs utilizes controlled microscopic phase separation facilitated by natural peptide cross-linking during hydrothermal processing. The resulting microstructure effectively suppresses aggregation-induced quenching (AIQ), enabling strong solid-state light emission. Both experimental and theoretical analysis support a role for extended π-conjugated polycyclic aromatic hydrocarbons (PAHs) trapped within these microstructures, which exhibit a progressive red shift in light absorption/emission toward the NIR range. Moreover, the highly spherical shape of CPMs endows them with innate photonic functionalities in combination with their intrinsic CD-based attributes. Harnessing their excitation wavelength-dependent photoluminescent (PL) property, a single CPM exhibits whispering-gallery modes (WGMs) that are emission-tunable from the DR to the NIR. This type of newly developed microresonator can serve as, for example, unclonable anti-counterfeiting labels. This innovative cross-cutting approach, combining photonics and chemistry, offers robust, bottom-up, built-in photonic functionality with diverse NIR applications.

Hypertrophic cardiomyopathy-related left ventricular pseudoaneurysm: A case report.

Background: Myocardial infarction-related left ventricular pseudoaneurysm (LVP), covered by the adjacent pericardial or scar tissue, is a fatal sequela of left ventricular rupture. Whereas hypertrophic cardiomyopathy (HCM) may cause left ventricular true aneurysm. Differentiating LVP from left ventricular true aneurysm is crucial because their natural histories and treatment strategies are distinct. However, the incidence and management of HCM-related LVP remain unknown. Case presentation: An 88-year-old man was admitted to our hospital with sudden-onset chest pain. Upon initial examination, vital signs were stable, and a grade 4/6 systolic murmur was noted. An electrocardiogram revealed atrial fibrillation and poor R-wave progression without ST-T changes or negative T-waves. An echocardiography showed mild left ventricular hypertrophy, mid-ventricular obstruction with a significant intraventricular pressure gradient, left ventricular outflow tract obstruction, and a small left ventricular apical outpouching. Cardiac computed tomography angiography (CCTA) assisted in the diagnosis of LVP, and an accompanying pericardial effusion suggested impending cardiac rupture. Because the patient initially refused our proposed urgent surgery, medication was initiated with continuous hemodynamic monitoring in the intensive care unit; however, the patient's condition did not improve. During a semi-urgent surgical repair of the aneurysmal wall, LVP was observed and confirmed by pathology. Myocardial tissue adjacent to the pseudoaneurysm was consistent with that of HCM. Subsequently, a final diagnosis of HCM-related LVP was made. The postoperative course was notable for transient profound hypotension. Thereafter, the patient died of non-occlusive mesenteric ischemia on day 6. Conclusions: To our knowledge, this is the first reported case of HCM-related LVP mimicking impending cardiac rupture. Our case highlights the importance of considering HCM-related LVP in patients with left ventricular outpouching and CCTA in the LVP diagnosis. In further research, data on the appropriate management of HCM-related LVP should be accumulated.

In vitro effects of the new oral ß-lactamase inhibitor xeruborbactam in combination with oral ß-lactams against clinical Mycobacterium abscessus isolates.

Non-tuberculosis mycobacteria (NTM), particularly Mycobacterium abscessus subsp. abscessus (M. abscessus), are increasingly being recognized as etiological agents of NTM pulmonary disease. However, treatment options for M. abscessus are limited owing to their natural resistance to most antibiotics, including ß-lactams. M. abscessus produces a class A ß-lactamase, whose activity is inhibited by cyclic boronic acid ß-lactamase inhibitors. We aimed to evaluate the in vitro effects of xeruborbactam, a cyclic boronic acid ß-lactamase inhibitor, against M. abscessus when combined with five ß-lactams (amoxicillin, tebipenem, cefdinir, cefuroxime, and cefoxitin). The drug susceptibilities of 43 M. abscessus clinical isolates obtained from 43 patients between August 2005 and May 2014 were tested. The MIC results for each ß-lactam with or without 4 µg/mL xeruborbactam were examined. Xeruborbactam lowered the MIC90 values of tebipenem, amoxicillin, cefuroxime, and cefdinir by 5, ≥4, 3, and 3 dilutions, respectively. The MIC90 values of cefoxitin without xeruborbactam were 32 µg/mL and did not change upon the addition of xeruborbactam. The lowest MIC90 value was obtained for tebipenem with xeruborbactam. Almost all isolates had an MIC of 4 µg/mL; one isolate had an MIC of 2 µg/mL. With respect to the susceptibility to the same family drug, the number of susceptible isolates increased from 1/43 (2%) to 43/43 (100%) for tebipenem with xeruborbactam. Combining tebipenem and xeruborbactam could be considered an effective all-oral regimen that benefits outpatient treatment of M. abscessus pulmonary disease. IMPORTANCE: Mycobacterium abscessus subsp. abscessus (M. abscessus) disease is treated in two phases; injectable drugs for initial followed by others for continuation. There is a need to develop all-oral treatment methods for M. abscessus infection, especially in the continuation phase. However, treatment options for M. abscessus are limited owing to their natural resistance to most antibiotics. This is the first report to evaluate the in vitro effects of xeruborbactam, a cyclic boronic acid ß-lactamase inhibitor capable of inhibiting the class A ß-lactamase produced by M. abscessus, against 43 M. abscessus clinical isolates when combined with five ß-lactam antibiotics. Xeruborbactam lowered the MIC90 values of tebipenem by five dilutions, and the number of susceptible isolates increased from 1/43 (2%) to 43/43 (100%). We showed that the tebipenem-xeruborbactam combination might be of interest to explore further as a potentially effective oral regimen for outpatient treatment of M. abscessus pulmonary disease.

Successful Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus with Celecoxib: A Promising Therapeutic Option.

BACKGROUND Nephrogenic diabetic insipidus (NDI) poses a challenge in clinical management, particularly when associated with lithium ingestion. Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for the treatment of numerous diseases worldwide, including NDI. However, many studies have reported the diverse adverse effects of long-term use of non-selective NSAIDs. Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is a better drug to relieve pain and inflammation in terms of long-term safety and efficacy than non-selective NSAIDs. Nevertheless, there are few reports describing the effectiveness of celecoxib in treating NDI. CASE REPORT We report a case of a 46-year-old woman with schizophrenia who presented with severe hypernatremia and refractory polyuria due to lithium-induced NDI. Cessation of lithium ingestion and traditional treatments, including trichlormethiazide and desmopressin, yielded minimal improvement in her hypernatremia and polyuria. Her sodium level needed to be strictly controlled with the infusion of dextrose 5% in water. Given the safety of celecoxib, we decided to initiate celecoxib as the treatment of lithium-induced NDI instead of indomethacin. Notably, the introduction of celecoxib led to a substantial and sustained amelioration of polyuria and hypernatremia without any celecoxib-associated adverse effects. Even after transfer to another hospital, stability in serum sodium levels persisted with celecoxib. CONCLUSIONS We presented a case of lithium-induced NDI successfully treated with celecoxib, a selective COX-2 inhibitor. To the best of our knowledge, this is the first reported case of successful treatment of lithium-induced NDI with celecoxib, and suggests celecoxib is a viable therapeutic option warranting further exploration. Physicians should consider its use when faced with the challenging management of lithium-induced NDI.

Respiratory-like movements during an apnea test.

Background: Despite the possible occurrence of spontaneous movements during an apnea test, respiratory-like movements are rare. Case Presentation: A 51-year-old man was transferred to our hospital when a sudden disturbance of consciousness developed into cardiac arrest. After spontaneous circulation returned, we diagnosed bilateral cerebellar hemorrhage. He remained comatose with dilated pupils, absent brainstem reflexes, spontaneous breathing, and electrocerebral activity. After being considered brain dead, his family opted for organ donation. The first legal brain death examination on day 5 was aborted because of respiratory-like movements mimicking repetitive abdominal respiration during the apnea test. However, an enhanced magnetic resonance image of the head indicated no blood flow and somatosensory evoked potential testing revealed no brain-derived potentials. Conclusion: Respiratory-like movements can occur during the apnea test in patients considered brain dead. Further research is required to understand this phenomenon.

Primary Ciliary Dyskinesia Caused by Homozygous DNAAF1 Mutations Resulting from a Consanguineous Marriage: A Case Report from Japan.

We present the case of a 58-year-old female patient with primary ciliary dyskinesia (PCD). She was born to parents with a consanguineous marriage. Chest computed tomography conducted at age 41 years indicated no situs inversus, and findings of bronchiectasis were limited to the middle and lingular lobes. Despite long-term macrolide therapy, bronchiectasis exacerbations frequently occurred. PCD was suspected because of the low nasal nitric oxide level (20.7 nL/min). Electron microscopy revealed outer and inner dynein arm defects, and a genetic analysis identified a homozygous single-nucleotide deletion in the DNAAF1 gene. Based on these results, the patient was diagnosed with PCD due to a biallelic DNAAF1 mutation.

A Case of Aggressive Lung Squamous Cell Carcinoma With Aberrant Cytoplasmic p53 Aggregation.

Background: Immunohistochemistry for p53 was a well-established method for cancer diagnosis in pathology. Aberrant cytoplasmic p53 positivity reflects the accumulation of p53 aggregates, which has been shown to be associated with chemoresistance and to be a predictive marker of a worse clinical course in ovarian cancer. Case Report: A 65-year-old Japanese man was diagnosed with lung cancer, and surgical resection was performed. Multiple metastasis were found 21 months post-surgery. The lesions were resistant to chemotherapy, and he succumbed to the disease 29 months post-surgery. The resected primary lesion was pathologically diagnosed as squamous cell carcinoma, with notable cytoplasmic p53 positivity indicated by immunohistochemistry. Conclusion: Notable aberrant cytoplasmic accumulation of p53 aggregate was observed in the cancer cells of this case. Chemotherapy was ineffective for the recurrent lesions, suggesting a role of p53 aggregates in chemoresistance. Pathological analysis of p53 via immunohistochemistry may be useful in predicting chemoresistance of lung squamous cell carcinoma.

Histological evaluation of tissue destruction in mouse tongues caused by cryosurgery.

Introduction: Cryosurgery is recognized as a treatment option for various types of oral lesions. Although cryosurgery is less invasive and easier to perform than surgical treatments, adverse events, such as stomatitis and scarring can occur if the freezing is excessive. There are few studies regarding the effects of cryosurgery on the surrounding soft tissues. Thus, this study investigated the extent of tissue destruction and healing progress in tongues of mice who underwent cryosurgery. Methods: Eight-week-old male BALB/c mice were used. An instrument cooled with liquid nitrogen was lightly touched on the right side of the tongue for 5 s, and a second test was performed 10 s later. Histological evaluation was performed 3, 7, and 14 days after cryosurgery. Blood vessels were evaluated with India ink at 1, 3, 7, 14, and 21 days after cryosurgery. Results: Destruction of the soft tissue spread to the left side of the tongue after 3 days. At 7 days, it was confirmed that the muscle tissue was in the process of repair and was completely repaired at 14 days. Although blood vessels were not confirmed at 3 days, they were visible after seven days and were confirmed at 21 days all over the tongue. Discussion and Conclusion: These results indicated that the tissue destruction caused by cryosurgery was extensive and suggest that the duration and frequency of freezing should be minimized for clinical use. Lay Summary: Cryosurgery is a treatment method for various types of oral lesions. Freezing the lesion causes the tissue to collapse, resulting in its disappearance. Although cryosurgery is less invasive and easier to perform than surgical treatments, adverse events, such as stomatitis and scarring can occur if the freezing is excessive. This study investigated the extent of tissue destruction and healing progress in tongues of mice who underwent cryosurgery.The right side of mice tongues were frozen by an instrument cooled with liquid nitrogen for 5 s, and a second test was performed 10 s later. The tissue destruction was evaluated at 3, 7, and 14 days after freezing. Blood vessels were evaluated with India ink at 1, 3, 7, 14, and 21 days after freezing. Tissue destruction spread to the left side of the tongue after 3 days. At 7 days, it was confirmed that the muscle tissue was in the process of repair and was completely repaired at 14 days. Blood vessel repair was confirmed at 21 days in the throughout tongue. These results indicated that the tissue destruction caused by cryosurgery was large and suggest that the duration and frequency of freezing should be minimized for clinical use.

Risk factors of medication-related osteonecrosis of the jaw: A clinical investigation.

Medication-related osteonecrosis of the jaw (MRONJ) is an intractable condition caused by drugs such as bisphosphonates and denosumab. This study investigated the changes in the incidence of MRONJ in the previous 10 years and examined the poor prognostic factors during surgery in at-risk patients. We compared 57 and 64 patients diagnosed with MRONJ at our hospital between January 2012 and December 2016 and January 2017 and December 2021, respectively. The disease stage and triggers at the time of initial diagnosis in eligible patients were investigated. Additionally, the adverse prognostic factors were examined in 166 patients at risk of MRONJ who underwent tooth extraction at our department during these 10 years. The results indicated that there was no change in the proportion of patients with osteoporosis and malignancy among those with MRONJ. The number of cases after tooth extraction decreased, and those after dental infections increased on comparing the recent 5 years and the preceding 5 years. The number of MRONJ patients receiving denosumab also increased. Denosumab was a significant post-extraction prognostic factor for delayed healing in the 166 patients at risk of MRONJ. The findings suggest that patients receiving denosumab should be closely monitored when undergoing surgery to prevent MRONJ.

Beyond 2D: A scalable and highly sensitive method for a comprehensive 3D analysis of kidney biopsy tissue.

The spatial organization of various cell populations is critical for the major physiological and pathological processes in the kidneys. Most evaluation of these processes typically comes from a conventional 2D tissue cross-section, visualizing a limited amount of cell organization. Therefore, the 2D analysis of kidney biopsy introduces selection bias. The 2D analysis potentially omits key pathological findings outside a 1- to 10-µm thin-sectioned area and lacks information on tissue organization, especially in a particular irregular structure such as crescentic glomeruli. In this study, we introduce an easy-to-use and scalable method for obtaining high-quality images of molecules of interest in a large tissue volume, enabling a comprehensive evaluation of the 3D organization and cellular composition of kidney tissue, especially the glomerular structure. We show that CUBIC and ScaleS clearing protocols could allow a 3D analysis of the kidney tissues in human and animal models of kidney disease. We also demonstrate that the paraffin-embedded human biopsy specimens previously examined via 2D evaluation could be applicable to 3D analysis, showing a potential utilization of this method in kidney biopsy tissue collected in the past. In summary, the 3D analysis of kidney biopsy provides a more comprehensive analysis and a minimized selection bias than 2D tissue analysis. Additionally, this method enables a quantitative evaluation of particular kidney structures and their surrounding tissues, with the potential utilization from basic science investigation to applied diagnostics in nephrology.