The Trends and Outcomes of Initial Palliative Chemotherapy in Patients with Pancreatic Cancer in Korea Based on National Health Insurance Service Data.

Background/Objectives: The survival rate of patients with pancreatic cancer (PC) has improved gradually since the introduction of FOLFIRINOX (FFX) and gemcitabine + albumin-bound paclitaxel (GnP) regimens. However, the trends and outcomes of initial palliative chemotherapy before and after the advent of these regimens and their contribution to survival rates are not well understood. This study aimed to investigate this in patients with PC in Korea using claims data from the National Health Insurance Service (NHIS). Methods: Patients diagnosed with PC who underwent initial palliative chemotherapy between 2007 and 2019 were identified from the NHIS database. Patient demographics, comorbidities, chemotherapy regimens, and survival rates were analyzed using follow-up data up to 2020. Results: In total, 14,760 patients (mean age, 63.78 ± 10.18 years; men, 59.19%) were enrolled. As initial palliative chemotherapy, 3823 patients (25.90%) received gemcitabine alone; 2779 (18.83%) received gemcitabine + erlotinib; 1948 (13.20%) received FFX; and 1767 (11.97%) received GnP. The median survival values were 15.00 months for FFX; 11.04 months for GnP; 8.40 months for gemcitabine alone; and 8.51 months for gemcitabine + erlotinib. The adjusted hazard ratio (aHR) for GnP vs. FFX was 1.291 (95% CI, 1.206-1.383) in the multivariate Cox regression analysis of mortality. Radiation therapy (aHR, 0.667; 95% CI, 0.612-0.728) and second-line chemotherapy (aHR, 0.639; 95% CI, 0.597-0.684) were significantly associated with improved survival. Conclusions: Our study found that first-line chemotherapy with FFX was associated with significantly longer survival than the other regimens, although caution is needed in interpreting the results.

Risk of Subsequent Primary Cancers in Thyroid Cancer Survivors according to the Dose of Levothyroxine: A Nationwide Cohort Study.

BACKGRUOUND: Current research has not investigated the effect of thyroid-stimulating hormone suppression therapy with levothyroxine on the risk for developing subsequent primary cancers (SPCs). This study aimed to investigate the association between levothyroxine dosage and the risk for SPCs in thyroid cancer patients. METHODS: We conducted a nationwide population-based retrospective cohort study form Korean National Health Insurance database. This cohort included 342,920 thyroid cancer patients between 2004 and 2018. Patients were divided into the non-levothyroxine and the levothyroxine groups, the latter consisting of four dosage subgroups according to quartiles. Cox proportional hazard models were performed to evaluate the risk for SPCs by adjusting for variables including cumulative doses of radioactive iodine (RAI) therapy. RESULTS: A total of 17,410 SPC cases were observed over a median 7.3 years of follow-up. The high-dose levothyroxine subgroups (Q3 and Q4) had a higher risk for SPC (adjusted hazard ratio [HR], 1.14 and 1.27; 95% confidence interval [CI], 1.05-1.24 and 1.17- 1.37; respectively) compared to the non-levothyroxine group. In particular, the adjusted HR of stomach (1.31), colorectal (1.60), liver and biliary tract (1.95), and pancreatic (2.48) cancers were increased in the Q4 subgroup. We consistently observed a positive association between high levothyroxine dosage per body weight and risk of SPCs, even after adjusting for various confounding variables. Moreover, similar results were identified in the stratified analyses according to thyroidectomy type and RAI therapy, as well as in a subgroup analysis of patients with good adherence. CONCLUSION: High-dose levothyroxine use was associated with increased risk of SPCs among thyroid cancer patients regardless of RAI therapy.

Impacts of Temperature on the Growth, Feed Utilization, Stress, and Hemato-Immune Responses of Cherry Salmon (Oncorhynchus masou).

Cherry salmon (Oncorhynchus masou) hold commercial value in aquaculture, and there is a need for controlled laboratory studies to isolate the specific effects of temperature on their growth, feeding, and well-being. We examined the effects of different temperatures (10 °C, 14 °C, 18 °C, and 22 °C) on juvenile cherry salmon (average mass 29.1 g) in triplicate tanks per treatment over eight weeks. The key parameters assessed included growth rate, feed efficiency, stress response, and hemato-immune responses. Our objectives were to determine the most and less favorable temperatures among the four designated temperatures and to assess the adverse effects associated with these less favorable temperatures. The results showed that body weight, growth rates, feed intake, and feed efficiency were significantly higher at 10 °C and 14 °C compared to 18 °C and 22 °C. Reduced appetite and feeding response were observed at 22 °C. Red blood cell parameters were significantly lower at 22 °C. At 10 °C, the results showed significantly increased plasma cortisol levels, gill Na+/K+-ATPase activity, body silvering, and decreased condition factors, suggesting potential smoltification. The potential smoltification decreased with increasing temperatures and disappeared at 22 °C. Furthermore, the plasma lysozyme concentrations significantly increased at 18 °C and 22 °C. In conclusion, our study identifies 10 °C and 14 °C as the temperatures most conducive to growth and feed performance in juvenile cherry salmon under these experimental conditions. However, temperatures of 22 °C or higher should be avoided to prevent compromised feeding, reduced health, disturbed immune responses, impaired growth, and feed performance.

Second Primary Malignancy After Radioiodine Therapy in Thyroid Cancer Patient: A Nationwide Study.

Objective: This study aimed to investigate the risk of second primary malignancy after radioiodine (RAI) therapy in patients with thyroid cancer, using the National Health Insurance Service (NHIS) database. Methods: We extracted data from the NHIS database of South Korea, which covers the entire population of the nation. Risk of second primary malignancy in the thyroid cancer patients who received RAI therapy were compared with the thyroid cancer patients who received surgery only. Results: Between January 1, 2004, and December 31, 2018, we identified 363,155 patients who underwent thyroid surgery due to thyroid cancer for analysis. The surgery only cohort was 215,481, and the RAI cohort was 147,674 patients. A total of 19,385 patients developed second primary malignancy (solid cancer, 18,285; hematologic cancer, 1,100). There was no significant increase in the risk of second primary malignancy in patients who received a total cumulative dose of 100 mCi or less (hazard ratio [HR], 1.013; 95% confidence interval [CI], 0.979-1.049). However, a statistically significant increase in the risk of second primary malignancy was observed in patients who received 101-200 mCi (HR, 1.214; 95% CI, 1.167-1.264), 201-300 mCi (HR, 1.422; 95% CI, 1.258-1.607), and > 300 mCi (HR, 1.693; 95% CI, 1.545-1.854). Conclusion: Total cumulative doses of 100 mCi or less of RAI can be safely administered without concerns about second primary malignancy. However, the risk of second primary malignancy increases in a dose-dependent manner, and the risk-benefit needs to be considered for doses over 100 mCi of RAI therapy.

Chronic disease management program applied to type 2 diabetes patients and prevention of diabetic complications: a retrospective cohort study using nationwide data.

BACKGROUND: The outcomes of education and counseling by medical professionals for patients with type 2 diabetes mellitus (T2DM) are unclear. This study examined the effects of the Chronic Disease Management Program (CDMP), a health insurance fee-for-service benefit, on the incidence of diabetic complications in patients newly diagnosed with T2DM using the National Health Insurance data. METHODS: Patients newly diagnosed with T2DM aged ≥ 20 years from 2010 to 2014 were followed up until 2015. Selection bias was minimized using propensity score matching. A stratified Cox proportional hazards model was used to analyze the association between the CDMP and the risk of incident diabetic complications. Subgroup analysis was performed for patients with high medication adherence, which was indicated by a medication possession ratio (MPR) ≥ 80. RESULTS: Among the 11,915 patients with T2DM in the cohort, 4,617 were assigned to the CDMP and non-CDMP group each. The CDMP helped reduce the overall and microvascular risks of complications compared to the non-CDMP group; however, the protective effect against macrovascular complications was only observed in those aged ≥ 40 years. Subgroup analysis of the group aged ≥ 40 years with high adherence (an MPR ≥ 80) showed that the CDMP effectively reduced the incidence of micro- and macrovascular complications. CONCLUSIONS: Effective management of T2DM is crucial in preventing complications in patients with the condition, and includes regular monitoring and adjustment of treatment by qualified physicians. Nevertheless, long-term prospective studies on the effects of CDMP are required to confirm this finding.

Prevalence and Treatment Patterns of Sleep Disorders in the Under 20 Population: analysis using a national health insurance claims database.

Objectives: Child and adolescent sleep is an important factor for brain and physical development. Therefore, it is necessary to investigate the prevalence of sleep disorders and nonorganic sleep disorders in children and adolescents and determine the type of utilization of medical institutions. This study analyzed the prevalence and type of medical institutions in Korean children and adolescents with sleep disorders and nonorganic sleep disorders. Methods: This study used data recorded in the Health Insurance Review and Assessment-National Patient Sample (HIRA-NPS) database from 2010 to 2017. Details of medical institution type and patient's sex, age, and treatment type were extracted for patients younger than 20 years with sleep disorders and nonorganic sleep disorders. Results: Among 2,536,478 patients under age 20, we identified 3,772 patients with sleep disorders or nonorganic sleep disorders. From 2010 to 2017, the prevalence of sleep disorders in children and adolescents was 0.07% to 0.09%. The utilization rate of Korean medical institutions was 30.47%. The prevalence of nonorganic sleep disorders and the utilization rate of Korean medical institutions were 0.06% to 0.08% and 45.99%, respectively. Conclusion: The prevalence of sleep disorders and nonorganic sleep disorders in the under-20 population was 0.14% to 0.16%. More than 70% of patients with nonorganic sleep disorder who were younger than 9 years used Korean medical institutions.

Effectiveness of Acupuncture, Mind and Body Practices, and Natural Products for Insomnia: an overview of systematic reviews.

Objectives: This overview summarizes the evidence for the effectiveness and safety of complementary therapies for insomnia through systematic reviews (SRs) and meta-analyses (MAs). Methods: A comprehensive literature search on SRs and MAs for complementary therapies for insomnia was conducted using six databases. Results: This overview included 30 SRs/MAs. The Pittsburgh Sleep Quality Index (PSQI) analysis of insomnia included 383 randomized controlled trials and 31,748 participants. Twenty-four SRs/MAs (80%) out of 30 SRs/MAs reported a positive result, and six SRs/MAs reported a partially positive result. The most frequently used form of acupuncture reported a positive effect in 89.5% (17/19) of SRs/MAs and a superior effect to western medicine, sham/placebo, and no treatment. The lack of protocol registration and the excluded studies list resulted in generally poor methodological and reporting quality in SRs/MAs with AMSTAR 2. Conclusion: This overview confirmed that complementary therapies positively affected the PSQI scores in patients with insomnia. However, better-designed primary studies are needed to strengthen the relevant evidence in the future. A more stringent assessment of multiple systematic reviews 2 must be followed when performing SR and MA.

Plasma concentration of dopamine varies depending on breed, sex, and the genotype of DRD4 in horses.

Dopamine (DA) is known to be a key modulator of animal behaviors. Thus, the plasma concentration of DA might be used as a biomarker for the behavioral characteristics of horses. The behavioral characteristics of horses vary depending on the breed, age, and sex. Moreover, the DA receptor genotypes are also related to horse behaviors. Thus, the aim of this study was to investigate the DA concentration variations of horse plasma by breed, age, sex, or genotype of its receptor. The horses were divided by breed into Thoroughbred (n = 13), Pony (n = 9), Warmblood (n = 4), and Haflinger (n = 5). The age variable was divided into three different groups: post-pubertal (2-5 years, n = 6), adult (6-13 years, n = 19), and aged horses (15-24 years, n = 6). The sex variable was divided into geldings (n = 8) and mares (n = 23). Approximately 10 mL of blood was collected, and an ELISA kit was used to measure the plasma concentration of DA. Polymerase chain reaction analysis was performed to identify the genetic variation in the DA D4 receptor gene (DRD4). SPSS statistical software was used for statistical analysis. The DA concentrations in geldings were significantly lower than those in mares. There was no significant difference in DA concentrations among breed and age groups. Horses with the GG and GA genotypes had significantly higher plasma concentrations of DA compared to horses with the AA genotype for the G292A gene. Briefly, the plasma concentration of DA varied depending on the sex and genotype of G292A. These factors should be considered when the concentration of DA is used as a biomarker for the behavioral characteristics of horses. In conclusion, the DA concentration or DRD4 genotype of horse plasma has the potential to be used as a biomarker that can predict the behavioral characteristics of horses.

Effects of Stocking Density on Stress, Hematological Responses, and Growth of Black Rockfish Sebastes schlegelii.

The objective of the current study was to evaluate the effect of stocking density on juvenile Black Rockfish Sebastes schlegelii (average weight = 12 g) in terms of stress, hematological responses, and growth performance during a 4-month growth trial in a flow-through system. The initial stocking densities were 1.3 kg/m3 (low), 1.8 kg/m3 (medium), and 2.3 kg/m3 (high), and the final densities were 4.9 kg/m3 (low), 5.6 kg/m3 (medium), and 6.3 kg/m3 (high). At the end of the trial, the high stocking density significantly affected growth characteristics, levels of growth hormone and insulin-like growth factor 1, and hematological indices (hematocrit, red blood cell count, and hemoglobin level) compared to the medium and low stocking densities. The plasma cortisol and immunoglobulin-M levels were significantly higher at the high density than at the other two densities. Taken together, while the low and medium stocking densities (final densities of up to 5.6 kg/m3 ) did not affect stress and hematological indices or growth, the high stocking density (final density of 6.3 kg/m3 ) significantly impacted those variables, which suggests an allostatic load at that density. Thus, the use of a final stocking density less than 6.3 kg/m3 should be considered to avoid compromising the stress and health condition and growth of Black Rockfish at this size and temperature range.

Improving Glycemic Control in Type 2 Diabetes Using Mobile Applications and e-Coaching: A Mixed Treatment Comparison Network Meta-Analysis.

OBJECTIVES: This study compared the effectiveness of glycemic control among usual care, care management using a mobile application (app), and management using an app with additional e-coaching for patients with type 2 diabetes mellitus (T2DM) using a mixed treatment comparison (MTC) network meta-analysis (NMA). METHODS: A systematic search for published randomized controlled trials (RCTs) was conducted, which included Pubmed, Web of Science, Cochrane Central Register of Controlled Trials, CINAL, Koreamed, KMbase, and ScienceOn, until October 2020. Among the 10,391 studies identified after removing duplicates, 14 RCTs were finally included in the MTC NMA. Data extraction and methodological quality assessment using version 2 of the Cochrane tool for assessing the risk-of-bias in randomized trials (RoB 2) was performed. The comparative efficacy was analyzed using the random-effects NMA based on a frequentist model by the intervention group and main outcome variables. RESULTS: At the 3-month follow-up after each intervention, a comparison of the P-scores revealed the app plus e-coaching intervention to be the most effective method for reducing the HbA1c level in a homogeneous gender ratio group (P-score 0.92). At the 6-month follow-up period, app intervention was the best in reducing the HbA1c level in the homogeneous gender ratio and under 60 years of age group (P-score 1.00). CONCLUSIONS: Based on MTC analysis using the data from published RCTs, mobile apps or apps with e-coaching interventions for T2DM patients were more effective in improving the HbA1c values, FBS, and hypoglycemia frequency than usual care. Nevertheless, further research will be needed to clarify the effects of adding e-coaching to the app. STUDY REGISTRATION: Research Registry UIN (reviewregistry780).

Nipple Reconstruction Using the Semilunar Flap and Omega-shaped Acellular Dermal Matrix Strut.

BACKGROUND: Various operative methods exist for nipple reconstruction. Selection of an appropriate skin flap and core strut material is imperative in achieving a satisfactory outcome in nipple reconstruction. Long-term maintenance of nipple projection requires further investigation by surgeons. We propose a new technique that uses a semilunar flap and omega-shaped acellular dermal matrix (ADM). METHODS: Total 53 nipples were reconstructed by this method. An omega-shaped ADM strut was inserted into the barrel made by a semilunar flap. The footplates of omega-shaped ADM struts were spread out under the subcutaneous tissue of the donor site of the semilunar flap to support the dome of the omega strut. RESULTS: The mean maintenance rate of nipple projection was 95.12 ± 6.30% at 3 weeks, 80.60 ± 8.93% at 3 months, and 71.70 ± 8.67% at 6 months postoperatively when compared to the projection observed in the immediate postoperative period. Thirty-five patients (66.0%) showed a maintenance rate over 70% at 6 months post operation, with most patients (94.3%) demonstrating a maintenance rate greater than 60%. CONCLUSIONS: Our study with the omega-shaped ADM strut showed superior maintenance rates of projection when compared to other studies on that used AlloDerm® as a core strut for nipple reconstruction. Omega-shaped struts, when made with cross-linked thick ADM, supported the skin flap quite well. We propose that our method combining the semilunar flap with an omega-shaped ADM may be a good option for nipple reconstruction. LEVEL OF EVIDENCE IV: "This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266 ."

Comparative Interrupted Time Series Analysis of Long-term Direct Medical Costs in Patients With Hip Fractures and a Matched Cohort: A Large-database Study.

BACKGROUND: Previous studies on medical costs in patients with hip fractures have focused on medical costs incurred for a short period after the injury. However, patients often had comorbidities before their hip fractures that would have affected medical costs even had they not sustained a fracture. Consequently, these studies may have overestimated the costs associated with hip fractures and did not characterize the duration of increased medical costs adequately. Without knowing this crucial information, it is difficult to craft thoughtful health policy to support these patients' needs. QUESTIONS/PURPOSES: (1) To compare the direct medical costs for 5 years before fracture and up to 5 years after injury in a group of patients who underwent hip fracture surgery with a matched group of patients who did not experience a hip fracture, (2) to analyze the duration over which the increased direct medical costs associated with a hip fracture continues, and (3) to analyze whether there is a difference in direct medical costs according to age group using a nationwide claims database in South Korea. METHODS: The National Health Insurance Service Sample cohort in South Korea consisted of 1 million patients who were selected using a systematic, stratified, random sampling method from 48,222,537 individuals on December 31, 2006. Under a compulsory social insurance system established by the National Health Insurance Act, all patients were followed until 2015. Patients with hip fractures and matched controls were selected from the National Health Insurance Service sample of South Korea. Patients with hip fractures were defined as those who were hospitalized with a diagnosis of femoral neck fracture or intertrochanteric fracture and who underwent surgical treatment. We excluded patients with hip fractures before January 1, 2007 to ensure a minimum 5-year period that was free of hip fractures. Patients with hip fractures were matched with patients of the same age and gender at the date of admission to an acute care hospital for surgery (time zero). If patients with hip fractures died during the follow-up period, we performed matching among patients whose difference from the time of death was within 1 month. This method of risk-set matching was repeated sequentially for the next patient until the last patient with a hip fracture was matched. We then sequentially performed 1:5 random sampling for each risk set. A total of 3583 patients in the hip fracture cohort (patients with hip fractures) and 17,915 patients in the matched cohort (those without hip fractures) were included in this study. The mean age was 76 ± 9 years, and 70% were women in both groups. Based on the Charlson comorbidity index score, medication, and medical history, the patients with hip fractures had more comorbidities. Person-level direct medical costs per quarter were calculated for 5 years before time zero and up to 5 years after time zero. Direct medical costs were defined as the sum of that insurer's payments (that is, the National Health Insurance Service's payments), and that patient's copayments, excluding uncovered payments. We compared direct medical costs between patients with hip fractures and the patients in the matched cohort using a comparative interrupted time series analysis. The difference-in-difference estimate is the ratio of the differences in direct medical costs before and after time zero in the hip fracture cohort to the difference in direct medical costs before and after time zero in the matched cohort; the difference in difference estimates were calculated each year after injury. To identify changes in direct medical cost trends in patients with hip fractures and all subgroups, joinpoint regression was estimated using statistical software. RESULTS: The direct medical costs for the patients with hip fractures were higher than those for patients in the matched cohort at every year during the observation period. The difference in direct medical costs between the groups before time zero has increased every year. The direct medical costs in patients with hip fractures was the highest in the first quarter after time zero. Considering the differential changes in direct medical costs before and after time zero, hip fractures incurred additional direct medical costs of USD 2514 (95% CI 2423 to 2606; p < 0.01) per patient and USD 264 (95% CI 166 to 361; p < 0.01) per patient in the first and second years, respectively. The increase in direct medical costs attributable to hip fracture was observed for 1.5 to 2 years (difference-in-difference estimate at 1 year 3.0 [95% CI 2.8 to 3.2]; p < 0.01) (difference-in-difference estimate at 2 years 1.2 [95% CI 1.1 to 1.3]; p < 0.01; joinpoint 1.5 year). In the subgroups of patients younger than 65, patients between 65 and 85, and patients older than 85 years of age, the increase in direct medical costs attributable to hip fracture continued up to 1 year (difference-in-difference estimate ratio at 1 year 2.7 [95% CI 2.1 to 3.4]; p < 0.01; joinpoint 1 year), 1.5 to 2 years (difference-in-difference estimate ratio at 1 year 2.8 [95% CI 2.6 to 3.1]; p < 0.01; difference-in-difference estimate ratio at 2 years 1.2 [95% CI 1.1 to 1.3]; p < 0.01; joinpoint 1.5 years), and 39 months to 5 years (difference-in-difference estimate ratio at 1 year 5.2 [95% CI 4.4 to 6.2]; p < 0.01; difference-in-difference estimate ratio at 5 years 2.1 [95% CI 1.4 to 3.1]; p < 0.01; joinpoint 39 months) from time zero, respectively. CONCLUSION: The direct medical costs in patients with hip fractures were higher than those in the matched cohort every year during the 5 years before and after hip fracture. The increase in direct medical costs because of hip fractures was maintained for 1.5 to 2 years and was greater in older patients. Based on this, we suggest that health policies should focus on patients' financial and social needs, with particular emphasis on the first 2 years after hip fracture with stratification based on patients' ages. LEVEL OF EVIDENCE: Level II, economic analysis.

Acupuncture and herbal medicine for female infertility: an overview of systematic reviews.

BACKGROUND: Acupuncture and herbal medicine have been used as additional treatments for infertility or as an adjuvant treatment of assisted reproductive technology (ART) in infertility. Many systematic reviews (SRs) and meta-analyses (MA) have been published. This paper reviews the SRs and MA of acupuncture and herbal medicine on infertility to provide evidence for clinical decision making. METHODS: A comprehensive literature search of SRs and MA for the effects of acupuncture and herbal medicine on infertility was conducted using nine databases. Two independent reviewers extracted the data of the selected SR and MA and evaluated their methodological quality using the 'Assessment of multiple systematic reviews 2 (AMSTAR2)'. RESULTS: Twenty-one studies were included in this analysis. Eight studies were published in China, and three studies each were published in the USA, UK, and Australia. Conflicting evidence on the efficacy of acupuncture for infertile women has been reported. Herbal medicine for infertile women undergoing ART, women with anovulation, and women with polycystic ovary syndrome helped improve the clinical pregnancy rate. The methodological quality of SRs and MAs evaluated by AMSTAR 2 was low or very low because the protocol or list of excluded studies were omitted. CONCLUSION: Herbal medicine tended to be effective in infertility, but acupuncture had low evidence of an effect on infertility. The methodological quality of the published SRs and MAs was underestimated because AMSTAR2 is a more rigorous assessment tool than the previous version.

Determinants of concurrent use of Biomedicine and Korean Medicine on the hypertension patients: a cross-sectional study.

BACKGROUND: This study assessed the utilization of biomedicine and Korean Medicine (KM) among hypertension patients. METHODS: The study was a cross-sectional analysis conducted using the Korean National Health and Nutrition Examination Survey (KNHANES), which is a nationwide survey conducted every year for a representative Korean population. The use of outpatient healthcare services for hypertension patients was analyzed, and the usage determinants adjusted by the demographic and health status variables were identified. A chi-square test and logistic regression analysis were used for statistical analysis using R (version 3.6.0). RESULTS: Among 3320 hypertension patients, 208 patients (6.27%, Weighted%: 5.99%) used the biomedicine and KM concurrently. Multivariable regression analyses revealed hypertension patients who were obese (OR: 1.417, CI: 1.007-1.995) and had an experience of sickness (OR: 2.323, CI: 1.561-3.457) to be more likely to use biomedicine and KM concurrently. CONCLUSION: The utilization rate and determinants of the concurrent use of biomedicine and KM were identified in patients with hypertension. Although the overall usage rate was not high, the health care patterns of healthcare consumers need to be understood. Therefore, further studies on its effectiveness and safety are recommended.

SCF-Slimb is critical for Glycogen synthase kinase-3ß-mediated suppression of TAF15-induced neurotoxicity in Drosophila.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder characterized pathologically by motor neuron degeneration and associated with aggregation of RNA-binding proteins. TATA-binding protein-associated factor 15 (TAF15) accumulates as cytoplasmic aggregates in neuronal cells, and clearance of these aggregates is considered a potential therapeutic strategy for ALS. However, the exact pathogenic mechanism of TAF15-induced neurotoxicity remains to be elucidated. Glycogen synthase kinase-3 (GSK-3) plays a critical role in the protection of ALS pathology. In the present study, we use a transgenic fly model over-expressing human TAF15 to study the protective effects of Shaggy/GSK3ß on TAF15-induced neuronal toxicity in Drosophila brain. Transgenic flies were examined for locomotor activity and lithium treatment. The expression level and solubility of TAF15 were assessed with western blotting, whereas immunohistochemistry was used to assess TAF15 aggregation in Drosophila brain. We have revealed that Shaggy/GSK3ß was abnormally activated in neurons of TAF15-expressing flies and its inhibition can suppress the defective phenotypes, thereby preventing retinal degeneration and locomotive activity caused by TAF15. We have also found that Shaggy/GSK3ß inhibition in neuronal cells leads to a reduction in TAF15 levels. Indeed, the F-box proteins Slimb and archipelago genetically interact with TAF15 and control TAF15 protein level in Drosophila. Importantly, SCFslimb is a critical regulator for Shaggy/GSK3ß-mediated suppression of TAF15-induced toxicity in Drosophila. The present study has provided an in vivo evidence supporting the molecular mechanism of GSK3ß inhibition for protection against TAF15-linked proteinopathies.

Differential Seawater Adaptability in Three Different Sizes of Under-yearling Steelhead Trout.

Seawater adaptability of steelhead trout increases along with the increase in the size of the fish, independent of parr-smolt transformation. Three 96 h seawater challenge tests were conducted to determine the size at which seawater adaptability of steelhead trout develops. Plasma Na+ and Cl- levels, moisture content, gill Na+/K+ ATPase activity, and mortality during the 96 h after direct transfer to seawater (32 ppt) were determined. Plasma Na+ and Cl- levels in 50 g fish continuously increased during the 96 h after the transfer to seawater (p<0.05), but the levels in 100 and 150 g fish leveled off after 24 h (p<0.05). Both 100 and 150 g size steelhead trout maintained muscle moisture content (%) better than 50 g size fish (p<0.05). Gill Na+/K+ ATPase activity in the 100 g size group increased in a time-dependent manner after transfer to seawater (p<0.05), whereas activity in the 50 and 150 g sizes did not increase (p>0.05), for which a possible explanation was discussed. A mere 2.6% mortality in both the 50 and 150 g size groups was observed. In conclusion, the current results indicate that 50 g size steelhead trout did not show development of a high level of hypoosmoregulatory capacity, whereas fish in the 100 and 150 g size groups showed a high level in our experimental conditions. Therefore, the steelhead trout larger than a 100 g size is recommended for transfer to seawater culture.

Recent Advances on the Role of GSK3ß in the Pathogenesis of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by progressive motor neuron degeneration. Although several studies on genes involved in ALS have substantially expanded and improved our understanding of ALS pathogenesis, the exact molecular mechanisms underlying this disease remain poorly understood. Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine-protein kinase that plays a critical role in the regulation of various cellular signaling pathways. Dysregulation of GSK3ß activity in neuronal cells has been implicated in the pathogenesis of neurodegenerative diseases. Previous research indicates that GSK3ß inactivation plays a neuroprotective role in ALS pathogenesis. GSK3ß activity shows an increase in various ALS models and patients. Furthermore, GSK3ß inhibition can suppress the defective phenotypes caused by SOD, TDP-43, and FUS expression in various models. This review focuses on the most recent studies related to the therapeutic effect of GSK3ß in ALS and provides an overview of how the dysfunction of GSK3ß activity contributes to ALS pathogenesis.

Effects of Hemicastration on Testes and Testosterone Concentration in Stallions.

The endocrine system is critical to the maintenance of testicular function. The homeostasis of sex hormone levels is orchestrated by positive and negative feedback systems controlled by the hypothalamic-pituitary-gonadal axis. This study investigated the long-term effects of hemicastration on testicular size and function in stallions. Four Thoroughbred stallions, 4-6 years of age, were included in this study. Several parameters, including testicular weight and volume, plasma testosterone concentrations, VASA-positive germ cell populations and cross-sectional areas of the seminiferous tubules were compared in stallions that underwent two hemicastrations, approximately 11 months apart. The weights and volumes of testes harvested at the second hemicastration were significantly higher than those of testes collected at the first hemicastration. However, VASA-positive germ cell populations and the cross-sectional areas of seminiferous tubules were not significantly different between testes harvested at the first and second hemicastrations. Similarly, plasma testosterone concentrations measured weekly for 3 weeks before the first hemicastration, 3 weeks after the first hemicastration, and 3 weeks before the second hemicastration were not significantly different. Our results suggest that hemicastration results in compensatory enlargement of the remaining testis and compensatory steroidogenesis to maintain normal reproductive function in stallions.

The adverse effects of selenomethionine on skeletal muscle, liver, and brain in the steelhead trout (Oncorhynchus mykiss).

Juvenile Oncorhynchus mykiss (average weight: 22.3 g) were fed one of five selenomethionine diets (1.09, 8.79, 15.37, 30.79, or 61.58 mg Se/kg diet). After 4 weeks, hepatic catalase activity over 15.37 mg Se/kg diets was significantly decreased, and the glutathione peroxidase activity over 30.79 mg Se/kg diets was elevated compared to the controls. In the brain, the dopamine levels at 61.58 mg Se/kg diet and the serotonin levels over 15.37 mg Se/kg diets were significantly increased, whereas the 3,4-dihydroxyphenylacetic acid, homovanillic acid, and dopamine turnover, and the 5-hydroxyindoleacetic acid and serotonin turnover over 30.79 mg Se/kg diets were decreased. In muscle, the 3-nitrotyrosine level over 15.37 mg Se/kg diets, acetylcholine esterase activity over 30.79 mg Se/kg diets, and histological alterations over 8.79 mg Se/kg diets were increased. Our current results showed that selenomethionine disrupted dopamine and serotonin metabolism in the brain and damaged the neuromuscular system in skeletal muscle.

Inhibition of biofilm and virulence properties of Pseudomonas aeruginosa by sub-inhibitory concentrations of aminoglycosides.

Aminoglycosides are a commonly used class of antibiotics; however, their application has been discontinued due to the emergence of multi-drug resistance bacterial strains. In the present study, the subinhibitory concentrations (sub-MIC) of several aminoglycosides were determined and tested as an antibiofilm and for their anti-virulence properties against Pseudomonas aeruginosa PAO1, which is an opportunistic foodborne pathogen. P. aeruginosa PAO1 exhibits multiple mechanisms of resistance, including the formation of biofilm and production of several virulence factors, against aminoglycoside antibiotics. The sub-MIC of these antibiotics exhibited biofilm inhibition of P. aeruginosa in alkaline TSB (pH 7.9). Moreover, various concentrations of these aminoglycosides also eradicate the mature biofilm of P. aeruginosa. In the presence of sub-MIC of aminoglycosides, the morphological changes of P. aeruginosa were found to change from rod-shaped to the filamentous, elongated, and streptococcal forms. Similar growth conditions and sub-MIC of aminoglycosides were also found to attenuate several virulence properties of P. aeruginosa PAO1. Molecular docking studies demonstrate that these aminoglycosides possess strong binding properties with the LasR protein, which is a well-characterized quorum-sensing receptor of P. aeruginosa. The present study suggests a new approach to revitalize aminoglycosides as antibiofilm and antivirulence drugs to treat infections caused by pathogenic bacteria.