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.

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.

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.

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.

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.

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.

Bilateral chylothorax following left neck dissection and literature review.

Chylothorax without chyle cervical leakage after neck dissection it is extremely rare. We report a case of bilateral chylothorax without chyle cervical leakage after left neck dissection, wherein partial left upper jaw resection and left radical neck dissection were performed in a 46-year-old woman who was diagnosed with left upper gingival cancer. The thoracic duct was ligated and cut during surgery and, although no obvious leakage of lymph was observed, dyspnea and cough reflex during deep inhalation were observed from the third postoperative day. Approximately 600 mL of yellowish-white pleural effusion was aspirated during bilateral thoracentesis, and chylothorax was diagnosed based on clinical findings and biochemical analysis results. The patient was put on a low-fat diet on the fourth postoperative day. Pleural effusion disappeared on imaging examination 16 days after thoracentesis.

Effect of the Phosphate Binder Sevelamer Carbonate on the Bioavailability of Enarodustat, an Oral Erythropoiesis Stimulating Agent.

Enarodustat is an orally available hypoxia-inducible factor-prolyl hydroxylase inhibitor which can correct the erythropoietic capacity and improve anemia in chronic kidney disease. Sevelamer carbonate, a non-calcium-based polymeric resin, is one of the commonly prescribed agents for the management of hyperphosphatemia in patients undergoing hemodialysis. This was an open-label, crossover study in healthy male subjects (N = 12) that evaluated the effect of sevelamer carbonate (2400 mg) on the bioavailability of enarodustat (25 mg) when the 2 drugs were administered together (Treatment B) or when enarodustat was administered 3 hours after (Treatment C) or 1 hour before (Treatment D) sevelamer carbonate compared to enarodustat alone (Treatment A). With coadministration of the 2 drugs (Treatment B), enarodustat Cmax and AUCinf reductions were 53% and 45%, respectively. For Treatment C, Cmax and AUCinf reductions were 11% and 6%, respectively, and for Treatment D the corresponding values were 8% and 20%. Thus, coadministration of enarodustat and sevelamer carbonate resulted in a substantial reduction (≈50%) in the oral bioavailability of enarodustat. However, the interaction was substantially mitigated by staggering the administration of enarodustat and sevelamer carbonate. Administration of 4 single oral doses of enarodustat 25 mg, with or without sevelamer carbonate, were safe and well tolerated in this study.

Prediction of Cochlear Implant Effectiveness With Surface-Based Morphometry.

OBJECTIVE: This study aimed to determine whether surface-based morphometry of preoperative whole-brain three-dimensional T1-weighted magnetic resonance imaging (MRI) images can predict the clinical outcomes of cochlear implantation. STUDY DESIGN: This was an observational, multicenter study using preoperative MRI data. SETTING: The study was conducted at tertiary care referral centers. PATIENTS: Sixty-four patients with severe to profound hearing loss (≥70 dB bilaterally), who were scheduled for cochlear implant (CI) surgery, were enrolled. The patients included 19 with congenital hearing loss and 45 with acquired hearing loss. INTERVENTIONS: Participants underwent CI surgery. Before surgery, high-resolution three-dimensional T1-weighted brain MRI was performed, and the images were analyzed using FreeSurfer. MAIN OUTCOME MEASURES: The primary outcome was monosyllable audibility under quiet conditions 6 months after surgery. Cortical thickness residuals within 34 regions of interest (ROIs) as per the Desikan-Killiany cortical atlas were calculated based on age and healthy-hearing control regression lines. RESULTS: Rank logistic regression analysis detected significant associations between CI effectiveness and five right hemisphere ROIs and five left hemisphere ROIs. Predictive modeling using the cortical thickness of the right entorhinal cortex and left medial orbitofrontal cortex revealed a significant correlation with speech discrimination ability. This correlation was higher in patients with acquired hearing loss than in those with congenital hearing loss. CONCLUSIONS: Preoperative surface-based morphometry could potentially predict CI outcomes and assist in patient selection and clinical decision making. However, further research with larger, more diverse samples is necessary to confirm these findings and determine their generalizability.

Impact of primary ciliary dyskinesia: Beyond sinobronchial syndrome in Japan.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by impaired motile cilia function, particularly in the upper and lower airways. To date, more than 50 causative genes related to the movement, development, and maintenance of cilia have been identified. PCD mostly follows an autosomal recessive inheritance pattern, in which PCD symptoms manifest only in the presence of pathogenic variants in both alleles. Several genes causing PCD have been recently identified that neither lead to situs inversus nor cause definitive abnormalities in ciliary ultrastructure. Importantly, the distribution of disease-causing genes and pathogenic variants varies depending on ethnicity. In Japan, homozygosity for a ∼27.7-kb deletion of DRC1 is estimated to be the most common cause of PCD, presumably as a founder mutation. The clinical picture of PCD is similar to that of sinobronchial syndrome, thus making its differentiation from diffuse panbronchiolitis and other related disorders difficult. Given the diagnostic challenges, many cases remain undiagnosed or misdiagnosed, particularly in adults. While no fundamental cure is currently available, lifelong medical subsidies are provided in Japan, and proper respiratory management, along with continued prevention and treatment of infections, is believed to mitigate the decline in respiratory function. Timely action will be necessary when specific treatments for PCD become available in the future. This narrative review focuses on variations in the disease status of PCD in a non-Western country.

Germline BRCA2 Pathogenic Variant in Primary Breast Cancer of a Down Syndrome Individual.

BACKGROUND Down syndrome (DS) is the most common genetic disorder, and individuals with DS are known to have a low risk for solid tumors, including breast cancer. In contrast, Breast Cancer Susceptibility Gene (BRCA) pathogenic variant can cause breast cancer. We report a case of primary breast cancer harboring a BRCA2 pathogenic variant in a 35-year-old woman with DS. CASE REPORT A 35-year-old woman with DS presented with a palpable 2-cm mass in the upper-inner quadrant of the left breast. A biopsy confirmed an invasive ductal carcinoma of the breast. Her clinical diagnosis was cT2, N0, M0, cStageIIA. A left modified radical mastectomy with axillary node dissection was performed. Her final pathological diagnosis was invasive ductal carcinoma (T2, pN1, M0, stageIIB), positive estrogen receptors, negative progesterone receptors, negative human epidermal receptor-2 status. She was started on adjuvant hormonal therapy. Unfortunately, 23 months after the operation, multiple metastases were detected. Testing for a BRCA pathogenic variant was performed, and a BRCA2 pathogenic variant was detected. Olaparib was orally administered, and the levels of tumor markers rapidly declined; however, the levels of the tumor markers started to increase again 5 months after the initiation of olaparib. Subsequently, she developed bilateral carcinomatous lymphangiomatosis and died 59 months after the operation. CONCLUSIONS This report highlights a rare case of primary breast cancer harboring a germline BRCA2 pathogenic variant in an individual with DS. Our study highlights the importance of genetic testing as part of breast cancer management in these patients.

Oral Intake Difficulty and Aspiration Pneumonia Assessment Using High-Resolution Manometry.

OBJECTIVE: The sequential generation of swallowing pressure (SP) from the nasopharynx to the proximal esophagus is important for the bolus to pass from the oral cavity to the esophagus. The purpose of this study was to investigate the correlation of the SP sequence mode on high-resolution manometry (HRM) with oral intake difficulty and aspiration pneumonia. METHODS: Consecutive patients with dysphagia who were admitted to our dysphagia clinic between November 2016 and November 2020 were enrolled in this cross-sectional study. We classified the HRM pressure topography data according to the SP sequence mode into type A, normal; B, partially decreased; C, totally decreased; and D, sequence disappeared, and according to the upper esophageal sphincter (UES) during pharyngeal swallowing into type 1, flattening and 2, non-flattening. Clinical dysphagia severity was determined based on oral intake difficulty and aspiration pneumonia. RESULTS: In total, 202 patients with dysphagia (mean [standard deviation] age, 68.3 [14.5] years; 140 [69.8%] male) were enrolled. Type C (odds ratio [OR], 10.48; 95% confidence interval [CI], 2.89-51.45), type D (OR, 19.90; 95% CI, 4.18-122.35), and type 2 (OR, 6.36; 95% CI, 2.88-14.57) were significantly related to oral intake difficulty. Type C (OR, 3.23; 95% CI, 1.08-11.12) and type 2 (OR, 4.18; 95% CI, 1.95-9.15) were significantly associated with aspiration pneumonia. CONCLUSION: The failure of sequential generation of SP was associated with higher risk of oral intake difficulty and aspiration pneumonia. These assessments are useful in understanding the pathophysiology and severity of dysphagia and in selecting safety nutritional management methods. LEVEL OF EVIDENCE: 4 Laryngoscope, 2023.

Disruption of CADM1-dependent cell-cell adhesion in human oral squamous cell carcinoma cells results in tumor progression, possibly through an increase of MMP-2 and MMP-9 expression.

OBJECTIVES: This study aimed to clarify the molecular mechanism underlying the higher invasion and metastasis abilities of LMF4 cells than those of HSC-3 cells by comparing the expression levels of the tumor suppressor factor, cell adhesion molecule 1 (CADM1). METHODS: We explored 1) whether CADM1 expression level was downregulated in LMF4 cells compared with HSC-3 cells, 2) whether CADM1 expression knockdown increased the expression levels of matrix metalloproteinases (MMPs), 3) the exact cellular signaling pathways responsible for increased MMP expression after knockdown of CADM1 expression, and 4) whether disruption of CADM1-dependent HSC-3 cell adhesion increased the migratory and invasive activities of HSC-3 cells. RESULTS: CADM1 expression was lower in the LMF4 than in the HSC-3 cells. The knockdown of CADM1 increased the expression of MMP-2 and MMP-9 in HSC-3 cells. In addition, the upregulation of MMP-2 expression after CADM1 knockdown was abrogated by the mitogen-activated protein (MAP)/extracellular signal-regulated kinase kinase (MEK) inhibitor U0126 and the phosphoinositide 3-kinase (PI3K) inhibitor LY294002. The upregulation of MMP-9 expression after the knockdown of CADM1 was abrogated by the c-Jun N-terminal kinase (JNK) inhibitor SP600125 and the p38 MAP kinase (MAPK) inhibitor SB203580 and LY294002. Anti-CADM1 neutralizing antibody evoked migratory and invasive abilities of HSC-3 cells. CONCLUSION: The disruption of CADM1-dependent cell-cell adhesion in human oral squamous cell carcinoma cells resulted in tumor progression, possibly through an increase in MMP-2 expression in a MEK/PI3K-dependent manner and an increase in MMP-9 expression in a JNK/p38 MAPK/PI3K-dependent manner.

FOXJ1 Variants Causing Primary Ciliary Dyskinesia with Hydrocephalus: A Case Report from Japan.

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by motile cilia dysfunction, mostly inherited in an autosomal recessive or X-linked manner. We herein report a 29-year-old woman with PCD caused by a heterozygous frameshift mutation due to a single nucleotide deletion in exon 3 of FOXJ1. Heterozygous de novo mutations in FOXJ1 have been reported as an autosomal-dominant cause of PCD. The patient had situs inversus, congenital heart disease, infertility, and hydrocephalus. However, the nasal nitric oxide level was normal. Long-term macrolide therapy was remarkably effective. This is the first case report of PCD caused by a FOXJ1 variant in Japan.

Matrix metalloproteinase-10 deficiency has protective effects against peritoneal inflammation and fibrosis via transcription factor NFκΒ pathway inhibition.

One of the most common causes of discontinued peritoneal dialysis is impaired peritoneal function. However, its molecular mechanisms remain unclear. Previously, by microarray analysis of mouse peritoneum, we showed that MMP (matrix metalloproteinase)-10 expression is significantly increased in mice with peritoneal fibrosis, but its function remains unknown. Chlorhexidine gluconate (CG) was intraperitoneally injected to wild-type and MMP-10 knockout mice to induce fibrosis to elucidate the role of MMP-10 on peritoneal injury. We also examined function of peritoneal macrophages and mesothelial cells obtained from wild-type and MMP-10 knockout mice, MMP-10-overexpressing macrophage-like RAW 264.7 cells and MeT-5A mesothelial cells, investigated MMP-10 expression on peritoneal biopsy specimens, and the association between serum proMMP-10 and peritoneal solute transfer rates determined by peritoneal equilibration test on patients. MMP-10 was expressed in cells positive for WT1, a mesothelial marker, and for MAC-2, a macrophage marker, in the thickened peritoneum of both mice and patients. Serum proMMP-10 levels were well correlated with peritoneal solute transfer rates. Peritoneal fibrosis, inflammation, and high peritoneal solute transfer rates induced by CG were all ameliorated by MMP-10 deletion, with reduction of CD31-positive vessels and VEGF-A-positive cells. Expression of inflammatory mediators and phosphorylation of NFκΒ subunit p65 at S536 were suppressed in both MMP-10 knockout macrophages and mesothelial cells in response to lipopolysaccharide stimulation. Overexpression of MMP-10 in RAW 264.7 and MeT-5A cells upregulated pro-inflammatory cytokines with phosphorylation of NFκΒ subunit p65. Thus, our results suggest that inflammatory responses induced by MMP-10 are mediated through the NFκΒ pathway, and that systemic deletion of MMP-10 ameliorates peritoneal inflammation and fibrosis caused by NFκΒ activation of peritoneal macrophages and mesothelial cells.

Married women's decision to delay childbearing, and loneliness, severe psychological distress, and suicidal ideation under crisis: online survey data analysis from 2020 to 2021.

BACKGROUND: The COVID-19 pandemic has affected every aspect of our lives, including the decision to become pregnant. Existing literature suggests that infertility and the decision to delay childbearing at a younger age are associated with a lower level of well-being and regrets when women start to desire a baby. Thus, the decision to delay childbearing due to the pandemic could negatively affect the well-being of women. This study focuses on how pregnancy decisions affect the well-being of women during the COVID-19 pandemic. METHODS: From the Japan COVID-19 and Society Internet Survey, a nationally representative web-based survey, 768 observations of married women aged 18 to 50 years who had the intention of getting pregnant during the pre-pandemic period (conducted in 2020 and 2021) were used. Loneliness, severe psychological distress, and suicidal ideation were used as well-being indicators. For pooled data, a generalised estimated equation (GEE) model was used to estimate how pregnancy decision related to well-being indicators. For a sub-analysis, the sample was divided by the survey year and a Poisson regression model was used. RESULTS: The GEE analysis showed an association between delaying childbearing and severe psychological distress, with the prevalence ratio (PR) being 2.06 [95% CI (1.40-3.03)]. Furthermore, loneliness and suicidal ideation that occurred after the beginning of the pandemic were significantly related to the decision to delay childbearing-1.55 [95% CI (1.03,2.34)] and 2.55 [95% CI (1.45-4.51)], respectively. Moreover, these PRs were larger for 2021 compared to 2020. CONCLUSION: During the COVID-19 pandemic, approximately one-fifth of married women who had childbearing intentions before the pandemic decided to postpone pregnancy. They exhibited a deteriorated mental health state. Furthermore, the negative associations were larger in 2021 compared to 2020. Loneliness has negative consequences for both mental and physical health, as well as elevated severe psychological distress and suicidal ideation among those who decided to postpone pregnancy. Therefore, the current results should not be overlooked by society.

Evaluation of Drug-Drug Interaction Potential of Enarodustat (JTZ-951) Using a Cytochrome P450 Probe Cocktail.

The drug interaction potential of enarodustat (doses: 25, 50 mg) on the activity of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated after once-daily administration for 15 days in a phase 1 multiple-ascending-dose study in healthy subjects. Probe substrates specific for the enzymes, i.e., caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4), were administered orally as a cocktail with (day 15) and without (day -3) enarodustat. Drug interaction was based on geometric mean maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from the time of dosing to infinity (AUCinf ) ratios (day 15/day -3) for CYP1A2, 2C9, 2C19, 2D6, 3A4, and urinary excretion of dextromethorphan metabolite dextrorphan for CYP2D6. At the 2 enarodustat doses, for caffeine, the geometric mean ratios (range) for Cmax and AUCinf were 0.99-1.06 and 1.61-1.63, respectively. The ratios for peak concentrations and total exposures were 0.98-1.07 and 0.71-1.78 for tolbutamide and omeprazole, respectively. For dextrorphan the Cmax and AUCinf ratios were 0.83-0.90 and 1.02-1.04, respectively. The mean dextrorphan cumulative amount excreted into the urine from the time of dosing to 24 hours values on day -3 and day 15 were 8.25 mg and 8.20 mg at the lower dose, and 9.40 mg and 9.51 mg at the higher dose. The ratios for midazolam Cmax and AUCinf were 1.42-1.63. Overall, there was a lack of enarodustat dose dependency regarding the geometric mean ratios and 90% confidence intervals and urinary excretion of dextrorphan. There were some cases where the 90% confidence intervals at the 2 enarodustat doses were outside the 0.80-1.25 range, but changes in the geometric mean ratios were all <2-fold.

Condyle Fracture Fixed with Custom-Made Titanium Mesh and a Miniplate: A Case Report.

BACKGROUND Open reduction and internal fixation of condyle fractures are sometimes difficult for the upper region. This report presents a case of condyle fracture at the upper neck region treated with a custom-made titanium mesh and a titanium miniplate, which makes it easy to reposition the fragment and keep it in place. CASE REPORT A 20-year-old man was injured during a soccer match and was referred to our hospital with the symptom of trismus and deviation of the mandible to the left with an opened mouth. Fracture of the right condyle neck region was diagnosed; open reduction and internal fixation was planned under general anesthesia. A custom-made titanium mesh was prepared to make it easy to reposition the fragment and keep it in place because the reduction and fixation were expected to be difficult. The fracture region was exposed using the modified Risdon-Strasbourg approach. The segments were gripped with custom-made titanium mesh, and the condyle head was reduced easily. The segments were fixed with titanium mesh, a miniplate, and screws. Nine months after the operation, the mouth opening was good at 40 mm, there was no deviation of the mandible, and there was no breakage on the titanium mesh or plate. CONCLUSIONS This report presents a case of condyle fracture at the upper neck region reduced and fixed with a custom-made titanium mesh and a titanium miniplate, which make it easy to reposition the fragment and keep it in place.

Chapter 1: Evaluation of kidney function in patients undergoing anticancer drug therapy, from clinical practice guidelines for the management of kidney injury during anticancer drug therapy 2022.

The prevalence of CKD may be higher in patients with cancer than in those without due to the addition of cancer-specific risk factors to those already present for CKD. In this review, we describe the evaluation of kidney function in patients undergoing anticancer drug therapy. When anticancer drug therapy is administered, kidney function is evaluated to (1) set the dose of renally excretable drugs, (2) detect kidney disease associated with the cancer and its treatment, and (3) obtain baseline values for long-term monitoring. Owing to some requirements for use in clinical practice, a GFR estimation method such as the Cockcroft-Gault, MDRD, CKD-EPI, and the Japanese Society of Nephrology's GFR estimation formula has been developed that is simple, inexpensive, and provides rapid results. However, an important clinical question is whether they can be used as a method of GFR evaluation in patients with cancer. When designing a drug dosing regimen in consideration of kidney function, it is important to make a comprehensive judgment, recognizing that there are limitations regardless of which estimation formula is used or if GFR is directly measured. Although CTCAEs are commonly used as criteria for evaluating kidney disease-related adverse events that occur during anticancer drug therapy, a specialized approach using KDIGO criteria or other criteria is required when nephrologists intervene in treatment. Each drug is associated with the different disorders related to the kidney. And various risk factors for kidney disease associated with each anticancer drug therapy.