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Background: While moderate-intensity statin therapy is recommended for primary prevention, statins may not be utilized at a recommended intensity due to dose-dependent adverse events, especially in an Asian population. However, evidence supporting the use of low-intensity statins in primary prevention is limited.Objective: We sought to compare clinical outcomes between a low-intensity statin plus ezetimibe and a moderate-intensity statin for primary prevention.Methods: This population-based retrospective cohort study used the Korean nationwide claims database (2002-2019). We included adults without atherosclerotic cardiovascular diseases who received moderate-intensity statins or low-intensity statins plus ezetimibe. The primary outcome was a composite of all-cause mortality, myocardial infarction, and ischemic stroke. The safety outcomes were liver and muscle injuries and new-onset diabetes mellitus (DM). We used standardized inverse probability of treatment weighting (sIPTW) and propensity score matching (PSM).Results: In the sIPTW model, 1717 and 36 683 patients used a low-intensity statin plus ezetimibe and a moderate-intensity statin, respectively. In the PSM model, each group included 1687 patients. Compared with moderate-intensity statin use, low-intensity statin plus ezetimibe use showed similar risks of the primary outcome (hazard ratio [HR] = 0.92, 95% CI = 0.81-1.12 in sIPTW and HR = 1.16, 95% CI = 0.87-1.56 in PSM model). Low-intensity statin plus ezetimibe use was associated with decreased risks of liver and muscle injuries (subHR [sHR] = 0.84, 95% CI = 0.74-0.96 and sHR = 0.87, 95% CI = 0.77-0.97 in sIPTW; sHR = 0.84, 95% CI = 0.72, 0.96 and sHR = 0.82, 95% CI = 0.72-0.94 in PSM model, respectively). For new-onset DM and hospitalization of liver and muscle injuries, no difference was observed.Conclusion and Relevance: Low-intensity statin plus ezetimibe may be an alternative to moderate-intensity statin for primary prevention. Our findings provide evidence on safety and efficacy of statin therapy in Asian population.

Pollution by perfluorooctanoic acid (PFOA), a highly persistent and toxic substance, is commonly addressed with several approaches, but the need for post-treatment affects their environmental and economic sustainability. Biodegradation, which can efficiently degrade micropollutants in water under optimal conditions, offers a promising solution, but faces challenges from the persistence of the C-F bond and the high reactivity of F-. Despite recent use of various microorganisms for PFOA degradation, performance issues persist. In this study, we aimed to simulate PFOA degradation while mixed culture anammox granules oxidize NH4+and to confirm the effects of electric potential and Fe(Ⅲ) applications on PFOA degradation. A control reactor containing only anammox granules exhibited NH4+and PFOA removal efficiencies of 11.52% and 19.2%, respectively, with traceable biodegradation at 3.7%. In contrast, a reactor that applied both electric potential and Fe(Ⅲ) demonstrated enhanced removal efficiencies of 41.98% and 50.93%, with traceable biodegradation at 35.03%. Bio-electrochemical properties also improved, showing an average current generation of 331.95 μA and Coulombic efficiency of 141.79 ± 7.6%. This study shows that mixed-culture anammox granules with electric potential and Fe(Ⅲ) can be introduced for efficient PFOA biodegradation and provides the basis for further studies on overcoming the limitations of PFOA biodegradation.

Background: Hot-melt extrusion (HME) significantly affects pharmaceutical manufacturing by enhancing drug solubility and bioavailability. Advancements in HME technology to produce FDA-approved drugs have highlighted its reliability and innovative potential in the pharmaceutical industry. Optimization of the processing parameters of HME-based drug products is aligned with the importance of high-quality drug production through an advanced manufacturing system. Area covered: This review covers the advancements in HME technology, focusing on pharmaceutical quality aspects and addressing unmet patient needs. Additionally, this review addresses the benefits of continuous manufacturing advancements for drug product quality and the importance of process analytical technology (PAT) tools. These tools are essential for monitoring product quality and consistency, maintaining the traceability of raw materials, and ensuring quality control during continuous pharmaceutical manufacturing. Expert opinion: The ongoing evolution of HME technology is a significant step towards creating more efficient and patient-focused drug products. Advances in processing parameters and PAT tools not only improve the quality and effectiveness of HME-based drug products but also satisfy unmet patient needs. The future of HME technology appears promising, with the potential to further refine drug delivery mechanisms and address both current and future unmet needs in pharmaceutical care.

Background: The inherent poor druggability of numerous active pharmaceutical ingredients (APIs) necessitate the modification of their physicochemical and biopharmaceutical properties to enhance their bioavailability and therapeutic effectiveness. Fatty acid conjugation, termed fattigation technology by our research group, represents a versatile pharmaceutical platform in drug delivery by chemically binding of carboxyl group of fatty acids and hydroxy or amine group of target molecules, resulting in modifying the physicochemical and biopharmaceutical properties of APIs or target molecules and creating diverse self-assembled amphiphilic structures. These fattigated structures offer several advantageous features, including 1) improved solubility of many poorly water-soluble drugs via nanonization process, 2) enhanced the membrane permeability, 3) induced enzyme-oriented degradation for controlled release of peptides/drugs, 3) enabled long-acting drug performance, and 4) enhanced anti-tumor activity by receptor-mediated drug delivery. Area covered: This review covers recent advances and relevant researches on fattigation technology, encompassing various aspects of fatty acid conjugation, including design principles involving different types of fatty acids and conjugation strategies, and their applications in the pharmaceutical fields. Expert opinion: We address the pharmaceutical challenges associated with fattigation technology. Particularly, we focus on the choice and substitution content of fatty acids in conjugates for self-assembly and nanonization to achieve desirable physicochemical and biopharmaceutical characteristics, such as solubility, permeability, release rate, controlled-cytotoxicity, bioavailability, targetability and therapeutic effectiveness. Additionally, we offer insights into the future prospects of this fattigation technology by introducing the application of noninvasive delivery of fattigated peptide/protein drugs and the potential delivery of fatty acids for synergistic biological activities to boost therapeutic outcomes.

Background: A small portion of patients are diagnosed with early gastric cancer (EGC) and undergo endoscopic submucosal dissection (ESD) at a young age. However, their clinical outcomes are rarely known. Aim: We investigated to identify the feasibility and clinical outcomes of ESD for EGC focusing on young patients. Methods: We analyzed the clinical characteristics and outscomes of patients who had undergone ESD for the treatment of EGC at < 50 years of age. We enrolled patients who had been diagnosed with EGC and had undergone ESD between 2006 and 2020. We divided them by age as follows: ≤ 50 and > 50 years into the young age (YA) and other age (OA) groups, respectively. Results: Altogether, 1681 patients underwent ESD for EGC (YA group: 124 [7.4%], OA group: 1557 [92.6%]). The YA group had less severe atrophy and more undifferentiated (37.1% vs. 13.9%, P< 0.001) and diffuse type (25% vs. 7.7%, P< 0.001) histology. The curative resection rate was not significantly different between the groups. However, among 1075 patients who had achieved curative resection and had been followed-up for > 12 months, the YA group had a lower incidence of MGN (5.2% vs. 17.5%, P= 0.004) and MGC (2.6% vs. 10.9%, P= 0.019) than those exhibited by the OA group. The YA group was a significant negative predictor of MGN (odds ratio [OR]: 2.983, 95% confidence interval [CI] 1.060–8.393, P= 0.038), and marginally negative predictor in MGC (OR: 3.909, 95% CI: 0.939–16.281, P= 0.061). Conclusion: ESD is a favorable and effective therapeutic modality for EGC patients aged < 50 years, once curative resection is achieved.

Introduction: Kabuki syndrome (KS) is a rare disorder characterized by typical facial features, skeletal anomalies, fetal fingertip pad persistence, postnatal growth retardation, and intellectual disabilities. Heterozygous variants of the KMT2Dand KDM6Agenes are major genetic causes of KS. This study aimed to report the clinical and genetic characteristics of KS. Methods: This study included 28 Korean patients (14 boys and 14 girls) with KS through molecular genetic testing, including direct Sanger sequencing, whole-exome sequencing, or whole-genome sequencing. Results: The median age at clinical diagnosis was 18.5 months (IQR 7–58 months), and the median follow-up duration was 80.5 months (IQR 48–112 months). Molecular genetic testing identified different pathogenic variants of the KMT2D(n= 23) and KDM6A(n= 3) genes, including 15 novel variants. Patients showed typical facial features (100%), such as long palpebral fissure and eversion of the lower eyelid; intellectual disability/developmental delay (96%); short stature (79%); and congenital cardiac anomalies (75%). Although 71% experienced failure to thrive in infancy, 54% of patients showed a tendency toward overweight/obesity in early childhood. Patients with KDM6Avariants demonstrated severe genotype-phenotype correlation. Conclusion: This study enhances the understanding of the clinical and genetic characteristics of KS.

Patients with cancer undergoing chemotherapy experience cachexia with anorexia, body weight loss, and the depletion of skeletal muscles and adipose tissues. Effective treatment strategies for chemotherapy‐induced cachexia are scarce. The growth differentiation factor 15 (GDF15)/GDNF family receptor alpha‐like (GFRAL)/rearranged during transfection (RET) axis is a critical signalling pathway in chemotherapy‐induced cachexia. In this study, we developed a fully human GFRAL antagonist antibody and investigated whether it inhibits the GDF15/GFRAL/RET axis, thereby alleviating chemotherapy‐induced cachexia in tumour‐bearing mice. Anti‐GFRAL antibodies were selected via biopanning, using a human combinatorial antibody phage library. The potent GFRAL antagonist antibody A11 was selected via a reporter cell assay and its inhibitory activity of GDF15‐induced signalling was evaluated using western blotting. To investigate the in vivofunction of A11, a tumour‐bearing mouse model was established by inoculating 8‐week‐old male C57BL/6 mice with B16F10 cells (n= 10–16 mice per group). A11 was administered subcutaneously (10 mg/kg) 1 day before intraperitoneal treatment with cisplatin (10 mg/kg). Animals were assessed for changes in food intake, body weight, and tumour volume. Plasma and key metabolic tissues such as skeletal muscles and adipose tissues were collected for protein and mRNA expression analysis. A11 reduced serum response element‐luciferase reporter activity up to 74% (P< 0.005) in a dose‐dependent manner and blocked RET phosphorylation up to 87% (P= 0.0593), AKT phosphorylation up to 28% (P= 0.0593) and extracellular signal regulatory kinase phosphorylation up to 75% (P= 0.0636). A11 inhibited the action of cisplatin‐induced GDF15 on the brainstem and decreased GFRAL‐positive neuron population expressing c‐Fos in the area postrema and nucleus of the solitary tract by 62% in vivo(P< 0.05). In a melanoma mouse model treated with cisplatin, A11 recovered anorexia by 21% (P< 0.05) and tumour‐free body weight loss by 13% (P< 0.05). A11 significantly improved the cisplatin‐induced loss of skeletal muscles (quadriceps: 21%, gastrocnemius: 9%, soleus: 13%, P< 0.05) and adipose tissues (epididymal white adipose tissue: 37%, inguinal white adipose tissue: 51%, P< 0.05). Our study suggests that GFRAL antagonist antibody may alleviate chemotherapy‐induced cachexia, providing a novel therapeutic approach for patients with cancer experiencing chemotherapy‐induced cachexia.

Fabry disease (FD), a lysosomal storage disorder, is caused by defective α-galactosidase (GLA) activity, which results in the accumulation of globotriaosylceramide (Gb3) in endothelial cells and leads to life-threatening complications such as left ventricular hypertrophy (LVH), renal failure, and stroke. Enzyme replacement therapy (ERT) results in Gb3 clearance; however, because of a short half-life in the body and the high immunogenicity of FD patients, ERT has a limited therapeutic effect, particularly in patients with late-onset disease or progressive complications. Because vascular endothelial cells (VECs) derived from FD-induced pluripotent stem cells display increased thrombospondin-1 (TSP1) expression and enhanced SMAD2 signaling, we screened for chemical compounds that could downregulate TSP1 and SMAD2 signaling. Fasudil reduced the levels of p-SMAD2 and TSP1 in FD-VECs and increased the expression of angiogenic factors. Furthermore, fasudil downregulated the endothelial-to-mesenchymal transition (EndMT) and mitochondrial function of FD-VECs. Oral administration of fasudil to FD mice alleviated several FD phenotypes, including LVH, renal fibrosis, anhidrosis, and heat insensitivity. Our findings demonstrate that fasudil is a novel candidate for FD therapy.

This study investigated the differences in light intensity, photosynthetic efficiency, and growth characteristics of paprika plants cultivated in a semi-closed greenhouse covered with low-iron diffuse glass (SG-LDG) and a conventional greenhouse covered with low-iron regular glass (CG-LRG). There was no significant difference in light intensity between the SG-LDG and CG-LRG from the apical meristem to below 100 cm. However, below 150 cm, the SG-LDG showed higher light intensity than the CG-LRG. The light response curve and atmospheric CO2response(A-Ca) curve, which represent photosynthetic efficiency, were not significantly affected by crop canopy differences between the two greenhouses during the early cultivation stage. However, after 12 weeks of planting, SG-LDG showed higher photosynthetic efficiency. The Jmaxand Vcmaxvalues showed no differences between the plants in the two greenhouses until 4 weeks after planting. 12 weeks after planting, plants in SG-LDG showed higher Jmaxand Vcmaxvalues than those in CG-LRG. All the growth characteristics of plants cultivated in SG-LDG were superior to those of plants cultivated in CG-LRG. Therefore, the improvement in light intensity and photosynthetic efficiency at the lower positions of plants in SG-LDG is considered to have a positive impact on crop quantity and quality.

Background: Hydrophilic Hydroxypropyl Methylcellulose (HPMC) matrix tablets arethe standard role model of the oral controlled-release formulation. Nevertheless, the HPMC kineticsfor the mechanistic understanding of drug release and hydrodynamic behaviors are rarely investigated.This study aims to investigate the release behaviors of both HPMC and paracetamol(model drug) from the hydrophilic matrix tablet. Methods: Two different viscosity grades of HPMC were used (Low viscosity: 6 cps, High viscosity:4,000 cps). Three different ratios of drug/HPMC (H:38.08%, M:22.85%, and L:15.23% (w/w)of HPMC amounts in total weight) matrix tablets were prepared by wet granulation technique. Therelease profiles of the drug and HPMC in a matrix tablet were quantitatively analyzed by HPLCand 1H-Nuclear Magnetic Resonance (NMR) spectroscopy. The hydrodynamic changes of HPMCwere determined by the gravimetric behaviors such as swelling and erosion rates, gel layer thickness,front movement data,and distributive Near-Infrared (NIR) chemical imaging of HPMC in amatrix tablet during the dissolution process. Results: High viscosity HPMC tablets showed slower release of HPMC than the release rate ofdrug, suggesting that drug release preceded polymer release.Different hydration phenomenon wasqualitatively identified and corresponded to the release profiles. The release behaviors of HPMCand drug in the tablet could be distinguished with the significant difference with fitted dissolutionkinetics model (Low viscosity HPMC 6cps; Korsmeyer-Peppas model, High viscosity HPMC4000cps; Hopfenberg model, Paracetamol; Weibull model) according to the weight of ingredientsand types of HPMC. Conclusion: The determination of HPMC polymer release correlating with drug release, hydrodynamicbehavior, and NIR chemical imaging of HPMC can provide new insights into the drug release-modulating mechanism in the hydrophilic matrix system.

Aspirin has emerged as a promising intervention in cancer in the past decade. However, there are existing controversies regarding the anticancer properties of aspirin as its mechanism of action has not been clearly defined. In addition, the risk of bleeding in the gastrointestinal tract from aspirin is another consideration that requires medical and pharmaceutical scientists to work together to develop more potent and safe aspirin therapy in cancer. This review presents the most recent studies of aspirin with regard to its role in cancer prevention and treatment demonstrated by highlighted clinical trials, mechanisms of action as well as approaches to develop aspirin therapy best beneficial to cancer patients. Hence, this review provides readers with an overview of aspirin research in cancer that covers not only the unique features of aspirin, which differentiate aspirin from other non-steroidal anti-inflammatory drugs (NSAIDs), but also strategies that can be used in the development of drug delivery systems carrying aspirin for cancer management. These studies convey optimistic messages on the continuing efforts of the scientist on the way of developing an effective therapy for patients with a low response to current cancer treatments.

Solid dispersions offer many advantages for oral drug delivery of poorly water-soluble drugs over other systems, including an increase in drug solubility and drug dissolution. An improvement in drug absorption and the higher bioavailability of active pharmaceutical ingredients in the gastrointestinal tract have been reported in various studies. In certain circumstances, a rapid pharmacological effect is required for patients. Fastdissolving solid dispersions provide an ideal formulation in such cases. This report will provide an overview of current studies on fast-dissolving solid dispersions, including not only solid dispersion powders with fast dissolution rates but also specific dose form for the controlled release of poorly water-soluble drugs. Specifically, the applications of fast-dissolving solid dispersions will be described in every specific case. Moreover, pharmaceutical approaches and the utilization of polymers will be summarized. The classification and analysis of fastdissolving solid dispersions could provide insight into strategies and potential applications in future drug delivery developments.

Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are the most common subtypes of RASopathy. As an effector of Ras, BRAF is one of the molecules responsible for RASopathy. We investigated the phenotypic and genotypic features of 26 patients with BRAF-associated RASopathy. The clinical diagnoses were CFC (n= 21, 80.8%), NS (n= 3, 11.5%), NS/CFC (n= 1, 3.8%), and undefined syndromic intellectual disability (ID) (n= 1, 3.8%). The mostly shared phenotypes were ID (90.5%), cutaneous manifestations (84.6%), congenital heart defects (76.9%), short stature (76.9%), and dysmorphic features such as short neck (65.4%) and low-set ears (65.4%). Importantly, moderate to severe ID (57.1%) and epilepsy (26.9%) were noted. Eighteen different missense mutations were found, including a novel mutation, p.Phe498Tyr. p.Gln257Arg (n= 9, 34.6%) was the most common mutation, and the mutations were clustered in the cysteine-rich domain or protein kinase domain. A review of previously reported cases along with our findings revealed the existence of multiple sub-phenotypes of RASopathy within a single genotype, indicating that BRAF-associated RASopathy is not variant-specific. Our study further delineated the diverse and expanded clinical phenotypes of BRAF-associated RASopathy with their molecular genetic characteristics.

BackgroundARID2 belongs to the Switch/sucrose non-fermenting complex, in which the genetic defects have been found in patients with dysmorphism, short stature and intellectual disability (ID). As the phenotypes of patients with ARID2mutations partially overlap with those of RASopathy, this study evaluated the biochemical association between ARID2 and RAS-MAPK pathway.MethodsThe phenotypes of 22 patients with either an ARID2heterozygous mutation or haploinsufficiency were reviewed. Comprehensive molecular analyses were performed using somatic and induced pluripotent stem cells (iPSCs) of a patient with ARID2haploinsufficiency as well as using the mouse model of Arid2haploinsufficiency by CRISPR/Cas9 gene editing.ResultsThe phenotypic characteristics of ARID2deficiency include RASopathy, Coffin-Lowy syndrome or Coffin-Siris syndrome or undefined syndromic ID. Transient ARID2knockout HeLa cells using an shRNA increased ERK1 and ERK2 phosphorylation. Impaired neuronal differentiation with enhanced RAS-MAPK activity was observed in patient-iPSCs. In addition, Arid2haploinsufficient mice exhibited reduced body size and learning/memory deficit. ARID2haploinsufficiency was associated with reduced IFITM1 expression, which interacts with caveolin-1 (CAV-1) and inhibits ERK activation.DiscussionARID2haploinsufficiency is associated with enhanced RAS-MAPK activity, leading to reduced IFITM1 and CAV-1 expression, thereby increasing ERK activity. This altered interaction might lead to abnormal neuronal development and a short stature.

A 21-year-old man was admitted to our hospital with recurrent bilateral pneumothorax and hemoptysis. Three years earlier, he underwent coil embolization due to a subarachnoid hemorrhage caused by an intracerebral aneurysm rupture. Two months after the coil embolization, he underwent an emergent total colectomy due to a massive infarction of the colon. One year after the colectomy, he started to have recurrent hemoptysis, and a few months later, multiple episodes of bilateral pneumothorax that required a chest tube placement began to occur. Notably, he had a history of easy bruising. He was taking Depakote and aspirin to prevent seizure and thromboembolic complications, respectively, both of which he began taking after the coil embolization. He denied the use of any illicit drugs. The histories of his parents and sister were not remarkable.

Adults with type 2 diabetes (T2D) experience decline in cognitive function compared with controls. Cognitive function is a major component in the performance of daily activities that involve motor components. The aim of this project was to evaluate working memory cognitive deficits and sensorimotor deficits in adults with T2D versus healthy participants. Ten community-dwelling persons with T2D and 10 age- and sex-matched healthy controls were recruited. Cognitive function, tactile function, motor function, and health state measures were evaluated. Reduced cognitive function, tactile function, and motor function were exhibited in the T2D group. Cognitive and motor functions remained impaired versus controls during tasks with both cognitive and motor components (dual tasks). Health state measures were found to covary with measures of interest. The conclusions of this article are as follows: (a) systemic deficits beyond tactile dysfunction contribute to reduced hand/finger function in T2D, and (b) participants with T2D demonstrate impairments in working memory, tactile function, and motor function.

The common cold is the most frequent acute respiratory illness that places a burden on society, both personally and economically. There is no standard therapy; only symptomatic therapy remains the mainstay of common cold treatment. Thus, interest in herbal medicines is on the rise. Eunkyosan and Samsoeum are used for the common cold in East Asian countries. Although Eunkyosan and Samsoeum are clinically used for the treatment of the common cold, their effectiveness and safety have yet to be studied. Therefore, we aimed to evaluate their effectiveness and safety.

Neurofibromatosis type 1 (NF1) is caused by heterozygous mutation in the NF1gene. NF1 is one of the most common human genetic diseases. However, the overall genotype–phenotype correlation has not been known, due to a wide spectrum of genotypic and phenotypic heterogeneity. Here we describe the detailed clinical and genetic features of 427 Korean NF1 patients from 389 unrelated families. Long range PCR and sequencing of genomic DNA with multiplex ligation-dependent probe amplification analysis identified 250 different NF1mutations in 363 families (93%), including 94 novel mutations. With an emphasis on phenotypes requiring medical attention (classified and termed: NF1+), we investigated the correlation of NF1+and mutation types. NF1+was more prevalent in patients with truncating/splicing mutations and large deletions than in those with missense mutations (59.6%, 64.3% vs. 36.6%, p= 0.001). This difference was especially significant in the patients younger than age 19 years. The number of items in NF1+was a higher in the former groups (0.95 ± 0.06, 1.18 ± 0.20 vs. 0.56 ± 0.10, p= 0.002). These results suggest that mutation types are associated not only with higher prevalence of severe phenotypes in NF1 but also with their earlier onset.

Extracellular vesicles have an excellent ability to transfer their contents to cells. Extracellular vesicles can also be engineered to deliver therapeutic molecules to target cells. Although a number of studies have exploited synthesized nanoparticles in the treatment of neurological disease in the past few years, extracellular vesicles have been investigated and shown tremendous promise for clinical applications because they are safe and have strong targeting specificity. Different types of extracellular vesicles have been studied and modified for delivering therapeutic factors in neurological disease, including extracellular vesicles loaded with natural therapeutic factors and therapeutic molecules. In this review, we discuss delivery systems using extracellular vesicles containing molecules of interest and then focus on main strategies used for EV loading and surface modification. Discussing these important issues will support and facilitate the design and development of promising techniques and products for neurological therapy.

BackgroundAmbroxol (ABX) has been suggested as an augmentative pharmacological agent for neuronopathic Gaucher disease (nGD). This study assessed the long-term safety and efficacy of combined therapy with high-dose ABX and enzyme replacement therapy (ERT) in nGD.MethodsABX+ERT therapy was administered for 4.5 years in four patients with nGD. ABX was initiated at a dose of 1.5 mg/kg/day, and the dose was escalated up to 27 mg/kg/day. The target plasma level was 10 µmol/L or less. The changes in glucocerebrosidase activity, biochemical, safety and neurocognitive findings were assessed.ResultsEnhanced residual GCcase activity was observed in all patients, as evidenced in both in vitro and in vivo studies. During the first 2 years of study with ABX (up to 21 mg/kg/day), mean seizure frequencies and neurocognitive function worsened. After ABX dosage was increased up to 27 mg/kg/day of ABX, its trough plasma concentration was 3.2–8.8 µmol/L. Drug-to-drug interaction, especially with antiepileptic drug significantly affected the pharmacokinetic parameters of ABX. Importantly, at 27 mg/kg/day of ABX, the seizure frequencies markedly decreased from the baseline, and the neurocognitive function was improved. In addition, Lyso-Gb1, a biomarker for the severity and progression of GD, was normalised in all patients. High-dose ABX was well-tolerated with no severe adverse events.ConclusionsLong-term treatment with high-dose ABX+ERT was safe and might help to arrest the progression of the neurological manifestations in GD.

Background Glechoma longituba(Nakai) Kuprian (GL) is primarily used to treat urinary tract infections and traumatic injuries in traditional medicine in East Asia. Various components of GL are reported to show beneficial activities on brain diseases, including cerebral infarction and brain trauma. We hypothesized that GL extract may potentially have a beneficial effect against traumatic brain injury (TBI) animal model.Purpose This study aims to investigate the effects of GL extract on TBI mouse model.Materials and Methods The water extract of GL (GLDW) was obtained by boiling with water. The TBI model was established using ICR mice with controlled cortical impact injury. The experimental groups were divided into sham, control, and three GLDW groups (30–300 mg/kg p.o.). Brain damage, neuronal density, and activated microglial density were evaluated. Motor functional deficits were evaluated using Rotarod test and Balance beam test, and cognitive functional deficits were done using novel object recognition (NOR) test and Y-maze test.Result Oral administration of GLDW did not reduce brain damage or neuronal death. However, it improved motor and cognitive functions in a dose-dependent manner in both motor tests and NOR test except Y-maze test.Conclusion GLDW can improve the impairment of motor and cognitive functions induced by TBI, but it does not have a protective effect against brain damage and neuronal death. Further studies are necessary in order to investigate the mechanisms GLDW’s functional recovery effect on TBI.

Currently, there is great interest in the development of ways to achieve the benefits of radiation treatments with reduced negative effects. The present study demonstrates the utilization of radio-luminescent particles (RLPs) as a means to achieve radio-sensitization and enhancement and their ability to affect head- and neck-cancer-cell cultures (in vitro) and xenografts (in vivo). Our approach utilizes a naturally abundant radio-luminescent mineral, calcium tungstate (CaWO4), in its micro or nanoparticulate form for generating secondary UV-A light by γ ray or X-ray photons. In vitro tests demonstrate that unoptimized RLP materials (uncoated CaWO4(CWO) microparticles (MPs) and PEG–PLA-coated CWO nanoparticles (NPs)) induce a significant enhancement of the tumor-suppressive effect of X-rays and γ rays in both radio-sensitive- and radio-resistant-cancer models; uncoated CWO MPs and PEG–PLA-coated CWO NPs demonstrate comparable radio-sensitization efficacies in vitro. Mechanistic studies reveal that concomitant CaWO4causes increased mitotic death in radio-resistant cells treated with radiation, whereas CaWO4sensitizes radio-sensitive cells to X-ray-induced apoptosis and necrosis. The radio-sensitization efficacy of intratumorally injected CaWO4particles (uncoated CWO MPs and PEG–PLA-coated CWO NPs) is also evaluated in vivo in mouse head- and neck-cancer xenografts. Uncoated CWO MPs suppress tumor growth more effectively than PEG–PLA-coated CWO NPs. On the basis of theoretical considerations, an argument is proposed that uncoated CWO MPs release subtoxic levels of tungstate ions, which cause increased photoelectric-electron-emission effects. The effect of folic acid functionalization on the in vitro radio-sensitization behavior produced by PEG–PLA-coated CWO NPs is studied. Surface folic acid results in a significant improvement in the radio-sensitization efficiency of CaWO4.

Eunkyosan(EKS) and Samsoeum(SSE), which are called Yin qiao sanand Shen su yinin Chinese, are commonly used herbal medicines for the common cold in East Asian countries. This study aimed to evaluate the effectiveness and safety of EKS and SSE for treating the common cold.

Whole exome sequencing (WES) is an effective tool for the genetic diagnosis of mitochondrial disorders due to various nuclear genetic defects. In this study, three patients affected by extremely rare mitochondrial disorders caused by nuclear genetic defects are described. The medical records of each patient were reviewed to obtain clinical symptoms, results of biochemical and imaging studies, and muscle biopsies. WES and massive parallel sequencing of whole mtDNA were performed for each patient. The oxygen consumption rate (OCR) and complex activity I and IV was measured. Patients 1 and 2 had exhibited global developmental delay and seizure since early infancy. Blood lactate, the lactate-to-pyruvate ratio, and urinary excretion of Krebs cycle intermediates were markedly elevated. Patient 1 also was noted for ophthalmoplegia. Patient 2 had left ventricular hypertrophy and ataxia. Patient 3 developed dysarthria, gait disturbance, and right-side weakness at age 29. Brain magnetic resonance imaging demonstrated abnormal signal intensity involving the bilateral thalami, midbrain, or pons. Based on WES, patient 1 had p.Glu415Gly and p.Arg484Trp variants in MTO1. In patient 2, p.Gln111ThrfsTer5 and RNA mis-splicing were identified in TSFM. Patient 3 carried p.Met151Thr and p.Met246Lys variants in AARS2. Skin fibroblasts of three patients exhibited decreased OCRs and complex 1 activity, and mitochondrial DNA was normal. These results demonstrate the utility of WES for identifying the genetic cause of extremely rare mitochondrial disorders, which has implications for genetic counseling.

Lysinuric protein intolerance (LPI) is caused by mutations in the SLC7A7gene at 14q11.2. Its clinical presentation includes failure to thrive, protein intolerance due to a secondary urea cycle defect, interstitial lung disease, renal tubulopathy, and immune disorders. Maternal uniparental disomy 14 (UPD14mat) is the most common cause of Temple syndrome (TS14), which is characterized by severe intrauterine and postnatal growth failure. Here, we describe a severe form of LPI accompanied by TS14 in an 11-month-old girl, which presented as profound failure to thrive and delayed development. LPI was diagnosed by the detection of a homozygous mutation of c.713 C>T (p.Ser238Phe) in SLC7A7, which was eventually found to co-occur with UPD14mat. Despite receiving a protein-restricted diet with citrulline and lysine supplementation, the severe failure to thrive has persisted at follow-up of the patient at 4 years of age.

Gliosis in Niemann-Pick type C (NP-C) disease is characterized by marked changes in microglia and astrocytes. However, the gliosis onset and progression in NP-C has not been systematically studied, nor has the mechanism underlying this finding. Here, we found early gliosis in the subventricular zone (SVZ) of NP-C mice. Neural progenitor damage by Npc1mutation suppressed vascular endothelial growth factor (VEGF) expression and further induced microglia activation followed by astrogliosis. Interestingly, excessive astrogliosis in the SVZ induced neural progenitor retention and/or migration into thalamus via astrocyte-derived VEGF, resulting in acceleration of thalamic and cortical gliosis through thalamo-cortical pathways. Transplantation of VEGF-overexpressing neural stem cells into the SVZ improved whole-brain pathology of NP-C mice. Overall, our data provide a new pathological perspective on NP-C neural pathology, revealing abnormalities in the subventricular-thalamo-cortical circuit of NP-C mouse brain and highlighting the importance of the SVZ microenvironment as a therapeutic target for NP-C disease.