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In recent years, a number of clinical trials have been published on the efficacy and safety of drug delivery using microneedles (MNs). This review aims to systematically summarize and analyze the current evidence including the clinical effect and safety of MNs. Three electronic databases, including PubMed, were used to search the literature for randomized controlled trials (RCTs) and clinical controlled trials (CCTs) that evaluated the therapeutic efficacy of MNs from their inception to 28 June 2018. Data were extracted according to the characteristics of study subjects; disorder, types, and details of the intervention (MNs) and control groups; outcome measurements; effectiveness; and incidence of adverse events (AEs). Overall, 31 RCTs and seven CCTs met the inclusion criteria. Although MNs were commonly used in skin-related studies, evaluating the effects of MNs was difficult because many studies did not provide adequate comparison values between groups. For osteoporosis treatment, vaccine, and insulin delivery studies, MNs were comparable to or more effective than the gold standard. Regarding the safety of MNs, most AEs reported in each study were minor (grade 1 or 2). A well-designed RCT is necessary to clearly evaluate the effectiveness of MNs in the future.

Recently, several clinical studies have been conducted using microneedles (MNs), and various devices have been developed. This study aimed to propose and confirm the feasibility of a placebo control for activating MN clinical research. A 0.5 mm MN stamp with 42 needles was used as a treatment intervention, and a placebo stamp with four acupressure-type needles that did not penetrate was proposed and designed as a control for comparison. First, to check whether the placebo stamp did not invade the skin and to set an appropriate level of pressure to be provided during skin stimulation, two participants were stimulated with five different forces on the forearm, and then the skin was dyed. Secondly, to evaluate the validity of the placebo control group, a blinded study between the MN and placebo stamps was performed on 15 participants. We confirmed that the placebo stamp did not penetrate the skin at any intensity or location. Both types of stamps reported relatively low pain levels, but the MN stamp induced higher pain compared to the placebo stamp. Based on the speculation regarding the type of intervention received, the MN stamp was successfully blinded (random guess), whereas the placebo stamp was unblinded. However, according to a subgroup analysis, it was confirmed that the group with low skin sensitivity was completely blind. Blinding the placebo MN stamp had limited success in participants with low skin sensitivity. Future research on suitable placebo controls, considering the variations in MN stamp length and needle count, is warranted.

Calsequestrin (CASQ) was discovered in rabbit skeletal muscle tissues in 1971 and has been considered simply a passive Ca2+-buffering protein in the sarcoplasmic reticulum (SR) that provides Ca2+ ions for various Ca2+ signals. For the past three decades, physiologists, biochemists, and structural biologists have examined the roles of the skeletal muscle type of CASQ (CASQ1) in skeletal muscle and revealed that CASQ1 has various important functions as (1) a major Ca2+-buffering protein to maintain the SR with a suitable amount of Ca2+ at each moment, (2) a dynamic Ca2+ sensor in the SR that regulates Ca2+ release from the SR to the cytosol, (3) a structural regulator for the proper formation of terminal cisternae, (4) a reverse-directional regulator of extracellular Ca2+ entries, and (5) a cause of human skeletal muscle diseases. This review is focused on understanding these functions of CASQ1 in the physiological or pathophysiological status of skeletal muscle.Muscle function: Multiple roles for a muscle modulatorAlthough previously considered merely a passive regulator of calcium levels, the protein calsequestrin is now known to perform a range of physiological activities essential to skeletal muscle function. The process of muscle contraction depends on the release of calcium ions from an intracellular structure called the sarcoplasmic reticulum (SR). Calsequestrin was originally identified as a “buffering” factor that maintains adequate calcium reserves in the SR, but Eun Hui Lee and colleagues at the Catholic University of Korea review diverse functions that have since been ascribed to this protein. For example, calsequestrin also helps reinforce the structure of the SR, and actively regulates the flux of calcium ions into muscle cells. Perturbations in calsequestrin function also appear to contribute to a number of muscular disorders, including a potential link to Duchenne muscular dystrophy.

Tripartite motif-containing protein 32 (TRIM32) is a member of the tripartite motif family and is highly conserved from flies to humans. Via its E3 ubiquitin ligase activity, TRIM32 mediates and regulates many physiological and pathophysiological processes, such as growth, differentiation, muscle regeneration, immunity, and carcinogenesis. TRIM32 plays multifunctional roles in the maintenance of skeletal muscle. Genetic variations in the TRIM32 gene are associated with skeletal muscular dystrophies in humans, including limb–girdle muscular dystrophy type 2H (LGMD2H). LGMD2H-causing genetic variations of TRIM32 occur most frequently in the C-terminal NHL (ncl-1, HT2A, and lin-41) repeats of TRIM32. LGMD2H is characterized by skeletal muscle dystrophy, myopathy, and atrophy. Surprisingly, most patients with LGMD2H show minimal or no dysfunction in other tissues or organs, despite the broad expression of TRIM32 in various tissues. This suggests more prominent roles for TRIM32 in skeletal muscle than in other tissues or organs. This review is focused on understanding the physiological roles of TRIM32 in skeletal muscle, the pathophysiological mechanisms mediated by TRIM32 genetic variants in LGMD2H patients, and the correlations between TRIM32 and Duchenne muscular dystrophy (DMD).

Injured or atrophied adult skeletal muscles are regenerated through terminal differentiation of satellite cells to form multinucleated muscle fibers. Transplantation of satellite cells or cultured myoblasts has been used to improve skeletal muscle regeneration. Some of the limitations observed result from the limited number of available satellite cells that can be harvested and the efficiency of fusion of cultured myoblasts with mature muscle fibers (i.e., terminal differentiation) upon transplantation. However, the possible use of immature myotubes in the middle of the terminal differentiation process instead of satellite cells or cultured myoblasts has not been thoroughly investigated. Herein, myoblasts (Mb) or immature myotubes on differentiation day 2 (D2 immature myotubes) or 3 (D3 immature myotubes) were transferred to plates containing D2 or D3 immature myotubes as host cells. The transferred Mb/immature myotubes on the plates were further co-differentiated with host immature myotubes into mature myotubes in six conditions: Mb-to-D2, D2-to-D2, D3-to-D2, Mb-to-D3, D2-to-D3, and D3-to-D3. Among these six co-differentiation conditions, the D2-to-D3 co-differentiation condition exhibited the most characteristic myotube appearance and the greatest availability of Ca2+ for skeletal muscle contraction. Compared with non-co-differentiated control myotubes, D2-to-D3 co-differentiated myotubes presented increased MyoD and myosin heavy chain II (MyHC II) expression and increased myotube width, accompanied by parallel and swirling alignment. These increases correlated with functional increases in both electrically induced intracellular Ca2+ release and extracellular Ca2+ entry due to the increased expression of ryanodine receptor 1 (RyR1), sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1a (SERCA1a), and stromal interaction molecule 1 (STIM1). These increases were not detected in any of the other co-differentiation conditions. These results suggest that in vitro-cultured D2-to-D3 co-differentiated mature myotubes could be a good alternative source of satellite cells or cultured myoblasts for skeletal muscle regeneration.

This study proposes a fire dynamics simulation method for combustion modeling using heat release and toxic gas emission experimental data. The feasibility of the proposed method is verified through simulations of a cable spreading room of a nuclear power plant where a high level of safety is required. In addition to CO and CO 2 , nine other toxic gases are detected in the simulations, and the toxic effect is assessed considering two aspects. First, the order of toxic gases reaching the toxicity criteria, which is identical to the order of the hazardousness, is assessed. The arrival times to the lowest allowable exposure limits are ranked as CO < NO 2 < SO 2 < HCl < HCN < HBr < HF < CH 2 CHCN < HCHO < CO 2 < H 2 S. The arrival time is inversely proportional to the degree of risk. Second, the comprehensive toxicity index (TI) and its time-weighted average are proposed to assess the combined effects of all emissions. The comprehensive TI of combined emissions is substantially larger than that of only CO. This implies that the conventional performance-based design method, typically used to assess the toxic and suffocation effects of only CO, CO 2 , and O 2 , may cause considerable error during risk assessment, because it ignores toxic effects of minor gases such as NO 2 , SO 2 , HCl, HCN, HBr, HF, CH 2 CHCN, HCHO, and H 2 S. The proposed experimental-data-based simulation method enables more advanced fire dynamics simulations for accurately assessing the hazardousness of toxic gases to humans, and thus, it can be used practically for establishing suitable fire emergency response plans and countermeasure strategies.

Ca2+ itself or Ca2+-dependent signaling pathways play fundamental roles in various cellular processes from cell growth to death. The most representative example can be found in skeletal muscle cells where a well-timed and adequate supply of Ca2+ is required for coordinated Ca2+-dependent skeletal muscle functions, such as the interactions of contractile proteins during contraction. Intracellular Ca2+ movements between the cytosol and sarcoplasmic reticulum (SR) are strictly regulated to maintain the appropriate Ca2+ supply in skeletal muscle cells. Added to intracellular Ca2+ movements, the contribution of extracellular Ca2+ entry to skeletal muscle functions and its significance have been continuously studied since the early 1990s. Here, studies on the roles of channel proteins that mediate extracellular Ca2+ entry into skeletal muscle cells using skeletal myoblasts, myotubes, fibers, tissue, or skeletal muscle-originated cell lines are reviewed with special attention to the proposed functions of transient receptor potential canonical proteins (TRPCs) as store-operated Ca2+ entry (SOCE) channels under normal conditions and the potential abnormal properties of TRPCs in muscle diseases such as Duchenne muscular dystrophy (DMD).

Calsequestrin 1 (CASQ1) in skeletal muscle buffers and senses Ca2+ in the sarcoplasmic reticulum (SR). CASQ1 also regulates store-operated Ca2+ entry (SOCE) by binding to stromal interaction molecule 1 (STIM1). Abnormal SOCE and/or abnormal expression or mutations in CASQ1, STIM1, or STIM2 are associated with human skeletal, cardiac, or smooth muscle diseases. However, the functional relevance of CASQ1 along with STIM2 has not been studied in any tissue, including skeletal muscle. First, in the present study, it was found by biochemical approaches that CASQ1 is bound to STIM2 via its 92 N-terminal amino acids (C1 region). Next, to examine the functional relevance of the CASQ1-STIM2 interaction in skeletal muscle, the full-length wild-type CASQ1 or the C1 region was expressed in mouse primary skeletal myotubes, and the myotubes were examined using single-myotube Ca2+ imaging experiments and transmission electron microscopy observations. The CASQ1-STIM2 interaction via the C1 region decreased SOCE, increased intracellular Ca2+ release for skeletal muscle contraction, and changed intracellular Ca2+ distributions (high Ca2+ in the SR and low Ca2+ in the cytosol were observed). Furthermore, the C1 region itself (which lacks Ca2+-buffering ability but has STIM2-binding ability) decreased the expression of Ca2+-related proteins (canonical-type transient receptor potential cation channel type 6 and calmodulin 1) and induced mitochondrial shape abnormalities. Therefore, in skeletal muscle, CASQ1 plays active roles in Ca2+ movement and distribution by interacting with STIM2 as well as Ca2+ sensing and buffering.

Stromal interaction molecule 1 (STIM1) is the main protein that, along with Orai1, mediates store-operated Ca2+ entry (SOCE) in skeletal muscle. Abnormal SOCE due to mutations in STIM1 is one of the causes of human skeletal muscle diseases. STIM1-R304Q (a constitutively active form of STIM1) has been found in human patients with skeletal muscle phenotypes such as muscle weakness, myalgia, muscle stiffness, and contracture. However, the pathological mechanism(s) of STIM1-R304Q in skeletal muscle have not been well studied. To examine the pathological mechanism(s) of STIM1-R304Q in skeletal muscle, STIM1-R304Q was expressed in mouse primary skeletal myotubes, and the properties of the skeletal myotubes were examined using single-myotube Ca2+ imaging, transmission electron microscopy (TEM), and biochemical approaches. STIM1-R304Q did not interfere with the terminal differentiation of skeletal myoblasts to myotubes and retained the ability of STIM1 to attenuate dihydropyridine receptor (DHPR) activity. STIM1-R304Q induced hyper-SOCE (that exceeded the SOCE by wild-type STIM1) by affecting both the amplitude and the onset rate of SOCE. Unlike that by wild-type STIM1, hyper-SOCE by STIM1-R304Q contributed to a disturbance in Ca2+ distribution between the cytosol and the sarcoplasmic reticulum (SR) (high Ca2+ in the cytosol and low Ca2+ in the SR). Moreover, the hyper-SOCE and the high cytosolic Ca2+ level induced by STIM1-R304Q involve changes in mitochondrial shape. Therefore, a series of these cellular defects induced by STIM1-R304Q could induce deleterious skeletal muscle phenotypes in human patients carrying STIM1-R304Q.

The combustion, smoke emission, and toxic gas emission characteristics of four types of flame-retardant cables and two types of fiber-optic cables were investigated. The thickness, flame retardancy, and volatile components of the polymeric materials constituting the cables mainly influenced their released heat and smoke emissions. The volatile components increased the magnitude of the first peak of heat release and shortened the interval between the time to ignition and first heat release. The thickness and flame retardancy caused the formation of a char layer, which caused the peak values associated with the secondary heat release and smoke production. Fiber-optic cables with zero halogens exhibited a lower flame retardancy than that of the flame-retardant cables as they were completely pyrolyzed early but emited small amounts of smoke and toxic gases. By considering trade-off between flame retardancy and toxicity, the improvements in fire protection strategies and amendment of cable design criteria are recommended.