Comparison of agranulocytosis and anti-neutrophil cytoplasmic antibody-associated vasculitis caused by two antithyroid drugs: A pharmacovigilance study using the WHO international database.

BACKGROUND: Methimazole (MMI) and propylthiouracil (PTU) are commonly used for patients with thyrotoxicosis. Agranulocytosis and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is associated with high morbidity and mortality, requiring appropriate interventions. In this study, we compared adverse drug effects associated with MMI and PTU using a real-world large pharmacovigilance database. METHODS: We searched all Individual Case Safety Reports reported to be associated with MMI and PTU, from VigiBase between 1967 and June 2, 2021. We conducted disproportionality analysis (case/non-case analysis) to analyze the difference in reported adverse drug reactions (ADRs) between antithyroid drugs (case) and the entire database (non-cases). We further analyzed information for the cases of agranulocytosis and AAV. RESULTS: Among 11 632 cases of ADRs reported after MMI intake, agranulocytosis occurred in 1633 cases and AAV occurred in 41 cases. For 5055 cases of ADRs reported after PTU intake, agranulocytosis occurred in 459 cases and AAV occurred in 110 cases. Agranulocytosis occurred after a median of 28 days after PTU intake and 33 days after MMI intake. More than 95% of the agranulocytosis cases were classified as serious, but most of them (65.1% for PTU and 70.4% for MMI) were reported to have recovered after dechallenge actions; mostly drug withdrawal. AAV occurred after a median of 668 days after PTU intake, and 1162 days after MMI intake. CONCLUSIONS: This is a pharmacoepidemiological study investigating agranulocytosis and AAV caused by MMI and PTU. Through this research, we could provide more specific insights into a safe prescription of antithyroid drugs in a real-world setting.

CRISPR-Cas9 mediated genome editing of Huntington's disease neurospheres.

BACKGROUND: Huntington's disease (HD) is a fatal genetic disease caused by polyglutamine aggregation encoded by an expanded CAG repeat in the huntingtin gene (HTT). In this study, we cultured neurospheres derived from R6/2 mice, a representative animal model of HD, as an in vitro model. GuideRNAs were designed to induce large deletion or frameshift indel mutation of CAG expansion. These gRNAs and Cas9 were delivered to the R6/2 neurospheres and disease-related phenotypes were observed. METHODS AND RESULTS: Deletion or indel mutation of the CAG repeat was confirmed by PCR, T7E1 assay and sequencing of the edited neurospheres. Edited neurospheres showed decreased polyglutamine aggregation compared with control HD neurospheres. In the edited neurosphere, we confirmed the upregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and brain-derived neurotrophic factor (BDNF), whose reduced expressions are closely involved in the disease progression. In addition, flow cytometry result showed an increase in cell viability with an overall decrease in necrotic and apoptotic populations among edited R6/2 neurospheres. Additional siRNA experiments confirmed that the increased viability was decreased through inhibition of PGC-1α or BDNF. CONCLUSION: Our study confirmed that CAG repeat of R6/2 mouse-derived neurospheres can be edited through CRISPR-Cas9. Editing of CAG repeat sequence decreases polyglutamine aggregation and cellular apoptosis of HD neurospheres, which may be related to the increased expressions of PGC-1α and BDNF. Our data provide the evidence that CRISPR-Cas9 mediated genome editing has therapeutic potential on HD neuronal cells.

Prior benzodiazepine use and mortality among adult patients with sepsis: A retrospective population-based cohort study in South Korea.

OBJECTIVES: This study investigated whether long-term benzodiazepine use is associated with increased 90-day mortality among patients with sepsis. METHODS: A retrospective population-based cohort study based on health records obtained from the National Health Insurance Service database in South Korea was conducted. All adult patients (≥18 years) admitted to the hospital with a primary diagnosis of sepsis or septic shock during 2010-2018 were included in the study. Sepsis and septic shock were diagnosed based on the International Classification of Diseases (10th revision: A40, A41 and R65.2). Benzodiazepine users were defined as individuals who were prescribed regular benzodiazepine continuously for over 6 months before admission. RESULTS: A total of 251 837 patients with sepsis were included in this study, 16 686 of which (6.6%) were benzodiazepine users, and 235 151 (93.4%) were non-users. After propensity score (PS) matching, 33 370 patients (16 685 in both groups) were ultimately included. Moreover, following PS matching, the 90-day mortality among benzodiazepine users and non-users was 60.9% (10 167) and 41.4% (6916), respectively. Cox regression analysis further revealed the hazard ratio (HR) for 90-day mortality in benzodiazepine users to be 1.75, compared with non-users [95% confidence interval (CI): 1.70-1.81; P < .001]. Sensitivity analyses showed that, compared with non-users, HRs for 90-day mortality in benzodiazepine users without and with other psychiatric illnesses were 1.43 (95% CI: 1.38-1.49; P < .001) and 1.89 (95% CI: 1.84-1.94; P < .001), respectively. CONCLUSION: Long-term benzodiazepine use is associated with increased 90-day mortality among adult patients with sepsis compared with non-users. This association was more evident in benzodiazepine users with other psychiatric diseases, such as depression or anxiety disorder.

A Comparison of Hemostatic Properties between Monopolar and Bipolar Hysteroscopic Surgery using Rotational Thromboelastometry: A Randomized Trial.

OBJECTIVE: Systemic absorption of irrigation fluid can lead to a disturbed coagulation cascade. We compared the changes in hemostatic properties on using nonelectrolyte solution in monopolar hysteroscopic surgery (HS) with that on using isotonic saline in bipolar HS via rotational thromboelastometry (ROTEM) analysis. METHODS: A total of 54 patients were randomized into 2 groups: 1 group underwent monopolar HS using a mixture of 2.7% sorbitol and 0.54% mannitol (the HSMP group), whereas the other group underwent bipolar HS using 0.9% isotonic saline (the HSBP group). The effects of these 2 methods on coagulation were assessed via pre and postoperative laboratory tests, including estimation of the international normalized ratio of prothrombin time and activated partial thromboplastin time and ROTEM analysis. In addition, the hemoglobin, hematocrit, and electrolyte levels and the platelet count were analyzed. RESULTS: Patient characteristics, volume of irrigation fluid absorbed, and type of procedure were comparable between the 2 groups. There were no significant differences in the pre and postoperative values of ROTEM parameters between the 2 groups. Most postoperative ROTEM parameters, as compared with preoperative values, changed in both groups; clot formation time was prolonged, and the α-angle and maximum clot firmness were decreased. All ROTEM parameters were maintained within the normal range. Hematological parameters, including hemoglobin and hematocrit levels and platelet count, were significantly decreased postoperatively in both groups compared to the preoperative values. No pre and postoperative hematological and hemostatic parameters were significantly different between the 2 groups. CONCLUSION: Irrigation fluid absorbed in healthy women during HS caused hypocoagulable changes in the blood, irrespective of the irrigant type, and no significant differences between HS using monopolar and bipolar electrodes were demonstrated.

OCULAR PERFUSION PRESSURE AND CHOROIDAL THICKNESS IN CENTRAL SEROUS CHORIORETINOPATHY AND PIGMENT EPITHELIOPATHY.

PURPOSE: To investigate ocular perfusion pressure (OPP) in patients with central serous chorioretinopathy (CSC) and pigment epitheliopathy (PE). METHODS: In this retrospective study, we included patients with acute idiopathic unilateral CSC and age- and sex-matched normal controls. The patients with CSC were classified into two groups according to the PE presence on their fellow eyes. We compared OPP among CSC patients with or without PE and normal controls. RESULTS: Among a total of 47 patients with CSC, 21 were classified into the PE group and 26 into the non-PE group. The mean OPP (±SD) of CSC and fellow eyes in the PE group (50.02 ± 4.98 and 50.83 ± 4.12 mmHg, respectively) was greater than that in the non-PE group (43.69 ± 6.88 and 44.0 ± 6.57 mmHg, respectively) and normal controls (45.64 ± 8.73 mmHg) (all, P < 0.05). The mean macular choroidal thickness of CSC and fellow eyes in the PE group (344.4 ± 31.8 and 310.1 ± 37.0 µm, respectively) was thicker than that in the non-PE group (318.5 ± 43.8 and 282.8 ± 36.1 µm, respectively) (all, P < 0.05). Greater macular choroidal thickness and higher OPP were associated with PE (P = 0.002 and P = 0.003). CONCLUSION: Forty-five percent of the patients with acute unilateral CSC had PE in their fellow eyes. Increased OPP may influence the development of bilateral CSC characteristics.

SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth.

SHARPIN, an adaptor for the linear ubiquitin chain assembly complex (LUBAC), plays important roles in NF-κB signaling and inflammation. Here, we have demonstrated a LUBAC-independent role for SHARPIN in regulating melanoma growth. We observed that SHARPIN interacted with PRMT5, a type II protein arginine methyltransferase, and increased its multiprotein complex and methyltransferase activity. Activated PRMT5 controlled the expression of the transcription factors SOX10 and MITF by SHARPIN-dependent arginine dimethylation and inhibition of the transcriptional corepressor SKI. Activation of PRMT5 by SHARPIN counteracted PRMT5 inhibition by methylthioadenosine, a substrate of methylthioadenosine phosphorylase, which is codeleted with cyclin-dependent kinase inhibitor 2A (CDKN2A) in approximately 15% of human cancers. Collectively, we identified a LUBAC-independent role for SHARPIN in enhancing PRMT5 activity that contributes to melanomagenesis through the SKI/SOX10 regulatory axis.

Meibomian Glands and Ocular Surface Changes After Closure of Meibomian Gland Orifices in Rabbits.

PURPOSE: To investigate changes in the corneal surface, tear film, and meibomian glands after meibomian gland orifice closure. METHODS: Seventy-two eyes of 36 rabbits were used. In the study group (n = 36), the meibomian gland orifices of both upper and lower eyelids in the right eyes were electrosurgically coagulated. The 36 untreated left eyes were used as controls. Corneal wetting properties were measured 1, 3, 7, and 14 days after coagulation. The eyelid sections were stained with anti-cytokeratin (CK)1, CK5, and CK6 antibody 8 weeks after coagulation. The area of the secretory acini around one meibomian gland duct was measured, and meibography of rabbits was performed 8 weeks after meibomian gland orifice closure. RESULTS: Three days after coagulation, the corneal wetting property was decreased compared with controls. The meibomian gland ducts gradually dilated in the study group over time. The epithelium of the central ducts in both groups was stained with CK5 and CK6, but not CK1. Although the mean area of the secretory acini in the study group (0.10 ± 0.04 mm) was significantly smaller than that of the control group (0.18 ± 0.04; P = 0.004), meibography showed normal morphology in both study and control groups. CONCLUSIONS: Meibomian gland orifice closure reduced corneal wetting property and induced meibomian gland duct dilation accompanied by shrinkage of secretory acini. Meibography could not detect early changes in the meibomian gland after closure of the orifice. Therefore, when the orifice is obstructed, more active treatments are needed before structural changes occur.

Comparing the Effects of Particulate Matter on the Ocular Surfaces of Normal Eyes and a Dry Eye Rat Model.

PURPOSE: To compare the effect of exposure to particulate matter on the ocular surface of normal and experimental dry eye (EDE) rat models. METHODS: Titanium dioxide (TiO2) nanoparticles were used as the particulate matter. Rats were divided into 4 groups: normal control group, TiO2 challenge group of the normal model, EDE control group, and TiO2 challenge group of the EDE model. After 24 hours, corneal clarity was compared and tear samples were collected for quantification of lactate dehydrogenase, MUC5AC, and tumor necrosis factor-α concentrations. The periorbital tissues were used to evaluate the inflammatory cell infiltration and detect apoptotic cells. RESULTS: The corneal clarity score was greater in the EDE model than in the normal model. The score increased after TiO2 challenge in each group compared with each control group (normal control vs. TiO2 challenge group, 0.0 ± 0.0 vs. 0.8 ± 0.6, P = 0.024; EDE control vs. TiO2 challenge group, 2.2 ± 0.6 vs. 3.8 ± 0.4, P = 0.026). The tear lactate dehydrogenase level and inflammatory cell infiltration on the ocular surface were higher in the EDE model than in the normal model. These measurements increased significantly in both normal and EDE models after TiO2 challenge. The tumor necrosis factor-α levels and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were also higher in the EDE model than in the normal model. CONCLUSIONS: TiO2 nanoparticle exposure on the ocular surface had a more prominent effect in the EDE model than it did in the normal model. The ocular surface of dry eyes seems to be more vulnerable to fine dust of air pollution than that of normal eyes.

The metabolites in peripheral blood mononuclear cells showed greater differences between patients with impaired fasting glucose or type 2 diabetes and healthy controls than those in plasma.

To determine differences between peripheral blood mononuclear cells and the plasma metabolites in patients with impaired fasting glucose or type 2 diabetes and healthy controls. In all, 65 nononobese patients (aged 30-70 years) with impaired fasting glucose or type 2 diabetes and 65 nonobese sex-matched healthy controls were included, and fasting peripheral blood mononuclear cell and plasma metabolomes were profiled. The diabetic or impaired fasting glucose patients showed higher circulating and peripheral blood mononuclear cell lipoprotein phospholipase A2 activities, high-sensitivity C-reactive protein and tumour necrosis factor-α than controls. Compared with controls, impaired fasting glucose or diabetic subjects showed increases in 11 peripheral blood mononuclear cell metabolites: six amino acids (valine, leucine, methionine, phenylalanine, tyrosine and tryptophan), l-pyroglutamic acid, two fatty acid amides containing palmitic amide and oleamide and two lysophosphatidylcholines. In impaired fasting glucose or diabetic patients, peripheral blood mononuclear cell lipoprotein phospholipase A2 positively associated with peripheral blood mononuclear cell lysophosphatidylcholines and circulating inflammatory markers, including tumour necrosis factor-α, high-sensitivity C-reactive protein and lipoprotein phospholipase A2 activities. In plasma metabolites between patients and healthy controls, we observed significant increases in only three amino acids (proline, valine and leucine) and decreases in only five lysophosphatidylcholines. This study demonstrates significant differences in the peripheral blood mononuclear cell metabolome in patients with impaired fasting glucose or diabetes compared with healthy controls. These differences were greater than those observed in the plasma metabolome. These data suggest peripheral blood mononuclear cells as a useful tool to better understand the inflammatory pathophysiology of diabetes.

Clinical Effectiveness of Monocanalicular Silicone Intubation for Congenital Nasolacrimal Duct Obstruction Under Nasal Endoscopic Visualization of the Terminal End of the Obstructed Nasolacrimal Duct.

PURPOSE: To evaluate the cause of nasolacrimal duct obstruction through confirmation by nasal endoscopic findings of Hasner's valve and to report the success rate of monocanalicular silicone intubation (MCI) for the management of congenital nasolacrimal duct obstruction (CNLDO). METHODS: Seventy-seven eyes of 56 patients with CNLDO underwent MCI under nasal endoscopic visualization of the terminal end of the obstructed nasolacrimal duct at the Korea University Ansan Hospital and Guro Hospital from October 2008 to March 2013. The following demographic information was analyzed: age, sex, endoscopic findings of Hasner's valve during operation, complications, and outcomes. The main outcome measures were disappearance of epiphora symptoms beginning the first 2 months after removal of the silicone tube. The silicone tube was removed under topical anesthesia in the office between 2 and 3 months, postoperatively. RESULTS: The mean (± SD) age of the study population was 29.8 (± 26.9) months (range: 6 months to 12 years). Under nasal endoscopic view, 45 ducts (58.4%) had a thin membranous obstruction or had a simple stenotic opening of Hasner's valve. Seven ducts (9.1%) had thick obstructing membranes with probe passage under the lateral nasal mucosa. Twenty-three ducts (29.9%) showed the probe tip protruding through balloon-like nasal mucosa. Two ducts (2.6%) appeared to have probe protrusion through a stretchable valve. The overall success rate was 89.6% (69/77). The incidence of tube prolapse and tube loss was 18.2% (14 eyes) and 13.0% (10 eyes), respectively. No other complications were observed. CONCLUSIONS: Monocanalicular silicone intubation under nasal endoscopic visualization of the terminal end of the obstructed nasolacrimal duct can be an effective procedure for the management of CNLDO.

PERIPAPILLARY CHOROIDAL THICKNESS IN CENTRAL SEROUS CHORIORETINOPATHY: Is Choroid Outside the Macula Also Thick?

PURPOSE: To investigate peripapillary choroidal thickness (CT) outside the macula in central serous chorioretinopathy (CSC). METHODS: We reviewed the medical records of 34 patients with unilaterally symptomatic idiopathic CSC and 34 age-matched controls. Subfoveal and peripapillary CT were measured from images obtained by spectral domain optical coherence tomography. The nasal peripapillary CT of the choroid outside the macula was determined. RESULTS: The subfoveal CT of CSC (369.74 ± 54.17 µm) and fellow eyes (316.18 ± 54.68 µm) of the patient group were thicker than those of the normal controls (281.90 ± 40.97 µm, all P < 0.05). The subfoveal CT in CSC was significantly thicker than those in the fellow eyes. Nasal CT was also thicker in CSC (217.59 ± 62.03 µm) and fellow eyes (206.66 ± 59.35 µm) of the patient group compared with the normal controls (179.52 ± 39.64 µm, all P < 0.05). However, there was no difference in nasal CT between CSC and fellow eyes (P = 0.150). CONCLUSION: This result may suggest that manifest CSC occurs in patients with thick choroids both within and outside the macula, especially when subfoveal CT is increased.

Stability of Y-splitting procedure combined with hang-back recession of the rectus muscle in rabbit eyes.

BACKGROUND: The Y-splitting procedure has been used both to treat up-shoots and down-shoots in Duane syndrome, and as a substitute for posterior fixation suture. The Y-split is often performed in conjunction with a hang-back recession when a large amount of recession or an adjustable suture is necessary. Herein, we evaluated the stability of Y-splitting hang-back recession in the rectus muscle. METHODS: Under general anesthesia, a 5-mm hang-back recession of the superior rectus muscle (SR) with Y-splitting was performed in ten eyes from ten rabbits (hang-back group). A conventional recession was performed in the SR of the fellow eye (control group). Six weeks after the procedure, the distance between the original insertion and the recessed SR (recession amount) and the width between the nasal and temporal halves of the SR were measured. These values were compared to the measurements taken at the time of surgery. RESULTS: The hang-back group had a significantly larger forward displacement than the control group (P < 0.001 for both the nasal and temporal halves). The width change between the nasal and temporal halves was also significantly larger in the hang-back group (4.94 ± 1.32 mm) than in the control group (1.14 ± 0.60 mm, P < 0.001). Additionally, the Y-configuration appeared to be more collapsed in the hang-back group than in the control group. CONCLUSION: Y-splitting of the rectus muscle may be unstable when it is combined with a hang-back recession. Surgeons should consider this possibility when performing Y-splitting procedures.

Calcium hydroxyapatite crystals in the anterior chamber of the eye in a patient with renal hyperparathyroidism.

PURPOSE: To report a case of calcium hydroxyapatite crystals in the anterior chamber of a patient with renal hyperparathyroidism. METHODS: Case report. RESULTS: A 54-year-old man visited our clinic with mild ocular pain and decreased visual acuity in his left eye. A slit-lamp examination showed peripheral corneal band keratopathy and multiple white crystals in the anterior chamber. The patient had chronic renal failure and was on regular hemodialysis treatment for 12 years. He had previously undergone total parathyroidectomy because of secondary renal hyperparathyroidism. Aqueous humor analysis showed elevated phosphate levels. Multiple crystals were removed using a manual irrigation and aspiration cannula and were found to be calcium hydroxyapatite crystals on elemental analysis using energy dispersive x-ray spectroscopy. Ocular pain and visual acuity improved and corneal edema and ocular inflammation decreased after the surgery. CONCLUSIONS: Calcium hydroxyapatite crystals can form in the anterior chamber of the eye in a patient with renal hyperparathyroidism.

Multiplex targeting, tracking, and imaging of apoptosis by fluorescent surface enhanced Raman spectroscopic dots.

We have developed multifunctional fluorescent surface enhanced Raman spectroscopic tagging material (F-SERS dots) composed of silver nanoparticle-embedded silica spheres with fluorescent organic dye and specific Raman labels for multiplex targeting, tracking, and imaging of cellular/molecular events in the living organism. In this study, F-SERS dots fabricated with specific target antibodies (BAX and BAD) were employed for the detection of apoptosis. The F-SERS dots did not show any particular toxicity in several cell lines. The F-SERS dots could monitor the apoptosis effectively and simultaneously through fluorescent images as well as Raman signals in both cells and tissues with high selectivity. Our results clearly demonstrate that F-SERS dots can be easily applicable to multiplex analysis of diverse cellular/molecular events important for maintaining cellular homeostasis.