Search

Abstract Background Neuromuscular hamartoma is a very rare tumor; with only five cases reported in the orbit. It often occurs in infants and young children and involves large peripheral nerves, but there has been only few reports of occurrence in the orbit and adults. Case presentation This paper describes a 70-year-old man with an incidental orbital mass detected by an imaging test and who later developed associated symptoms. The mass was diagnosed as neuromuscular hamartoma. Superior rectus muscle recession and inferior rectus muscle resection were performed in the right eye for hypertropia secondary to postoperative inferior rectus muscle palsy. Hypertropia in the right eye and diplopia improved after surgery, and regular follow-up is underway. Conclusion This is the first case of an incidentally detected orbital mass diagnosed by histologic examination as a neuromuscular hamartoma in an older patient whose proptosis progressed after a long period of inactivity.

Seizures and movement disorders both involve abnormal movements and are often difficult to distinguish due to their overlapping phenomenology and possible etiological commonalities. Paroxysmal movement disorders, which include three paroxysmal dyskinesia syndromes (paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, paroxysmal exercise-induced dyskinesia), hemiplegic migraine, and episodic ataxia, are important examples of conditions where movement disorders and seizures overlap. Recently, many articles describing genes associated with paroxysmal movement disorders and epilepsy have been published, providing much information about their molecular pathology. In this review, we summarize the main genetic disorders that results in co-occurrence of epilepsy and paroxysmal movement disorders, with a presentation of their genetic characteristics, suspected pathogenic mechanisms, and detailed descriptions of paroxysmal movement disorders and seizure types.

Abstract Background Recently, several studies suggested potential involvements of α-synuclein in Alzheimer’s disease (AD) pathophysiology. Higher concentrations of α-synuclein were reported in cerebrospinal fluid (CSF) of AD patients with a positive correlation towards CSF tau, indicating its possible role in AD. We analyzed the CSF biomarkers to verify whether α-synuclein could be an additional supported biomarker in AD diagnosis. Methods In this cross-sectional study, CSF samples of 71 early-onset AD, 34 late-onset AD, 11 mild cognitive impairment, 17 subjective cognitive decline, 45 Parkinson’s disease, and 32 healthy control (HC) were collected. CSF amyloid-β1-42 (A), total tau (N), and phosphorylated tau181 (T) were measured by commercial ELISA kits, and in-house ELISA kit was developed to quantify α-synuclein. The cognitive assessments and amyloid-PET imaging were also performed. Results CSF α-synuclein manifested a tendency to increase in AD and to decreased in Parkinson’s disease compared to HC. The equilibrium states of total tau and α-synuclein concentrations were changed significantly in AD, and the ratio of total tau/α-synuclein (N/αS) was dramatically increased in AD than HC. Remarkably, N/αS revealed a strong positive correlation with tau phosphorylation rate. Also, the combination of N/αS with amyloid-β1-42/phosphorylated tau181 ratio had the best diagnosis performance (AUC = 0.956, sensitivity = 96%, specificity = 87%). In concordance analysis, N/αS showed the higher diagnostic agreement with amyloid-β1-42 and amyloid-PET. Analysis of biomarker profiling with N/αS had distinctive characteristics and clustering of each group. Especially, among the group of suspected non-Alzheimer’s disease pathophysiology, all A−T+N+ patients with N/αS+ were reintegrated into AD. Conclusions The high correlation of α-synuclein with tau and the elevated N/αS in AD supported the involvement of α-synuclein in AD pathophysiology. Importantly, N/αS improved the diagnostic performance, confirming the needs of incorporating α-synuclein as a biomarker for neurodegenerative disorders. The incorporation of a biomarker group [N/αS] could contribute to provide better understanding and diagnosis of neurodegenerative disorders.

Abstract Background Combination therapy with glucocorticoids and adjunctive immunomodulating drugs has been generally accepted as a standard treatment regimen for meningoencephalomyelitis of unknown etiology (MUE). We hypothesized that treatment with MMF as an adjunctive agent along with glucocorticoids would be effective and well-tolerated protocol in dogs with MUE. Eighty-six dogs with MUE between May 2009 and June 2017 were included (59 females and 27 males; mean age of 5.93 years; mean body weight of 3.83 kg). The medical records of dogs with MUE treated with prednisolone and MMF were retrospectively evaluated to determine the therapeutic response, survival time, and treatment-related adverse effects. Results A partial or complete response (CR) was recorded for 75 dogs. The overall median survival time from the initiation of treatment was 558 days. Dogs that showed CR with no relapse over the treatment period (from diagnosis to death) had significantly longer median survival times. A significantly higher mortality hazard ratio of 4.546 was recorded in dogs that failed to achieve CR. The interval between the onset of clinical signs and the clinical presentation was not significantly associated with CR, relapse rate, and survival time. Adverse effects included gastrointestinal upsets in 26 dogs (30.23%), sporadic infections in 17 dogs (19.77%), and pancreatitis in seven dogs (8.14%). Conclusions The results suggest that adjunctive MMF treatment for MUE is safe and comparable to other immunosuppressive protocols. The treatment should focus on the achievement of CR and preventing relapse for successful management.

Abstract Oleanolic acid has been used only as a subsidiary agent in cosmetic products. The aim of the study is to show the effect of oleanolic acid as an active ingredient for the alleviation of wrinkles in humans and to develop a polymeric micelle formulation that enables poorly soluble oleanolic acid to be used as a main ingredient in cosmetic products for reducing wrinkles. The solubility of oleanolic acid was evaluated in solubilizers, surfactants, and polymers. The particle sizes and shapes of polymeric micelles containing oleanolic acid were evaluated by electrophoretic light scattering spectrophotometer and scanning electron cryomicroscopy. Encapsulation efficiency and skin permeation were measured by HPLC. Stability of the polymeric micelles stored at 40 °C for 3 months was evaluated by visual observation, particle size measurement, and oleanolic acid content measurement. Polymeric micelles in final product ampoule form were applied around the eyes of 23 female subjects for 8 weeks. Five skin parameters were evaluated by optical profilometry every 4 weeks for 8 weeks. In addition, professionals made visual observations of the skin and a human skin irritation study was conducted. Polymeric micelles of oleanolic acid with a particle size of less than 100 nm were prepared using Capryol 90® and poloxamer. The skin permeation rate of the oleanolic acid in the polymeric micelles was higher than that in the other solutions made of oleanolic acid dispersed in 2 different surfactants. No significant changes in particle size, color, or oleanolic acid content were observed, and the polymeric micelles stored at 40 °C for 3 months did not undergo phase separation. After 8 weeks of application, skin irritation had not developed and all five parameters evaluated by optical profilometry as well as the visual evaluation scores were significantly improved. This study showed that the polymeric micelles of oleanolic acid prepared in this study were stable and effective at alleviating wrinkles in humans as the principal active ingredient. Based on these findings, it is expected that polymeric micelles of oleanolic acid can be widely used in cosmetic applications.

Abstract Larotrectinib is an orally administered drug and the first and only selective pan-tropomyosin receptor kinase (TRK) inhibitor in clinical development to treat cancer patients harboring a neurotrophic receptor tyrosine kinase gene fusion. In this study, an analytical method to quantify the TRK inhibitor in mouse and human plasma was developed and validated using LC-MS/MS following protein precipitation with acetonitrile. Larotrectinib and an internal standard (carbamazepine) were separated from endogenous substances using an Xterra C18 column with acetonitrile containing 0.1% formic acid as the mobile phase. The ions m/z 429.8 → 342.8 for larotrectinib and m/z 237.0 → 194.0 for carbamazepine detected in multiple reaction monitoring mode were used for the quantitation. The detector response of larotrectinib was linear within the concentration range 5–10,000 ng/mL with a correlation coefficient (r 2) of not less than 0.999. The intra- and inter-day precision and accuracy were less than 10.48% and within − 8.99%, respectively, in mouse and human plasma. Larotrectinib was stable under various storage and handling conditions, and no significant matrix effect was observed in both mouse and human plasma. Finally, the assay was successfully applied to the pharmacokinetic study of larotrectinib after its intravenous and oral administration to mice.

Abstract Background Gastric cancer is among the most lethal human malignancies. Previous studies have identified molecular aberrations that constitute dynamic biological networks and genomic complexities of gastric tumors. However, the clinical translation of molecular-guided targeted therapy is hampered by challenges. Notably, solid tumors often harbor multiple genetic alterations, complicating the development of effective treatments. Methods To address such challenges, we established a comprehensive dataset of molecularly annotated patient derivatives coupled with pharmacological profiles for 60 targeted agents to explore dynamic pharmacogenomic interactions in gastric cancers. Results We identified lineage-specific drug sensitivities based on histopathological and molecular subclassification, including substantial sensitivities toward VEGFR and EGFR inhibition therapies in diffuse- and signet ring-type gastric tumors, respectively. We identified potential therapeutic opportunities for WNT pathway inhibitors in ALK-mutant tumors, a significant association between PIK3CA-E542K mutation and AZD5363 response, and transcriptome expression of RNF11 as a potential predictor of response to gefitinib. Conclusions Collectively, our results demonstrate the feasibility of drug screening combined with tumor molecular characterization to facilitate personalized therapeutic regimens for gastric tumors.

This paper presents a novel disturbance observer (DOB) for overcoming the limitation of uniformly bounded stability in existing DOB-based control systems and to attain asymptotic stability. The DOB is derived by considering the residual disturbance remaining after disturbance decoupling is performed. It focuses on the elimination of the residual disturbance as well as minimization of the estimation error. By considering the system state and the residual disturbance simultaneously in a Lyapunov stability function, the proposed DOB cancels the residual disturbance term and attains asymptotic stability. In contrast, existing DOBs consider these factors separately in different Lyapunov functions. A basic novel DOB is initially derived for achieving asymptotic stability and is later combined with the existing DOB. This forms a novel extended DOB that achieves a better estimation rate and better performance with regard to DOB-based control than those of existing DOBs.

Purpose Preoperative endoscopic clipping is a popular method in identifying the location of tumors during total laparoscopic or robotic gastrectomy. We investigated the usefulness of additional intraoperative abdominal radiographs to identify the location of clips. Methods We retrospectively analyzed 331 patients with early gastric cancer who underwent endoscopic clipping before total laparoscopic or robotic gastrectomy between September 2012 and September 2018. Endoscopists applied two clips 1 cm from the proximal aspect of the upper margin of the tumor which was located above the angle of the stomach. We compared outcomes of patients who underwent preoperative abdominal radiographs only (group A) and those who underwent additional abdominal radiographs (group B). Results Of the total patients, 80 (24.2%) underwent additional intraoperative abdominal radiographs. The rates of positive frozen biopsy in the two groups were not significantly different (group A vs. group B: 2.8% vs. 3.8%, P=0.456). The additional resection rate was significantly higher in group B compared to group A (8.8% vs. 2.8%, P=0.048). The mean distance from the tumor was 3.3 cm (±2.4) in group A and 2.4 cm (±1.3) in group B (P

Purpose Prenatal diagnosis of cardiac rhabdomyoma is suggestive of the presence of tuberous sclerosis complex (TSC), which is commonly associated with epilepsy. This study investigated the diagnostic rate of TSC, the incidence and treatment outcomes of epilepsy, and long-term neurodevelopmental outcomes in children with fetal cardiac rhabdomyoma. Methods We retrospectively reviewed the medical records of 50 patients with fetal cardiac rhabdomyoma between 1995 and 2017 at the Asan Medical Center Children’s Hospital. Twelve patients were excluded because of incomplete data or a follow-up of less than 1 year. Patients’ medical records were assessed for the occurrence of epilepsy during follow-up, including treatment and outcomes, electroencephalography and magnetic resonance imaging, genetic analysis findings, and neurodevelopmental status. Results Thirty-eight patients (23 males) were diagnosed with TSC. Twenty-eight (73.7%) developed epilepsy. Infantile spasms were observed in 22 patients (78.6%), and 21 (95.5%) received vigabatrin as the first treatment, achieving subsequent freedom from seizures. At the final evaluation, 17 patients (60%) were seizure-free for over 12 months. Seizure remission was not associated with seizure onset age, the presence of cortical tubers, or TSC1/2 mutations. Patients with epilepsy had a higher prevalence of poor neurodevelopmental outcomes than did those without epilepsy (P=0.008). Conclusion A high TSC diagnostic rate and a high incidence of early-onset epilepsy were observed in patients with prenatal cardiac rhabdomyoma, and children with TSC and epilepsy showed poor neurodevelopmental outcomes. Therefore, monitoring with electroencephalography follow-up of infants with fetal cardiac rhabdomyoma may be helpful for the early detection and treatment of epilepsy.

Objective: We performed a randomized two-way crossover study to evaluate the pharmacokinetic profiles of two high-dose ascorbic acid (AA) after IV infusion in healthy beagle dogs. Materials and Methods: The dogs were administered IV AA at two doses of 1.5 and 3 gm/kg for 4 h, and the AA concentration in plasma and urine pH was measured before and after administration. Results: The plasma concentrations of AA in both groups peaked 3 h after administration. Among the two groups, the urine pH was not significantly different (p = 0.12990.7944). High-dose IV AA did not induce serious adverse events in dogs. Conclusion: The results of this study suggest that the high dose of AA which reaches the therapeutic dose for cancer and supports the safety of high-dose IV AA in dogs. [J Adv Vet Anim Res 2019; 6(4.000): 481-485]

Purpose The aim of this study was to evaluate the efficacy and tolerability of everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, for the treatment of tuberous sclerosis complex (TSC) manifestations. Methods A retrospective analysis was conducted using an in-house research database with the keywords “tuberous sclerosis AND everolimus.” Twenty patients were treated with everolimus for TSC from 2013 to February 2019. Results The mean age of the 20 patients was 25.6 years (range, 0 to 57), and the average duration of everolimus treatment was 87.6 weeks (range, 0 to 290). Everolimus was given with a usual daily dosage of 5 to 10 mg (mean, 7.1) or 0.0625 to 0.5 mg for neonates. Twelve patients were prescribed everolimus for more than 1 year for kidney angiomyolipoma (AML). Two of those patients (16.7%) experienced reductions of >50% in tumor size, and four patients (33.3%) experienced reductions of 25% to 50%. The four patients who were prescribed everolimus for subependymal giant cell astrocytoma (SEGA) had 25% to 50% reductions. Neonates with cardiac rhabdomyoma showed significant tumor reduction with everolimus, but their tumors exhibited rebound size increases after treatment was halted. Of the three patients with intractable seizures, one patient became seizure-free, and two patients had >50% reductions. Overall, everolimus therapy was well tolerated. Conclusion Everolimus, an mTOR inhibitor, was effective for seizure control and size reduction of kidney AML, SEGA, and cardiac rhabdomyoma tumors in patients with TSC. However, clinicians should also be aware of the adverse event profile of everolimus.

Koi herpesvirus (KHV) is a highly contagious virus that causes high mortality in koi and common carp, leading to a reduction in production worldwide. Recent diagnostic tests based on molecular methods alone (nucleic acid amplification) and indirect immunoassay methods (antibody detection) can be confirmed over KHV infections or prior exposure and latent infections. Unfortunately, there is no established method to detect KHV virus particles, especially when virus titers are low. Therefore, we propose an alternative, direct immunoassay method for viral detection using a single-chain variable fragment (scFv), a specific region of IgG antibodies that binds specifically to KHV particles. The results of functional analyses indicated that four putative scFv candidates, C5, F8, F6, and E4, were specific to KHV, but only F6 and C5 had a high binding affinity. The binding characteristics were confirmed by indirect competitive and sandwich enzyme-linked immunosorbent assays, which indicated that F6 and C5 have a broad penetration area to the binding region and share a similar epitope with commercial KHV monoclonal antibodies. These characteristics were further confirmed by their interactions with purified KHV coat protein by indirect ELISA and Western blot analyses. In conclusion, the F6 and C5 scFvs have adequate binding affinity to KHV particles to permit their use in immunoassays.

Cysteine–cysteine chemokine receptor 5 (CCR5) has been discovered as a co-receptor for cellular entry of human immunodeficiency virus (HIV). Moreover, the role of CCR5 in a variety of cancers and various inflammatory responses was also discovered. Despite the fact that several CCR5 antagonists have been investigated in clinical trials, only Maraviroc has been licensed for use in the treatment of HIV patients. This indicates that there is a need for novel CCR5 antagonists. Keeping this in mind, the present study was designed. The active CCR5 inhibitors with known IC50 value were selected from the literature and utilized to develop a ligand-based common feature pharmacophore model. The validated pharmacophore model was further used for virtual screening of drug-like databases obtained from the Asinex, Specs, InterBioScreen, and Eximed chemical libraries. Utilizing computational methods such as molecular docking studies, molecular dynamics simulations, and binding free energy calculation, the binding mechanism of selected inhibitors was established. The identified Hits not only showed better binding energy when compared to Maraviroc, but also formed stable interactions with the key residues and showed stable behavior throughout the 100 ns MD simulation. Our findings suggest that Hit1 and Hit2 may be potential candidates for CCR5 inhibition, and, therefore, can be considered for further CCR5 inhibition programs.

Mycobacterium abscessus (MAB) is one of the rapidly growing, multidrug-resistant non-tuberculous mycobacteria (NTM) causing various diseases including pulmonary disorder. Although it has been known that type I interferons (IFNs) contribute to host defense against bacterial infections, the role of type I IFNs against MAB infection is still unclear. In the present study, we show that rIFN-β treatment reduced the intracellular growth of MAB in macrophages. Deficiency of IFN-α/β receptor (IFNAR) led to the reduction of nitric oxide (NO) production in MAB-infected macrophages. Consistently, rIFN-β treatment enhanced the expression of iNOS gene and protein, and NO production in response to MAB. We also found that NO is essential for the intracellular growth control of MAB within macrophages in an inhibitor assay using iNOS-deficient cells. In addition, pretreatment of rIFN-β before MAB infection in mice increased production of NO in the lungs at day 1 after infection and promoted the bacterial clearance at day 5. However, when alveolar macrophages were depleted by treatment of clodronate liposome, rIFN-β did not promote the bacterial clearance in the lungs. Moreover, we found that a cytosolic receptor nucleotide-binding oligomerization domain 2 (NOD2) is required for MAB-induced TANK binding kinase 1 (TBK1) phosphorylation and IFN-β gene expression in macrophages. Finally, increase in the bacterial loads caused by reduction of NO levels was reversed by rIFN-β treatment in the lungs of NOD2-deficient mice. Collectively, our findings suggest that type I IFNs act as an intermediator of NOD2-induced NO production in macrophages and thus contribute to host defense against MAB infection.