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The homeostatic balance between effector T cells and regulatory T cells (Tregs) is crucial for adaptive immunity; however, epigenetic programs that inhibit phosphorylation to regulate Treg development, peripheral expression, and suppressive activity are elusive. Here, we found that the Ssu72 phosphatase is activated by various T-cell receptor signaling pathways, including the T-cell receptor and IL-2R pathways, and localizes at the cell membrane. Deletion of Ssu72 in T cells disrupts CD4(+) T-cell differentiation into Tregs in the periphery via the production of high levels of the effector cytokines IL-2 and IFNγ, which induce CD4(+) T-cell activation and differentiation into effector cell lineages. We also found a close correlation between downregulation of Ssu72 and severe defects in mucosal tolerance in patients. Interestingly, Ssu72 forms a complex with PLCγ1, which is an essential effector molecule for T-cell receptor signaling as well as Treg development and function. Ssu72 deficiency impairs PLCγ1 downstream signaling and results in failure of Foxp3 induction. Thus, our studies show that the Ssu72-mediated cytokine response coordinates the differentiation and function of Treg cells in the periphery.

Background: The thoracic paravertebral block is an effective analgesic technique for postoperative pain management after breast surgery. The ultrasound-guided retrolaminar block (RLB) is a safer alternative to conventional paravertebral block. Thus, we assessed the analgesic efficacy of ultrasound-guided RLB for postoperative pain management after breast surgery. Methods: Patients requiring breast surgery were randomly allocated to group C (retrolaminar injection with saline) and group R (RLB with local anesthetic mixture). The RLB was performed at the level of T3 with local anesthetic mixture (0.75% ropivacaine 20 mL + 2% lidocaine 10 mL) under general anesthesia before the skin incision. The primary outcome was cumulative morphine consumption using intravenous patient-controlled analgesia (IV-PCA) at 24 hour postoperatively. The secondary outcomes were the visual analogue scale (VAS) scores at 1, 6, 24, and 48 hour postoperatively and the occurrence of adverse events and patient satisfaction after the surgery. Results: Forty-six patients were included, 24 in group C and 22 in group R. The cumulative morphine consumption using IV-PCA did not differ between the two groups (P = 0.631). The intraoperative use of remifentanil was higher in group C than in group R (P = 0.025). The resting and coughing VAS scores at 1 hour postoperatively were higher in group R than in group C (P = 0.011, P = 0.004). The incidence of adverse events and patient satisfaction was not significantly different between the two groups. Conclusions: A single injection of ultrasound-guided RLB did not reduce postoperative analgesic requirements following breast surgery.

Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, ranges from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is a more aggressive form characterized by hepatocyte injury, inflammation, and fibrosis. Increasing evidence suggests that NASH is a risk factor for hepatocellular carcinoma (HCC), which is the fifth most common cancer worldwide and the second most common cause of cancer-related death. Recent studies support a strong mechanistic link between the NASH microenvironment and HCC development. The liver has a large capacity to remove circulating pathogens and gut-derived microbial compounds. Thus, the liver is a central player in immunoregulation. Altered immune responses are tightly associated with the development of NASH and HCC. The objective of this study was to differentiate the roles of specific immune cell subsets in NASH and HCC pathogenesis., Liver disease: Immune cells in disease progression Clarifying the role of specific cells in the immune system in the transition from non-alcoholic fatty liver disease (NAFLD) to liver cancer will help to understand disease progression and may open avenues towards new preventive and therapeutic strategies. NAFLD is the most common chronic liver disease. Growing evidence suggests that its most aggressive form, non-alcoholic steatohepatitis (NASH), can promote the development of liver cancer, the second most common cause of cancer deaths worldwide. Chang-Woo Lee and colleagues at Sungkyunkwan University, Suwon, South Korea review the immunological distinction between NASH and liver cancer, focusing on the levels and activities of six key types of immune system cells. Chronic inflammation mediated by the immune system can create conditions for NAFLD, NASH and liver cancer to develop and worsen.

Background/Aims: Low-level viremia (LLV) after nucleos(t)ide analog treatment was presented as a possible cause of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). However, detailed information on patients’ adherence in the real world was lacking. This study aimed to evaluate the effects of LLV on HCC development, mortality, and cirrhotic complications among patients according to their adherence to entecavir (ETV) treatment.Methods: We performed a retrospective observational analysis of data from 894 consecutive adult patients with treatment-naïve CHB undergoing ETV treatment. LLV was defined according to either persistent or intermittent episodes of P=0.031). Good adherence group comprised 617 patients (69.0%). No significant difference was found between maintained virologic response and LLV groups in terms of the incidence of liver-related death or transplantation, HCC, and hepatic decompensation in good adherence group, according to multivariate analyses.Conclusions: In patients with treatment-naïve CHB and good adherence to ETV treatment in the real world, LLV during treatment is not a predictive factor for HCC and cirrhotic complications. It may be unnecessary to adjust their antiviral agent for patients with good adherence who experience LLV during ETV treatment.

Adherence to medication and maintained virologic response (MVR) are related to the risk of adverse clinical outcomes. This study aimed to compare the efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) in relation to the adverse clinical outcomes among chronic hepatitis B (CHB) patients stratified according to adherence to medication and MVR. A total of 1794 treatment-naive CHB patients treated with ETV (n = 894) or TDF (n = 900) for > 1 year were identified. Adherence rates were significantly higher in the TDF than in the ETV (93.4% vs. 89.1%, respectively; P

Objectives: The purpose of this study was to compare the effects of combined epidural-general anesthesia with those of general anesthesia alone on hemodynamic instability (intraoperative hypotension and hypertensive crisis) during pheochromocytoma and sympathetic paraganglioma surgery. Methods: A total of 119 patients' medical records were reviewed who were diagnosed as having pheochromocytoma and sympathetic paraganglioma on the basis of histological findings. Intraoperative hypotension was defined as a mean blood pressure < 60 mmHg or a decrease > 30% in baseline systolic blood pressure after adrenal vein ligation. Hypertensive crisis was defined as a systolic blood pressure > 200 mmHg or an increase > 30% in baseline systolic blood pressure during the operation. The predictor variables for intraoperative hypotension and hypertensive crisis were analyzed with logistic regression models. Data were presented as adjusted odds ratio with 95% confidence interval. Results: The independent predictors of intraoperative hypotension were an increased attenuation number on unenhanced computed tomography (1.112 [1.009-1.226], p = 0.033), a high baseline mean blood pressure (1.063 [1.012-1.117], p = 0.015), and the combined epidural-general anesthesia (5.439 [1.410-20.977], p = 0.014). In contrast, an increased attenuation number on unenhanced computed tomography was the only independent predictor of hypertensive crisis (1.087 [1.021-1.158], p = 0.009). Conclusions: The combined epidural-general anesthesia was not effective in attenuating hypertensive responses, but could have exacerbated intraoperative hypotension. These findings should be taken into account before selecting the anesthetic technique in pheochromocytoma and sympathetic paraganglioma surgery.

Background Danggwijagyaksan (DJS) has been one of the most widely used herbal medicines for gynecological disorders in traditional East Asian medicine. Several clinical studies about DJS have shown improvement in menopausal symptoms. This pilot study aimed to evaluate the efficacy, safety and feasibility of DJS for treating climacteric syndrome with a blood-deficiency-dominant pattern. Methods This was a randomized, double-blind, placebo-controlled pilot trial. A group of 45-to 60-year-old women with climacteric syndrome were registered for the trial. The participants received treatment over a 4-week period and were then followed for 4 weeks. The primary outcome measure was the mean change in the Menopause Rating Scale (MRS). Secondary outcome measures included the World Health Organization Quality of Life-BREF (WHOQOL-BREF), the Blood-Deficiency Scoring System (BDSS), lean body mass, and serum hormone levels, including follicle-stimulating hormone (FSH) and estradiol (E2) levels. Results The MRS and BDSS scores decreased significantly in both groups, but the differences between two groups were not significant. The WHOQOL-BREF scores increased in the control group. No statistically meaningful differences in serum hormone levels or lean body mass were observed in both groups. There were no serious adverse events, and the laboratory tests were within the normal range. The recruitment rate, completion rate and medication adherence rate were over 90% in both groups, indicating high feasibility. Conclusions DJS showed clinical effectiveness in the treatment of climacteric syndrome with a blood-deficiency-dominant pattern. Additionally, DJS was shown to be safe and feasible for a large-scale study to confirm the efficacy of the treatment. Trial registration: Clinical Research Information Service (CRIS, https://cris.nih.go.kr ): KCT0002387.

Background : The objective of this study was to compare the impact of citrate dialysate (CD) and standard acetate dialysate (AD) in hemodialysis by central delivery system (CDS) on heparin demand, and clinical parameters. Methods : We retrospectively evaluated 75 patients on maintenance hemodialysis with CDS. Patients underwent hemodialysis with AD over a six-month period (AD period), followed by another six-month period using CD (CD period). Various parameters including mean heparin dosage, high sensitivity C-reactive protein (hsCRP), calcium-phosphate product (CaxP), intact parathyroid hormone (iPTH), and urea reduction ratio (URR) were collated at the end of each period. Results : Patients were 60.5 ± 14.7 years old, of whom 62.7% were male. Patients required less heparin when receiving CD (AD period: 1,129 ± 1,033 IU/session vs. CD period: 787 ± 755 IU/session, P < 0.001). After the CD period (ΔCD), pre-dialysis total CO2 increased to 1.21 ± 2.80 mmol/L, compared to −2.44 ± 2.96 mmol/L (P < 0.001) after the AD period (ΔAD). After the CD period, concentrations of iPTH (ΔAD: 73.04 ± 216.34 pg/mL vs. ΔCD: −106.66 ± 251.79 pg/mL, P < 0.001) and CaxP (ΔAD: 4.32 ± 16.63 mg2/dL2 vs. ΔCD: −4.67 ± 15.27 mg2/dL2, P = 0.015) decreased. While hsCRP levels decreased after the CD period (ΔAD: 0.07 ± 4.09 mg/L vs. ΔCD: −0.75 ± 4.56 mg/L, P = 0.705), the change was statistically insignificant. URR remained above clinical guideline of 65% after both periods (ΔAD: 72.33 ± 6.92% vs. ΔCD period: 69.20 ± 4.49%, P = 0.046). Conclusion : Our study confirmed that the use of CD in CDS required lower heparin doses compared to the use of AD. The use of CD also provided a more stable acid-base status.

The objectives of this study were: 1) to determine biofilm formation abilities of 11 emetic toxin producing Bacillus cereus strains along with two reference strains ATCC 14579 and KCTC 13153 on stainless steel and plastic coupons; 2) to examine the correlation between biofilm formation ability and genotypic and phenotypic characteristics of four selected strains. Crystal violet assay results indicated that the biofilm formation behavior was highly variable depending on strain and surface. Cell enumeration and scanning electron microscopy (SEM) analysis showed complex cell clusters with extracellular polymeric substances (EPS) for high biofilm forming strains and single layer of cell clusters with few EPS for low biofilm forming strains. Phenotypic characteristics of planktonically grown cells such as hydrophobicity were positively correlated with biofilm formation behavior. However, antibiotic susceptibility of B. cereus strains was not correlated with biofilm formation, although resistance to benzalkonium chloride showed a clear correlation with biofilm formation ability. Expression levels of two genes spo0A and abrB involved in the regulation of cell differentiation and mobility of B. cereus were positively correlated with biofilm formation. Results of this study indicate that multiple factors are involved in biofilm formation by emetic toxin producing B. cereus.

Endoplasmic reticulum stress has been considered a major cause of pancreatic β-cell dysfunction and apoptosis leading to diabetes. Glucagon-like peptide-1 receptor activation and chemical chaperones have been known to reduce endoplasmic reticulum stress and improve β-cell function and survival. The purpose of this study was to prepare and evaluate the chemical chaperone tauroursodeoxycholic acid-conjugated exendin-4 as a protective agent for pancreatic β-cells. Mono-tauroursodeoxycholic acid-Lys27-exendin-4 conjugate (TUM1-Ex4) showed better receptor binding affinity than other conjugates with strong in vitro insulinotropic activity in rat pancreatic β-cells and in vivo hypoglycemic activity in type 2 diabetic db/db mice. In INS-1 cells under endoplasmic reticulum stress induced by thapsigargin, TUM1-Ex4 promoted cell survival in a dose-dependent manner. In western blot analysis, TUM1-Ex4 reduced the expression of the endoplasmic reticulum stress marker GRP78 and phosphorylation of the translation initiation factor eIF2α. These results reveal that TUM1-Ex4 accelerates translational recovery and contributes to β-cell protection and survival. The present study indicates that the chemical chaperone-coupled glucagon-like peptide-1 receptor agonist is a feasible therapeutic strategy to enhance β-cell function and survival.

Background Atherogenic lipoprotein profile of plasma is an important risk factor for atherosclerosis. The atherogenic index of plasma (AIP) has been suggested as a novel marker for atherosclerosis. Hypothesis AIP is a useful marker of advanced subclinical coronary artery disease (CAD) in subjects without overt renal dysfunction. Methods A total of 6928 subjects with estimated glomerular filtration rate > 60 mL/minutes/1.73 m2 evaluated by coronary computed tomography angiography (CCTA) for health check‐up were included. The relation of AIP to advanced CAD (heavy coronary calcification, defined as coronary artery calcium score [CACS] >100 or obstructive coronary plaque [OCP], defined as plaque with >50% stenosis) was evaluated. Results All participants were stratified into four groups based on AIP quartiles. The prevalence of CACS >100 (group I [lowest] 4.7% vs group II 7.0% vs group III 8.8% vs group IV 10.0%) and OCP (group I 3.7% vs group II 6.4% vs group III 8.8% vs group IV 10.9%) (all P 100 (odds ratio [OR] 1.057, 95% confidence interval (CI) 1.010 to 1.106, P = .017; relative risk (RR) 1.048, 95% CI 1.009‐1.089, and P = .015) and OCP (OR 1.079, 95% CI 1.033‐1.127, P = .001; RR 1.069, 95% CI 1.031‐1.108, P 60 years, male sex, hypertension, diabetes mellitus, dyslipidaemia, obesity, and proteinuria. Conclusion AIP is independently associated with advanced subclinical CAD beyond traditional risk factors.

Bronchoscopy has a lower diagnostic yield for peripheral lung lesions (PLL). Endobronchial ultrasound guide sheath transbronchial lung biopsy (EBUS GS TBLB) has been used to overcome such limitation. Recent studies revealed that combined methods (e.g., EBUS GS TBLB plus electromagnetic navigation [EMN] or virtual bronchoscopic navigation [VBN]) further improve the diagnostic yield. However, those systems are associated with a high cost burden. Accordingly, we attempted to use VBN by computed tomography (CT) workstation (Aquarius iNtuition, TeraRecon) not dedicated only for VBN as an adjunctive tool for EBUS GS TBLB. We performed a prospective registry study to investigate whether VBN by CT workstation could improve the diagnostic yield of PLL. Between February 2017 and February 2018, 128 patients with PLL were divided into 2 groups (VBN and non-VBN [NVBN]). In NVBN group (n = 64), EBUS GS TBLB was performed using a hand-drawn bronchial map based on CT images. VBN group (n = 64) underwent EBUS GS TBLB using VBN images. VBN using CT workstation did not improve the diagnostic yield of EBUS GS TBLB for PLL (VBN vs NVBN, 72% vs 80%, P = .284). VBN slightly reduced procedure time (minute [mean ± SD], 25.31 ± 10.33 vs 25.81 ± 9.22), navigation time (time to find the lesion) (9.10 ± 7.88 vs 9.50 ± 7.14), and fluoroscopy time (2.23 ± 2.39 vs 2.86 ± 4.61), while these differences were not statistically significant. The diagnostic yield of EBUS GS TBLB was not improved with VBN (compared with using a hand-drawn bronchial map). Although VBN slightly shortened the procedure-related times, which were not significantly different.

Background Homocysteine has been known as a risk factor for cardiovascular disease. This study sought to evaluate the influence of homocysteine on the risk of subclinical coronary atherosclerosis in asymptomatic individuals. Methods We reviewed 3,186 asymptomatic individuals (mean age 53.8 ± 8.0 years, 2,202 men [69.1%]) with no prior history of coronary artery disease who voluntarily underwent coronary computed tomographic angiography (CCTA) and laboratory tests as part of a general health examination. The subjects were stratified into tertiles according to their homocysteine levels. The degree and extent of subclinical coronary atherosclerosis were assessed by CCTA. Logistic regression analysis was used to determine the association between homocysteine levels and subclinical coronary atherosclerosis. Results The prevalence of significant coronary artery stenosis, any atherosclerotic, calcified, mixed, and non-calcified plaques increased with homocysteine tertiles (all p < 0.05). However, after adjustment for cardiovascular risk factors, there were no statistically significant differences in the adjusted odds ratios (ORs) for any atherosclerotic plaque (OR 1.06; 95% CI [confidence interval] 0.85–1.32; p = 0.610), calcified plaques (OR 1.17; 95% CI 0.92–1.48; p = 0.199), non-calcified plaques (OR 0.80; 95% CI 0.61–1.04; p = 0.089), and mixed plaques (OR 1.42; 95% CI 0.96–2.11; p = 0.077) between the third and first homocysteine tertiles. In addition, the adjusted OR for significant coronary artery stenosis (OR 0.92; 95% CI 0.63–1.36; p = 0.687) did not differ between the first and third tertiles. Conclusions In asymptomatic individuals, homocysteine is not associated with an increased risk of subclinical coronary atherosclerosis.

The aim of this study was to evaluate whether the amount of fracture displacement affects postoperative stability of isolated zygomaticomaxillary complex fractures and to determine whether the 1-point fixation method is as stable as 2- or 3-point fixation methods. The authors investigated 14 patients with 1-point fixation in the zygomaticomaxillary area (group A), 14 patients with 2-point fixation in the zygomaticomaxillary and frontozygomatic area (group B), and 13 patients with 3-point fixation in the zygomaticomaxillary, frontozygomatic, and infraorbital rim area (group C). Stability of the reduced zygomaticomaxillary complex was assessed by comparing immediate postoperative cone beam computed tomography images with those obtained at least 3 months later. Preoperatively, the total mean displacement was 3.79 ± 1.36 mm in group A, 3.43 ± 0.89 mm in group B, and 3.86 ± 1.57 mm in group C. The total postoperative orbital and screw changes were 0.91 ± 0.18 and 0.72 ± 0.08 mm, respectively, in group A; 0.92 ± 0.19 and 0.68 ± 0.09 mm, respectively, in group B; and 0.91 ± 0.11 and 0.66 ± 0.10 mm, respectively, in group C. There were no significant relationships between postoperative stability and amount of fracture displacement in any of the 3 groups, or between the 3 groups (P > 0.05). There was little difference in postoperative stability between the 3 groups. Hence, the amount of displacement is not a very important consideration when deciding the fixation method, including the number and location of miniplates applied for fixation.

Objectives The aim of this study was to evaluate the impact of CSC on insensitivity to radiotherapy in HNSCC. Methods A radioresistant cell line, FaDu-R, was established using fractionated ionizing radiation. Cells with high and low CD44/ALDH activity were isolated. Results FaDu-R cells demonstrated significantly increased cell viability after radiation exposure compared with parental cells. CD44 high /ALDH high FaDu-R cells demonstrated significantly faster wound closure (p high /ALDH high FaDu cells or the CD44 low /ALDH low FaDu-R cells. There was a significant difference in tumor volume between the CD44 high /ALDH high FaDu-R cells and the CD44 high /ALDH high FaDu cells (p low /ALDH low FaDu-R cells (p Conclusion Cancer stem cells (CSC) were associated with invasion and tumorigenesis in a radioresistant head and neck squamous cell carcinoma (HNSCC) cell line. This concept might help to improve the understanding of these mechanisms and to develop drugs that can overcome radioresistance during radiotherapy.

Congenital muscular torticollis (CMT) is known to concur with some conditions such as developmental dysplasia of the hip or brachial plexus injury, which gives us some insights for pathogenesis of CMT. Although clavicular fracture is the most common fracture in newborns, little is known about concurrence of CMT and clavicular fracture. Our clinical experience led us to realize that concurrence of CMT and clavicular fracture tended to occur on the contralateral side for each other rather than the ipsilateral side. This study aimed to verify contralateral concurrence of CMT and clavicular fracture. This is a retrospective cohort study in a tertiary hospital, including 996 subjects with CMT. Concurrent clavicular fracture was found in 20 of 996 subjects with CMT, with the concurrence rate being 2.01%. Concurrent clavicular fracture and clavicular fracture occurred on the contralateral side for each other in 18 subjects (90%) rather than the ipsilateral side. This contralateral concurrence between side of CMT and clavicular fracture was significant (P = 0.001), with an odds ratio of 81 (P = 0.0032). Concurrent clavicular fracture and clavicular fracture seem to occur significantly more on the contralateral side for each other. Underlying mechanism for consistent contralateral concurrence needs to be verified in the near future.

Objective This study aimed to investigate the factors affecting the geographic differences in antibiotic prescription rates in pediatric upper respiratory tract infections (URI) patients in South Korea. Materials and methods We performed a nationwide cross-sectional study using 228 administrative districts of Korea, which are the unit of analysis. Prescription rate of antibiotics, the outcome variable, was measured as the proportion of antibiotic prescription days out of total visit days for the treatment of acute URIs using National Health Insurance Service (NHIS) claims data for 2012. Multivariate regression analysis was performed to identify factors affecting geographic variation in antibiotic prescription rates. Results The socioeconomic status of the district, as measured by the amount of local property tax payable and the proportion of individuals with higher level of education, were negatively correlated with prescription rate. The degree of competition in the hospital market within a district was positively associated with it. Patients living in areas with better access to family medicine physicians and those living in rural areas were less likely to use antibiotics to treat URIs. Conclusion Our findings indicate the importance of considering demand factors as well as supply factors when developing intervention strategies for antibiotic overuse. .

Background This study aims to explore the safety, efficacy, and feasibility of Danggwijagyaksan (DJS) for alleviating climacteric syndrome in peri- and postmenopausal women with a blood-deficiency dominant pattern. Methods/design This is a randomized, double-blind, placebo-controlled pilot clinical trial. A total of 34 women with climacteric syndrome who have signed informed consent forms will be registered in this study. Placebo or DJS will be randomly assigned to the participants in an equal proportion. The participants will visit the clinical trial center every 2 weeks and receive placebo or DJS granules. The treatment period is 4 weeks and the administration frequency is three times daily. Data will be collected from the participants at baseline, at week 5, and at week 9 after random allocation. The primary outcome measure will be the mean change in the Menopause Rating Scale from baseline to week 5. Secondary outcome measures will include the World Health Organization Quality of Life-BREF (WHOQOL-BREF) score, the Blood Deficiency Scoring System score, lean body mass, and blood tests, including serum follicle-stimulating hormone and estradiol concentration. To assess the safety of DJS, a laboratory test will be conducted before and after treatment and the participants will be asked about any occurrence of adverse events every visit. The recruitment rate, completion rate, and medication adherence will also be calculated, to assess feasibility. Discussion The findings of this study will provide the basis for a full-scale randomized controlled trial to confirm the safety and efficacy of DJS for the treatment of climacteric syndrome in peri- and postmenopausal women. Trial registration Clinical Research Information Service (CRIS), Republic of Korea, KCT0002387. Registered on 25 July 2017. Electronic supplementary material The online version of this article (doi:10.1186/s13063-018-2443-8) contains supplementary material, which is available to authorized users.

The aim of this study was to develop mechanical homogenization processes to fabricate protein-based nanoparticles. The high-pressure homogenizer (HPH) and high-speed homogenizer (HSH); were used to encapsulate the hydrophobic drug, tamoxifen, in albumin nanoparticles. The results revealed that the rotational speed with HSH and the pressure with HPH were the main factors affecting the size, while increasing the residence time led to more homogenous nanoparticles. Seven homogenization cycles at 14917 psi and 8.24 min of mixing at 17360 rpm ensured a drug loading of 14.2 ± 1.9% and 11.6 ± 2.3% for HPH and HSH, respectively. We found a direct correlation between the obtained size and energy input and retention time with both homogenizing devices. The characteristics of the optimized nanoparticles were within the desired range to meet the requirements of intravenous injection. The surface morphology of the nanoparticles determined by transmission electron microscopy showed semi-spherical nanoparticle shapes. Further, the secondary structure of albumin in nanoparticles was determined via circular dichroism, which showed only slight structural changes versus native albumin, making it a promising, self-targeted drug delivery system. Finally, BT474 viability assays and western blot analysis showed the effectiveness of the tamoxifen-loaded albumin nanoparticles prepared via homogenization.

Sanguiin H-6 is a dimer of casuarictin linked by a bond between the gallic acid residue and one of the hexahydroxydiphenic acid units. It is an effective compound extracted from Rubus coreanus. It has an anticancer effect against several human cancer cells; however, its effect on breast cancer cells has not been clearly demonstrated. Thus, we aimed to investigate the anticancer effect and mechanism of action of sanguiin H-6 against two human breast carcinoma cell lines (MCF-7 and MDA-MB-231). We found that sanguiin H-6 significantly reduced cell viability in a concentration-dependent manner. It also increased the rates at which MCF-7 and MDA-MB-231 cells underwent apoptosis. Furthermore, sanguiin H-6 induced the cleavage of caspase-8, caspase-3, and poly(ADP-ribose) polymerase, which resulted in apoptosis. However, cleavage of caspase-9 was only detectable in MCF-7 cells. In addition, sanguiin H-6 increased the ratio of Bax to Bcl-2 in both MCF-7 and MDA-MB-231 cells. These findings suggest that sanguiin H-6 is a potent therapeutic agent against breast cancer cells. In addition, it exerts its anticancer effect in an estrogen-receptor-independent manner.

Background Atherosclerotic cardiovascular (CV) events commonly occur in individuals with a low CV risk burden. This study evaluated the ability of the triglyceride glucose (TyG) index to predict subclinical coronary artery disease (CAD) in asymptomatic subjects without traditional CV risk factors (CVRFs). Methods This retrospective, cross-sectional, and observational study evaluated the association of TyG index with CAD in 1250 (52.8 ± 6.5 years, 46.9% male) asymptomatic individuals without traditional CVRFs (defined as systolic/diastolic blood pressure ≥ 140/90 mmHg; fasting glucose ≥126 mg/dL; total cholesterol ≥240 mg/dL; low-density lipoprotein cholesterol ≥160 mg/dL; high-density lipoprotein cholesterol 2; current smoking; and previous medical history of hypertension, diabetes, or dyslipidemia). CAD was defined as the presence of any coronary plaque on coronary computed tomographic angiography. The participants were divided into three groups based on TyG index tertiles. Results The prevalence of CAD increased with elevating TyG index tertiles (group I: 14.8% vs. group II: 19.3% vs. group III: 27.6%; P P P Conclusions TyG index is an independent marker for predicting subclinical CAD in individuals conventionally considered healthy.

BACKGROUND Permanent jobs are in decline world-wide, and are being replaced with temporary, casual, part-time, and contract jobs. We investigated the characteristics and occupational safety and health (OSH) vulnerabilities of workers with nonstandard and standard employment. METHODS We used the Korean Working Conditions Survey of 2017 to compare working conditions and OSH vulnerabilities of workers with standard and nonstandard employment in five major job categories. RESULTS Workers with nonstandard employment were older, less educated, had lower monthly incomes, were employed in smaller businesses, worked fewer hours per week, had shorter work durations, and were more likely to report exposure to physical/chemical and ergonomic hazards, and musculoskeletal and mental symptoms. Among nonstandard workers, the rates of occupational hazards and work-related health problems depended on the type of work performed. In particular, nonstandard male workers who were unskilled manual workers, older, had less education, and earned low wages had a greater risk of working in unstable occupations, greater exposures to occupational hazards, and more musculoskeletal pain (back pain: odds ratio [OR], 2.4; upper extremity pain: OR, 2.1; and lower extremity pain: OR, 1.7) than those performing other types of work. CONCLUSION Male unskilled manual workers with nonstandard employment were most vulnerable to OSH problems. Our findings suggest the need for OSH programs that specifically target nonstandard workers especially those in manual unskilled occupations.

Rapid change and zoonotic transmission to humans have enhanced the virulence of the influenza A virus (IAV). Neutralizing antibodies fail to provide lasting protection from seasonal epidemics. Furthermore, the effectiveness of anti-influenza neuraminidase inhibitors has declined because of drug resistance. Drugs that can block viral attachment and cell entry independent of antigenic evolution or drug resistance might address these problems. We show that multivalent 6'-sialyllactose-polyamidoamine (6SL-PAMAM) conjugates, when designed to have well-defined ligand valencies and spacings, can effectively inhibit IAV infection. Generation 4 (G4) 6SL-PAMAM conjugates with a spacing of around 3 nm between 6SL ligands (S3-G4) showed the strongest binding to a hemagglutinin trimer (dissociation constant of 1.6 × 10

The paired immunoglobulin-like type 2 receptor (PILR) family consists of two functionally opposite members, inhibitory PILRα and activating PILRβ receptors. PILRs are widely expressed in various immune cells and interact with their ligands, especially CD99 expressed on activated T cells, to participate in immune responses. Here we investigated whether PILR-derived agonists inhibit β1 integrin activity as ligands for CD99. PILR-derived peptides as well as PILR-Fc fusion proteins prevented cell adhesion to fibronectin through the regulation of β1 integrin activity. Especially, PILRpep3, a representative 3-mer peptide covering the conserved motifs of the PILR extracellular domain, prevented the clustering and activation of β1 integrin by dephosphorylating FAK and vinculin, which are major components of focal adhesion. In addition, PILRpep3 inhibited transendothelial migration of monocytes as well as endothelial cell tube formation. Furthermore, upon intraperitoneal injection of PILRpep3 into mice with collagen-induced arthritis, the inflammatory response of rheumatoid arthritis was strongly suppressed. Taken together, these results suggest that PILR-derived agonist ligands may prevent the inflammatory reactions of rheumatoid arthritis by activating CD99.

Antibody–drug conjugates (ADCs) are tumor-targeted therapeutic agents that combine the specificity of monoclonal antibodies (mAbs) with the potent anti-tumor effects of cytotoxic drugs. Over the past few years, ADCs have become a powerful tool in the field of cancer chemotherapy. Recently, two ADC products, brentuximab vedotin (Adcetris®) and trastuzumab emtansine (Kadcyla®), have received FDA approval and there are more than 40 ADC candidates in clinical trials for the treatment of various cancers. Despite the success of some products, considerable interests for the next generation of ADCs have focused on the development of homogeneous conjugates because most of the current ADCs are highly heterogeneous with different drug-to-antibody ratios and drug conjugation sites. Recent studies have demonstrated that the site-specific conjugation of drugs to mAbs could produce homogeneous ADC with better pharmacokinetic properties and improved therapeutic index. A number of approaches, including the use of engineered cysteines, the insertion of unnatural amino acids, and enzymatic ligation, have addressed the challenging issues for the synthesis of homogeneous ADC. This review discusses the limitations of current ADC technologies and describes recent site-specific conjugation methods that can be used to prepare homogeneous ADCs for targeted anticancer drug delivery.

Objective Study results on the effects of coffee consumption on serum uric acid (UA) have been conflicting. The aim of this study is to analyze the literature regarding the effect of coffee consumption on serum UA. Methods We searched MEDLINE, EMBASE, the Cochrane library, and KoreaMed for all articles published before January 2015. Studies with quantitative data on coffee consumption and serum UA level were included. Coffee consumption and serum UA level were identified with/without the risk of gout. Results Nine studies published between 1999 and 2014 were included, containing a total of 175,310 subjects. Meta-analysis demonstrated that coffee has a significantly lowering effect on serum UA, where there are gender differences in the amount of coffee required to lower serum UA. Women (4–6 cups/day) need more coffee to lower serum UA than men (1–3 cups/day). Meta-analysis showed that coffee intake of 1 cup/day or more was significantly associated with reduction of the risk of gout, with a negative correlation with the amount of daily coffee intake for both genders. Conclusions This is the first systematic review on the effects of coffee consumption on serum UA. Based on our study, moderate coffee intake might be advocated for primary prevention of hyperuricemia and gout in both genders.

Smilacis Chinae Rhizome (SCR) has been used as an oriental folk medicine for various biological activities. However, its effect on atopic dermatitis (AD) remains undetermined to date. We assessed the effect of orally administered hot-water extract of SCR on AD-like skin lesions in mice and its underlying mechanisms. AD-like murine model was prepared by repeated alternate application of house dust mite (Dermatophagoides farinae) extract (DFE) and 2,4-dinitrochlorobenzene (DNCB) for 4 weeks, topically to the ears. Daily oral administration of SCR for 3 and 4 weeks significantly reduced inflammatory ear thickening, with the effect being enhanced at the earlier start and longer period of administration. This effect was accompanied by a significant decrease in both Th2 and Th1 serum antibodies (total IgE, DFE-specific IgE, and IgG2a). Histological analysis showed that SCR markedly decreased the epidermal/dermal ear thickening and the dermal infiltration of inflammatory cells. Furthermore, SCR suppressed DFE/DNCB-induced expression of IL-4, IL-13, IL-17, IL-18, TSLP, and IFN-γ genes in the ear tissue. Taken together, our observations demonstrate that chronic oral administration of SCR exerts beneficial effect in mouse AD model, suggesting that SCR has the therapeutic potential as an orally active treatment of AD by modulating both Th1 and Th2 responses.

Objective To identify the correlation between change in spinal deformities after surgical release and age at the time of surgery, and the effectiveness of surgical release in patients with neglected congenital muscular torticollis (CMT). Methods This was a retrospective study of 46 subjects with neglected CMT who had undergone surgical release at age ≥5 years at a tertiary medical center between January 2009 and January 2014. Spinal deformities were measured on anteroposterior plain radiographs of the cervical and whole spine, both preoperatively and postoperatively, to assess 3 parameters: cervicomandibular angle (CMA), lateral shift (LS), and Cobb angle (CA). We analyzed the change in spinal deformities after surgical release in consideration of age at the time of surgery. Results The median age at the time of surgery was 12.87 years. All 3 parameters showed significant improvement after surgical release (median values, pre- to post-surgery: CMA, 12.13° to 4.02°; LS, 18.13 mm to 13.55 mm; CA, 6.10° to 4.80°; all p

Sepsis is a potentially fatal complication of infections and there are currently no effective therapeutic options for severe sepsis. In this study, we revealed the secretion mechanism of transforming growth factor β-induced protein (TGFBIp) that was recently identified as a therapeutic target for sepsis, and designed TGFBIp acetylation inhibitory peptide (TAIP) that suppresses acetylation of lysine 676 in TGFBIp. To improve bioavailability and biodegradation of the peptide, TAIP was conjugated to polyamidoamine (PAMAM) dendrimers. Additionally, the cell-penetrating peptide (CPP) was conjugated to the TAIP-modified PAMAM dendrimers for the intracellular delivery of TGFBIp. The resulting nanostructures, decorated with TAIP and CPP via poly(ethylene glycol) linkage, improved the mortality and organ damage in the septic mouse model and suppressed lipopolysaccharide-activated severe vascular inflammatory responses in endothelial cells. Thus, the dendrimer-based nanostructures for delivery of TAIP using CPP show great promise in practical applications in sepsis therapy.

Solid dosage forms of biopharmaceuticals such as therapeutic proteins could provide enhanced bioavailability, improved storage stability, as well as expanded alternatives to parenteral administration. Although numerous drying methods have been used for preparing dried protein powders, choosing a suitable drying technique remains a challenge. In this review, the most frequent drying methods, such as freeze drying, spray drying, spray freeze drying, and supercritical fluid drying, for improving the stability and bioavailability of therapeutic proteins, are discussed. These technologies can prepare protein formulations for different applications as they produce particles with different sizes and morphologies. Proper drying methods are chosen, and the critical process parameters are optimized based on the proposed route of drug administration and the required pharmacokinetics. In an optimized drying procedure, the screening of formulations according to their protein properties is performed to prepare a stable protein formulation for various delivery systems, including pulmonary, nasal, and sustained-release applications.

The purpose of this study was to prepare spray freeze-dried particles of immunoglobulin G (IgG) using various combinations of trehalose and different amino acids (leucine, phenylalanine, arginine, cysteine, and glycine), and investigate the effect of the amino acids on the stability of IgG during the spray freeze-drying (SFD) process and storage. The morphology and structural integrity of the processed particles were evaluated by physical and spectroscopic techniques. SFD-processed IgG without any excipient resulted in the formation of aggregates corresponding to approximately 14% of IgG. In contrast, IgG formulations stabilized using an optimal level of leucine, phenylalanine, or glycine in the presence of trehalose displayed aggregates2.2%. In particular, phenylalanine combined with trehalose was most effective in stabilizing IgG against shear, freezing, and dehydration stresses during SFD. Arginine and cysteine were destabilizers displaying aggregation and fragmentation of IgG, respectively. Aggregation and fragmentation were evaluated by dynamic light scattering, ultraviolet spectrophotometry, size-exclusion chromatography, and microchip capillary gel electrophoresis. The IgG formulations prepared with leucine, phenylalanine, or glycine in the presence of trehalose showed good stability after storage at 40 °C and 75% relative humidity for 2 months. Thus, a combination of the excipients trehalose and uncharged, nonpolar amino acids appears effective for production of stable SFD IgG formulations.

Colchicine is an alkaloid widely used for the treatment of inflammatory diseases, such as gout. It suppresses cell division by inhibiting mitosis. We investigated the anticancer effects of colchicine on human hypopharyngeal cancer cells and the mechanisms underlying its anticancer effects. XTT cell proliferation assay showed that colchicine inhibited the growth and proliferation of human hypopharyngeal cancer cells (FaDu and SNU1041) in a dose- and time-dependent manner. Colchicine also inhibited the migration, invasion, and adhesion of hypopharyngeal cancer cells in a dose-dependent manner. The levels of mRNA expression and activity of matrix metalloproteinase-9 (MMP9) and urokinase-type plasminogen activator (uPA) decreased after treatment with colchicine. Further investigation revealed that colchicine inhibited the phosphorylation of the FAK/SRC complex and paxillin. Tumor volume ratios in colchicine-treated mice (0.1 mg/kg, every 2 days for 14 days) increased less than in control mice. To our knowledge, this is the first report showing that colchicine can suppress cell invasion, migration, and adhesion through reduced expression of MMP9, the uPA system, and the FAK/SRC complex. Colchicine has the potential to prevent disease progression in hypopharyngeal cancer and may have application as an adjunctive treatment.

Despite intensive investigation of molecular mechanisms underlying the pathogenesis of sepsis, many aspects of sepsis remain unresolved; this hampers the development of appropriate therapeutics. In the present study, we developed a biologic nanomedicine containing a cationic antimicrobial decapeptide KSLW (KKVVFWVKFK), self-associated with biocompatible and biodegradable PEGylated phospholipid micelles (PLM), and analyzed its efficacy for treating sepsis. KSLW was modified with polyethylene glycol (PEG)-aldehyde or was conjugated with distearoylphosphatidylethanolamine (DSPE) -PEG-aldehyde. We compared the antibacterial and antiseptic effects of PEG-KSLW and PLM-KSLW with those of unmodified KSLW both in vitro and in vivo. We found that the PLM-KSLW improved the survival rate of sepsis mouse models without undesired immune responses, and inhibited lipopolysaccharide (LPS)-induced severe vascular inflammatory responses in human umbilical vein endothelial cells compared with unmodified KSLW or PEG-KSLW. Furthermore, PLM-KSLW dramatically reduced the bacterial count and inhibited bacterial growth. We also found a new role of PLM-KSLW in tightening vascular barrier integrity by binding to the glycine/tyrosine-rich domain of occludin (OCLN). Our results showed that PLM-KSLW had a more effective antiseptic effect than KSLW or PEG-KSLW, possibly because of its high affinity toward OCLN. Moreover, PLM-KSLW could be potentially used to treat severe vascular inflammatory diseases, including sepsis and septic shock.

Recent studies have shown that plumbagin has anti-inflammatory, anti-allergic, antibacterial, and anti-cancer activities; however, it has not yet been shown whether plumbagin suppresses alpha-melanocyte stimulating hormone (α-MSH)-induced melanin synthesis to prevent hyperpigmentation. In this study, we demonstrated that plumbagin significantly suppresses α-MSH-stimulated melanin synthesis in B16F10 mouse melanoma cells. To understand the inhibitory mechanism of plumbagin on melanin synthesis, we performed cellular or cell-free tyrosinase activity assays and analyzed melanogenesis-related gene expression. We demonstrated that plumbagin directly suppresses tyrosinase activity independent of the transcriptional machinery associated with melanogenesis, which includes micropthalmia-associated transcription factor (MITF), tyrosinase (TYR), and tyrosinase-related protein 1 (TYRP1). We also investigated whether plumbagin was toxic to normal human keratinocytes (HaCaT) and lens epithelial cells (B3) that may be injured by using skin-care cosmetics. Surprisingly, lower plumbagin concentrations (0.5–1 μM) effectively inhibited melanin synthesis and tyrosinase activity but do not cause toxicity in keratinocytes, lens epithelial cells, and B16F10 mouse melanoma cells, suggesting that plumbagin is safe for dermal application. Taken together, these results suggest that the inhibitory effect of plumbagin to pigmentation may make it an acceptable and safe component for use in skin-care cosmetic formulations used for skin whitening.

Recent studies have shown that vanillin has anti-cancer, anti-mutagenic, and anti-metastatic activity; however, the precise molecular mechanism whereby vanillin inhibits metastasis and cancer progression is not fully elucidated. In this study, we examined whether vanillin has anti-cancer and anti-metastatic activities via inhibition of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in A2058 and A375 human malignant melanoma cells. Immunoblotting and quantitative real time (RT)-PCR analysis revealed that vanillin down-regulates HIF-1 alpha protein accumulation and the transcripts of HIF-1 alpha target genes related to cancer metastasis including fibronectin 1 (FN1), lysyl oxidase-like 2 (LOXL2), and urokinase plasminogen activator receptor (uPAR). It was also found that vanillin significantly suppresses HIF-1 alpha mRNA expression and de novo HIF-1 alpha protein synthesis. To understand the suppressive mechanism of vanillin on HIF-1 alpha expression, chromatin immunoprecipitation was performed. Consequently, it was found that vanillin causes inhibition of promoter occupancy by signal transducer and activator of transcription 3 (STAT3), but not nuclear factor-kappa B (NF-kappa B), on HIF1A. Furthermore, an in vitro migration assay revealed that the motility of melanoma cells stimulated by hypoxia was attenuated by vanillin treatment. In conclusion, we demonstrate that vanillin might be a potential anti-metastatic agent that suppresses metastatic gene expression and migration activity under hypoxia via the STAT3-HIF-1 alpha signaling pathway.

Supplemental Digital Content is available in the text, Anthropometric measurements are simple and useful methods for predicting metabolic syndrome (MetS) because obesity is a predominant feature of MetS. Although carotid intima-medial thickness (IMT) is generally used to evaluate subclinical atherosclerosis, the relationship between the optimal cut-off anthropometric values for predicting MetS and carotid IMT has not been analyzed in a Korean population. Anthropometric measurements including waist circumference (WC), waist hip ratio (WHR), waist height ratio (WHtR), body mass index (BMI), and carotid IMT were assessed in 2560 Korean subjects without previous history of cardiovascular disease, cerebrovascular disease, neurological abnormalities, or malignancy who participated in baseline health examinations in a self-referral setting in the Seoul area between April 2010 and November 2012. MetS was defined using the National Cholesterol Education Program–Adult Treatment Panel III criteria. In both men and women, the levels of all anthropometric indices were significantly higher in subjects with MetS than in those without MetS. According to the receiver operating characteristic curve, the values of 80.8 cm for WC, 0.87 for WHR, 0.52 for WHtR, and 24.6 kg/m2 for BMI were the optimal cut-offs for predicting MetS in women. The values of 89.3 cm for WC, 0.90 for WHR, 0.52 for WHtR, and 25.1 kg/m2 for BMI were the optimal cut-offs for predicting MetS in men. After adjusting for confounding factors, the WC optimal cut-off values for predicting MetS were independently associated with carotid IMT in both women and men (women: β = 0.016, P = .008; men: β = 0.033, P = .009). The optimal BMI cut-off value was independently associated with carotid IMT in men only (β = 0.027, P = .032). Among anthropometric indices including WC, WHR, WHtR, and BMI, the WC optimal cut-off values for MetS were independently associated with an increased carotid IMT in both women and men in a Korean population.

Background Climacteric women experience various disorders, including hot flush, depression, insomnia, arthralgia, and hand and foot numbness. Dangguijakyaksan is among the most common treatments for climacteric syndrome, and its effect on depression, insomnia, hot flush and quality of life (QOL) in climacteric women has been reported multiple times. A recent animal study found dangguijakyaksan decreased serum lipid factors and improved blood circulation in a menopausal rat model; however, these effects have not been assessed in clinical trials. This study aims to assess the clinical effects and safety of dangguijakyaksan for lower-extremity blood circulation disturbances in climacteric women. Methods This is a single-center, randomized, double-blinded, placebo-controlled pilot study that will be conducted at Dunsan Korean Medicine Hospital at Daejeon University. Forty-six climacteric women with lower-extremity blood circulation disturbances will be recruited and randomized (1:1) into either the dangguijakyaksan or placebo group. After 8 weeks of administration, the effects and safety of dangguijakyaksan will be assessed.The primary outcome is the visual analogue scale for lower-extremity blood circulation disturbances, and it will be assessed on visits 1, 2, and 3. The secondary outcomes, Kupperman's index and blood deficiency scoring system, will be assessed on visits 1, 2, and 3, and accelerated photoplethysmography and digital infrared thermal imaging will be performed on visits 1 and 3. Moreover, blood lipid profile, follicle-stimulating hormone, and estradiol levels will be measured at the screening visit and visit 3. Blood tests will be performed at the screening visit and visit 3 to assess the safety of dangguijakyaksan. Statistical analysis will be performed using R-3.3.3 (Another Canoe), and within-group study variable differences after drug administration will be analyzed using paired t-test or Wilcoxon signed-rank test. Discussion We expect to confirm the effects and safety of dangguijakyaksan on lower-extremity blood circulation disturbances in menopause, which would provide foundational data for planning subsequent studies.

The separation mechanism of PEGylated peptides in reversed-phase high-performance liquid chromatography (RP-HPLC) is complex, because the PEGylated molecules exhibit physicochemical properties that are different from those of the parent molecules and have heterogeneous structure. Since most separation studies have focused on the hydrophobicity of the peptide relative to poly(ethylene glycol) (PEG), the role of PEG in the separation of PEGylated peptides on RP-HPLC is not clear. To elucidate the effect of the attached PEG on the retention of PEGylated peptides on RP-HPLC, the mono-PEGylated forms of collagen pentapeptide and octreotide were fractionated drop-by-drop from the outlet of the HPLC system and each drop was subjected to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). This approach demonstrated that the dispersity of the attached PEG leads to the peak broadness of PEGylated peptides in RP-HPLC and the elution order inside the HPLC peak of PEGylated peptides was dependent on the attached PEG chain length. The retention time of PEGylated peptide increased as the attached PEG chain increased in length. When uniform PEG was conjugated to octreotide, its well-resolved positional isomers of the mono-PEGylated forms showed narrow peaks comparable to native peptide peak under the same HPLC conditions, which confirmed the effect of the attached PEG dispersity on the chromatographic behavior of PEGylated peptides. In conclusion, this study indicates that the chromatographic behavior of PEGylated peptides is affected by the PEG chain length dispersity as well as the peptide's hydrophobicity.

Grisel syndrome is a rare, non-traumatic atlanto-axial subluxation associated with an inflammatory or infectious process in the upper neck. According to the two-hit hypothesis, which is widely accepted for the pathogenesis of Grisel syndrome, preexisting ligamentous laxity of the atlanto-axial joint is regarded as the first hit. An inflammatory or infectious process of the atlanto-axial joint acts as the second hit, resulting in non-traumatic atlanto-axial subluxation. We report on a 6-year-old girl with atlanto-axial subluxation following retropharyngeal and cervical lymphadenitis. She was diagnosed with Grisel syndrome, for which an initial computed tomography did not show any preexisting ligamentous laxity of the atlanto-axial joint. A literature review found only 4 case reports on Grisel syndrome with an initially normal atlanto-axial joint. The present case offers some evidence that a single hit, such as inflammatory changes in the atlanto-axial joint, might cause Grisel syndrome, even without underlying ligamentous laxity.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a potential cause of hyponatremia of the central nervous system (CNS). Although SIADH has been reported to be associated with many other central nervous disorders, its association with neuromyelitis optica (NMO) or NMO spectrum disorders are rare. NMO is a demyelinating disorder characterized by optic neuritis and transverse myelitis. Aquaporin-4 (AQP4), which is the target antigen for a NMO autoantibody, is the predominant CNS water channel. However, some NMO patients show seronegative AQP4 antibody results. The spectrum of NMO has been changed, and new findings about the disease have been reported. Here, we report a case of seronegative NMO spectrum disorder associated with SIADH.

Introduction: Since exendin-4 (exenatide) was approved for diabetes therapy in 2005, several exendin analogs have been developed for the treatment of type 2 diabetes mellitus. As exenatide is a relatively short-acting injectable agent, major approaches have focused on developing long-acting exendin analogs to improve patient compliance and convenience.Areas covered: In this review, the authors report on patents related to exendins and exendin analogs from 2012 to 2015. The patents have been divided into three categories based on the technologies used to develop the new chemical entities: 1) chemical bioconjugate analogs; 2) recombinant fusion protein analogs; and 3) multifunctional peptide analogs.Expert opinion: Recently, research on exendins and their analogs has grown significantly, leading to the development of long-acting analogs and multifunctional peptides. While long-acting injectable agents are still the major products in the pharmaceutical industry, a significant growth is expected in th...

Exendin-4 (EX4), a glucagon-like peptide-1 receptor (GLP-1R) agonist that regulates blood glucose levels, has been used in the management of type-2 diabetes mellitus. EX4 can be PEGylated to improve its antidiabetic effects by enhancing its stability and extending the circulation half-life. Here, to determine whether PEGylated EX4 is effective for the treatment of sepsis, C-terminal thiol-specific PEGylated EX4s with linear maleimide-PEG-2K, -5K, -20K and trimeric maleimide-PEG-50K (hereafter referred to as EX4-2K, EX4-5K, EX4-20K, and EX4-50K, respectively) were prepared, and their antiseptic responses were investigated. These PEGylated EX4s reduced cecal ligation and puncture (CLP)-induced organ injury by decreasing hyperpermeability, and suppressing interactions between leukocytes and endothelial cells. The binding avidity and stability of EX4-50K toward GLP-1R were superior to that of wild-type EX4, as was the circulation half-life of EX4-50K. In addition, the antiseptic effects of EX4-50K were superior to those of other PEGylated EX4s, which may be attributed to enhanced proteolytic stability, longer circulation half-life, and higher receptor-binding affinity of EX4-50K due to its trimeric PEG structure. Therefore, EX4-50K may decrease CLP-induced septic mortality in vivo. There are currently neither effective preventatives against nor treatment options for sepsis; our results show that EX4-50K has the potential to treat sepsis.

Primary Sjögren's syndrome (pSS) is characterized by lymphocytic infiltration of the exocrine glands resulting in decreased saliva and tear production. It uncommonly involves the kidneys in various forms, including tubulointerstitial nephritis, renal tubular acidosis, Fanconi syndrome, and rarely glomerulonephritis. Its clinical symptoms include muscle weakness, periodic paralysis, and bone pain due to metabolic acidosis and electrolyte imbalance. Herein, we describe the cases of two women with pSS whose presenting symptoms involve the kidneys. They had hypokalemia and normal anion gap metabolic acidosis due to distal renal tubular acidosis and positive anti-SS-A and anti-SS-B autoantibodies. Since one of them experienced femoral fracture due to osteomalacia secondary to renal tubular acidosis, an earlier diagnosis of pSS is important in preventing serious complications.

Objective To present our experience with ear splint therapy for babies with ear deformities, and thereby demonstrate that this therapy is an effective and safe intervention without significant complications. Methods This was a retrospective study of 54 babies (35 boys and 19 girls; 80 ears; age ≤3 months) with ear deformities who had received ear splint therapy at the Center for Torticollis, Department of Physical Medicine and Rehabilitation, Ajou University Hospital between December 2014 and February 2016. Before the initiation of ear splint therapy, ear deformities were classified with reference to the standard terminology. We compared the severity of ear deformity before and after ear splint therapy by using the physician's ratings. We also compared the physician's ratings and the caregiver's ratings on completion of ear splint therapy. Results Among these 54 babies, 41 children (58 ears, 72.5%) completed the ear splint therapy. The mean age at initiation of therapy was 52.91±18.26 days and the treatment duration was 44.27±32.06 days. Satyr ear, forward-facing ear lobe, Darwinian notch, overfolded ear, and cupped ear were the five most common ear deformities. At the completion of therapy, the final physician's ratings of ear deformities were significantly improved compared to the initial ratings (8.28±1.44 vs. 2.51±0.92; p