Cumulative creep response of viscoelastic lumbar tissue as a function of work-rest schedule.

We explore the effect of stress-recovery schedule on the cumulative creep response of lumbar tissues. Twelve participants performed a 48-minute protocol that consisted of 12 min of full trunk flexion and 36 min of upright standing. Two stress-recovery (work-rest) schedules were considered: a) three minutes of full trunk flexion followed by twelve minutes of upright standing (3:12), and b) one minute of full trunk flexion followed by four minutes of upright standing (1:4). Lumbar kinematics and EMG activity of erector spinae muscles were collected. Cumulative creep deformation was explored by considering the changes in peak lumbar flexion angles during full flexion and changes in the angles of flexion-relaxation (EMG-off) of the lumbar extensor musculature after the 48-minute protocol. The results of time-dependent lumbar flexion angle during full flexion revealed a noticeable creep response in both work-rest schedules, but the cumulative creep response was significantly greater in the 3:12 schedule (Δ3.5°) than in the 1:4 schedule (Δ1.6°). Similarly, the change in the EMG-off lumbar flexion angle in the 3:12 schedule was significantly greater than in the 1:4 schedule (Δ2.5° vs -Δ0.2°, respectively). These results indicate that the passive lumbar tissues recover their force producing capability more rapidly with shorter cycle times.

Effects of a Passive Back-Support Exosuit on Postural Control and Cognitive Performance During a Fatigue-Inducing Posture Maintenance Task.

OBJECTIVE: To evaluate the effectiveness of passive back-support exosuit on postural control and cognitive performance during a fatigue-inducing posture maintenance task. BACKGROUND: Wearable support systems (exoskeletons/exosuits) reduce physical demands but may also influence postural control and cognitive performance by reducing muscular fatigue. METHOD: Eighteen participants visited on two different days to test an exosuit system and performed dual-task cognitive assessments based on human information processing (information acquisition, information integration, and action implementation) while maintaining a 35° trunk flexion posture for 16 minutes. Center-of-pressure (CoP), cognitive performance, and perceived workload were recorded, while erector spinae muscle activity was captured to quantify muscle fatigue. RESULTS: The exosuit was effective in reducing erector spinae muscle fatigue during the static posture maintenance task (61% less in Δmedian frequency: -9.5 Hz (EXO-Off) versus -3.7 Hz (EXO-On)). The fatigue-inducing task increased CoP velocity as a function of time (29% greater: 9.3 mm/sec (pre) versus 12.0 mm/sec (post)), and exosuit use decreased CoP velocity (23% less: 12.1 mm/sec (EXO-Off) versus 9.4 mm/sec (EXO-On)). The exosuit was also effective at mitigating cognitive degradation, as evidenced by a higher hit-to-signal ratio (8% greater: 81.3 (EXO-Off) versus 87.9 (EXO-On)) in the information integration task and reducing perceived workload in all stages of human information processing. CONCLUSION: Exosuit provided benefits of postural control and information integration processing during a 16-min static posture maintenance task. APPLICATION: Torso exoskeletons/suits can have positive implications for occupations with concurrent physical and cognitive demands.

Quantifying the effectiveness of a passive trunk-support exosuit at reducing erector spinae muscle fatigue during a quasi-static posture maintenance task.

The objective of this study was to explore the effectiveness of a passive back-support exosuit at reducing low back muscle fatigue during an 18-minute trunk posture maintenance task. On two separate days sixteen participants performed an 18-minute trunk posture profile that reflected trunk flexion postures observed during a challenging vascular surgery procedure. On one day they performed the procedure with the support of the exosuit, on the other day without. Test contractions were performed every three minutes to capture the time-dependent electromyographic activity of the bilateral erector spinae muscles. Time domain (amplitude) and frequency domain (median frequency) measures of erector spinae muscle fatigue were assessed. Results revealed that the exosuit significantly reduced the measures of erector spinae muscle fatigue in terms of both amplitude (6.1%) and median frequency (5.3%), demonstrating a fatigue reduction benefit of the exosuit in a realistic surgical posture maintenance task.

To examine the potential adoption of a back-support exosuit system in the surgical environment, this study used an 18-minute posture maintenance task that reflected trunk flexion postures observed during a vascular surgery procedure and suggests that the exosuit system can effectively reduce low back muscle fatigue during a vascular surgical procedure.

Effects of a Passive Back-Support Exosuit on Erector Spinae and Abdominal Muscle Activity During Short-Duration, Asymmetric Trunk Posture Maintenance Tasks.

OBJECTIVE: To examine the effects of asymmetry and lower extremity mobility restrictions on the effectiveness of a passive back-support exosuit in short-duration, static trunk flexion postures. BACKGROUND: The effectiveness of trunk exoskeletons/suits for sagittally symmetric trunk posture maintenance has been investigated, but there has been limited study of the effects of asymmetric trunk postures or lower extremity motion restriction. METHOD: Sixteen participants held trunk flexion postures involving trunk flexion (20°, 40°, 60°), asymmetry (0°, 30°), and lower extremity mobility (Free, Restricted) for 3 s. Participants held these postures with and without an exosuit while erector spinae and abdominal muscle activities were collected. RESULTS: There were no significant interactions between exosuit and asymmetry or exosuit and lower extremity motion restrictions, indicating no significant effects of these factors on the effectiveness of the exosuit at reducing trunk muscle activity. The exosuit was found to be effective at reducing erector spinae muscle activity regardless of asymmetry of posture or lower extremity restrictions (average 21%, from 11.2% MVC to 8.8% MVC). The magnitude of the erector spinae activity at 60° of trunk flexion with the exosuit was similar to that seen at 20° without the exosuit. CONCLUSION: The exosuit consistently provided biomechanical benefit through reduced activation of the erector spinae muscles and neither asymmetry of trunk posture nor lower extremity restriction influenced this effectiveness. APPLICATION: Trunk exoskeletons/suits can reduce trunk muscle activation and understanding how characteristics of the trunk postures assumed impact these responses may help target tasks wherein these devices may be effective.

Creep deformation of viscoelastic lumbar tissue during sustained submaximal trunk flexion postures.

Most in-vivo human experiments exploring creep deformation of viscoelastic lumbar tissue have used a maximum trunk flexion posture to engage the lumbar passive tissues. Recent evidence suggests that static trunk flexion tasks requiring submaximal trunk flexion can lead to gradual changes in the lumbar lordosis and this leads to our hypothesis that maintaining submaximal trunk flexion postures may lead to significant creep deformation of the viscoelastic lumbar tissues. Sixteen participants maintained a trunk flexion posture that was ten degrees less than the trunk flexion posture eliciting flexion-relaxation phenomenon for 12 min with breaks for a maximal trunk flexion protocol every three minutes. Trunk kinematic and extensor EMG measures were captured during the static, submaximal trunk flexion protocol as well as during the maximal trunk flexion protocol to provide evidence of creep development in the lumbar passive tissues. Results revealed that 12-minutes of submaximal trunk flexion led to significant increases in peak lumbar flexion angle (1.3°) and EMG-off lumbar flexion angle for L3/L4 paraspinals (2.9°). During the submaximal trunk flexion protocol, the changes in the lumbar flexion angle at 3-6 min and 6-9 min (average Δ5.4°) were significantly greater than at 0-3 min (Δ2.0°). The contribution of this study is the demonstration that sustained submaximal trunk flexion posture (i.e., constant global system) can lead to creep deformation of the viscoelastic lumbar tissue due to the increased lumbar flexion (i.e., altered local system) and may be attributed to a reduction in lumbar lordosis as the extensor muscles fatigue.

Effect of trunk flexion angle and time on lumbar and abdominal muscle activity while wearing a passive back-support exosuit device during simple posture-maintenance tasks.

Quantifying the trunk flexion angles at which wearable support systems (exoskeletons/exosuits) provide substantial trunk extension moment during posture maintenance tasks (such as those seen in surgical environments) can provide a deeper understanding of this potential intervention strategy. Understanding how time (i.e. adaptation/learning) might impact the reliance on wearable support is also of value. Sixteen participants were asked to maintain specific trunk flexion angles (range 0-60°) with and without an exosuit system while erector spinae and rectus abdominis muscle activity were captured using surface electromyography. The effects of the exosuit showed a statistically significant (p < 0.007) effect on the activity of the erector spinae muscles at 10-60°-an effect that became 'large' (Cohen's d = 0.84) after 20° of trunk flexion. There were no meaningful time-dependent trends in the levels of muscle activation indicating there was no adaptation/learning effect of the exosuit in the task studied.Practitioner summary: This study examined the effectiveness of a back-support exosuit as a function of trunk flexion angle and time of use. The results revealed that the exosuit significantly reduced erector spinae muscle activity beyond 20° of trunk flexion but did not show a meaningful adaption/learning effect.Abbreviations: LBP: low back pain; EMG: electromyography; NEMG: normalized electromyography; IMU: inertial measurement unit; ES: erector spinae; RA: rectus abdominis; MVC: maximum voluntary contraction; FFT: Fast Fourier Transform.

Alternative to Reduced Stresses on the Upper Extremity in a Standing Workstation.

OBJECTIVE: This study evaluated a standing armrest to provide more acceptable ergonomic guidelines that may reduce the cost of standing computer workstations. BACKGROUND: Of the many advantages of standing workstations, there have been no efforts to minimize the biomechanical cost, such as larger wrist extension and greater forearm muscle activity than sitting. METHOD: Sixteen participants were asked to perform a typing task under a combination of the following factors: (1) desk shape (rectangular and concave); (2) desk height (0, +5, -5 cm from 90° elbow flexion); and (3) monitor height (0, -10 cm from the eyes). During the trials, the trunk kinematics, muscle activation levels, and CoP were recorded. RESULTS: Both arms were further away from the upper body under the concave and +5 desk height than under the normal condition, but significant decreases in the extensor carpi radialis (8.6%), anterior deltoid (28.8%), and L4 paraspinals (5.5%) were observed. Similarly, the wrist extension angle decreased by 10.5° (42%) under this condition, but the posture required a 2.2° (19%) increase in wrist adduction angle. The CoP irregularity was greater under the concave workstation, indicating more complex motion. CONCLUSION: A higher and concave desk can provide an armrest effect while engaged in a standing workstation by reducing the wrist extension and related muscle activation level, but at the cost of a larger wrist adduction angle. APPLICATION: Providing a standing armrest (+5 cm height and concave desk) could reduce the stresses on the upper extremities, but a split keyboard should be considered to minimize wrist adduction.

Significance of Lower Body Postures in Chair Design.

OBJECTIVE: This study examined a system-level perspective to investigate the changes in the whole trunk and head postures while sitting with various lower extremity postures. BACKGROUND: Sitting biomechanics has focused mainly on the lumbar region only, whereas the anatomy literature has suggested various links from the head and lower extremity. METHOD: Seventeen male participants were seated in six lower extremity postures, and the trunk kinematics and muscle activity measures were captured for 5 s. RESULTS: Changes in the trunk-thigh angle and the knee angle affected the trunk and head postures and muscle recruitment patterns significantly, indicating significant interactions between the lower extremity and trunk while sitting. Specifically, the larger trunk-thigh angle (T135°) showed more neutral lumbar lordosis (4.0° on average), smaller pelvic flexion (1.8°), smaller head flexion (3.3°), and a less rounded shoulder (1.7°) than the smaller one (T90°). The smaller knee angle (K45°) revealed a more neutral lumbar lordosis (6.9°), smaller pelvic flexion (9.2°), smaller head flexion (2.6°), and less rounded shoulder (2.4°) than the larger condition (K180°). The more neutral posture suggested by the kinematic measures confirmed significantly less muscular recruitment in the trunk extensors, except for a significant antagonistic co-contraction. CONCLUSION: The lower and upper back postures were more neutral, and back muscle recruitment was lower with a larger trunk-thigh angle and a smaller knee angle, but at the cost of antagonistic co-contraction. APPLICATION: The costs and benefits of each lower extremity posture can be used to design an ergonomic chair and develop an improved sitting strategy.

Effect of standing desk use on cognitive performance and physical workload while engaged with high cognitive demand tasks.

It is clear that the cognitive resources invested in standing are greater than in sitting, but six of eight previous studies suggested that there is no difference in cognitive performance. This study investigated the effects of sitting and standing workstations on the physical workload and cognitive performance under variable cognitive demand conditions. Fifteen participants visited two times for testing sitting and standing workstations, and were asked to play two difficulty levels of Tetris game for 40 min while kinematic variables, CoP regularity, CoP SD, and cognitive performances were captured every 5 min. Results revealed a more neural posture in standing than in sitting, but using the standing workstation degraded attention and executive function. The CoP SD was 7 times greater in standing, but the CoP regularity was 1/4 in sitting, denoting greater attentional investment while engaged at the standing workstation.

Defect Visualization of a Steel Structure Using a Piezoelectric Line Sensor Based on Laser Ultrasonic Guided Wave.

We studied the detection and visualization of defects in a test object using a laser ultrasonic guided wave. The scan area is irradiated by a laser generated from a Nd:YAG 532 nm Q-switched laser generator through a galvanometer scanner. The laser irradiation causes the surface temperature to suddenly rise and then become temporarily adiabatic. The locally heated region reaches thermal equilibrium with the surroundings. In other words, heat energy propagates inside the object in the form of elastic energy through adiabatic expansion. This thermoelastic wave is typically acquired by a piezoelectric sensor, which is sensitive in the ultrasonic domain. A single piezoelectric sensor has limited coverage in the scan area, while multi-channel piezoelectric sensors require many sensors, large-scale wiring, and many channeling devices for use and installation. In addition, the sensors may not acquire signals due to their installed locations, and the efficiency may be reduced because of the overlap between the sensing areas of multiple sensors. For these reasons, the concept of a piezoelectric line sensor is adopted in this study for the first time. To verify the feasibility of the line sensor, I- and L-shaped sensors were attached to a steel structure, and the ultrasound signal from laser excitation was obtained. If the steel structure has defects on the back, the ultrasonic propagation image will be distorted in the defect area. Thus, we can detect the defects easily from the visualization image. Three defects were simulated for the test. The results show that the piezoelectric line sensor can detect defects more precisely and accurately compared to a single piezoelectric sensor.

Characterization of the Ohmyungsamycin Biosynthetic Pathway and Generation of Derivatives with Improved Antituberculosis Activity.

The cyclic depsipeptides ohmyungsamycin (OMS) A (1) and B (2), isolated from the marine-derived Streptomyces sp. SNJ042, contain two non-proteinogenic amino acid residues, ß-hydroxy-l-phenylalanine (ß-hydroxy-l-Phe) and 4-methoxy-l-tryptophan (4-methoxy-l-Trp). Draft genome sequencing of Streptomyces sp. SNJ042 revealed the OMS biosynthetic gene cluster consisting of a nonribosomal peptide synthetase (NRPS) gene and three genes for amino acid modification. By gene inactivation and analysis of the accumulated products, we found that OhmL, encoding a P450 gene, is an l-Phe ß-hydroxylase. Furthermore, OhmK, encoding a Trp 2,3-dioxygenase homolog, and OhmJ, encoding an O-methyltransferase, are suggested to be involved in hydroxylation and O-methylation reactions, respectively, in the biosynthesis of 4-methoxy-l-Trp. In addition, the antiproliferative and antituberculosis activities of the OMS derivatives dehydroxy-OMS A (4) and demethoxy-OMS A (6) obtained from the mutant strains were evaluated in vitro. Interestingly, dehydroxy-OMS A (4) displayed significantly improved antituberculosis activity and decreased cytotoxicity compared to wild-type OMS A.

In Vitro and In Vivo Assessment of FK506 Analogs as Novel Antifungal Drug Candidates.

FK506 (tacrolimus) is an FDA-approved immunosuppressant indicated for the prevention of allograft rejections in patients undergoing organ transplants. In mammals, FK506 inhibits the calcineurin-nuclear factor of activated T cells (NFAT) pathway to prevent T-cell proliferation by forming a ternary complex with its binding protein, FKBP12, and calcineurin. FK506 also exerts antifungal activity by inhibiting calcineurin, which is essential for the virulence of human-pathogenic fungi. Nevertheless, FK506 cannot be used directly as an antifungal drug due to its immunosuppressive action. In this study, we analyzed the cytotoxicity, immunosuppressive activity, and antifungal activity of four FK506 analogs, 31-O-demethyl-FK506, 9-deoxo-FK506, 9-deoxo-31-O-demethyl-FK506, and 9-deoxo-prolyl-FK506, in comparison with that of FK506. The four FK506 analogs generally possessed lower cytotoxicity and immunosuppressive activity than FK506. The FK506 analogs, except for 9-deoxo-prolyl-FK506, had strong antifungal activity against Cryptococcus neoformans and Candida albicans, which are two major invasive pathogenic yeasts, due to the inhibition of the calcineurin pathway. Furthermore, the FK506 analogs, except for 9-deoxo-prolyl-FK506, had strong antifungal activity against the invasive filamentous fungus Aspergillus fumigatus Notably, 9-deoxo-31-O-demethyl-FK506 and 31-O-demethyl-FK506 exhibited robust synergistic antifungal activity with fluconazole, similar to FK506. Considering the antifungal efficacy, cytotoxicity, immunosuppressive activity, and synergistic effect with commercial antifungal drugs, we selected 9-deoxo-31-O-demethyl-FK506 for further evaluation of its in vivo antifungal efficacy in a murine model of systemic cryptococcosis. Although 9-deoxo-31-O-demethyl-FK506 alone was not sufficient to treat the cryptococcal infection, when it was used in combination with fluconazole, it significantly extended the survival of C. neoformans-infected mice, confirming the synergistic in vivo antifungal efficacy between these two agents.

Evaluation of the broad-spectrum lytic capability of bacteriophage cocktails against various Salmonella serovars and their effects on weaned pigs infected with Salmonella Typhimurium.

The broad-spectrum lytic capability of Salmonella bacteriophages against various Salmonella species was evaluated to determine their potential as an alternative for antibiotics, and the safety and preventive effects of the bacteriophages were assessed on mice and pigs. Four bacteriophage cocktails were prepared using 13 bacteriophages, and the lytic capability of the four bacteriophage cocktails was tested using Salmonella reference strains and field isolates. Bacteriophage cocktail C (SEP-1, SGP-1, STP-1, SS3eP-1, STP-2, SChP-1, SAP-1, SAP-2; ≥109 pfu/ml) showed the best lytic activity against the Salmonella reference strains (100% of 34) and field isolates (92.5% of 107). Fifty mice were then orally inoculated with bacteriophage cocktail C to determine the distribution of bacteriophages in various organs, blood and feces. The effects of bacteriophages on Salmonella infection in weaned pigs (n=15) were also evaluated through an experimental challenge with Salmonella Typhimurium after treatment with bacteriophage cocktail C. All mice exhibited distribution of the bacteriophages in all organs, blood and feces until 15 days post infection (dpi). After 35 dpi, bacteriophages were not detected in any of these specimens. As demonstrated in a pig challenge study, treatment with bacteriophage cocktail C reduced the level of Salmonella shedding in feces. The metagenomic analyses of these pig feces also revealed that bacteriophage treatment decreased the number of species of the Enterobacteriaceae family without significant disturbance to the normal fecal flora. This study showed that bacteriophages effectively controlled Salmonella in a pig challenge model and could be a good alternative for antibiotics to control Salmonella infection.

Characterisation of the antibacterial properties of the recombinant phage endolysins AP50-31 and LysB4 as potent bactericidal agents against Bacillus anthracis.

The recombinant phage endolysins AP50-31 and LysB4 were developed using genetic information from bacteriophages AP50 and B4 and were produced by microbial cultivation followed by chromatographic purification. Subsequently, appropriate formulations were developed that provided an acceptable stability of the recombinant endolysins. The bacteriolytic properties of the formulated endolysins AP50-31 and LysB4 against several bacterial strains belonging to the Bacillus genus including Bacillus anthracis (anthrax) strains were examined. AP50-31 and LysB4 displayed rapid bacteriolytic activity and broad bacteriolytic spectra within the Bacillus genus, including bacteriolytic activity against all the B. anthracis strains tested. When administered intranasally, LysB4 completely protected A/J mice from lethality after infection with the spores of B. anthracis Sterne. When examined at 3 days post-infection, bacterial counts in the major organs (lung, liver, kidney, and spleen) were significantly lower compared with those of the control group that was not treated with endolysin. In addition, histopathological examinations revealed a marked improvement of pathological features in the LysB4-treated group. The results of this study support the idea that phage endolysins are promising candidates for developing therapeutics against anthrax infection.

Successful introduction of Model for End-stage Liver Disease scoring in deceased donor liver transplantation in Korea: analysis of first 1 year experience at a high-volume transplantation center.

BACKGROUNDS/AIMS: Model for End-stage Liver Disease (MELD) score was adopted in June 2016 in Korea. METHODS: We analyzed changes in volumes and outcomes of deceased donor liver transplantation (DDLT) for 1 year before and after introduction of MELD scoring at Asan Medical Center. RESULTS: There were 64 cases of DDLT in 1 year before MELD introduction and 106 in 1 year after MELD introduction, an increase of 65%. The volume of DDLTs abruptly increased during first 3 months, but then returned to its usual level before MELD introduction, which indicated 3-month depletion of accumulated recipient pool with high MELD scores. The number of pediatric DDLT cases increased from 3 before MELD introduction to 11 after it, making up 21.4% and 47.8% of all cases of pediatric liver transplantation, respectively. The number of cases of retransplanted DDLTs increased from 4 to 27, representing 6.3% and 25.5% of all DDLT cases, respectively. The number of status 1 DDLT cases increased from 5 to 12, being 7.8% and 11.3% of all cases. Patient survival outcomes were similar before and after MELD introduction. CONCLUSIONS: The number of DDLTs temporarily increased after adoption of MELD scoring due to accumulated recipient pool with high MELD scores. The numbers of retransplanted and pediatric DDLT cases significantly increased. Patient survival in adult and pediatric DDLT was comparable before and after adoption of MELD scoring. These results imply that Korean MELD score-based allocation system was successfully established within its first year.

Pharmacokinetics and Tolerance of the Phage Endolysin-Based Candidate Drug SAL200 after a Single Intravenous Administration among Healthy Volunteers.

This study was a phase 1, single-center, randomized, double-blind, placebo-controlled, single-dosing, and dose-escalating study of intravenous SAL200. It is a new candidate drug for the treatment of antibiotic-resistant staphylococcal infections based on a recombinant form of the phage endolysin SAL-1. The study evaluated the pharmacokinetics, pharmacodynamics, and tolerance among healthy male volunteers after the intravenous infusion of single ascending doses of SAL200 (0.1, 0.3, 1, 3, and 10 mg/kg of body weight). SAL200 was well tolerated, and no serious adverse events (AEs) were observed in this clinical study. Most AEs were mild, self-limiting, and transient. The AEs reported in more than three participants were fatigue, rigors, headache, and myalgia. No clinically significant values with respect to the findings of clinical chemistry, hematology, and coagulation analyses, urinalysis, vital signs, and physical examinations were observed, and no notable trends in our electrocardiogram (ECG) results for any tested dose were noticed. A greater-than-dose-proportional increase with regard to systemic exposure and the maximum serum concentration was observed when the SAL200 dose was increased from 0.1 mg/kg to 10 mg/kg. This investigation constitutes the first-in-human phase 1 study of an intravenously administered, phage endolysin-based drug. (This study has been registered at ClinicalTrials.gov under identifier NCT01855048 and at the Clinical Research Information Service [https://cris.nih.go.kr/cris/] under identifier KCT0000968.).

Pharmacokinetics of the phage endolysin-based candidate drug SAL200 in monkeys and its appropriate intravenous dosing period.

SAL200 is a new phage endolysin-based candidate drug for the treatment of staphylococcal infections. An intravenous administration study was conducted in monkeys to obtain pharmacokinetic information on SAL200 and to assess the safety of a short SAL200 dosing period (<1 week). Maximum serum drug concentrations and systemic SAL200 exposure were proportional to the dose and comparable in male and female monkeys. SAL200 was well tolerated, and no adverse events or laboratory abnormalities were detected after injection of a single dose of up to 80 mg/kg per day, or injection of multiple doses of up to 40 mg/kg per day.

The herbal-derived honokiol and magnolol enhances immune response to infection with methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA).

The emergence of antibiotic resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) reminds us an urgent need to develop a new immune-modulating agent for preventing S. aureus infection. In this study, we found that herbal medicines, honokiol and magnolol, caused a significant cellular immune modulatory effect during S. aureus infection. In mouse macrophages, these compounds drove upregulation of an antioxidant effect in response to S. aureus, resulting in a dampened total cellular reactive oxygen species (ROS) production and decreased production of inflammatory cytokines/chemokines, whereas honokiol induced increased types I and III interferon messenger RNA (mRNA) expression levels in response to MSSA infection. Moreover, the internalization of S. aureus by human alveolar epithelial cells was inhibited by these compounds. Furthermore, honokiol and magnolol treatment promoted a delay in killing during MSSA infection in Caenorhabditis elegans, suggesting antimicrobial function in vivo. In conclusion, honokiol and magnolol may be considered as attractive immune-modulating treatment for S. aureus infection.

Preclinical safety evaluation of intravenously administered SAL200 containing the recombinant phage endolysin SAL-1 as a pharmaceutical ingredient.

Phage endolysins have received increasing attention as potent antibacterial agents. However, although safety evaluation is a prerequisite for the drug development process, a good laboratory practice (GLP)-compliant safety evaluation has not been reported for phage endolysins. A safety evaluation of intravenously administered SAL200 (containing phage endolysin SAL-1) was conducted according to GLP standards. No animals died in any of the safety evaluation studies. In general toxicity studies, intravenously administered SAL200 showed no sign of toxicity in rodent single- and repeated-dose toxicity studies. In the dog repeated-dose toxicity test, there were no abnormal findings, with the exception of transient abnormal clinical signs that were observed in some dogs when daily injection of SAL200 was continued for more than 1 week. In safety pharmacology studies, there were also no signs of toxicity in the central nervous and respiratory system function tests. In the cardiovascular function test, there were no abnormal findings in all tested dogs after the first and second administrations, but transient abnormalities were observed after the third and fourth administrations (2 or 3 weeks after the initial administration). All abnormal findings observed in these safety evaluation studies were slight to mild, were apparent only transiently after injection, and resolved quickly. The safety evaluation results for SAL200 support the implementation of an exploratory phase I clinical trial and underscore the potential of SAL200 as a new drug. We have designed an appropriate phase I clinical trial based on the results of this study.