Post Transplantation Bilirubin Nanoparticles Ameliorate Murine Graft Versus Host Disease via a Reduction of Systemic and Local Inflammation.

Allogeneic stem cell transplantation is a curative immunotherapy where patients receive myeloablative chemotherapy and/or radiotherapy, followed by donor stem cell transplantation. Graft versus host disease (GVHD) is a major complication caused by dysregulated donor immune system, thus a novel strategy to modulate donor immunity is needed to mitigate GVHD. Tissue damage by conditioning regimen is thought to initiate the inflammatory milieu that recruits various donor immune cells for cross-priming of donor T cells against alloantigen and eventually promote strong Th1 cytokine storm escalating further tissue damage. Bilirubin nanoparticles (BRNP) are water-soluble conjugated of bilirubin and polyethylene glycol (PEG) with potent anti-inflammatory properties through its ability to scavenge reactive oxygen species generated at the site of inflammation. Here, we evaluated whether BRNP treatment post-transplantation can reduce initial inflammation and subsequently prevent GVHD in a major histocompatibility (MHC) mismatched murine GVHD model. After myeloablative irradiation, BALB/c mice received bone marrow and splenocytes isolated from C57BL/6 mice, with or without BRNP (10 mg/kg) daily on days 0 through 4 post-transplantation, and clinical GVHD and survival was monitored for 90 days. First, BRNP treatment significantly improved clinical GVHD score compared to untreated mice (3.4 vs 0.3, p=0.0003), and this translated into better overall survival (HR 0.0638, p=0.0003). Further, BRNPs showed a preferential accumulation in GVHD target organs leading to a reduced systemic and local inflammation evidenced by lower pathologic GVHD severity as well as circulating inflammatory cytokines such as IFN-γ. Lastly, BRNP treatment post-transplantation facilitated the reconstitution of CD4+ iNK T cells and reduced expansion of proinflammatory CD8α+ iNK T cells and neutrophils especially in GVHD organs. Lastly, BRNP treatment decreased ICOS+ or CTLA-4+ T cells but not PD-1+ T cells suggesting a decreased level of T cell activation but maintaining T cell tolerance. In conclusion, we demonstrated that BRNP treatment post-transplantation ameliorates murine GVHD via diminishing the initial tissue damage and subsequent inflammatory responses from immune subsets.

High-Speed Screening of Lipoprotein Components Using Online Miniaturized Asymmetrical Flow Field-Flow Fractionation and Electrospray Ionization Tandem Mass Spectrometry: Application to Hepatocellular Carcinoma Plasma Samples.

This study introduces a high-speed screening method for the quantitative analysis of lipoprotein components in human plasma samples using online miniaturized asymmetrical flow field-flow fractionation and electrospray ionization-tandem mass spectrometry (mAF4-ESI-MS/MS). Using an mAF4 channel, high-density lipoproteins and low-density lipoproteins can be fractionated by size at a high speed (<10 min) and directly fed to ESI-MS/MS for the simultaneous screening of targeted lipid species and apolipoprotein A1 (ApoA1). By employing the heated electrospray ionization probe as an ionization source, an mAF4 effluent flow rate of up to a few tens of microliters per minute can be used, which is adequate for direct feeding to MS without splitting the outflow, resulting in a consistent feed rate to MS for stable MS detection. mAF4-ESI-MS/MS was applied to hepatocellular carcinoma (HCC) plasma samples for targeted quantification of 25 lipid biomarker candidates and ApoA1 compared with healthy controls, the results of which were in statistical agreement with the quantified results obtained by nanoflow ultrahigh performance liquid chromatography-tandem mass spectrometry. Moreover, the present method provided the simultaneous detection of changes in lipoprotein size and the relative amount. This study demonstrated the potential of mAF4-ESI-MS/MS as an alternative high-speed screening platform for the top-down analysis of targeted lipoprotein components in patients with HCC, which is applicable to other diseases that involve the perturbation of lipoproteins.

The Clinical Significance of Anastomotic Ulcers After Ileocolic Resection to Predict Postoperative Recurrence of Crohn's Disease.

BACKGROUND: The Rutgeerts score is used to predict postoperative recurrence in CD patients after ileocolic resection and is primarily based on endoscopic findings at the neoterminal ileum. However, the optimal assessment of anastomotic ulcers (AUs) remains subject to debate. AIMS: We aimed to investigate the association between anastomotic ulcers (AUs) and endoscopic recurrence in postoperative Crohn's disease (CD) patients. METHODS: This single-center retrospective study, conducted between 2000 and 2016, evaluated postoperative CD patients with endoscopic remission at the first ileocolonoscopy within 1 year after ileocolic resection and those who underwent subsequent ileocolonoscopic follow-up. The study outcome was the clinical significance of AUs in predicting endoscopic recurrence. RESULTS: Among 116 patients who were in endoscopic remission defined as the RS of i0 to i1 at the index postoperative ileocolonoscopy, 84.5% (98/116) underwent subsequent ileocolonoscopies. During the median 30.0 months (interquartile range, 21.3-53.3) of follow-up after the first ileocolonoscopy, 56.1% (55/98) of patients showed endoscopic recurrence. Furthermore, 65.8% (48/73) with AUs and 75.5% (40/53) with major AUs, defined as either an ulcer occupying ≥ 1/4 of the circumference, ≥ 3 ulcers confined to anastomotic ring, or any ulcers extending to the ileocolonic mucosa, showed endoscopic recurrence. On multivariable analysis, AUs (adjusted hazard ratio [aHR], 4.33; 95% confidence interval [CI], 1.87-10.0; P < 0.001) and major AUs (aHR, 3.64; 95% CI, 1.95-79; P < 0.001) were associated with endoscopic recurrence. CONCLUSIONS: AUs are associated with a significantly high risk of endoscopic recurrence in postoperative CD patients who are in endoscopic remission.

Factors Affecting the Incidence of Hospitalized Pneumonia after Influenza Infection in Korea Using the National Health Insurance Research Database, 2014-2018: Focusing on the Effect of Antiviral Therapy in the 2017 Flu Season.

BACKGROUND: This study aimed to investigate the effect of antiviral therapy following influenza outpatient episodes on the incidence of hospitalized pneumonia episodes, one of secondary complications of influenza. METHODS: In the National Health Insurance Research Database, data from July 2013 to June 2018 were used. All of the claim data with diagnoses of influenza and pneumonia were converted to episodes of care after applying 100 days of window period. With the 100-day episodes of care, the characteristics of influenza outpatient episodes and antiviral therapy for influenza, the incidence of hospitalized pneumonia episodes following influenza, and the effect of antiviral therapy for influenza on hospitalized pneumonia episodes were investigated. RESULTS: The crude incidence rate of hospitalized pneumonia after influenza infection was 0.57% in both males and females. Factors affecting hospitalized pneumonia included age, income level except self-employed highest (only in females), municipality, medical institution type, precedent chronic diseases except hepatitis (only in females) and antiviral therapy. In the 2017 flu season, the relative risk was 0.38 (95% confidence interval [CI], 0.29-0.50) in males aged 0-9 and 0.43 (95% CI, 0.32-0.57) in females aged 0-9 without chronic diseases, and it was 0.51 (95% CI, 0.42-0.61) in males aged 0-9 and 0.42 (95% CI, 0.35-0.50) in females aged 0-9 with one or more chronic diseases in the aspect of the effect of antiviral therapy on pneumonia. It suggests that antiviral therapy may decrease the incidence of pneumonia after influenza infection. CONCLUSION: After outpatient episode incidence of influenza, antiviral treatment has been shown to reduce the incidence of hospitalized pneumonia, especially in infants and children, during pandemic season 2017. Antiviral therapy for influenza is recommended to minimize burden caused by influenza virus infection and to reduce pneumonia. In addition, medical costs of hospitalization may decrease by antiviral therapy, especially in infants and children.

Femoral arteriovenous fistula associated with surgery of proximal femoral fracture: a systematic review of the literature and case presentation.

BACKGROUND: Proximal femoral fracture (PFF), such as intertrochanteric femoral fracture or femur neck fracture, and its management are crucial issues to surgeons. PFF has been dramatically is becoming exponentially prevalent, and it is at high risk of complication and mortality because it is frequently associated with serious trauma and advanced age, especially in patients treated with anticoagulants or antiplatelet agents. Surgical management is essential for the treatment of PFF. Unfortunately, current surgical procedures have been related to accompanied by vascular complications, including laceration, hemorrhage, thrombosis, embolism, intimal flap tear and pseudoaneurysm. Furthermore, these vascular injuries following surgical management of PFF are potentially limb- and life-threatening. Of the complications after operation of PFF, femoral arteriovenous fistula (AVF) is rare, but remains a challenging problem because it is frequently associated with significantly high mortality and morbidity and is very difficult to treat. METHODS: A systematic literature review was conducted using the PRISMA guidelines with no language restriction. We searched scientific publications via PubMed, Embase, Cochrane central register of controlled trial, Google Scholar, the KoreaMed and the Research Information Sharing Service database. The goal of this study was to report on the incidence, clinical presentation, diagnosis, treatment, associated complications, morbidity and mortality of femoral AVF caused by PFF and to draw special attention to its prevention and management. RESULTS: A total of 7 case reports on femoral AVF associated with operation of PFF were identified, and one our case was added to the systematic analysis. Of the 8 cases, 4 were male and 4 were female under the age of 67.87±18.44; 6 (75.0%) survived without any events, 1 (12.5%) survived with a sequela of peroneal nerve impairment, and 1 (12.5%) died of multi-organ failure and hypovolemia. CONCLUSIONS: The incidence of femoral AVF associated with PFF is extremely low, though it appears to increase with the rising frequency of PFF. With a very few exceptions, complications following internal fixation are potentially limb- and life-threatening. There is still no definite consensus on the standardized diagnostic or therapeutic modalities. Therefore, surgeons should keep in mind that this serious complication requires early diagnosis and prompt treatment, which should not be underestimated. Femoral AVF following operation of PFF should be meticulously managed, because untreated fistulae result in serious unexpected complications including renin-mediated hypertension, high-output heart failure and venous and/or arterial insufficiency. Surgical treatment is still the gold standard for such cases, but in limited cases endovascular procedures using embolization and closure device can be a good treatment option.

Age-Period-Cohort Analysis of Influenza in Koreans: the National Health Insurance Research Database, 2009-2018.

BACKGROUND: This study aimed to identify the incidence rate of episodes diagnosed with influenza and the effects of age-period-cohort (APC) in Koreans. METHODS: The 2009-2018 National Health Insurance Research Database was used for analysis. All time-related claims connected relatively short window period in 100 days. The case definition was defined by all codes diagnosed with J09, J10, and J11. Calculation of the incidence rate and APC analysis adjusted income levels by insurance type, metropolitan city was performed to identify the characteristics of episodes diagnosed with influenza. RESULTS: Incidence rate by age and cohort gradually increased since 2014. The incidence rate of males aged 0-4 years was 171.02 and that of females was 173.31 in 2015-2016 season. In males, 29.19 in 1963 cohort and 243.79 in 2013 cohort were confirmed as high incidence rates in 2017-2018 season. In the females, a high incidence was confirmed in 1953-1967 cohort and 1978-1987 cohort, and the incidence was 251.38 in 2013-2017 cohort. APC effects showed a high relative risk in the infants, the pandemic influenza season in 2010 (1/7/2009 to 30/6/2010) and the adults of 1978-1987 cohort. CONCLUSION: Since 2014, influenza outbreaks have been increasing every year. The start year of free vaccination decreased the incidence in infants and adults over 65 years of age but the incidence increased from the following year. Because influenza can be primarily prevented by vaccination, reinforcement of vaccination in infants may reduce the disease burden in their parents, and also the risk of infection caused by family transmission. A new vaccination strategy is needed to reduce the incidence and burden of diseases caused by influenza infection.

Tip-in versus conventional endoscopic mucosal resection for flat colorectal neoplasia 10 mm or larger in size.

PURPOSE: A modified endoscopic mucosal resection (EMR) technique, Tip-in EMR, was recently introduced to enhance the complete resection of colorectal neoplasia (CRN). We aimed to evaluate the feasibility of Tip-in EMR for flat CRNs. METHODS: From January to September 2018, conventional or Tip-in EMR was consecutively performed for 112 flat CRNs ≥ 10 mm in diameter. Tip-in EMR was performed when en bloc snaring was impossible with conventional EMR or when a lesion was inadequately lifted owing to a previous forceps biopsy. We retrospectively collected the clinical, procedural, and histologic data of the conventional and Tip-in EMR groups and compared the en bloc resection rate, complete resection rate, and complications between the two groups. RESULTS: Among 112 flat CRNs of 80 patients, conventional EMR and Tip-in EMR were performed for 74 and 38 lesions, respectively. The median lesion size was 12 (10-27) mm. Tip-in EMR was superior to conventional EMR in terms of en bloc resection (94.7% vs. 77.0%, p = 0.018) and histologic complete resection (76.3% vs. 54.1%, p = 0.022). There was no difference in postprocedural bleeding between the two groups; however, overall adverse events, including bleeding and postpolypectomy electrocoagulation syndrome, were more frequent in the Tip-in EMR group. CONCLUSIONS: Tip-in EMR is a feasible technique for flat colorectal lesions ≥ 10 mm and is superior to conventional EMR with respect to en bloc and complete resection rates. The safety profiles of Tip-in EMR and conventional EMR should be compared via large-scale prospective studies.

Drive-Through Screening Center for COVID-19: a Safe and Efficient Screening System against Massive Community Outbreak.

As the coronavirus disease 2019 (COVID-19) outbreak is ongoing, the number of individuals to be tested for COVID-19 is rapidly increasing. For safe and efficient screening for COVID-19, drive-through (DT) screening centers have been designed and implemented in Korea. Herein, we present the overall concept, advantages, and limitations of the COVID-19 DT screening centers. The steps of the DT centers include registration, examination, specimen collection, and instructions. The entire service takes about 10 minutes for one testee without leaving his or her cars. Increased testing capacity over 100 tests per day and prevention of cross-infection between testees in the waiting space are the major advantages, while protection of staff from the outdoor atmosphere is challenging. It could be implemented in other countries to cope with the global COVID-19 outbreak and transformed according to their own situations.

Association of Faecal Calprotectin Level and Combined Endoscopic and Radiological Healing in Patients With Crohn's Disease Receiving Anti-tumour Necrosis Factor Therapy.

BACKGROUND AND AIMS: Combined endoscopic and radiological healing, or deep healing, is associated with favourable outcomes in patients with Crohn's disease; thus, a non-invasive biomarker for predicting deep healing would be invaluable. We evaluated the usefulness of faecal calprotectin for predicting deep healing in patients with Crohn's disease receiving anti-tumour necrosis factor [TNF] therapy. METHODS: We analysed the records of patients with Crohn's disease who received anti-tumour necrosis factor therapy and underwent endoscopic evaluation, radiological evaluation, and faecal calprotectin measurement within a period of 3 months between August 2017 and November 2018. Results of endoscopic and radiological studies were independently reviewed by two gastrointestinal endoscopists and a gastrointestinal radiologist, respectively. Serum C-reactive protein and albumin were also measured. RESULTS: Out of 268 patients analysed, 77 [28.7%] had deep healing, 36 [13.4%] had endoscopic healing only, 36 [13.4%] had radiological healing only, and 119 [44.4%] had neither. The median duration of anti-TNF treatment was 40.0 months. The deep healing group had the lowest median faecal calprotectin level [56.5 mg/kg] among the four groups [p <0.001]. The faecal calprotectin cutoff level of 81.1 mg/kg showed a sensitivity of 0.623 and a specificity of 0.817 in predicting deep healing (area under the receiver operating characteristic curve [AUROC], 0.767; 95% confidence interval, 0.702-0.832). Adding serum C-reactive protein and serum albumin to faecal calprotectin further increased the AUROC to 0.805 [95% confidence interval, 0.752-0.858]. CONCLUSIONS: Faecal calprotectin, when combined with serum C-reactive protein and albumin, showed acceptable performance in predicting deep healing in patients with Crohn's disease.

PEGylated Bilirubin-coated Iron Oxide Nanoparticles as a Biosensor for Magnetic Relaxation Switching-based ROS Detection in Whole Blood.

Rationale: Magnetic relaxation switching (MRSw) induced by target-triggered aggregation or dissociation of superparamagnetic iron oxide nanoparticles (SPIONs) have been utilized for detection of diverse biomarkers. However, an MRSw-based biosensor for reactive oxygen species (ROS) has never been documented. Methods: To this end, we constructed a biosensor for ROS detection based on PEGylated bilirubin (PEG-BR)-coated SPIONs (PEG-BR@SPIONs) that were prepared by simple sonication via ligand exchange. In addition, near infra-red (NIR) fluorescent dye was loaded onto PEG-BR@SPIONs as a secondary option for fluorescence-based ROS detection. Results: PEG-BR@SPIONs showed high colloidal stability under physiological conditions, but upon exposure to the model ROS, NaOCl, in vitro, they aggregated, causing a decrease in signal intensity in T2-weighted MR images. Furthermore, ROS-responsive PEG-BR@SPIONs were taken up by lipopolysaccharide (LPS)-activated macrophages to a much greater extent than ROS-unresponsive control nanoparticles (PEG-DSPE@SPIONs). In a sepsis-mimetic clinical setting, PEG-BR@SPIONs were able to directly detect the concentrations of ROS in whole blood samples through a clear change in T2 MR signals and a 'turn-on' signal of fluorescence. Conclusions: These findings suggest that PEG-BR@SPIONs have the potential as a new type of dual mode (MRSw-based and fluorescence-based) biosensors for ROS detection and could be used to diagnose many diseases associated with ROS overproduction.

Concordance regarding disease type and phenotypic characteristics among patients with familial inflammatory bowel disease.

BACKGROUND AND AIMS: The phenotypic concordance among familial cases of inflammatory bowel disease (IBD) has been rarely reported. Thus, the present study aimed to evaluate the concordance regarding disease type and phenotypic features in a large cohort of Korean patients with IBD. METHODS: A total of 6647 patients with IBD who visited the Asan Medical Center between June 1989 and September 2016 were enrolled in the study. When at least two familial cases existed in our cohort, they were included in the concordance analysis (κ index). The concordance between younger and older members for IBD type [Crohn's disease (CD) and ulcerative colitis (UC)] and phenotypic characteristics such as disease extent and location, disease behavior, the use of medication, and need for surgery were evaluated. RESULTS: A positive family history of IBD was noted in 216 patients with CD (7.0%) and in 238 patients with UC (6.7%). Of all patients, 167 consanguineous pairs in 146 families were identified. The crude concordance rate for IBD type was 82.6% with a κ index of 0.656 [95% confidence interval (CI): 0.545-0.768, good concordance]. There was mild concordance for disease location in CD (κ = 0.256; 95% CI: 0.007-0.505) and for the use of antitumor necrosis factor agents in UC (κ = 0.354; 95% CI: -0.049-0.757). The concordance for IBD type and several phenotypes in first-degree relative pairs was better than that in the entire pairs. CONCLUSIONS: Disease type and phenotypic characteristics of patients with familial IBD may be anticipated.

Comparison of Disease-related Knowledge of Patients With Inflammatory Bowel Disease Between the West and the East Using an Updated Questionnaire (IBD-KNOW).

GOALS: The study aimed to compare the level and characteristics of disease-related knowledge of patients with inflammatory bowel disease (IBD) between the West and the East using an international version of a questionnaire regarding knowledge of inflammatory bowel disease (IBD-KNOW). BACKGROUND: The authors recently developed a new questionnaire regarding IBD-KNOW, which showed excellent test characteristics in Korea. STUDY: The IBD-KNOW questionnaire was administered to 100 patients with IBD from tertiary referral hospitals in the United States and Korea. Scores were calculated and compared between US and Korean patients, and factors associated with high scores were analyzed. RESULTS: A total of 196 (100 US and 96 Korean) patients with IBD completed the questionnaires. Analysis of the baseline characteristics revealed that male sex, smoking status, disease duration, history of IBD-related operations, family history of IBD, and use of corticosteroids or biologics were significantly different between US and Korean patients. The mean IBD-KNOW score was higher in US patients than in Korean patients (14.8 vs. 11.3; P<0.001). Multivariate analyses showed that a high IBD-KNOW score (top 25%) was associated with a positive family history of IBD (odds ratio, 2.90; P=0.025) in US patients with IBD and with the use of biologics (odds ratio, 3.65; P=0.008) in Korean patients with IBD. CONCLUSIONS: The IBD-KNOW questionnaire, an updated assessment tool of IBD-related knowledge, is simple, reliable, and available in various patient populations. IBD-KNOW can be used to identify the factors affecting the level of IBD-related knowledge to improve the quality of care in patients with IBD through a personalized approach.

Genetic Counseling and Surveillance Focused on Lynch Syndrome.

Lynch syndrome is a hereditary cancer syndrome caused by germline mutations in one of several DNA mismatch repair genes. Lynch syndrome leads to an increased lifetime risk of various cancers, particularly colorectal, and endometrial cancers. After identifying patients suspected of having Lynch syndrome by clinical criteria, computational prediction models, and/or universal tumor testing, genetic testing is performed to confirm the diagnosis. Before and after genetic testing, genetic counseling should be provided. Genetic counseling should involve a detailed personal and family history, information on the disorder and genetic tests, discussion of the management and surveillance of the disease, career plan, family plan, and psychosocial support. Surveillance of colorectal cancer and other malignancies is of paramount importance for properly managing Lynch syndrome. This review focuses on important considerations in genetic counseling and the latest insights into the surveillance of individuals and families with Lynch syndrome.

Priming mobilization of hair follicle stem cells triggers permanent loss of regeneration after alkylating chemotherapy.

The maintenance of genetic integrity is critical for stem cells to ensure homeostasis and regeneration. Little is known about how adult stem cells respond to irreversible DNA damage, resulting in loss of regeneration in humans. Here, we establish a permanent regeneration loss model using cycling human hair follicles treated with alkylating agents: busulfan followed by cyclophosphamide. We uncover the underlying mechanisms by which hair follicle stem cells (HFSCs) lose their pool. In contrast to immediate destructive changes in rapidly proliferating hair matrix cells, quiescent HFSCs show unexpected massive proliferation after busulfan and then undergo large-scale apoptosis following cyclophosphamide. HFSC proliferation is activated through PI3K/Akt pathway, and depletion is driven by p53/p38-induced cell death. RNA-seq analysis shows that HFSCs experience mitotic catastrophe with G2/M checkpoint activation. Our findings indicate that priming mobilization causes stem cells to lose their resistance to DNA damage, resulting in permanent loss of regeneration after alkylating chemotherapy.

Effects of glycyrrhizin on lipopolysaccharide-induced acute lung injury in a mouse model.

BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are serious clinical disease entities characterized by inflammatory pulmonary edema, which lead to acute hypoxic respiratory failure through various etiologies. According to the studies to date, ALI/ARDS has been recognized as a form of multiorgan failure related to overactive immune response, and overproduction of proinflammatory cytokines released from activated inflammatory cells are considered to play a key role in the development of ALI. Glycyrrhizin (GL) is an extractive component derived from Glycyrrhiza glabra (licorice), which has recently been reported to have various pharmacological effects like anti-inflammatory, anti-tumor, hepato-protective, and anti-viral activities. Nevertheless, the therapeutic effect of GL in ALI is still unclear. The aim of this study was to investigate therapeutic effects of GL on lipopolysaccharide (LPS)-induced ALI in a mouse model and to elucidate explicable mechanisms involved. METHODS: A total of 36 BALB/c mice (6-week-old, 27.7±1.9-gram body weight) were randomly divided into 3 groups: the control group (normal saline was administered intravenously, n=10), the LPS group (LPS 50 mg/kg was intraperitoneally administered, n=13), and the LPS + GL group (GL was administered intravenously immediately and 12 hours after LPS injection, n=13). Mice were sacrificed after 24 hours, and bronchoalveolar lavage fluid (BALF) was collected for the estimation of protein content, inflammatory cell counts, proinflammatory cytokines, myeloperoxidase (MPO) activity, and expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nuclear factor kappa B (NF-κB). Then, the lungs were excised for molecular target, histopathological, and immunohistochemical examinations. RESULTS: Compared to the LPS group, GL significantly decreased protein content, inflammatory cell counts, tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-6, MPO activity, and expressions of COX-2, iNOS, and NF-κB in the LPS + GL group. GL attenuated migration and infiltration of inflammatory cells, showing a marked decrease in CD 11b-positive cells (26.77%±0.83% vs. 41.77%±0.81% vs. 23.23%±1.92%, P<0.05) as well as CXCR4-/CXCR1-positive cells (CXCR4: 37.23%±1.00% vs. 59.37%±2.37% vs. 47.45%±4.36%; CXCR1: 32.10%±1.56% vs. 47.03%±1.99% vs. 21.70%±6.50%; all P<0.05) in the control, LPS, and LPS + GL groups. Additionally, immunohistochemistry showed that the expression of Toll-like receptor 4 (TLR-4) was inhibited by GL. CONCLUSIONS: The results of this study indicate that GL may have anti-inflammatory and protective effects on LPS-induced ALI in mice. GL inhibited proinflammatory cytokines playing a key role in the initial phase of inflammatory response, which suggests that inhibition of the TLR-4/NF-κB signal pathway would be a possible mechanism underlying the action of GL. Thus, GL can be used as a novel therapeutic strategy for pulmonary inflammation.

Spontaneous lumbar artery rupture and massive retroperitoneal hematoma, successfully treated with arteriographic embolization.

BACKGROUND AND OBJECTIVE: Massive retroperitoneal hematoma caused by lumbar artery rupture is generally associated with trauma or retroperitoneal malignancy. However, despite recent advances in technologies and tools, spontaneous lumbar artery rupture is a very rare disease entity but remains a challenging problem because it is frequently associated with significantly high mortality and morbidity and is very difficult to make a correct diagnosis. METHODS: We evaluated the databases of the PubMed, Embase, Cochrane Central Register of Controlled Trial, Google Scholar, the KoreaMed and the Research Information Sharing Service databases, and a detailed systematic review was performed by searching in PubMed. The initial search was performed on 3 February 2018 and a second search conducted in 29 January 2019. RESULTS: A total of 10 case reports on massive hemoperitoneum caused by spontaneous lumbar artery rupture were identified. Of the 10 case reports involving 14 patients, eight were male and six were female under 62.71 ± 13.93. Of the 14 patients, 9 (64.3%) surviving with transcatheter arterial embolization, three (21.4%) died of multi-organ failure or hypovolemia, and two (14.3%) had no definite records on survival or death. CONCLUSIONS: A massive retroperitoneal hematoma caused by lumbar artery rupture should be considered in patients with late-onset shock accompanied by blunt abdominal/pelvic trauma. Furthermore, early detection and urgent embolization would prevent further complications and eliminate the need for surgical interventions.

UVB-induced depletion of donor-derived dendritic cells prevents allograft rejection of immune-privileged hair follicles in humanized mice.

Dendritic cells (DCs) are key targets for immunity and tolerance induction; they present donor antigens to recipient T cells by donor- and recipient-derived pathways. Donor-derived DCs, which are critical during the acute posttransplant period, can be depleted in graft tissue by forced migration via ultraviolet B light (UVB) irradiation. Here, we investigated the tolerogenic potential of donor-derived DC depletion through in vivo and ex vivo UVB preirradiation (UV) combined with the injection of anti-CD154 antibody (Ab) into recipients in an MHC-mismatched hair follicle (HF) allograft model in humanized mice. Surprisingly, human HF allografts achieved long-term survival with newly growing pigmented hair shafts in both Ab-treated groups (Ab-only and UV plus Ab) and in the UV-only group, whereas the control mice rejected all HF allografts with no hair regrowth. Perifollicular human CD3+ T cell and MHC class II+ cell infiltration was significantly diminished in the presence of UV and/or Ab treatment. HF allografts in the UV-only group showed stable maintenance of the immune privilege in the HF epithelium without evidence of antigen-specific T cell tolerance, which is likely promoted by normal HFs in vivo. This immunomodulatory strategy targeting the donor tissue exhibited novel biological relevance for clinical allogeneic transplantation without generalized immunosuppression.

Nanoparticle-Assisted Transcutaneous Delivery of a Signal Transducer and Activator of Transcription 3-Inhibiting Peptide Ameliorates Psoriasis-like Skin Inflammation.

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in psoriatic skin inflammation and acts as a key player in the pathogenesis and progression of this autoimmune disease. Although numerous inhibitors that intervene in STAT3-associated pathways have been tested, an effective, highly specific inhibitor of STAT3 has yet to be identified. Here, we evaluated the in vitro and in vivo biological activity and therapeutic efficacy of a high-affinity peptide specific for STAT3 (APTstat3) after topical treatment via intradermal and transcutaneous delivery. Using a preclinical model of psoriasis, we show that intradermal injection of APTstat3 tagged with a 9-arginine cell-penetrating peptide (APTstat3-9R) reduced disease progression and modulated psoriasis-related cytokine signaling through inhibition of STAT3 phosphorylation. Furthermore, by complexing APTstat3-9R with specific lipid formulations led to formation of discoidal lipid nanoparticles (DLNPs), we were able to achieve efficient skin penetration of the STAT3-inhibiting peptide after transcutaneous administration, thereby effectively inhibiting psoriatic skin inflammation. Collectively, these findings suggest that DLNP-assisted transcutaneous delivery of a STAT3-inhibiting peptide could be a promising strategy for treating psoriatic skin inflammation without causing adverse systemic events. Moreover, the DLNP system could be used for transdermal delivery of other therapeutic peptides.

Inositol 1,4,5-trisphosphate 3-kinase A overexpressed in mouse forebrain modulates synaptic transmission and mGluR-LTD of CA1 pyramidal neurons.

Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) regulates the level of the inositol polyphosphates, inositol trisphosphate (IP3) and inositol tetrakisphosphate to modulate cellular signaling and intracellular calcium homeostasis in the central nervous system. IP3K-A binds to F-actin in an activity-dependent manner and accumulates in dendritic spines, where it is involved in the regulation of synaptic plasticity. IP3K-A knockout mice exhibit deficits in some forms of hippocampus-dependent learning and synaptic plasticity, such as long-term potentiation in the dentate gyrus synapses of the hippocampus. In the present study, to further elucidate the role of IP3K-A in the brain, we developed a transgenic (Tg) mouse line in which IP3K-A is conditionally overexpressed approximately 3-fold in the excitatory neurons of forebrain regions, including the hippocampus. The Tg mice showed an increase in both presynaptic release probability of evoked responses, along with bigger synaptic vesicle pools, and miniature excitatory postsynaptic current amplitude, although the spine density or the expression levels of the postsynaptic density-related proteins NR2B, synaptotagmin 1, and PSD-95 were not affected. Hippocampal-dependent learning and memory tasks, including novel object recognition and radial arm maze tasks, were partially impaired in Tg mice. Furthermore, (R,S)-3,5-dihydroxyphenylglycine-induced metabotropic glutamate receptor long-term depression was inhibited in Tg mice and this inhibition was dependent on protein kinase C but not on the IP3 receptor. Long-term potentiation and depression dependent on N-methyl-d-aspartate receptor were marginally affected in Tg mice. In summary, this study shows that overexpressed IP3K-A plays a role in some forms of hippocampus-dependent learning and memory tasks as well as in synaptic transmission and plasticity by regulating both presynaptic and postsynaptic functions.

Aqueous Red-Emissive Probe for the Selective Fluorescent Detection of Cysteine by Deprotection/Cyclization Cascade Resulting in Large Stokes' Shift.

Cysteine plays a crucial role in cellular functions and in human pathologies. However, the development of cysteine probes with extremely accurate detection is still a key challenge for the field. Herein, we have fully characterized and developed a novel selective fluorescent probe: red emission, aqueous detection and large Stokes' shift for cysteine (Reals-C). Key in the probe synthesis is a Michael addition onto an acroylate group and subsequent intramolecular cyclization. The probe exhibits analyte detection via an intricate role set up by the leaving groups so to discriminate and form the red-emissive analyte sensing platform (λex =471 nm, λem =637 nm) through a chemical cascade pathway. Furthermore, the sensing ability of the probe was demonstrated by both in vitro and in vivo assays. This probe enables for successfully endogenous cysteine sensing in HaCaT human keratinocytes through comparison with a commercial thiol-sensitive probe; Reals-C shows excellent in vivo cysteine detection in a drug-induced animal liver injury model.