Endoscopic Management of a Case of Spontaneous Cerebrospinal Fluid Leaks in Anterior Skull Base.

Spontaneous cerebrospinal fluid (sCSF) leaks are rare, and their diagnosis and treatment often present significant challenges. This paper discusses and reports cases experienced at our facility. We retrospectively reviewed three of five cases of sCSF leaks experienced at the Department of Otolaryngology and Head and Neck Surgery, Kyushu University, from December 2020 to December 2022, excluding CSF otorrhea. All three patients were female; their mean age was 56 years (44-71 years). Two of the three patients were obese (first degree), and one was average weight (according to the criteria of the Japan Society for the Study of Obesity). Two patients had hypertension, and one had sleep apnea syndrome as an underlying disease. In all cases, leakage sites, which were all the cribriform plate, can be endoscopically identified, and all could be closed by an endoscopic intranasal approach. We reviewed cases of sCSF leaks. Although some patients had difficulty identifying the leakage site in a narrow and complex nasal cavity, an endoscopic survey was useful in identifying the leakage site. All cases were closed and there were no signs of recurrence. Identifying the site of leakage and selecting the appropriate closure method depending on the extent of the leakage is essential in treating such cases.

Preservation of nasal function in paramedian endoscopic endonasal approaches: patient series.

BACKGROUND: The endoscopic endonasal approach to paramedian skull base lesions has garnered increasing attention in recent reports. However, it is still a challenging approach. While the primary objective of the approach is the maximal removal of tumors through a minimally invasive procedure, discussions of the approach rarely include information about the maximum preservation of nasal structures. This study aimed to retrospectively review the clinical outcomes of patients who had undergone an endoscopic endonasal approach to paramedian lesions, describe the technical and anatomical nuances related to this approach at the authors' institution, and discuss the maximal preservation of nasal structures. OBSERVATIONS: The authors conducted a descriptive retrospective study of 17 surgical cases of paramedian endoscopic endonasal approaches performed jointly by otolaryngologists and neurosurgeons from August 2018 to August 2022 at a tertiary hospital. LESSONS: The approach to the paramedian region of the skull base was examined. Creating an appropriate corridor to maximize the surgical field is essential to allow a safe and accurate procedure. From an otolaryngologist's perspective, the endoscopic modified medial maxillectomy is an essential procedure that maximizes the surgical corridor and maximally preserves nasal morphology. https://thejns.org/doi/10.3171/CASE24218.

Plasma cell differentiation is regulated by the expression of histone variant H3.3.

The differentiation of B cells into plasma cells is associated with substantial transcriptional and epigenetic remodeling. H3.3 histone variant marks active chromatin via replication-independent nucleosome assembly. However, its role in plasma cell development remains elusive. Herein, we show that during plasma cell differentiation, H3.3 is downregulated, and the deposition of H3.3 and chromatin accessibility are dynamically changed. Blockade of H3.3 downregulation by enforced H3.3 expression impairs plasma cell differentiation in an H3.3-specific sequence-dependent manner. Mechanistically, enforced H3.3 expression inhibits the upregulation of plasma cell-associated genes such as Irf4, Prdm1, and Xbp1 and maintains the expression of B cell-associated genes, Pax5, Bach2, and Bcl6. Concomitantly, sustained H3.3 expression prevents the structure of chromatin accessibility characteristic for plasma cells. Our findings suggest that appropriate H3.3 expression and deposition control plasma cell differentiation.

Type I interferon promotes the fate of Toll-like receptor 9-stimulated follicular B cells to plasma cell differentiation.

The activation and differentiation of B cells into plasma cells (PCs) play critical roles in the immune response to infections and autoimmune diseases. Toll-like receptor 9 (TLR9) responds to bacterial and viral DNA containing unmethylated CpG motifs and triggers immune responses in B cells; however, abnormal recognition of self-DNA by TLR9 can cause autoimmune diseases. When stimulated with TLR9 agonists, follicular (FO) B cells, a subset of B cells residing in the FO regions of secondary lymphoid organs, exhibit a propensity for activation but fail to give rise to PCs. The factors that enable the transition of TLR9-activated FO B cells from activation to differentiation into PCs remain unclear. In this study, we show that type I interferon-alpha (IFNα) signaling causes FO B cells activated by CpG stimulation to differentiate into PCs. Although CpG stimulation alone only temporarily increased interferon regulatory factor 4 (IRF4) expression in FO B cells, co-stimulation with both CpG and IFNα enhanced and maintained high IRF4 expression levels, ultimately enabling the cells to differentiate into PCs. Overexpression of IRF4 in FO B cells results in CpG-induced PC transition without IFN signaling. Furthermore, co-stimulation of TLR9 and IFNα receptors significantly enhanced mammalian target of rapamycin (mTOR) signaling, which regulates IRF4 expression and PC generation. These findings suggest that IFNα may play a key role in promoting the fate of PC differentiation in FO B cells activated by TLR9 stimulation.

The importance of the palatine bone for endoscopic endonasal skull base surgery.

Endoscopic endonasal skull base surgery is increasingly prevalent, with its scope expanding from pathogens in the midline region to those in the paramedian region. Maximizing anterior sphenoidectomy is important for the median approach, and lateralizing the pterygopalatine fossa is crucial for the paramedian approach. Maximizing the surgical corridor in the nasal cavity and minimizing damage to neurovascular structures are vital for establishing a surgical field with minimal bleeding, ensuring safe, precise, and gentle procedures. However, the relationship between the maxillofacial and skull base bones in endoscopic endonasal skull base surgery is difficult to understand because these bones are intricately articulated, making it challenging to visualize each bone's outline. Understanding important bones and their related neurovascular structures is essential for all skull base surgeons to maximize the surgical corridor and minimize iatrogenic injury to neurovascular structures. This study aimed to elucidate the role of the palatine bone from a microsurgical anatomical perspective. Three dry skulls were used to demonstrate the structure of the palatine bone and its relationship with surrounding bones. A formalin-perfused cadaveric head was dissected to show the related neurovascular structures. The arteries and veins of the cadaveric heads were injected with red- and blue-colored silicon. Dissection was performed using a surgical microscope and endoscope. In addition, the utilization of the palatine bone as a landmark to identify neurovascular structures, which aids in creating a wider surgical field with less bleeding, was shown in two representative cases. The palatine bone consists of unique complex structures, including the sphenoidal process, ethmoidal crest, pterygopalatine canal, and sphenopalatine notch, which are closely related to the sphenopalatine artery, maxillary nerve, and its branches. The ethmoidal crest of the palatine bone is a well-known structure that is useful for identifying the sphenopalatine foramen, controlling the sphenopalatine artery and nerve, and safely opening the pterygopalatine fossa. The sphenoidal process of the palatine bone is a valuable landmark for identifying the palatovaginal artery, which is a landmark used to safely and efficiently expose the vidian canal. The sphenoidal process is easily cracked with an osteotome and removed to expose the palatovaginal artery, which runs along the pharyngeal groove, just medial to the vidian canal. By opening the pterygopalatine canal (also known as the greater palatine canal), further lateralization of the periosteum-covered pterygopalatine fossa contents can be achieved. Overall, the sphenoidal process and ethmoidal crest can be used as important landmarks to maximize the surgical corridor and minimize unnecessary injury to neurovascular structures.

Double Negativity of MRI-Detected and Pathologically-Diagnosed Extramural Venous Invasion is a Favorable Prognostic Factor for Rectal Cancer.

BACKGROUND: Extramural venous invasion (EMVI) is a prognostic factor in rectal cancer. There are two types: EMVI detected by magnetic resonance imaging (MRI) (mr-EMVI) and EMVI detected by pathology (p-EMVI). They have been separately evaluated, but they have not yet been concurrently evaluated. We therefore evaluate both mr-EMVI and p-EMVI in rectal cancer at the same time and clarify their association with prognosis. PATIENTS AND METHODS: Included were the 186 consecutive patients who underwent complete radical resection of tumors ≤ stage III at Wakayama Medical University Hospital, Japan, between 2010 and 2018. All underwent preoperative MRI examination, and were reassessed for EMVI by a radiologist. Surgically resected specimens were then reassessed for EMVI by a pathologist. We assessed the correlation between positivity of mr-EMVI and p-EMVI and prognosis, and the clinicopathological background behind them. RESULTS: Patients with double negativity for mr-EMVI and p-EMVI had better prognosis than patients with mr-EMVI or p-EMVI positivity (p < 0.0001). Positivity for mr-EMVI or p-EMVI was a poor independent prognostic factor in multivariate analysis. CONCLUSIONS: Combined analysis of mr-EMVI and p-EMVI may enable prediction of postoperative prognosis of rectal cancer. Patients with double negativity of mr-EMVI and p-EMVI had better prognosis than patients with some form of positivity. Stated differently, patients with positivity of mr-EMVI, p-EMVI, or both had a poorer prognosis than those with double negativity. Postoperative adjuvant chemotherapy may improve poor prognosis. Combined evaluation of mr-EMVI and p-EMVI may be used to predict clinical outcomes and may be an effective prognostic predictor of rectal cancer.

Safe and efficient oral allergy immunotherapy using one-pot-prepared mannan-coated allergen nanoparticles.

Allergen immunotherapy (AIT) is the only curative treatment for allergic diseases. However, AIT has many disadvantages related to efficiency, safety, long-term duration, and patient compliance. Dendritic cells (DCs) have an important role in antigen-specific tolerance induction; thus, DC-targeting strategies to treat allergies such as glutaraldehyde crosslinked antigen to mannoprotein (MAN) have been established. However, glutaraldehyde crosslinking may reduce the antigen presentation efficiency of DCs. To overcome this, we developed a MAN-coated ovalbumin (OVA) nanoparticle (MDO), which uses intermolecular disulfide bond to crosslink OVA and MAN. MDO effectively targeted DCs resulting in tolerogenic DCs, and promoted higher antigen presentation efficiency by DCs compared with OVA or glutaraldehyde crosslinked nanoparticles. In vitro and in vivo experiments showed that DCs exposed to MDO induced Treg cells. Moreover, MDO had low reactivity with anti-OVA antibodies and did not induce anaphylaxis in allergic mice, demonstrating its high safety profile. In a mouse model of allergic asthma, MDO had significant preventative and therapeutic effects when administered orally or subcutaneously. Therefore, MDO represents a promising new approach for the efficient and safe treatment of allergies.

Social anxiety disorder in adolescents who stutter: A risk for school refusal.

BACKGROUND: Stuttering is a childhood-onset fluency disorder. Part of the counseling for middle and high school students with persistent stuttering is related to school refusal. Anxiety disorders are known to contribute to school refusal. However, it is not known whether social anxiety disorder (SAD) is a factor in school refusal among adolescents who stutter. METHODS: In our first study, we examined the relationship between school refusal and SAD in 84 middle and high school students who stutter; 26% of the 84 students were in the school refusal group and the remaining 74% were in the school attendance group. The second study examined whether SAD was associated with 10 factors related to speech and stuttering frequency using the Japanese version of the Liebowitz Social Anxiety Scale for Children and Adolescents to determine the presence of SAD. Of the 84 students in the first study, 40 participated in the second study. RESULTS: The school refusal group of adolescents who stutter had significantly higher rates of SAD than the school attendance group. Fifty percent of adolescents who stutter met the criteria for SAD. Moreover, adolescents who stutter with SAD had significantly higher scores on the items "When speaking in public, do you experience tremors in your limbs?" and "After you stutter, do you have negative thoughts about yourself?" than the adolescents who stutter without SAD. CONCLUSIONS: When examining adolescents who stutter, checking for comorbid SAD may lead to better support. Moreover, noticing their repetitive negative thinking, nervousness, and trembling during speech may help to resolve SAD.

Primary Hepatic Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorders After Methotrexate Therapy.

Prior reports described cases of lymphoproliferative diseases occurring after methotrexate (MTX) administration, which are called methotrexate-associated lymphoproliferative disorders (MTX-LPDs). It has become clear that these lymphoproliferative diseases also occur following treatment with other immunosuppressive drugs, and they have been termed as other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs). In most of these cases, the duration of immunosuppressive drugs is very long, on the order of years. In the present study, we evaluated the development of lymphoproliferative disease despite the short duration of immunosuppressive treatment and determined the tumor doubling time. A 71-year-old woman was diagnosed with adult-onset Still's disease. The patient was administered prednisone 30 mg per day starting on February 25, 2022 and MTX 6 mg per week starting 2 weeks later. Because she was a hepatitis B virus (HBV) carrier, nucleic acid analog therapy was also started to prevent HBV activation. Eight weeks later, biweekly tocilizumab was started. After 5 months of MTX administration, a solitary liver tumor measuring 37 × 32 mm2 was detected. Three months later, repeat computed tomography revealed that the liver tumor had grown rapidly to 7 cm in diameter. We considered the possibility of OIIA-LPDs and stopped MTX therapy. Biopsy specimens of the liver tumor exhibited lymphocyte proliferation, which was consistent with OIIA-LPDs. The doubling time for tumor growth was 33 days. Despite withdrawing MTX for 6 weeks, the tumor continued to grow, and thus, the patient was referred to the hematology unit. In previously reported cases of MTX-LPDs of hepatic origin, the average duration of MTX administration was 7.3 (2 - 13) years. This report describes a primary hepatic OIIA-LPDs-associated tumor that rapidly increased in size after an extremely short period of MTX administration.

One-pot preparation of mannan-coated antigen nanoparticles using human serum albumin as a matrix for tolerance induction.

Nanoparticles (NPs) for allergen immunotherapy have garnered attention for their high efficiency and safety compared with naked antigen proteins. In this work, we present mannan-coated protein NPs, incorporating antigen proteins for antigen-specific tolerance induction. The heat-induced formation of protein NPs is a one-pot preparation method and can be applied to various proteins. Here, the NPs were formed spontaneously via heat denaturation of three component proteins: an antigen protein, human serum albumin (HSA) as a matrix protein, and mannoprotein (MAN) as a targeting ligand for dendritic cells (DCs). HSA is non-immunogenic, therefore suitable as a matrix protein, while MAN coats the surface of the NP. We applied this method to various antigen proteins and found that the self-disperse after heat denaturation was a requirement for incorporation into the NPs. We also established that the NPs could target DCs, and the incorporation of rapamycin into the NPs enhanced the induction of a tolerogenic phenotype of DC. The MAN coating provided steric hindrance and heat denaturation destroyed recognition structures, successfully preventing anti-antigen antibody binding, indicating the NPs may avoid anaphylaxis induction. The MAN-coated NPs proposed here, prepared by a simple method, have the potential for effective and safe allergies treatment for various antigens.

Tokyo's COVID-19: An urban perspective on factors influencing infection rates in a global city.

This research investigates the relationship between COVID-19 and urban factors in Tokyo. To understand the spread dynamics of COVID-19, the study examined 53 urban variables (including population density, socio-economic status, housing conditions, transportation, and land use) in 53 municipalities of Tokyo prefecture. Using spatial models, the study analysed the patterns and predictors of COVID-19 infection rates. The findings revealed that COVID-19 cases were concentrated in central Tokyo, with clustering levels decreasing after the outbreaks. COVID-19 infection rates were higher in areas with a greater density of retail stores, restaurants, health facilities, workers in those sectors, public transit use, and telecommuting. However, household crowding was negatively associated. The study also found that telecommuting rate and housing crowding were the strongest predictors of COVID-19 infection rates in Tokyo, according to the regression model with time-fixed effects, which had the best validation and stability. This study's results could be useful for researchers and policymakers, particularly because Japan and Tokyo have unique circumstances, as there was no mandatory lockdown during the pandemic.

Variation in the rate of detection of minute and small early gastric cancers at diagnostic endoscopy may reflect the performance of individual endoscopists.

OBJECTIVE: The documented variation in gastric cancer (GC) detection among endoscopists has often been dismissed as a coincidental artefact of the low incidence of gastric neoplasms; it is not considered associated with differences in physicians' performance of the esophagogastroduodenoscopy procedure. This study is to confirm whether significant variations among endoscopists in early GC detection suggest the individual performance of the upper endoscopy. DESIGN: A retrospective observational study at a single centre in Japan assessed the results of 218 early GCs detected during 25 688 routine esophagogastroduodenoscopies by 12 endoscopists. The main outcome was the rate of early GC detection for each endoscopist under the same circumstances. Other measures included the major diameters and locations of the lesions, Helicobacter pylori infection status, and baseline patient characteristics that could affect the prevalence of GC. RESULTS: The early GC detection rates exhibited wide variation among endoscopists (0.09%-2.87%) despite performing routine esophagogastroduodenoscopies in a population with a similar background. Endoscopists were assigned to a low-detection group (n=6; detection rate: 0.47% (range: 0.09%-0.55%)) and a high-detection group (n=5; detection rate: 0.83% (range: 0.63%-1.12%)), with the single highest detector analysed separately due to his distinct detection rate (2.87%). Endoscopists in the high-detection group had better detection rates for minute (major diameter ≤5 mm) and small (major diameter 6-10 mm) GCs than the low-detection group (0.19%/0.23% vs 0.085%/0.098%). These differences were significant (p<0.01), although there were no significant differences in detection of larger tumours (major diameter ≥11 mm; 0.40% vs 0.28%; p=0.13). The tumour location and H. pylori status were similar in the low-detection group, high-detection group and for the highest detector. CONCLUSION: Significant variation in the detection of hard-to-find, smaller GCs may reflect individual performance of the examination.

Lip and facial training improves lip-closing strength and facial morphology.

OBJECTIVE: Childhood is an important period for lip-closing strength (LCS) development, and failure to acquire LCS during childhood leads to various adverse health effects, such as mouth breathing. The purpose of this study was to examine the effectiveness of device-free lip and facial training in preschool children. DESIGN: The participants were divided into training and control groups. Both groups comprised 123 children aged 3-4 years, and only the training group received lip and facial training (i.e., opening and closing the lips and protruding the tongue) for 1 year. A two-way repeated measures analysis of variance was applied to compare the interaction effects of LCS and facial linear distance and angle by year (initial year vs. 1 year later) and group (training vs. control group). In addition, paired t-tests were used to test the changes in LCS and facial linear distance and angle after 1 year in both groups. Furthermore, the same analysis was performed in children with weak LCS in both groups (incompetent lip seal [ILS]). RESULTS: The LCS of children in the training group significantly increased after training compared with that in the control group, whether the analysis included all children or children with ILS alone. Lip and facial training for children with ILS reduced both the upper and lower lip protrusion; children with ILS without training had increased lip protrusion after 1 year. CONCLUSIONS: Lip and facial training for children with ILS effectively improved LCS and lip morphology, thereby preventing increased lip protrusion.

Diagnostic value of the serum lactate level as a predictor of bacteremia in patients with acute cholangitis.

BACKGROUND: Patients with acute cholangitis (AC) have increased mortality when associated with bacteremia. This study aimed to evaluate the predictive ability of serum lactate (Lac) for positive bacteremia in patients with acute cholangitis. METHODS: In this single-center, retrospective study, 138 consecutive patients with AC were analyzed. Their blood samples were collected and Lac was measured. RESULTS: A total of 50 patients showed grade I, 50 showed grade II, and 38 showed grade III severity according to the Tokyo Guidelines 2018. Positive bacteremia was observed in 71 patients, of which 15 showed grade I, 25 showed grade II, and 31 showed grade III severity. Logistic regression analysis showed that Lac was a significant predictor of bacteremia. The area under the curve of Lac and procalcitonin (PCT) for bacteremia were 0.737 and 0.780, respectively. The optimal cutoff values for bacteremia were 17 mg/dL and 2.8 ng/mL, with sensitivity of 69.0% and 68.3%, respectively. Sensitivity of Lac and PCT for bacteremia in grade I was 58.3% and 25.0%, respectively. Three patients died from AC, all of whom were positive for bacteremia and hyperlactatemia. CONCLUSION: Lac is useful for predicting bacteremia in patients with AC.

Histology of metastatic colorectal cancer in a lymph node.

BACKGROUND: A primary colorectal cancer (CRC) tumor can contain heterogeneous cancer cells. As clones of cells with different properties metastasize to lymph nodes (LNs), they could show different morphologies. Cancer histologies in LNs of CRC remains to be described. METHODS: Our study enrolled 318 consecutive patients with CRC who underwent primary tumor resection with lymph node dissection between January 2011 and June 2016. 119 (37.4%) patients who had metastatic LNs (mLNs) were finally included in this study. Cancer histologies in LNs were classified and compared with pathologically diagnosed differentiation in the primary lesion. The association between histologies in lymph node metastasis (LNM) and prognosis in patients with CRC was investigated. RESULTS: The histologies of the cancer cells in the mLNs were classified into four types: tubular, cribriform, poorly differentiated, and mucinous. Same degree of pathologically diagnosed differentiation in the primary tumor produced various histological types in LNM. In Kaplan-Meier analysis, prognosis was worse in CRC patients with moderately differentiated adenocarcinoma who had at least some mLN also showing cribriform carcinoma than for those whose mLNs all showed tubular carcinoma. CONCLUSIONS: Histology in LNM from CRC might indicate the heterogeneity and malignant phenotype of the disease.