Cholesterol Crystal Embolism: Autopsy-proven Gastrointestinal Lesions, Pancreatitis, and End-stage Kidney Disease Which Developed after Undergoing Selective Abdominal Angiography.

A 78-year-old man with atherosclerosis was diagnosed with hepatocellular carcinoma by transfemoral angiography of the celiac and superior mesenteric arteries (SMA). After surgery, a serum examination revealed progressive renal failure with eosinophilia, leading to end-stage kidney disease, in addition to active gastric ulcers and pancreatitis. Cyanosis in the bilateral toes showed a cholesterol crystal embolism (CCE) in a skin biopsy. Autopsy revealed that CCE involved the arterioles of multiple organs, and its distribution was anatomically consistent with the vascular territories of the celiac artery and SMA. CCE should therefore be considered in patients presenting with multiple types of tissue damage in the vascular territories after angiography.

Accuracy of the Majority Voting Method with Multiple IOL Power Formulae.

Purpose: This study aimed to evaluate the efficacy of a majority decision algorithm that integrates intraoperative aberrometry (IA) and two intraocular lens (IOL) frequency formulas. The primary objective was to compare the accuracy of three formulas (IA; Sanders, Retzlaff, and Kraff/Theoretical (SRK/T); and Barrett Universal II (BUII)), in achieving emmetropia in eyes implanted with TFNT lenses (Alcon). Patients and Methods: A total of 145 eyes of 145 patients were included in the evaluation. Preoperative data were obtained from IOLMaster 700, while intraoperative data were collected from ORA SYSTEMTM. Visual acuity ≥0.8 at the 3-month post-surgery mark was confirmed. We assessed refractive prediction error (RPE), which is the difference between predicted refraction (PR) and postoperative subjective refraction. This evaluation aimed to identify the optimal IOL power with the implemented algorithm. Results: Among the 145 eyes evaluated, 55.9%, 78.7%, and 97.2% achieved postoperative subjective refraction within ±0.13 Diopters (D), ±0.25 D, and ±0.50 D, respectively. The percentages of eyes within ±0.25 D of PR varied by formula type, with values of 57%, 57%, and 54% for IA, BUII, and SRK/T, respectively. For eyes with short to medium axial length (AL<26.00 mm), the percentages within ±0.25 D of RPE were 52%, 58%, and 58% for IA, SRK/T, and BUII, respectively. In contrast, for eyes with long axial length (≥26.00 mm) the percentages were 68%, 52%, and 45% for IA, BUII, and SRK/T, respectively. Conclusion: The proposed majority decision algorithm incorporating IA and two IOL frequency formulas was effective in reducing postoperative refractive error. IA was particularly beneficial for eyes with long axial length. These findings suggest the algorithm has potential to optimize IOL power selection to improve quality of life of patients and clinical practice outcomes.

A novel cell source for therapy of knee osteoarthritis using atelocollagen microsphere-adhered adipose-derived stem cells: Impact of synovial fluid exposure on cell activity.

Introduction: Administration of adipose-derived stem cells (ADSCs) into the joint cavity has been shown to alleviate the symptoms of knee osteoarthritis (OA) by releasing exosomes and anti-inflammatory cytokines. However, the therapeutic effect of these cells is limited by their rapid disappearance after administration. Thus, it is necessary to prolong cell survival in the joint cavity. This study aimed to investigate the potential application of ADSCs adhered to atelocollagen microspheres (AMSs) for cell therapy of knee OA. Methods: ADSCs were cultured for 2, 4, and 7 days in AMS suspension or adherent culture dishes. The supernatants were analyzed for IL-10 and exosome secretion via enzyme-linked immunosorbent assay and Nanosight. The effect of AMS was compared with that of adherent-cultured ADSCs (2D-cultured ADSCs) using transcriptome analysis. Moreover, the solubility of AMS and viability of ADSCs were evaluated using synovial fluid (SF) from patients with knee OA. Results: Compared with 2D-cultured ADSCs, AMS-cultured ADSCs exhibited a significant increase in secretion of exosomes and IL-10, and the expression of several genes involved in extracellular matrix and immune regulation were altered. Furthermore, when AMS-cultured ADSCs were cultured in SF from knee OA patients to mimic the intra-articular environment, the SF dissolved the AMSs and released viable ADSCs. In addition, AMS-cultured ADSCs showed significantly higher long-term cell viability than 2D-cultured ADSCs. Conclusion: Increased survival of AMS-adhered ADSCs was observed in the intra-articular environment, and AMSs were found to gradually dissipate. These results suggest that AMS-adhered ADSCs are promising source for cell therapy of knee OA.

Safety and efficacy of bronchial thermoplasty in refractory asthma with severe obstructive respiratory dysfunction.

BACKGROUND: Bronchial thermoplasty (BT) is a recently developed non-pharmacological therapy for refractory bronchial asthma. Although increasing evidence has suggested that BT is effective for various phenotypes of severe asthma, its safety and efficacy in patients with severe irreversible impaired lung function are unclear. OBJECTIVES: To assess the efficacy and safety of BT in patients with refractory asthma, including patients with a severely impaired forced expiratory volume in 1 second (FEV1). DESIGN: This was a single-center, retrospective, observational cohort study. METHODS: We retrospectively reviewed the medical records of 15 patients with refractory asthma (Global Initiative for Asthma step 4 or 5), including patients with severely impaired airflow limitation (% predicted pre-bronchodilator FEV1 <60%), who had undergone BT between June 2016 and January 2022. We analyzed the efficacy (change in asthma symptoms, exacerbation rate, pulmonary function, asthma medication, and serum inflammatory chemokine/cytokines before and after BT) and complications in all patients. We compared these data between patients with severe obstructive lung dysfunction [group 1(G1)] and patients with FEV1 ⩾ 60% [group 2 (G2)]. RESULTS: Six patients were in G1 and nine were in G2. Clinical characteristics, T2 inflammation, and concurrent treatment were equivalent in both groups. BT significantly improved asthma-related symptoms (measured using the Asthma Control Test and Asthma Quality of Life Questionnaire scores) in both groups. FEV1 was significantly improved in G1 but not in G2. Four patients in G2, but none in G1, experienced asthma exacerbation requiring additional systemic corticosteroids (including two requiring prolonged hospitalization) after BT. Long-term responders (patients who reduced systemic or inhaled corticosteroid without newly adding biologics in a follow-up > 2 years) of BT were identified in G1 and G2 (n = 2, 33.3% and n = 4, 44.4%, respectively). CONCLUSION: BT in patients with refractory asthma and severe airflow limitation is equally safe and efficacious as that in patients with moderate airflow limitation.

Chronic ingestion of soy peptide supplementation reduces aggressive behavior and abnormal fear memory caused by juvenile social isolation.

Juvenile loneliness is a risk factor for psychopathology in later life. Deprivation of early social experience due to peer rejection has a detrimental impact on emotional and cognitive brain function in adulthood. Accumulating evidence indicates that soy peptides have many positive effects on higher brain function in rodents and humans. However, the effects of soy peptide use on juvenile social isolation are unknown. Here, we demonstrated that soy peptides reduced the deterioration of behavioral and cellular functions resulting from juvenile socially-isolated rearing. We found that prolonged social isolation post-weaning in male C57BL/6J mice resulted in higher aggression and impulsivity and fear memory deficits at 7 weeks of age, and that these behavioral abnormalities, except impulsivity, were mitigated by ingestion of soy peptides. Furthermore, we found that daily intake of soy peptides caused upregulation of postsynaptic density 95 in the medial prefrontal cortex and phosphorylation of the cyclic adenosine monophosphate response element binding protein in the hippocampus of socially isolated mice, increased phosphorylation of the adenosine monophosphate-activated protein kinase in the hippocampus, and altered the microbiota composition. These results suggest that soy peptides have protective effects against juvenile social isolation-induced behavioral deficits via synaptic maturation and cellular functionalization.

Parent Artery Occlusion for a Dissecting Posterior Cerebral Artery Aneurysm in the P4 Segment Presenting with Ischemic Stroke and Rapid Growth: A Case Report.

A dissecting aneurysm in the P4 segment of the posterior cerebral artery (PCA) is extremely rare, and its treatment is sometimes challenging. Endovascular parent artery occlusion (PAO) was performed for an unruptured P4 segment dissecting PCA aneurysm presenting with ischemic stroke and rapid growth. A 70-year-old man was rushed to our emergency department due to a right-sided headache and a visual field defect. Head magnetic resonance imaging showed a right occipital lobe ischemic stroke, with right PCA occlusion and aneurysm formation in the P4 segment. The diagnosis was PCA dissection in the calcarine artery, and oral aspirin was started. Within a week, the dissecting aneurysm had enlarged progressively to 6.2 mm in diameter. Thus, PAO with coils was performed as a preventive measure against aneurysm rupture, assuming that complication risks were low because the tributary area of the dissecting PCA had already infarcted. A 6-Fr guiding sheath was introduced from the right brachial artery to the right vertebral artery, and a microcatheter/microguidewire was placed into the true lumen of the calcarine artery distal to the aneurysm. PAO with coils was performed, and the blood flow to the aneurysm was completely obliterated. After the treatment, the known infarction in the right occipital lobe was enlarged, but no new neurological symptoms developed. The patient was discharged independently on postoperative day 3. Treatment for a distal PCA dissecting aneurysm is challenging. PAO with coils is one of the reasonable choices, especially when a visual field defect has already developed.

Development of an Eye Irritation Test Method Using an In-House Fabrication of a Reconstructed Human Cornea-like Epithelium Model for Eye Hazard Identification.

In a previous study, a novel human corneal-like epithelium model utilizing an immortalized human corneal epithelial cell line (iHCE-NY1) was developed as an alternative to animal models to identify chemicals not classified under the United Nations Globally Harmonized System of Classification and Labeling of Chemicals (GHS) and was evaluated following the criteria of Test Guideline 492 of the Organization for Economic Co-operation and Development (OECD). In the present study, our aim was to establish an eye irritation test protocol using the iHCE-NY1 model to classify liquid chemicals under the GHS ocular hazard categories: no effect, no classification (No Cat.), Category 2 (Cat. 2) reversible effects, and Category 1 (Cat. 1) irreversible eye damage. The protocol involved exposing the iHCE-NY1 model to 31 liquid test chemicals for 5 min, followed by observation at post-incubation periods (PIPs) to assess recovery. Classification was based on cell viability, and histopathological findings on PIP days 7, 14, and 21. The outcomes were compared with an established database of classifications. All Cat. 1 liquid chemicals, 62.5% of No Cat., and 63.2% of Cat. 2 were correctly categorized. This study demonstrates that the iHCE-NY1 model can not only distinguish No Cat. test liquid chemicals but also differentiate between Cat. 2 and Cat. 1 liquid chemicals.

Fluctuations in plasma adrenocorticotropic hormone concentration may predict the onset of immune checkpoint inhibitor-related hypophysitis.

Immune checkpoint inhibitor (ICI)-related hypophysitis (RH) is a common immune-related adverse event. The early detection of ICI-RH prevents life-threatening adrenal insufficiency. However, good predictors of secondary adrenal insufficiency in ICI-RH have not yet been reported. We hypothesized that fluctuations in plasma adrenocorticotropic hormone (ACTH) and cortisol levels occur similarly to those in thyroid-stimulating hormone and thyroid hormone (thyroxine and triiodothyronine) levels in ICI-related thyroiditis. Here, we sought to test this hypothesis. Patients who used ICI and had a history of measurement of plasma ACTH and serum cortisol concentrations were retrieved from electronic medical records, and those with a history of glucocorticoid use were excluded from the analysis. We evaluated fluctuations in plasma ACTH and serum cortisol concentrations and the development of ICI-RH. For patients with ICI-RH, data at three points (before ICI administration (pre), maximum ACTH concentration (peak), and onset of ICI-RH) were analyzed to evaluate hormone fluctuations. A total of 202 patients were retrieved from the medical record. Forty-three patients were diagnosed with ICI-RH. Twenty-six out of 43 patients had sufficient data to evaluate fluctuations in plasma ACTH and serum cortisol concentrations and no history of glucocorticoid use. ACTH concentrations changed from 37.4 (29.9­48.3) (pre) to 64.4 (46.5­106.2) (peak) pg/mL (1.72­fold increase, p=0.0026) in the patients with ICI-RH before the onset. There were no differences in cortisol concentrations between the pre and peak values in patients with ICI-RH. We also evaluated the fluctuations in plasma ACTH and serum cortisol levels in patients who did not receive ICI-RH (62 cases). However, elevation of plasma ACTH levels was not observed in patients without ICI-RH, suggesting that transient elevation of plasma ACTH levels is a unique phenomenon in patients with ICI-RH. In conclusion, plasma ACTH levels were transiently elevated in some patients with ICI-RH before the onset of secondary adrenal insufficiency. Monitoring the ACTH levels and their fluctuations may help predict the onset of ICI-RH.

Effects of the Cortisol Milieu on Tumor-Infiltrating Immune Cells in Corticotroph Tumors.

CONTEXT: Corticotrophs are susceptible to lymphocyte cytotoxicity, as seen in hypophysitis, suggesting that an immunological approach may be a potential strategy for corticotroph-derived tumors. OBJECTIVE: We aimed to clarify whether corticotroph tumors that induce hypercortisolemia (ACTHomas) could be targets for immunotherapy. METHODS: Tumor-infiltrating immune cells were immunohistochemically analyzed. ACTHomas were compared with other pituitary tumors, and further divided into 3 different cortisol-exposed milieus: Naïve (ACTHomas without preoperative treatment), Met (ACTHomas with preoperative metyrapone), and SCA (silent corticotroph adenomas). A 3-dimensional cell culture of resected tumors was used to analyze the effects of immune checkpoint inhibitors. RESULTS: The number of tumor-infiltrating lymphocytes (TILs) was low in ACTHomas. Among these, the number of CD8+ cells was lower in ACTHomas than in both somatotroph and gonadotroph tumors (both P < .01). Then we compared the differences in TILs among Naïve, Met, and SCA. The number of CD4+ cells, but not CD8+ cells, was higher in both Met and SCA than in Naïve. Next, we investigated tumor-associated macrophages, which could negatively affect T cell infiltration. The numbers of CD163+ and CD204+ cells were positively associated with cortisol levels. Moreover, tumor size was positively correlated with the number of CD204+ cells. CONCLUSION: We found the possibility that ACTHomas were immunologically cold in a cortisol-independent manner. In contrast, the tumor infiltration of CD4+ cells and M2-macrophages were associated with the cortisol milieu. Future studies are needed to validate these results and develop effective immunotherapy while considering the cortisol milieu.

Lens capsule pathological characteristics in cases of intraocular lens dislocation with atopic dermatitis.

PURPOSE: To explore lens capsule pathological characteristics in intraocular lens (IOL) dislocation after cataract surgery in patients with atopic dermatitis (AD). SETTING: University hospital department of ophthalmology. DESIGN: Case series with clinicopathological correlations. METHODS: Lens capsules and surrounding tissues excised during surgery from eyes with AD (AD group) and eyes without AD (non-AD group) with IOL dislocation were histologically evaluated. Hematoxylin and eosin staining was used to assess abnormal changes in lens epithelial cells (LECs). Masson trichrome staining distinguished the fibrous metaplasia around the lens capsule into high-density and low-density fibrosis. Capsular splitting (thinning) was identified in both stained preparations. RESULTS: The IOL dislocation morphology in the AD group (10 eyes of 10 patients) included 7 cases of capsular bag dislocation (CBD) and 3 cases of dead bag syndrome (DBS), with an average duration to IOL dislocation of 11.5 ± 5.6 years. All patients in the non-AD group (12 eyes of 12 patients) had CBD, averaging 10.2 ± 5.7 years to dislocation. Abnormal LECs, low-density fibrosis, and capsular splitting were observed in 9 (90), 9 (90), and 6 (60) of the patients in the AD group compared with 6 (50), 3 (25), and 2 (18), respectively, in the non-AD group (total n [%]). CONCLUSIONS: Compared with the non-AD group, the AD group exhibited higher frequencies of morphological changes in LECs, low-density fibrosis around the lens capsule, and capsular splitting characteristics of DBS. These results suggest LEC degeneration and increased lens capsule fragility occurred in patients with AD.

Outer layer of Vb neurons in medial entorhinal cortex project to hippocampal dentate gyrus in mice.

Entorhinal cortical (EC)-hippocampal (HPC) circuits are crucial for learning and memory. Although it was traditionally believed that superficial layers (II/III) of the EC mainly project to the HPC and deep layers (V/VI) receive input from the HPC, recent studies have highlighted the significant projections from layers Va and VI of the EC into the HPC. However, it still remains unknown whether Vb neurons in the EC provide projections to the hippocampus. In this study, using a molecular marker for Vb and retrograde tracers, we identified that the outer layer of Vb neurons in the medial EC (MEC) directly project to both dorsal and ventral hippocampal dentate gyrus (DG), with a significant preference for the ventral DG. In contrast to the distribution of DG-projecting Vb cells, anterior thalamus-projecting Vb cells are distributed through the outer to the inner layer of Vb. Furthermore, dual tracer injections revealed that DG-projecting Vb cells and anterior thalamus-projecting Vb cells are distinct populations. These results suggest that the roles of MEC Vb neurons are not merely limited to the formation of EC-HPC loop circuits, but rather contribute to multiple neural processes for learning and memory.

Optical Biopsies Using Probe-Based Confocal Laser Endomicroscopy for Autoimmune Pulmonary Alveolar Proteinosis.

INTRODUCTION: Increasing numbers of cases of mild asymptomatic pulmonary alveolar proteinosis (PAP) are being reported with the recent increase in chest computed tomography (CT). Bronchoscopic diagnosis of mild PAP is challenging because of the patchy distribution of lesions, which makes it difficult to obtain sufficient biopsy samples. Additionally, the pathological findings of mild PAP, particularly those that differ from severe PAP, have not been fully elucidated. This study aimed to clarify the pathological findings of mild PAP and the usefulness of optical biopsy using probe-based confocal laser endomicroscopy (pCLE). METHODS: We performed bronchoscopic optical biopsy using pCLE and tissue biopsy in 5 consecutive patients with PAP (three with mild PAP and two with severe PAP). We compared the pCLE images of mild PAP with those of severe PAP by integrating clinical findings, tissue pathology, and chest CT images. RESULTS: pCLE images of PAP showed giant cells with strong fluorescence, amorphous substances, and thin alveolar walls. Images of affected lesions in mild PAP were equivalent to those obtained in arbitrary lung lesions in severe cases. All 3 patients with mild PAP spontaneously improved or remained stable after ≥3 years of follow-up. Serum autoantibodies to granulocyte-macrophage colony-stimulating factor were detected in all 5 cases. CONCLUSION: Optical biopsy using pCLE can yield specific diagnostic findings, even in patients with mild PAP. pCLE images of affected areas in mild and severe PAP showed similar findings, indicating that the dysfunction level of pathogenic alveolar macrophages in affected areas is similar between both disease intensities.

The combination of doxazosin and metyrosine as a preoperative treatment for pheochromocytomas and paragangliomas.

PURPOSE: Preoperative medical management is critical to prevent intraoperative cardiovascular complications in patients with pheochromocytomas and paragangliomas (PPGLs). Initial treatment involves α-adrenergic receptor blockers. However, while the routine use of metyrosine alongside these blockers is not strongly recommended due to a lack of evidence supporting its efficacy and associated safety concerns, there are previous studies on combination therapy with phenoxybenzamine and metyrosine. There are few reports on combination therapy with the selective α1-adrenergic receptor blocker doxazosin. Therefore, we investigated this combination treatment, which theoretically can affect perioperative outcomes in patients with PPGLs. To our knowledge, this is the first such study. METHODS: This retrospective single-center observational study involved 51 patients who underwent surgical resection of PPGLs at Kobe University Hospital between 2014 and 2022. All patients received doxazosin at maximum doses. Fourteen patients received concomitant metyrosine, while 37 received doxazosin alone. Their perioperative outcomes were compared. RESULTS: No severe event, such as acute coronary syndrome, was observed in either group. Intraoperatively, the doxazosin + metyrosine group exhibited a lower median minimum systolic blood pressure (56 [54-60] vs. 68 [59-74] mmHg, P = 0.03) and required lower median remifentanil (P = 0.04) and diltiazem (P = 0.02) doses than the doxazosin-alone group. CONCLUSION: The combination of metyrosine and doxazosin as a preoperative treatment for PPGLs affects intraoperative circulatory hemodynamics, such as a reduced occurrence of blood pressure elevation during surgery. Further research is necessary to identify patients who will benefit most from this combination treatment.

Controllable Chiral Light Generation and Vortex Field Investigation Using Plasmonic Holes Revealed by Cathodoluminescence.

Control of the angular momentum of light is a key technology for next-generation nano-optical devices and optical communications, including quantum communication and encoding. We propose an approach to controllably generate circularly polarized light from a circular hole in a metal film using an electron beam by coherently exciting transition radiation and light scattering from the hole through surface plasmon polaritons. The circularly polarized light generation is confirmed by fully polarimetric four-dimensional cathodoluminescence mapping, where angle-resolved spectra are simultaneously obtained. The obtained intensity and Stokes maps show clear interference fringes as well as almost fully circularly polarized light generation with controllable parities by the electron beam position. By applying this approach to a three-hole system, a vortex field with a phase singularity is visualized in the middle of three holes.

The aortic knob index as a novel predictor of new-onset atrial fibrillation after off-pump coronary artery bypass grafting.

PURPOSE: To validate the predictive value of the aortic knob index for identifying new-onset postoperative atrial fibrillation (POAF) after off-pump coronary artery bypass grafting (OPCAB). METHODS: Among 156 patients who underwent isolated OPCAB, 138 consecutive patients without a history of atrial fibrillation were enrolled in this retrospective observational cohort study. The patients were divided into two groups based on the development of POAF. We compared the baseline clinical characteristics; preoperative radiographic characteristics of the aorta, including aortic knob measurements; and perioperative data, between the groups. Logistic regression analysis was performed to identify the predictors of new-onset POAF. RESULTS: New-onset POAF developed in 35 (25.4%) patients. Multivariate logistic regression analysis revealed that the aortic knob index was an independent predictor of POAF and yielded that the risk of POAF increased by 1.85 times when the aortic knob index increased by 0.1 (odds ratio, 1.853; confidence interval, 1.326-2.588; P < 0.001). Receiver operating characteristic analysis revealed that an aortic knob index of 1.364 constituted a cutoff value for new-onset POAF with 80.0% sensitivity and 65.0% specificity. CONCLUSIONS: The aortic knob index on preoperative chest radiography was a significant and independent predictor of new-onset POAF following OPCAB.

A case of meningoencephalitis caused by multisystem inflammatory syndrome in adult SARS-CoV-2 infection.

A 37-year-old woman was hospitalized with fever and consciousness disturbance. She showed systemic inflammation with stress cardiomyopathy. Brain computed tomography showed diffuse brain edema. Cerebrospinal fluid (CSF) findings revealed markedly elevated cerebrospinal fluid pressure with pleocytosis, elevated protein, and elevated interleukin 6. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nicking enzyme amplification reaction test using a nasopharyngeal swab was positive, and the patient was diagnosed with SARS-CoV-2 infection. From the negative result of the CSF SARS-CoV-2 polymerase chain reaction test and no findings of bacterial or viral infection, we diagnosed meningoencephalitis by multisystem inflammation syndrome in adults (MIS-A). Intravenous methylprednisolone pulse therapy improved her symptoms and brain edema. There have been no cases of MIS-A with meningoencephalitis, and no initial treatment strategy has been established, especially in emergency cases of suspected MIS-A. The present case suggested Early intravenous methylprednisolone pulse with anti-coronaviral therapies after the exclusion of bacterial infection would be useful in suspected MIS-A with emergent meningoencephalitis cases.

Newer parameters of the octreotide test in patients with acromegaly.

PURPOSE: Predicting the therapeutic effects of first-generation somatostatin receptor ligands (fg-SRLs) is important when assessing or planning effective treatment strategies in patients with acromegaly. The oft-used maximum growth hormone (GH) suppression rate parameter of the octreotide test has a suboptimal predictive value. Therefore, this study explored newer parameters of the octreotide test for predicting the therapeutic effect of long-acting fg-SRLs. METHODS: In this single-center retrospective study, the octreotide test parameters and the therapeutic effects of fg-SRL at 3 months were investigated in 45 consecutive treatment-naïve patients with acromegaly between April 2008 and March 2023. Additionally, the relationship between the octreotide test parameters and the therapeutic effects of fg-SRLs was investigated. Tumor shrinkage was evaluated based on changes in the longitudinal diameter of the macroadenomas. The area GH suppression rate-time under the curve (AUC) and the time to nadir GH level were calculated and compared with the maximum GH suppression rate. RESULTS: The AUC estimated reductions in serum insulin-like growth factor I, and tumor shrinkage. The time to nadir GH level predicted tumor shrinkage more robustly than the maximum GH suppression rate in patients with macroadenoma. CONCLUSION: The AUC and time to nadir GH level may potentially be newer parameters of the octreotide test for estimating the therapeutic effect of fg-SRLs.

Mitochondrial-targeting effector RsIA_CtaG/Cox11 in Rhizoctonia solani AG-1 IA has two functions: plant immunity suppression and cell death induction mediated by a rice cytochrome c oxidase subunit.

Rhizoctonia solani AG-1 IA causes a necrotrophic rice disease and is a serious threat to rice production. To date, only a few effectors have been characterized in AG-1 IA. We previously identified RsIA_CtaG/Cox11 and showed that infiltration of the recombinant protein into rice leaves caused disease-like symptoms. In the present study, we further characterized the functionality of RsIA_CtaG/Cox11. RsIA_CtaG/Cox11 is an alternative transcript of cytochrome c oxidase copper chaperone Cox11 that starts from the second AUG codon, but contains a functional secretion signal peptide. RNA interference with RsIA_CtaG/Cox11 reduced the pathogenicity of AG-1 IA towards rice and Nicotiana benthamiana without affecting its fitness or mycelial morphology. Transient expression of the RsIA_CtaG/Cox11-GFP fusion protein demonstrated the localization of RsIA_CtaG/Cox11 to mitochondria. Agro-infiltration of RsIA_CtaG/Cox11 into N. benthamiana leaves inhibited cell death by BAX and INF1. In contrast to rice, agro-infiltration of RsIA_CtaG/Cox11 did not induce cell death in N. benthamiana. However, cell death was observed when it was coinfiltrated with Os_CoxVIIa, which encodes a subunit of cytochrome c oxidase. Os_CoxVIIa appeared to interact with RsIA_CtaG/Cox11. The cell death triggered by coexpression of RsIA_CtaG/Cox11 and Os_CoxVIIa is independent of the leucine-rich repeat receptor kinases BAK1/SOBIR1 and enhanced the susceptibility of N. benthamiana to AG-1 IA. Two of the three evolutionarily conserved cysteine residues at positions 25 and 126 of RsIA_CtaG/Cox11 were essential for its immunosuppressive activity, but not for cell death induction. This report suggests that RsIA_CtaG/Cox11 appears to have a dual role in immunosuppression and cell death induction during pathogenesis.

Dual biologics for severe asthma and atopic dermatitis: Synopsis of two cases and literature review.

The efficacy and safety of the combination of biologic therapies remain unclear with an ineffective and insufficient single biologic for managing asthma. Herein, we report two cases using dual biologics for severe asthma and atopic dermatitis. A 52-year-old male patient who received dupilumab and mepolizumab, benralizumab, or tezepelumab, followed by bronchial thermoplasty, and a 41-year-old male patient who received dupilumab and omalizumab, both experienced improved asthma and atopic dermatitis. To date, 38 cases are using dual biologics for severe asthma. The success rate was 84%, with no major adverse effects. We report the first case of severe asthma receiving dual biologics with tezepelumab and furthermore bronchial thermoplasty, and comprehensive literature review on dual biologics. Dual biologics may be an effective treatment method for severe asthma, requiring further investigation.