Isolated Adrenocorticotropic Hormone Deficiency Diagnosed After the Cessation of Glucocorticoid Therapy for Eosinophilic Esophagitis: A Case Report.

Isolated adrenocorticotropic hormone deficiency (IAD) is a rare pituitary disorder that can cause adrenal insufficiency. However, due to its nonspecific symptoms, its diagnosis is often difficult and may be delayed. Patients with IAD require lifelong glucocorticoid (GC) replacement therapy. Contrastingly, GC-induced secondary adrenal insufficiency is a reversible condition that arises when patients receiving GC therapy reduce their GC dosage or discontinue therapy. Differentiating between IAD and GC-induced secondary adrenal insufficiency is clinically crucial. We report a unique case that required differentiation between these two conditions. A 71-year-old Japanese woman presented with symptoms of adrenal insufficiency after discontinuation of GC therapy for eosinophilic esophagitis. We conducted detailed interviews and repeated the endocrinological examinations. We concluded that her symptoms were owing to IAD rather than GC-induced secondary adrenal insufficiency. She began a lifelong hydrocortisone replacement therapy. This case suggests that when caring for patients undergoing GC therapy, it is important to consider the possibility of coexisting IAD and arrange endocrinological examinations if signs of adrenal insufficiency arise during the gradual reduction of GC treatment.

Involvement of mitogen- and stress-activated protein kinase (MSK)1 in BMP-6-induced chondrocyte differentiation.

Bone morphogenetic proteins (BMPs) are involved in several cellular responsive actions, such as development, cell differentiation, and apoptosis, via their specific transmembrane receptors. In particular, BMPs promote the differentiation and maturation of bone and cartilage from mesenchymal stem cells. Based on comprehensive analyses performed with a large number of antibodies, mitogen- and stress-activated protein kinase (MSK)1 was found to be immediately phosphorylated in the mouse chondrocyte precursor cell line, ATDC5, upon BMP-6 stimulation. The overexpression and knockdown of MSK1 in ATDC5 cells also enhanced and suppressed BMP-6-induced chondrocyte differentiation, respectively. Similar to ATDC5 cells, an ex vivo organ culture system using mouse embryonic metatarsal bones also demonstrated that BMP-6-mediated MSK1 activation might play a role in chondrocyte differentiation. Using several inhibitors, the p38 kinase pathway was confirmed to be implicated in BMP-6-induced phosphorylation of MSK1. Furthermore, MSK1 mutants lacking kinase activities and those lacking serine/threonine residues targeted by p38 kinase severely impaired their ability to potentiate BMP-6-induced chondrogenic differentiation of ATDC5 cells. Interestingly, a loss-of-function study for Smad4 perturbed BMP-6-induced phosphorylation of p38 kinase to inhibit BMP-6-mediated chondrocyte differentiation via MSK1 activation. Overall, both Smad-dependent and independent pathways require BMP-6-induced chondrocyte differentiation via MSK1 activation in ATDC5 cells.

AB052. A multicenter prospective exploratory phase II study of neoadjuvant bevacizumab for newly diagnosed malignant glioma.

BACKGROUND: We conducted a multicenter study for neoadjuvant bevacizumab (neoBev) for newly diagnosed glioblastoma (nGB). In this study, median overall survival (mOS) related to radiological response, of which reliability as a prediction of overall survival (OS) was explored. METHODS: A total of 15 patients with nGB were enrolled, and given ring enhancement and perifocal edema on magnetic resonance imaging (MRI). Two weeks after neoBev, the tumor volumes on T1 weighted image with contrast medium (T1CE) and fluid attenuated inversion recovery (FLAIR) were assessed. Three to four weeks after neoBev, surgery was performed. Clinical outcomes including mOS as well as the safety of neoBev were evaluated. RESULTS: Severe adverse events were observed in two of 15 patients as one postoperative hematoma and one wound infection. The average volume decrease rates on T1CE and FLAIR were -37% and -54%, respectively. The decrease rate on T1CE was not correlated with that on FLAIR. Based on MRI, good (GR) and poor responders (PR) on T1CE were defined as more or less of the average volume reduction rate, respectively. In addition, there was a case with discordance in tumor volume changes between T1CE and FLAIR. And OS in a discordant case was 20.4 months, which was not unfavorable. mOS of GR and PR on T1CE were 19.8 and 12.9 months, respectively. In contrast, mOS of GR and PR on FLAIR were 16.0 and 17.0 months, respectively. CONCLUSIONS: Preoperative neoBev was confirmed a safe procedure. mOS in the present cohort was not significantly prolonged. Early tumor volume regression on T1CE but not FLAIR after neoBev therapy has a significant prognostic indicator for mOS in nGB.

Surgical Outcomes in Patients Exhibiting Muscular Weakness Postadolescence Due to Tight Filum Terminale.

INTRODUCTION: Tight filum terminale is a neurological condition marked by various symptoms, including muscle weakness. There is a notable lack of literature addressing muscle weakness, particularly in cases emerging during adolescence and beyond. The diagnosis is challenging due to a lack of radiological abnormalities, and the literature on its treatment, especially untethering, in adults is limited. This study aims to evaluate the effectiveness of untethering in improving muscle weakness and other symptoms in postadolescent patients diagnosed with tight filum terminale. METHODS: A retrospective analysis was conducted on seven postadolescent patients diagnosed with tight filum terminale and presenting muscle weakness who underwent untethering at our institution between January 2018 and August 2022. Patients were monitored for muscle strength improvement, lumbar and lower extremity pain, and bowel and bladder dysfunction (BBD) after untethering. RESULTS: Muscle weakness improved in all cases after untethering, with a mean duration of 9.1 weeks for the improvement. Patients unable to walk independently regained mobility in an average of 22.3 weeks. Lumbar and lower limb pain improved in all cases within an average of 8.1 weeks, while BBD improved in six of the seven cases within an average of 1.9 weeks. CONCLUSIONS: Our findings suggest that untethering is an effective surgical intervention for postadolescent patients diagnosed with tight filum terminale and presenting muscle weakness.

Comparative analyses of immune cells and alpha-smooth muscle actin-positive cells under the immunological microenvironment between with and without dense fibrosis in primary central nervous system lymphoma.

Histopathologic examinations of primary central nervous system lymphoma (PCNSL) reveal concentric accumulation of lymphocytes in the perivascular area with fibrosis. However, the nature of this fibrosis in "stiff" PCNSL remains unclear. We have encountered some PCNSLs with hard masses as surgical findings. This study investigated the dense fibrous status and tumor microenvironment of PCNSLs with or without stiffness. We evaluated by silver-impregnation nine PCNSLs with stiffness and 26 PCNSLs without stiffness. Six of the nine stiff PCNSLs showed pathological features of prominent fibrosis characterized by aggregation of reticulin fibers, and collagen accumulations. Alpha-smooth muscle actin (αSMA)-positive spindle cells as a cancer-associated fibroblast, the populations of T lymphocytes, and macrophages were compared between fibrous and control PCNSLs. Fibrous PCNSLs included abundant αSMA-positive cells in both intra- and extra-tumor environments (5/6, 87% and 3/6, 50%, respectively). Conversely, only one out of the seven control PCNSL contained αSMA-positive cells in the intra-tumoral area. Furthermore, the presence of extra-tumoral αSMA-positive cells was associated with infiltration of T lymphocytes and macrophages. In conclusion, recognizing the presence of dense fibrosis in PCNSL can provide insights into the tumor microenvironment. These results may help stratify patients with PCNSL and improve immunotherapies for these patients.

Attitudes toward smoking cessation according to smoking status among dentists in the Aichi Dental Association in Japan.

INTRODUCTION: The prevalence of smoking, including heated tobacco products (HTPs), among Japanese dentists was reported to be 16.5%, significantly higher than that among Japanese physicians and United States dentists. However, large-scale studies on smoking cessation implementation based on dentists' smoking status and perceptions since the introduction of HTPs are lacking. Therefore, we aimed to investigate and assess dentists' attitudes toward smoking, including HTP use and smoking cessation, according to smoking status. METHODS: A self-administered questionnaire comprising six major items was mailed to 3883 dentists who were members of the Aichi Dental Association in August 2019. The primary outcome was smoking cessation status. The secondary outcome was the impact of smoking on intervention for smoking cessation. This study was reported using the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. RESULTS: Among the 1317 (42%) dentists analyzed, men were more positive toward smoking than women. Current and former smokers were more positive about smoking than never smokers/users, regardless of the tobacco product type. Additionally, the current smoker group using conventional cigarettes was less likely to ask for their patients' smoking status than the never smoker group. Furthermore, the current smoker (OR=2.0; 95% CI: 1.3-3.1 vs never smoker) and HTP user (OR=1.9; 95% CI: 1.2-3.1 vs never user) groups were less likely to engage in smoking cessation than the never smoker/user groups, regardless of the tobacco product type. CONCLUSIONS: Since the smoking status of dentists affects the implementation of smoking cessation interventions, it is crucial to encourage them to quit using all tobacco products to promote smoking cessation interventions in dental practice. Additionally, providing proper smoking prevention education to dentists is an important task.

Long-term outcomes of below-the-knee bypass surgery using heparin-bonded expanded polytetrafluoroethylene grafts.

PURPOSE: To report the outcomes of below-the-knee (BK) bypass surgery using heparin-bonded expanded polytetrafluoroethylene (ePTFE) grafts, performed in two centers since its launch in Japan. METHODS: We conducted a retrospective analysis of databases from two medical centers, evaluating 51 limbs in 42 consecutive patients with peripheral arterial disease (PAD), who underwent BK bypass surgery using heparin-bonded ePTFE grafts between October, 2013 and April, 2023. RESULTS: Thirty-three limbs (64.7%) were classified as Rutherford category 4-6 and 33 limbs (64.7%) had a history of ipsilateral revascularization. Technical success was achieved in 98% of the patients. The 30 day mortality rate was 2.4% (n = 1) and the overall 30 day complication rate was 9.5% (n = 4). The median follow-up period was 38 (interquartile range 13-67) months. Three patients required major amputation and 14 died during follow-up. Primary patency rates at 1, 3, and 5 years were 67.8%, 57.5%, and 46.5%, respectively, while secondary patency rates for these periods were 84.6%, 70.0%, and 66.0%, respectively. Overall survival rates at 1, 3, and 5 years were 90.1%, 74.5%, and 70.9%, respectively. CONCLUSIONS: BK bypass surgery using heparin-bonded ePTFE graft is a viable and durable option for patients with PAD, who are deemed unsuitable for autologous vein bypass surgery.

Near-unity angular anisotropy of circularly polarized luminescence from microspheres of monodispersed chiral conjugated polymers.

A microsphere, assembled from a chiral π-conjugated polymer with narrow polydispersity, features a well-organized twisted-bipolar structure and exhibits highly biased circularly polarized luminescence (CPL). The CPL emitted toward the equatorial direction is 61-fold greater than that emitted along the zenith direction, which is the highest anisotropy among existing microscopic CPL emitters.

Functional oligo- and polypeptide assemblies for photochemical, optical and electronic applications.

The primary and secondary structures of peptides are useful as scaffolds to sequentially arrange functional groups of molecules. In this review, we review self-assembled functional peptides, whereby peptides with appropriate amino acid sequences can assemble using functional groups on their side chains. First, we apply our design strategies for the synthesis of peptide-based materials with sequenced side chains with polar moieties, organic dyes and metal complexes. The synthetic oligopeptides thus obtained exhibit inherent photoinduced charge separation and electrochemical redox activities, as well as responses to bio-sequences. Next, catalytic and photocatalytic oxidation reduction reactions and hydrogen evolution reactions are shown by utilizing the peptides with separated functionalities on both sides of ß-sheets by hybridizing with electro- and photoactive graphene oxide and metal nanoparticles. Finally, the self-assembled natural proteins that form micrometre-scale spherical geometry and fibres are utilized for optical and electronic applications. The silk fibroin forms well-defined microspheres with smooth surface morphology, leading to properties suitable for use in optical resonators, which can sense external humidity because of the hygroscopic nature of silk fibroin. Dragline silk fibres can act as optical waveguides that can perform intermediate natural polymer-based optical logic operations. These functional peptides are utilizable for various applications in catalysis, optics and electronics.

Popliteal vein entrapment syndrome associated with an accessory slip of the lateral head of the gastrocnemius muscle.

Popliteal vein entrapment syndrome (PVES) is a rare subtype of popliteal entrapment syndrome that leads to symptoms of chronic venous stasis. We report a case of isolated PVES in a young patient associated with an accessory slip of the lateral head of the gastrocnemius muscle. The patient underwent resection of the anomalous muscle, and the symptoms were relieved postoperatively. PVES should be considered in young patients with unexplained symptoms or signs of venous stasis. Surgical resection of the causative lesion compressing the popliteal vein is indicated for selected patients.

Effective Management of Sacral Stress Fractures in Gastric Cancer: Iliosacral Screw Fixation Following a Type 3 Hemipelvectomy.

Metastatic pelvic tumors pose a significant challenge in oncologic orthopedics due to their complex management and the high potential for postoperative complications. This case study discusses a 75-year-old male with a sacral stress fracture following a type 3 internal hemipelvectomy for a metastatic lesion from gastric cancer in the left pubic bone. Initial conservative treatments failed to yield satisfactory improvement, leading to surgical intervention. Open reduction and internal fixation with an iliosacral screw, despite complications, significantly alleviated pain and improved mobility. This case underscores the difficulty in diagnosing sacral stress fractures versus metastatic lesions and highlights the effectiveness of iliosacral screw fixation in managing postoperative sacral stress fractures. It emphasizes the procedure's role in providing early pain relief and enhancing daily activity levels. Additionally, it points out the importance of addressing altered bone metabolism in the postoperative care of patients with metastatic pelvic tumors. This contributes to the literature by stressing the incidence of sacral stress fractures as a critical, though often overlooked, complication and demonstrating the benefits of iliosacral screw fixation in such scenarios for better recovery and quality of life.

Sex-based differences in neck selectivity in total hip arthroplasty using a modular femoral neck system.

BACKGROUND: Dislocation is a major complication of total hip arthroplasty (THA). The modular femoral neck system provides practical advantages by allowing adjustment of neck version and length in the presence of intraoperative instability. Anatomical studies have identified morphological differences in the hip joint between men and women. Despite sex-based differences in hip morphology, it remains unclear whether such differences affect neck selectivity in THA using a modular neck system and whether this approach achieves anatomical reconstruction, thereby reducing complications such as dislocation. This study aimed to investigate gender differences in neck selectivity in THA with the modular neck system and assess the clinical impact of the modular neck system. METHODS: A total of 163 THAs using a modular neck system were included in this study. Data on the type of modular neck and intraoperative range of motion (ROM) were retrieved from patient records. Pre- and post-operative leg length differences (LLD) were examined as part of the radiographic assessment. Dislocation was investigated as a postoperative complication. RESULTS: Neck selectivity did not significantly differ between men and women. The comparison of pre- and post-operative LLD revealed a tendency for varus necks to improve LLD more than version-controlled necks. Furthermore, no significant correlation was found between intraoperative ROM and neck selectivity, or postoperative dislocation and neck selectivity. CONCLUSIONS: This study on THA with a modular neck system provided valuable insights into sex-based differences in neck selectivity and highlighted the potential benefits of the modular neck system in addressing LLD and preventing postoperative dislocation.

Status of alternative angiogenic pathways in glioblastoma resected under and after bevacizumab treatment.

Glioblastoma multiforme (GBM) acquires resistance to bevacizumab (Bev) treatment. Bev affects angiogenic factors other than vascular endothelial growth factor (VEGF), which are poorly understood. We investigated changes in angiogenic factors under and after Bev therapy, including angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), placental growth factor (PLGF), fibroblast growth factor 2, and ephrin A2 (EphA2). Fifty-four GBM tissues, including 28 specimens from 14 cases as paired specimens from the same patient obtained in three settings: initial tumor resection (naïve Bev), tumors resected following Bev therapy (effective Bev), and recurrent tumors after Bev therapy (refractory Bev). Immunohistochemistry assessed their expressions in tumor vessels and its correlation with recurrent MRI patterns. PLGF expression was higher in the effective Bev group than in the naïve Bev group (p = 0.024) and remained high in the refractory Bev group. ANGPT2 and EphA2 expressions were higher in the refractory Bev group than in the naïve Bev group (p = 0.047 and 0.028, respectively). PLGF expression was higher in the refractory Bev group compared with the naïve Bev group for paired specimens (p = 0.036). PLGF was more abundant in T2 diffuse/circumscribe patterns (p = 0.046). This is the first study to evaluate angiogenic factors other than VEGF during effective and refractory Bev therapy in patient-derived specimens.

Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms.

ABSTRACT: Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS.

Closed reduction of dislocated hip prosthesis using a traction table.

This article describes three cases in which a dislocated hip prosthesis was reduced by a new reduction technique - that we previously described - using traction table. The dissociation of a prosthesis is a rare but serious complication of closed reduction manoeuvre. The new reduction manoeuvre using a traction table may be a good option to avoid dissociation of the prosthesis during closed reduction for treatment of dislocation after total hip arthroplasty.

Keratin Microspheres as Promising Tool for Targeting Follicular Growth.

Skin is the body barrier that constrains the infiltration of particles and exogenous aggression, in which the hair follicle plays an important role. Recent studies have shown that small particles can penetrate the skin barrier and reach the hair follicle, making them a potential avenue for delivering hair growth-related substances. Interestingly, keratin-based microspheres are widely used as drug delivery carriers in various fields. In this current study, we pursue the effect of newly synthesized 3D spherical keratin particles on inducing hair growth in C57BL/6 male mice and in human hair follicle dermal papilla cells. The microspheres were created from partially sulfonated, water-soluble keratin. The keratin microspheres swelled in water to form spherical gels, which were used for further experiments. Following topical application for a period of 20 days, we observed a regrowth of hair in the previously depleted area on the dorsal part of the mice in the keratin microsphere group. This observation was accompanied by the regulation of hair-growth-related pathways as well as changes in markers associated with epidermal cells, keratin, and collagen. Interestingly, microsphere keratin treatment enhanced the cell proliferation and the expression of hair growth markers in dermal papilla cells. Based on our data, we propose that 3D spherical keratin has the potential to specifically target hair follicle growth and can be employed as a carrier for promoting hair growth-related agents.

An exploratory prospective phase II study of preoperative neoadjuvant bevacizumab and temozolomide for newly diagnosed glioblastoma.

PURPOSE: This multi-institutional phase I/II study was conducted to confirm the safety and explore the clinical utility of preoperative Bevacizumab (Bev) for newly diagnosed glioblastoma (GB). METHODS: Patients were enrolled based on magnetic resonance imaging (MRI) findings typically suggestive of GB. Preoperative Bev and temozolomide (TMZ) were administered at doses of 10 mg/kg on day 0 and 150 mg/m2 on days 1-5, respectively. Surgical resection was performed between days 21 and 30, inclusive. The safety and efficacy were evaluated in a total of 15 cases by progression-free survival (PFS), changes in tumor volume, Karnofsky Performance Scale (KPS) and Mini-Mental State Examination (MMSE) scores after preoperative therapy. RESULTS: Tumor resection was performed on a mean of day 23.7. Pathological diagnosis was GB, isocitrate dehydrogenase (IDH)-wildtype in 14 cases and GB, IDH-mutant in 1 case. Severe adverse events possibly related to preoperative Bev and TMZ were observed in 2 of the 15 patients, as wound infection and postoperative hematoma and thrombocytopenia. KPS and MMSE scores were significantly improved with preoperative therapy. Tumor volume was decreased in all but one case on T1-weighted imaging with contrast-enhancement (T1CE) and in all cases on fluid-attenuated inversion recovery, with mean volume decrease rates of 36.2% and 54.0%, respectively. Median PFS and overall survival were 9.5 months and 16.5 months, respectively. CONCLUSION: Preoperative Bev and TMZ is safe as long as the instructions are followed. The strategy might be useful for GB in some patients, not only reducing tumor burden, but also improving patient KPS preoperatively. TRIAL REGISTRATION NUMBER: UMIN000025579, jRCT1031180233 https://jrct.niph.go.jp/latest-detail/jRCT1031180233 . Registration Date: Jan. 16, 2017.

On the persistence of near-surface temperature dynamics in a warming world.

We consider issues related to the effect of climate change on the persistence of (trend-corrected) temperatures using global gridded data for both land and oceans. We first discuss how the presence of trends and additive noise affects inference about persistence. Ignoring a trend induces an upward bias, while not accounting for noise induces a downward bias. We show that the increase in persistence in the commonly used Warm Spell Duration Index is simply an artifact of increasing temperatures. To purge the impact of both trends and noise, we adopt a simple state-space model. Of separate interest, we document a much larger noise component for land than for oceans. The estimates of the persistence are much larger for oceans than for land. Inspection of the estimates across various subsamples and the application of tests for structural changes suggest the same pattern of persistence for both land and oceans across time, with few minor exceptions. Hence, our results show that surface temperature persistence has remained constant during the observed period.