Fixing hair using a hair-fixing sheet: better than hairpins?

Identifying tumors or wounds on the scalp is difficult because hair blocks the vision during surgery and suturing. In the meantime, we have commonly used hairpins to hold the hair for a clearer view; however, we would like to suggest a new method, a "hair-fixing sheet," consisting of hook-like surface. We applied the two methods, hair-fixing sheets and hairpins, assuming several situations. In these situations, it was possible to fix a wider range or various shapes more conveniently using a hair-fixing sheet than using several hairpins at a similarly low cost. In addition, it was easy to change the hair to be fixed, remove it postoperatively, and prevent the hair from being pulled out, thereby preventing additional postoperative pain.

Factors affecting length of stay according to bronchopulmonary dysplasia severity: a nationwide cohort study in Korea.

BACKGROUND: Longer hospitalizations for preterm infants with bronchopulmonary dysplasia (BPD) delay developmental outcomes, increase the risk for hospital-acquired complications, and exert a substantial socioeconomic burden. This study aimed to identify factors associated with an extended length of stay (LOS) at different levels of severity of BPD. METHODS: A cohort study was conducted using the Korean Neonatal Network registry of very low birth weight infants with BPD between 2013 and 2017 through retrospective analysis. RESULTS: A total of 4263 infants were diagnosed with BPD. For mild BPD, infants requiring surgical treatment for patent ductus arteriosus needed a longer LOS [eadjusted ß coefficients (adj ß) 1.041; 95% confidence interval (CI): 0.01-0.08] and hydrocephalus (eadj ß 1.094; 95% CI 0.01-0.17). In moderate BPD, infants administered steroids or with intraventricular hemorrhage required a longer LOS (eadj ß 1.041; 95% CI 0.00-0.07 and eadj ß 1.271; 95% CI 0.11-0.38, respectively). In severe BPD, infants with comorbidities required a longer LOS: pulmonary hypertension (eadj ß 1.174; 95% CI 0.09-0.23), administrated steroid for BPD (eadj ß 1.116; 95% CI 0.07-0.14), sepsis (eadj ß 1.062; 95% CI 0.01-0.11), patent ductus arteriosus requiring surgical ligation (eadj ß 1.041; 95% CI 0.00-0.08), and intraventricular hemorrhage (eadj ß 1.016; 95% CI 0.05-0.26). Additionally, the higher the clinical risk index score, the longer the LOS needed for infants in all groups. CONCLUSIONS: The factors affecting LOS differed according to the severity of BPD. Individualized approaches to reducing LOS may be devised using knowledge of the various risk factors affecting LOS by BPD severity.

First Experience of Single-Port Robotic Areolar Approach Thyroidectomy.

OBJECTIVES: Numerous minimally invasive thyroidectomy techniques have been developed and are actively utilized in hospitals around the globe. Herein, we describe a recently developed minimally invasive thyroidectomy technique that employs the da Vinci SP, and we present the preliminary clinical outcomes of single-port robotic areolar thyroidectomy (SPRA). METHODS: A 3-cm semi-circular incision on the right areola and a small 8-mm incision on the left areola were created. Using hydro-dissection and an advanced bipolar device, a subcutaneous skin flap was created, extending from the areola to the thyroid cartilage. The da Vinci SP was then inserted through the incision in the right areola. Between December 2022 and March 2023, 21 SPRA procedures were conducted. Patients' medical records and surgical videos were subsequently reviewed. RESULTS: Lobectomy was performed in 17 patients, isthmectomy in 2 patients, and total thyroidectomy in 2 patients. The mean flap time was 14.9±4.2 minutes and the console time was 62.4±17.1 minutes. The mean tumor size was 0.89± 0.65 cm and the number of retrieved lymph nodes was 3.94±3.98 (range, 0-12). There were no observed instances of vocal cord palsy or hypoparathyroidism. CONCLUSION: We successfully developed and performed the novel SPRA for the first time worldwide. Unlike other robotic surgery. METHODS: SPRA is less invasive and leaves no visible scars. This technique employs a sophisticated single-port robotic device. However, to assess the efficacy of this method, we need to analyze more cases and conduct comparative studies in the near future.

Association of Blood Pressure With Cardio-Renal Events and Mortality in Type 2 DM: A National Health Insurance Database.

CONTEXT: The relationship of blood pressure (BP) with cardio-renal events and all-cause mortality in type 2 diabetes mellitus (T2DM) is still controversial. OBJECTIVE: To investigate the optimal BP target in Korean individuals with T2DM. METHODS: Using the Korean National Health Insurance System database, data of individuals with T2DM who underwent regular health checks from January 1, 2007, to December 31, 2007, were extracted (N = 1 800 073). Among them, a total of 326 593 individuals were included in the final study. The study population was divided into 7 groups according to their observed systolic blood pressure (SBP) (<110, 110-119, 120-129, 130-139, 140-149, 150-159, 160-169, and ≥170 mmHg) and diastolic blood pressure (DBP) (<65, 65-69, 70-74, 75-79, 80-84, 85-89, and ≥90 mmHg). Hazard ratios (HRs) of cardio-renal events and all-cause mortality according to BP categories were analyzed. RESULTS: Compared with SBP of 120-129 mmHg and DBP of 75-79 mmHg, SBP of ≥130 mmHg and DBP of ≥ 80 mmHg were associated with an increase in HR of major cardiovascular adverse events (MACEs). SBP of 120-129 mmHg and DBP 75-79 mmHg were associated with the lowest HR of all-cause mortality. Both lower BP (SBP/DBP <120/70 mm) and higher BP (SBP/DBP ≥130/80 mmHg) were associated with an increased HR of all-cause mortality. Contrary to MACE, the lower the SBP, the lower the HR of renal events. CONCLUSION: In patients with T2DM, the optimal cutoff value of BP associated with a lower incidence of MACE and mortality may be 120-129 mmHg for SBP and 75-79 mmHg for DBP. However, lower SBP may be helpful for T2DM patients with a high risk of renal disease.

Effects of positive end-expiratory pressure on pulmonary atelectasis after paediatric laparoscopic surgery as assessed by ultrasound: A randomised controlled study.

INTRODUCTION: Positive end-expiratory pressure (PEEP) following alveolar recruitment manoeuvre (RM) can effectively prevent anaesthesia-induced atelectasis in children. We aimed to evaluate the individual effect of PEEP following RM on atelectasis at the end of laparoscopic surgery in infants and small children. METHODS: Children undergoing laparoscopic inguinal hernia repair aged 5 weeks to 2 years were randomly allocated to either the PEEP or control group. A progressive RM was performed after intubation in all cases. The PEEP group received PEEP of 5 cmH2O until the end of mechanical ventilation, while the control group did not receive any PEEP. Lung ultrasonography was performed to compare the number of atelectatic regions between the two groups after anaesthesia induction, after RM, and at the end of surgery in 12 thoracic regions. RESULTS: Overall, 432 ultrasonographic images were acquired from 36 children. At the end of surgery, the number of atelectatic regions (median [interquartile range]) was significantly lower in the PEEP group compared to the control group (2.0 [1.0-3.0] versus 4.0 [3.0-4.0] out of 12 regions, respectively; p = 0.02). While no difference was observed between the number of atelectatic regions after induction and at the end of surgery in the control group (p = 0.30), a decrease was observed in the PEEP group (3.0 [2.0-4.0] to 2.0 [1.0-3.0], respectively; p = 0.02). CONCLUSION: RM followed by a PEEP of 5 cmH2O can effectively reduce the regions of pulmonary atelectasis at the end of laparoscopic surgery in infants and small children.

Quality of Recovery of Patients Who Underwent Curative Pancreatectomy: Comparison of Total Intravenous Anesthesia Versus Inhalation Anesthesia Using the QOR-40 Questionnaire.

BACKGROUND: There has been increasing attention on the subjective recovery of patients undergoing cancer surgery. Total intravenous anesthesia (TIVA) and inhaled anesthesia with volatile anesthetics (INHA) are safe and common anesthetic techniques. Currently, TIVA and INHA have only been compared for less invasive and less complex surgeries. This prospective randomized trial aimed to compare the quality of recovery between TIVA and INHA in patients undergoing pancreatoduodenectomy (PD) or distal pancreatectomy (DP) using the Quality of Recovery (QOR)-40 questionnaire. METHODS: We enrolled 132 patients who were randomly assigned to either the desflurane (DES) (INHA, balanced anesthesia with DES and remifentanil infusion) or TIVA (effect-site target-controlled infusion of propofol and remifentanil) groups and completed the QOR-40 questionnaire postoperatively. RESULTS: The mean global QOR-40 score on postoperative day 3 was significantly higher in the TIVA group than in the DES group. In the PD group, the total QOR-40 score was significantly higher in the TIVA group than in the DES group. Moreover, the TIVA group had significantly higher scores in the physical comfort and psychological support QOR-40 dimensions than the DES group. CONCLUSION: TIVA provides better quality of recovery scores on POD 3 for patients undergoing curative pancreatectomy. CLINICAL TRIAL REGISTRATION NUMBER: NCT03447691.

Effect of upper respiratory infection on anaesthesia induced atelectasis in paediatric patients.

Upper respiratory tract infection (URI) symptoms are known to increase perioperative respiratory adverse events (PRAEs) in children undergoing general anaesthesia. General anaesthesia per se also induces atelectasis, which may worsen with URIs and yield detrimental outcomes. However, the influence of URI symptoms on anaesthesia-induced atelectasis in children has not been investigated. This study aimed to demonstrate whether current URI symptoms induce aggravation of perioperative atelectasis in children. Overall, 270 children aged 6 months to 6 years undergoing surgery were prospectively recruited. URI severity was scored using a questionnaire and the degree of atelectasis was defined by sonographic findings showing juxtapleural consolidation and B-lines. The correlation between severity of URI and degree of atelectasis was analysed by multiple linear regression. Overall, 256 children were finally analysed. Most children had only one or two mild symptoms of URI, which were not associated with the atelectasis score across the entire cohort. However, PRAE occurrences showed significant correspondence with the URI severity (odds ratio 1.36, 95% confidence interval 1.10-1.67, p = 0.004). In conclusion, mild URI symptoms did not exacerbate anaesthesia-induced atelectasis, though the presence and severity of URI were correlated with PRAEs in children.Trial registration: Clinicaltrials.gov (NCT03355547).

Correlation of Intraoperative End-Tidal Carbon Dioxide Concentration on Postoperative Hospital Stay in Patients Undergoing Pylorus-Preserving Pancreaticoduodenectomy.

BACKGROUND: Hypocapnia has been traditionally advocated during general anesthesia, even though it may induce deleterious physiological effects that result in unfavorable outcomes in patients. This study investigated the association between intraoperative end-tidal carbon dioxide (EtCO2) and length of hospital stay (LOS) in patients who underwent pylorus-preserving pancreaticoduodenectomy (PPPD). METHODS: The medical records of 759 patients from 2006 to 2015 were reviewed. The patients were divided into two groups based on the mean EtCO2 value during general anesthesia: the hypocapnia group (< 35 mmHg) and the normocapnia group (≥ 35 mmHg). The primary outcome was LOS between the groups. Secondary outcomes included the length of intensive care unit (ICU) stay, postoperative 30-day, 1-year, and 2-year mortality, and perioperative factors associated with LOS. RESULTS: A total of 727 patients were finally analyzed. The median LOS of the hypocapnia group was significantly longer than that of the normocapnia group (22 days vs. 18 days, respectively; p < 0.001). Postoperative mortality did not differ between the groups. Cox regression analysis revealed that hypocapnia was an independent risk factor for longer LOS (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.37-1.89; p < 0.001). Age and postoperative pancreatic fistula were also risk factors for a longer LOS. CONCLUSIONS: It was concluded that low levels of intraoperative EtCO2 during general anesthesia were associated with an increased LOS for patients undergoing PPPD.

Comparison of Monotherapy Versus Combination of Intravenous Ibuprofen and Propacetamol (Acetaminophen) for Reduction of Postoperative Opioid Administration in Children Undergoing Laparoscopic Hernia Repair: A Double-Blind Randomized Controlled Trial.

BACKGROUND: Extensive efforts have been made toward reducing postoperative opioid use in children. In this study, we assessed whether propacetamol, or a nonsteroidal anti-inflammatory drug (NSAID), or their combination could effectively reduce opioid use in children after laparoscopic inguinal hernia repair. METHODS: This randomized, double-blind clinical trial included 159 children aged 6 months to 6 years. Children were allocated into 1 of the following 3 groups: group I was treated with 10 mg·kg-1 ibuprofen, group P was treated with 30 mg·kg-1 propacetamol, and group I + P was treated with both drugs in their respective concentrations. If the face-legs-activity-crying-consolability (FLACC) score was ≥4 during the postanesthesia care unit stay, 1.0 µg·kg-1 fentanyl was administered as a rescue analgesic. The number of patients who received rescue fentanyl in the postanesthesia care unit was defined as the primary outcome; this was analyzed using the χ2 test. The secondary outcomes included the FLACC and the parents' postoperative pain measure (PPPM) scores until the 24-hour postoperative period. RESULTS: Among the 144 enrolled patients, 28.6% in group I, 66.7% in group P, and 12.8% in group I + P received rescue fentanyl in the postanesthesia care unit (P < .001). The highest FLACC score was lower in group I + P than in either group I or P (P = .007 and P < .001, respectively). Group I + P presented significantly lower PPPM scores than group P at 4 and 12 hours postoperative (P = .03 and .01, respectively). CONCLUSIONS: The use of ibuprofen plus propacetamol immediately following laparoscopic hernia repair surgery in children resulted in the reduced use of an opioid drug compared with the use of propacetamol alone.

Comparison of Sufentanil- and Fentanyl-based Intravenous Patient-controlled Analgesia on Postoperative Nausea and Vomiting after Laparoscopic Nephrectomy: A Prospective, Double-blind, Randomized-controlled Trial.

Background: The incidence of postoperative nausea and vomiting (PONV) remains high. The effects of sufentanil for PONV is not firmly confirmed. The aim of this study was to compare the effect of sufentanil- and fentanyl-based intravenous patient-controlled analgesia (IV-PCA) on the incidence of PONV after laparoscopic nephrectomy. Methods: Eighty-six patients were randomly allocated to receive either the sufentanil (n =43) or fentanyl (n =43). IV-PCA was prepared using either sufentanil 3 µg/kg or fentanyl 20 µg/kg, ramosetron 0.3 mg, and ketorolac 120 mg. The primary outcome of was the incidence of PONV during 24 h after post anesthesia care unit (PACU) discharge. The secondary outcomes were the modified Rhodes index and patient satisfaction scores at 24 h after PACU discharge, need for rescue antiemetics, pain score, need for additional analgesics, and cumulative consumption of IV-PCA Results: The incidence of PONV was comparable between the sufentanil and fentanyl groups (64.3% vs. 65%, p = 0.946; respectively). The number of patients who required antiemetics (p = 0.946) and the modified Rhodes index at 24 h after post-anesthesia care unit discharge (p = 0.668) were also comparable in both groups. No significant differences were found in the secondary outcomes, including the analgesic profiles and adverse events between the groups. Conclusions: In conclusion, sufentanil- and fentanyl-based IV-PCA showed similar incidence of PONV with comparable analgesic effects after laparoscopic nephrectomy. Based on these results, we suggest that sufentanil and fentanyl may provide comparable effects for IV-PCA after laparoscopic nephrectomy.

Primary orbital tuberculosis on the lower eyelid with cold abscess.

Orbital tuberculosis is a rare form of extrapulmonary tuberculosis, even in endemic areas. It may involve the soft tissue, lacrimal gland, periosteum, or bones of the orbital wall. We present a case of orbital tuberculosis on the lower eyelid. An 18-year-old woman with no underlying disease visited our clinic for evaluation of an oval nodule (1.5× 1.2 cm) on the right lower eyelid. Incision and drainage without biopsy was performed 2 months ago in ophthalmology department, but the periorbital mass had deteriorated, as the patient had erythematous swelling, tenderness, and cervical lymphadenopathy. Visual acuity was normal; there were no signs of proptosis, diplopia, or ophthalmoplegia. Computed tomography revealed a small abscess cavity without bony involvement. We performed an excision and biopsy through a percutaneous incision under local anesthesia. Histological examination revealed a granuloma and was diagnosed as orbital tuberculosis. The patient was additionally treated with anti-tuberculosis therapy for 6 months and recovered without complication or recurrence by 7 months. Orbital tuberculosis occurs in patients with or without associated pulmonary tuberculosis, and should be considered as a differential diagnosis in patients with inflammatory orbital disease and an orbital mass. If recurrence occurs despite adequate initial treatment, we recommend an additional examination and excisional biopsy.

SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions.

SIRT3 (sirtuin 3), a mitochondrial protein deacetylase, maintains respiratory function, but its role in the regulation of innate immune defense is largely unknown. Herein, we show that SIRT3 coordinates mitochondrial function and macroautophagy/autophagy activation to promote anti-mycobacterial responses through PPARA (peroxisome proliferator activated receptor alpha). SIRT3 deficiency enhanced inflammatory responses and mitochondrial dysfunction, leading to defective host defense and pathological inflammation during mycobacterial infection. Antibody-mediated depletion of polymorphonuclear neutrophils significantly increased protection against mycobacterial infection in sirt3-/- mice. In addition, mitochondrial oxidative stress promoted excessive inflammation induced by Mycobacterium tuberculosis infection in sirt3-/- macrophages. Notably, SIRT3 was essential for the enhancement of PPARA, a key regulator of mitochondrial homeostasis and autophagy activation in the context of infection. Importantly, overexpression of either PPARA or TFEB (transcription factor EB) in sirt3-/- macrophages recovered antimicrobial activity through autophagy activation. Furthermore, pharmacological activation of SIRT3 enhanced antibacterial autophagy and functional mitochondrial pools during mycobacterial infection. Finally, the levels of SIRT3 and PPARA were downregulated and inversely correlated with TNF (tumor necrosis factor) levels in peripheral blood mononuclear cells from tuberculosis patients. Collectively, these data demonstrate a previously unappreciated function of SIRT3 in orchestrating mitochondrial and autophagic functions to promote antimycobacterial responses. Abbreviations: Ab: antibody; BCG: M. bovis Bacillus Calmette-Guérin; Baf-A1: bafilomycin A1; BMDMs: bone marrow-derived macrophages; CFU: colony forming unit; CXCL5: C-X-C motif chemokine ligand 5; EGFP: enhanced green fluorescent protein; ERFP: enhanced red fluorescent protein; FOXO3: forkhead box O3; HC: healthy controls; H&E: haematoxylin and eosin; HKL: honokiol; IHC: immunohistochemistry; IL1B: interleukin 1 beta; IL6: interleukin 6; IL12B: interleukin 12B; MDMs: monocyte-derived macrophages; MMP: mitochondrial membrane potential; Mtb: Mycobacterium tuberculosis; PBMC: peripheral blood mononuclear cells; PBS: phosphate buffered saline; PMN: polymorphonuclear neutrophil; PPARA: peroxisome proliferator activated receptor alpha; ROS: reactive oxygen species; SIRT3: sirtuin 3; TB: tuberculosis; TEM: transmission electron microscopy; TFEB: transcription factor EB; TNF: tumor necrosis factor.

GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections.

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain; however, the roles of GABA in antimicrobial host defenses are largely unknown. Here we demonstrate that GABAergic activation enhances antimicrobial responses against intracellular bacterial infection. Intracellular bacterial infection decreases GABA levels in vitro in macrophages and in vivo in sera. Treatment of macrophages with GABA or GABAergic drugs promotes autophagy activation, enhances phagosomal maturation and antimicrobial responses against mycobacterial infection. In macrophages, the GABAergic defense is mediated via macrophage type A GABA receptor (GABAAR), intracellular calcium release, and the GABA type A receptor-associated protein-like 1 (GABARAPL1; an Atg8 homolog). Finally, GABAergic inhibition increases bacterial loads in mice and zebrafish in vivo, suggesting that the GABAergic defense plays an essential function in metazoan host defenses. Our study identified a previously unappreciated role for GABAergic signaling in linking antibacterial autophagy to enhance host innate defense against intracellular bacterial infection.

Lysyl-tRNA synthetase-expressing colon spheroids induce M2 macrophage polarization to promote metastasis.

Lysyl-tRNA synthetase (KRS) functions canonically in cytosolic translational processes. However, KRS is highly expressed in colon cancer, and localizes to distinct cellular compartments upon phosphorylations (i.e., the plasma membranes after T52 phosphorylation and the nucleus after S207 phosphorylation), leading to probably alternative noncanonical functions. It is unknown how other subcellular KRSs crosstalk with environmental cues during cancer progression. Here, we demonstrate that the KRS-dependent metastatic behavior of colon cancer spheroids within 3D gels requires communication between cellular molecules and extracellular soluble factors and neighboring cells. Membranous KRS and nuclear KRS were found to participate in invasive cell dissemination of colon cancer spheroids in 3D gels. Cancer spheroids secreted GAS6 via a KRS-dependent mechanism and caused the M2 polarization of macrophages, which activated the neighboring cells via secretion of FGF2/GROα/M-CSF to promote cancer dissemination under environmental remodeling via fibroblast-mediated laminin production. Analyses of tissues from clinical colon cancer patients and Krs-/+ animal models for cancer metastasis supported the roles of KRS, GAS6, and M2 macrophages in KRS-dependent positive feedback between tumors and environmental factors. Altogether, KRS in colon cancer cells remodels the microenvironment to promote metastasis, which can thus be therapeutically targeted at these bidirectional KRS-dependent communications of cancer spheroids with environmental cues.

ESRRA (estrogen-related receptor α) is a key coordinator of transcriptional and post-translational activation of autophagy to promote innate host defense.

The orphan nuclear receptor ESRRA (estrogen-related receptor α) is a key regulator of energy homeostasis and mitochondrial function. Macroautophagy/autophagy, an intracellular degradation process, is a critical innate effector against intracellular microbes. Here, we demonstrate that ESRRA is required for the activation of autophagy to promote innate antimicrobial defense against mycobacterial infection. AMP-activated protein kinase pathway and SIRT1 (sirtuin 1) activation led to induction of ESRRA, which is essential for autophagosome formation, in bone marrow-derived macrophages. ESRRA enhanced the transcriptional activation of numerous autophagy-related (Atg) genes containing ERR response elements in their promoter regions. Furthermore, ESRRA, operating in a feed-forward loop with SIRT1, was required for autophagy activation through deacetylation of ATG5, BECN1, and ATG7. Importantly, ESRRA deficiency resulted in a decrease of phagosomal maturation and antimicrobial responses against mycobacterial infection. Thus, we identify ESRRA as a critical activator of autophagy via both transcriptional and post-translational control to promote antimicrobial host responses.

Ohmyungsamycins promote antimicrobial responses through autophagy activation via AMP-activated protein kinase pathway.

The induction of host cell autophagy by various autophagy inducers contributes to the antimicrobial host defense against Mycobacterium tuberculosis (Mtb), a major pathogenic strain that causes human tuberculosis. In this study, we present a role for the newly identified cyclic peptides ohmyungsamycins (OMS) A and B in the antimicrobial responses against Mtb infections by activating autophagy in murine bone marrow-derived macrophages (BMDMs). OMS robustly activated autophagy, which was essentially required for the colocalization of LC3 autophagosomes with bacterial phagosomes and antimicrobial responses against Mtb in BMDMs. Using a Drosophila melanogaster-Mycobacterium marinum infection model, we showed that OMS-A-induced autophagy contributed to the increased survival of infected flies and the limitation of bacterial load. We further showed that OMS triggered AMP-activated protein kinase (AMPK) activation, which was required for OMS-mediated phagosome maturation and antimicrobial responses against Mtb. Moreover, treating BMDMs with OMS led to dose-dependent inhibition of macrophage inflammatory responses, which was also dependent on AMPK activation. Collectively, these data show that OMS is a promising candidate for new anti-mycobacterial therapeutics by activating antibacterial autophagy via AMPK-dependent signaling and suppressing excessive inflammation during Mtb infections.

PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism.

The role of peroxisome proliferator-activated receptor α (PPAR-α) in innate host defense is largely unknown. In this study, we show that PPAR-α is essential for antimycobacterial responses via activation of transcription factor EB (TFEB) transcription and inhibition of lipid body formation. PPAR-α deficiency resulted in an increased bacterial load and exaggerated inflammatory responses during mycobacterial infection. PPAR-α agonists promoted autophagy, lysosomal biogenesis, phagosomal maturation, and antimicrobial defense against Mycobacterium tuberculosis or M. bovis bacillus Calmette-Guérin. PPAR-α agonists regulated multiple genes involved in autophagy and lysosomal biogenesis, including Lamp2, Rab7, and Tfeb in bone marrow-derived macrophages. Silencing of TFEB reduced phagosomal maturation and antimicrobial responses, but increased macrophage inflammatory responses during mycobacterial infection. Moreover, PPAR-α activation promoted lipid catabolism and fatty acid ß-oxidation in macrophages during mycobacterial infection. Taken together, our data indicate that PPAR-α mediates antimicrobial responses to mycobacterial infection by inducing TFEB and lipid catabolism.

Effect of poly-L-arginine in inhibiting scrapie prion protein of cultured cells.

Biological effect of poly-L-arginine (PLR), the linear homopolymer comprised of L-arginine, was investigated to determine the activity of suppressing prions. PLR decreased the level of scrapie prion protein (PrPSc) in cultured cells permanently infected with prions in a concentration-dependent manner. The PrPSc inhibition efficacy of PLR was greater than that of another prion-suppressant poly-L-lysine (PLK) in a molecular mass-dependent fashion. The effective concentration of PLR to inhibit prions was achieved safely below the cytotoxic concentrations, and overall cytotoxicity of PLR was similar to that of PLK. PLR did not alter the cellular prion protein (PrPC) level and was unable to change the states of preformed recombinant PrP aggregates and PrPSc from prion-infected cells. These data eliminate the possibility that the action mechanism of PLR is through removal of PrPC and pre-existing PrPSc. However, PLR formed complexes with plasminogen that stimulates prion propagation via conversion of PrPC to the misfolded isoform, PrPSc. The plasminogen-PLR complex demonstrated the greater positive surface charge values than the similar complex with PLK, raising the possibility that PLR interferes with the role of cofactor for PrPSc generation better than PLK.

Ionizing Radiation Induces Innate Immune Responses in Macrophages by Generation of Mitochondrial Reactive Oxygen Species.

During radiotherapy for tumors, the innate immune system also responds to ionizing radiation and induces immune modulation. However, little is known about the molecular mechanisms by which radiation modulates innate immune responses. In this study, we observed that radiation triggered the generation of mitochondrial reactive oxygen species (mROS), leading to innate immune responses in murine bone marrow-derived macrophages (BMDM). Radiation-induced mROS was essential for robust induction of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-12p40 mRNA and protein in BMDM. Exposure to radiation also led to rapid activation of the mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB pathways in BMDM. Notably, radiation-induced MAPK activation and NF-κB signaling were regulated by mROS in macrophages. Additionally, radiation-induced expression of TNF-α, IL-6 and IL-12p40 was dependent on JNK, p38 and NF-κB activation in BMDM. These data suggest a key role for radiation-induced pro-inflammatory responses and activation of the MAPK and NF-κB pathways through a triggering mechanism involving mROS generation.

Mycobacterium abscessus ESX-3 plays an important role in host inflammatory and pathological responses during infection.

Mycobacterial ESX systems are often related to pathogenesis during infection. However, little is known about the function of ESX systems of Mycobacterium abscessus (Mab). This study focuses on the Mab ESX-3 cluster, which contains major genes such as esxH (Rv0288, low molecular weight protein antigen 7; CFP-7) and esxG (Rv0287, ESAT-6 like protein). An esx-3 (MAB 2224c-2234c)-deletional mutant of Mab (Δesx) was constructed and used to infect murine and human macrophages. We then investigated whether Mab Δesx modulated innate host immune responses in macrophages. Mab Δesx infection resulted in less pathological and inflammatory responses. Additionally, Δesx resulted in significantly decreased activation of inflammatory signaling and cytokine production in macrophages compared to WT. Moreover, recombinant EsxG·EsxH (rEsxGH) proteins encoded by the ESX-3 region showed synergistic enhancement of inflammatory cytokine generation in macrophages infected with Δesx. Taken together, our data suggest that Mab ESX-3 plays an important role in inflammatory and pathological responses during Mab infection.