The Transcription Factor Ets1 Suppresses T Follicular Helper Type 2 Cell Differentiation to Halt the Onset of Systemic Lupus Erythematosus.

Single-nucleotide polymorphisms in ETS1 are associated with systemic lupus erythematosus (SLE). Ets1-/- mice develop SLE-like symptoms, suggesting that dysregulation of this transcription factor is important to the onset or progression of SLE. We used conditional deletion approaches to examine the impact of Ets1 expression in different immune cell types. Ets1 deletion on CD4+ T cells, but not B cells or dendritic cells, resulted in the SLE autoimmunity, and this was associated with the spontaneous expansion of T follicular helper type 2 (Tfh2) cells. Ets1-/- Tfh2 cells exhibited increased expression of GATA-3 and interleukin-4 (IL-4), which induced IgE isotype switching in B cells. Neutralization of IL-4 reduced Tfh2 cell frequencies and ameliorated disease parameters. Mechanistically, Ets1 suppressed signature Tfh and Th2 cell genes, including Cxcr5, Bcl6, and Il4ra, thus curbing the terminal Tfh2 cell differentiation process. Tfh2 cell frequencies in SLE patients correlated with disease parameters, providing evidence for the relevance of these findings to human disease.

A mechanogenetic role for the actomyosin complex in branching morphogenesis of epithelial organs.

The actomyosin complex plays crucial roles in various life processes by balancing the forces generated by cellular components. In addition to its physical function, the actomyosin complex participates in mechanotransduction. However, the exact role of actomyosin contractility in force transmission and the related transcriptional changes during morphogenesis are not fully understood. Here, we report a mechanogenetic role of the actomyosin complex in branching morphogenesis using an organotypic culture system of mouse embryonic submandibular glands. We dissected the physical factors arranged by characteristic actin structures in developing epithelial buds and identified the spatial distribution of forces that is essential for buckling mechanism to promote the branching process. Moreover, the crucial genes required for the distribution of epithelial progenitor cells were regulated by YAP and TAZ through a mechanotransduction process in epithelial organs. These findings are important for our understanding of the physical processes involved in the development of epithelial organs and provide a theoretical background for developing new approaches for organ regeneration.

Elongation of intercostal nerve cutaneous branches for breast and nipple neurotization during breast reconstruction after mastectomy for breast cancer: case-control study.

BACKGROUND: To restore sensation after breast reconstruction, a modified surgical approach was employed by identifying the cut fourth intercostal lateral cutaneous branch, elongating it with intercostal nerve grafts, and coapting it to the innervating nerve of the flap or by using direct neurotization of the spared nipple/skin. METHODS: This was a retrospective case-control study including 56 patients who underwent breast neurotization surgery. Breast operations included immediate reconstruction after nipple-sparing mastectomy (36 patients), skin-sparing mastectomy (8 patients), and delayed reconstruction with nipple preservation (7 patients) or without nipple preservation (5 patients). Patients who underwent breast reconstruction without neurotization were included as the non-neurotization negative control group. The contralateral normal breasts were included as positive controls. RESULTS: The mean(s.d.) monofilament test values were 0.07(0.10) g for the positive control breasts and 179.13(143.31) g for the breasts operated on in the non-neurotization group. Breasts that underwent neurotization had significantly better sensation after surgery, with a mean(s.d.) value of 35.61(92.63) g (P < 0.001). The mean(s.d.) sensory return after neurotization was gradual; 138.17(143.65) g in the first 6 months, 59.55(116.46) g at 7-12 months, 14.54(62.27) g at 13-18 months, and 0.37(0.50) g at 19-24 months after surgery. Two patients had accidental rupture of the pleura, which was repaired uneventfully. One patient underwent re-exploration due to a lack of improvement 1.5 years after neurotization. CONCLUSION: Using the lateral cutaneous branch of the intercostal nerve as the innervating stump and elongating it with intercostal nerve grafts is a suitable technique to restore sensation after mastectomy. This method effectively innervates reconstructed breasts and spares the nipple/skin with minimal morbidity.

Seasonal vitamin D levels and lupus low disease activity state in systemic lupus erythematosus.

BACKGROUND: Seasonal variation and sunlight exposure can impact serum vitamin D levels, potentially influencing lupus symptoms. We investigated seasonal vitamin D levels and their correlation with clinical manifestations and disease activity in systemic lupus erythematosus (SLE). METHODS: Serum 25(OH) vitamin D3 (25(OH)D3) levels were categorised as deficient (25(OH)D3 < 10 ng/mL), insufficient (10-30 ng/mL) and sufficiency (>30 ng/mL) in participants analysed in winter (n = 407) and summer (n = 377). Logistic regression analysis was performed to assess the impact of vitamin D levels on achieving a lupus low disease activity state (LLDAS), stratified by season. RESULTS: The mean serum 25(OH)D3 levels differed significantly between the winter and summer measurement groups (22.4 vs. 24.2 ng/mL; p = .018). The prevalences of vitamin D deficiency, insufficiency and sufficiency in the winter group were 12.8%, 66.6% and 20.6%, respectively, compared with 4.5%, 67.9% and 27.6% in the summer group. Achieving LLDAS was highest in the vitamin D sufficiency group (winter: 56.6%, summer: 55%) and lowest in the vitamin D deficiency group (winter: 15.4%, summer: 13.6%), with significant differences (all p < .001). Multivariate analysis identified SLE disease activity index ≤4, normal anti-double-stranded DNA and vitamin D sufficiency as significant factors for achieving LLDAS in both seasons. CONCLUSIONS: Sufficient vitamin D levels are important for achieving LLDAS in patients with SLE during winter and summer. Therefore, physicians should pay attention to the adequacy of vitamin D levels and consider recommending vitamin D supplementation for patients with vitamin D insufficiency.

Strategically shifting paradigms: the new era of DIEP flaps with minimally invasive mastectomy: a retrospective cross-sectional study.

BACKGROUND: The free deep inferior epigastric artery perforator (DIEP) flap is the gold standard in autologous breast reconstruction. Asian patients often present with a smaller body mass index with relatively insufficient tissue. To restore appropriate symmetry, a larger flap inset ratio must be transferred. Supercharging of the second vein or inclusion of bilateral pedicle is commonly required. Current paradigm shifts in mastectomy has also resulted in more minimally invasive surgeries (MIS) espousing smaller lateral incisions, leading to a significant change in available recipient vessels. This study aimed to demonstrate our experience in changing strategies of DIEP flaps following the evolution of mastectomy techniques. METHODS: Between October 2008 and March 2022, retrospective data was gathered for 278 patients who underwent breast reconstruction surgery utilizing DIEP flaps by a single plastic surgeon. These patients were divided into two distinct groups based on their operation dates, with November 2018 marking a pivotal moment when the first MIS, including endoscopic-assisted and robot-assisted mastectomy, was introduced. RESULTS: A total of 278 patients were included. Bipedicle vessel utilization for flap supercharge saw a significant increase (15.9% vs. 7%, p < 0.001), while the use of the superior inferior epigastric vein (SIEV) decreased (5.1% vs. 17.1%, p = 0.01). Preceding MIS, SIEV was the primary choice for flap supercharge (96.0%, p < 0.001), whereas post-introduction, the contralateral DIEP pedicle gained prominence (75.9%, p < 0.001). There was also an increased utilization of thoracodorsal artery and lateral thoracic artery following MIS. CONCLUSION: These findings underscore the profound impact of MIS on the strategic choices made in DIEP flap-based breast reconstruction. TRIAL REGISTRATION: This study is retrospectively registered on ClinicalTrials.gov (NCT06321549).

The possible association of dietary fiber intake with the incidence of depressive symptoms in the Korean population.

OBJECTIVES: This study investigates the effect of dietary fiber on the prevention of depressive symptoms. METHODS: In a cohort of 88,826 Korean adults (57,284 men and 31,542 women), we longitudinally evaluated the risk of depressive symptoms according to quartiles of dietary fiber intake for 5.8 years of follow-up. A food frequency questionnaire was used in evaluating dietary fiber intake. Depressive symptoms were assessed by the Center for Epidemiological Studies-Depression (CES-D) scale, in which CES-D ≥ 16 was defined as depressive symptoms. The Cox proportional hazards model was used to calculate the adjusted hazard ratio (HR) and 95% confidence intervals (CI) for depressive symptoms (adjusted HR [95% CI]). Subgroup analysis was performed for gender and BMI (≥25 or <25). RESULT: In men, the risk of depressive symptoms significantly decreased with the increase of dietary fiber (quartile 1: reference, quartile 2: 0.93 [0.87-0.99], quartile 3: 0.91 [0.85-0.98] and quartile 4: 0.84 [0.77-0.92]). This association was more prominently observed in men with BMI ≥ 25 (quartile 1: reference, quartile 2: 0.95 [0.86-1.06], quartile 3: 0.88 [0.79-0.99] and quartile 4: 0.84 [0.73-0.97]). Women did not show a significant association between quartile groups of dietary fiber intake and the risk of depressive symptoms across subgroup analysis for BMI. CONCLUSION: High intake of dietary fiber is potentially effective in reducing depressive symptoms in Korean men. The protective effect of dietary fiber on depressive symptoms may vary by gender and obesity.

Chinese visceral adiposity index and its relation to abnormal left ventricular remodeling assessed by relative wall thickness and left ventricular mass index.

BACKGROUND AND AIMS: The Chinese visceral adipose index (CVAI) is more significantly associated with cardiometabolic risk factors than other obesity indices. This study investigated the relationship between CVAI and left ventricular (LV) remodeling. METHODS AND RESULTS: This study included 75,132 Koreans who underwent echocardiography during a health checkup. They were grouped according to quartile levels of the CVAI, body mass index (BMI), waist circumference (WC), and visceral adiposity index (VAI). LV remodeling was defined as the presence of abnormal relative wall thickness (ARWT) and left ventricular hypertrophy (LVH). Multivariate adjusted logistic regression analysis (adjusted OR [95% confidence interval]) was used to analyze the association between ARWT and LVH according to the quartile levels of each index. Receiver operating characteristic (ROC) graphs and areas under the curve (AUC) were calculated to identify the predictive ability of the indices for ARWT and LVH. ARWT was associated proportionally with CVAI quartiles in both men (second quartile: 1.42 [1.29-1.56], third quartile: 1.61 [1.46-1.77], fourth quartile: 2.01 [1.84-2.21]), and women (second quartile: 1.06 [0.78-1.45], third quartile: 1.15 [0.86-1.55], and fourth quartile: 2.09 [1.56-2.80]). LVH was significantly associated with third (1.74 [1.07-2.83]) and fourth quartile (1.94 [1.18-3.20]) groups of CVAI in women. ROC and AUC analyses indicated that CVAI was superior to other indices in predicting ARWT in men and LVH and ARWT in women. CONCLUSION: The CVAI is an effective surrogate marker of LV remodeling, particularly in women.

The longitudinal analysis for the association between smoking and the risk of depressive symptoms.

BACKGROUND: Despite high smoking rate in people with depressive symptoms, there is ongoing debate about relationship between smoking and depressive symptoms. METHODS: Study participants were 57,441 Korean men. We collected their baseline data between 2011 and 2012, and conducted follow-up from 2013 to 2019. They were categorized by smoking status (never: < 100 cigarettes smoking in life time, former: currently quitting smoking, and current smoker: currently smoking), smoking amount (pack/day and pack-year) and urine cotinine excretion. The development of depressive symptoms was determined in CES-D score ≥ 16. Cox proportional hazards model was used to analyze the multivariable-adjusted hazard ratio (HR) and 95% confidence intervals (CI) for depressive symptoms in relation to smoking status, smoking amount, and urine cotinine excretion. RESULTS: During 6.7 years of median follow-up, the risk of depressive symptoms increased in order of never (reference), former (HR = 1.08, 95% CI: 1.01-1.15) and current smoker (HR = 1.24, 95% CI: 1.16-1.32). Among current smoker, the risk of depressive symptoms increased proportionally to daily smoking amount (< 1 pack; HR = 1.21, 95% CI: 1.13-1.29, and ≥ 1 pack; HR = 1.34, 95% CI: 1.23 - 1.45). This pattern of relationship was consistently observed for pack-year in former smoker and current smoker. Additionally, urine cotinine excretion was proportionally associated with the risk of depressive symptoms. CONCLUSION: Exposure to smoking was associated with the increased risk of depressive symptoms. Dose dependent relationship was observed between smoking amount and the risk of depressive symptoms.

Novel role of LLGL2 silencing in autophagy: reversing epithelial-mesenchymal transition in prostate cancer.

PURPOSE: Prostate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo. METHODS: PC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model. RESULTS: In patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition. CONCLUSION: Defective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.

Patient preference, efficacy, and compliance with zoledronic acid for glucocorticoid-induced osteoporosis in patients with autoimmune diseases.

PURPOSE: We evaluated the preference, patient satisfaction, and efficacy of zoledronic acid compared with oral bisphosphonates (BPs) for glucocorticoid-induced osteoporosis (GIOP) in patients with autoimmune diseases. METHODS: We enrolled 50 patients with new fractures or osteoporosis detected on follow-up bone densitometry after at least 1 year of oral BP use among patients diagnosed with GIOP during treatment for autoimmune diseases. After 1 year of zoledronic acid treatment, patients completed a survey for preference and satisfaction assessment. Treatment efficacy was analysed by comparing bone mineral density changes and fractures with those in a control group of patients who continued oral BP use. RESULTS: Age, sex, treatment duration, and medication history did not differ significantly between the two groups. Among the participants, 86.7% preferred and were more satisfied with intravenous zoledronic acid than with oral BPs, primarily because of the convenience of its administration interval. Only two patients (4%) reported infusion-related adverse events with zoledronic acid. Furthermore, no significant differences were observed in the annualized percentage change in the bone mineral density of the lumbar spine, femur neck, and hip between patients receiving zoledronic acid and those receiving oral BPs. The occurrence of new fractures was consistent across both groups, with two cases in each, showing no significant differences. CONCLUSION: Patients showed a preference for and greater satisfaction with zoledronic acid, and its efficacy in treating osteoporosis was comparable to that of oral BPs. Therefore, zoledronic acid is a suitable treatment option for GIOP in patients with autoimmune diseases.

Dietary Intake of Antioxidant Vitamins and Its Relation to the Progression of Chronic Kidney Disease in Adults With Preserved Renal Function.

OBJECTIVE: It is expected that antioxidants contribute to slow the progression of chronic kidney disease (CKD). However, there are no data on the protective effect of dietary antioxidant vitamins on CKD. The purpose of study was to evaluate the renoprotective effect of dietary antioxidant vitamins in the general population. DESIGN AND METHODS: The study participants were 127,081 Korean adults with preserved renal function with estimated glomerular filtration rate ≥60 mL/min/1.73 m2. They were categorized into 3 groups by tertile levels of dietary antioxidant vitamins intake including vitamins C, E, and A. Cox proportional hazard assumption was used to calculate multivariable hazard ratios and 95% confidence interval for the incident moderate to severe CKD (adjusted hazard ratio [95% confidence interval]) according to tertile levels of dietary intake of antioxidant vitamins. Subgroup analysis was conducted to evaluate the risk of progression from normal to mildly decreased renal function, and from mildly decreased renal function to moderate to severe CKD. RESULTS: The risk of moderate to severe CKD was not significantly associated with the third tertile of dietary antioxidant vitamin intake including vitamin C (1.02 [0.78-1.34]), E (0.96 [0.73-1.27]), and A (0.98 [0.74-1.29]). Additionally, any tertile groups didn't show the significant association with the risk of moderate to severe CKD. Subgroup analysis also didn't show the decreased risk of progression from normal to mildly decreased renal function, and from mildly decreased renal function to moderate to severe CKD in any tertile groups. CONCLUSION: Dietary intake of vitamins C, E, and A was not significantly associated with the risk of CKD progression.

Small flaps in microsurgical breast reconstruction: Selection between the profunda artery perforator and small deep inferior epigastric artery perforator flaps and associated outcomes and complications.

BACKGROUND: The deep inferior epigastric artery perforator (DIEP) flap is widely used in breast reconstruction and the profunda artery perforator (PAP) flap as alternative. However, the difference between the two flaps in smaller breast reconstruction remains lacking, in particular, the donor site complications. In this case series, the results of small breast reconstruction (≤300 g) using PAP or small DIEP flaps were explored. METHODS: Unilateral immediate breast reconstruction using a free PAP flap or small DIEP flap (≤300 g) from 2011 to 2021 were reviewed retrospectively. Excluding patients with delayed reconstruction, 28 patients, including 17 PAP flaps and 11 small DIEP flaps were enrolled. Flap characteristics, breast and donor site complications, and revision surgeries were reviewed. BREAST-Q™ was used for quality-of-life assessment. RESULTS: Compared with a small DIEP flap, a PAP flap was narrow (7.5 ± 1.1 vs. 10.6 ± 0.7 cm, p < .001), short (20.0 ± 2.6 vs. 25.5 ± 1.8 cm, p < .001) and had a shorter pedicle (5.9 ± 1.6 vs. 9.1 ± 1.0 cm, p < .001). There were no significant differences in acute and late complications of wound healing and fat necrosis, but the average number of revisions in the PAP group was significantly higher (1.9 ± 1.3 vs. 0.8 ± 1.4, p = .041). Patient-reported outcomes using BREAST-Q™ displayed no significant difference between the two groups. CONCLUSION: The outcomes of PAP and small DIEP flaps at the breasts and donor sites are satisfactory, despite that a higher tendency of donor site complications in PAP flap and more aesthetic refinement required in the PAP group. The overall outcomes are acceptable.

Anti-TCP1 Antibody Is a Potential Biomarker for Diagnosing Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease caused by autoantibodies. Serum samples from patients with SLE (n = 10) were compared with those from normal controls (NCs, n = 5) using 21K protein chip analysis to identify a biomarker for SLE, revealing 63 SLE-specific autoantibodies. The anti-chaperonin-containing t-complex polypeptide-1 (TCP1) antibody exhibited higher expression in patients with SLE than in NCs. To validate the specificity of the anti-TCP1 antibody in SLE, dot blot analysis was conducted using sera from patients with SLE (n = 100), rheumatoid arthritis (RA; n = 25), Behçet's disease (BD; n = 28), and systemic sclerosis (SSc; n = 30) and NCs (n = 50). The results confirmed the detection of anti-TCP1 antibodies in 79 of 100 patients with SLE, with substantially elevated expression compared to both NCs and patients with other autoimmune diseases. We performed an enzyme-linked immunosorbent assay to determine the relative amounts of anti-TCP1 antibodies; markedly elevated anti-TCP1 antibody levels were detected in the sera of patients with SLE (50.1 ± 17.3 arbitrary unit (AU), n = 251) compared to those in NCs (33.9 ± 9.3 AU), RA (35 ± 8.7 AU), BD (37.5 ± 11.6 AU), and SSc (43 ± 11.9 AU). These data suggest that the anti-TCP1 antibody is a potential diagnostic biomarker for SLE.

Inhibition of Toll-like Receptors Alters Macrophage Cholesterol Efflux and Foam Cell Formation.

Arterial macrophage cholesterol accumulation and impaired cholesterol efflux lead to foam cell formation and the development of atherosclerosis. Modified lipoproteins interact with toll-like receptors (TLR), causing an increased inflammatory response and altered cholesterol homeostasis. We aimed to determine the effects of TLR antagonists on cholesterol efflux and foam cell formation in human macrophages. Stimulated monocytes were treated with TLR antagonists (MIP2), and the cholesterol efflux transporter expression and foam cell formation were analyzed. The administration of MIP2 attenuated the foam cell formation induced by lipopolysaccharides (LPS) and oxidized low-density lipoproteins (ox-LDL) in stimulated THP-1 cells (p < 0.001). The expression of ATP-binding cassette transporters A (ABCA)-1, ABCG-1, scavenger receptor (SR)-B1, liver X receptor (LXR)-α, and peroxisome proliferator-activated receptor (PPAR)-γ mRNA and proteins were increased (p < 0.001) following MIP2 administration. A concentration-dependent decrease in the phosphorylation of p65, p38, and JNK was also observed following MIP2 administration. Moreover, an inhibition of p65 phosphorylation enhanced the expression of ABCA1, ABCG1, SR-B1, and LXR-α. TLR inhibition promoted the cholesterol efflux pathway by increasing the expression of ABCA-1, ABCG-1, and SR-B1, thereby reducing foam cell formation. Our results suggest a potential role of the p65/NF-kB/LXR-α/ABCA1 axis in TLR-mediated cholesterol homeostasis.

DIEP Donor Site Satisfaction between Patients with and without History of Pregnancy.

BACKGROUND: With the success of free autologous breast reconstruction, the abdominal donor site is now an important consideration, especially in patients of childbearing age. In our institution, there are increasing patients who have successfully undergone the deep inferior epigastric artery perforator (DIEP) flap despite previous pregnancy. This study aims to answer questions on the effect of the donor site on pregnancy and vice versa. METHODS: A retrospective cohort study was conducted to identify breast cancer patients who received a free DIEP flap for breast reconstruction from January 2018 to August 2020. Patients were allocated to two groups according to whether they had prior pregnancies with successful deliveries. Demographics, flap-related parameters, surgical outcomes on breast and abdomen, and patient-reported outcome (Breast-Q questionnaire) were analyzed. Patients were excluded if follow-up time was less than 1 year, or if there was incomplete medical records or Breast-Q replies. RESULTS: Ninety-nine of 116 patients had had successful pregnancies with delivery, 17 of them remained nulliparous. No statistically significant differences existed between groups regarding demographic data, flap-related parameters, surgical outcomes on breast and abdomen. Nulliparous patients exhibited significantly lower score in physical well-being in the abdomen domain compared with delivery-experienced patients (62.1 vs. 73.4, p = 0.025). Significantly, nulliparous patients felt more tightness and pulling of the abdominal wall than the delivery-experienced patients (2.9 vs. 3.7; p = 0.05 and 3.5 vs. 4.0; p = 0.04). CONCLUSION: Free DIEP flap can be transferred safely in nulliparous patients despite a slight increase in abdominal tightness and abdominal pulling. Precise flap design and surgical approaches may help to minimize the abdominal discomfort especially on young, normal body mass index, and nonchildbearing patients.

Proteome profiling highlights mechanisms underlying pigment and tocopherol accumulation in red and black rice seeds.

Rice is a major component of the human diet and feeds more than 50 million people across the globe. We previously developed two pigmented rice cultivars, Super-hongmi (red seeds) and Super-jami (black seeds), that are highly rich in antioxidants and exhibit high levels of radical scavenging activities. However, the molecular mechanism underlying the accumulation of pigments and different antioxidants in these rice cultivars remains largely elusive. Here, we report the proteome profiles of mature Super-hongmi and Super-jami seeds, and compared them with the Hopum (white seeds) using a label-free quantitative proteomics approach. This approach led to the identification of 5127 rice seed proteins of which 1628 showed significant changes in the pigmented rice cultivar(s). The list of significantly modulated proteins included a phytoene desaturase (PDS3) which suggested accumulation of ζ-carotene in red seeds while the black seeds seem to accumulate more of anthocyanins because of the higher abundance of dihydroflavonol 4-reductase. Moreover, proteins associated with lignin and tocopherol biosynthesis were highly increased in both red and black cultivars. Taken together, these data report the seed proteome of three different colored rice seeds and identify novel components associated with pigment accumulation in rice.

Neuroprotective Effects of Water Extract from Brown Algae Petalonia binghamiae in an Experimental Model of Focal Cerebral Ischemia In Vitro and In Vivo.

Focal cerebral ischemia (fCI) can result in brain injury and sensorimotor deficits. Brown algae are currently garnering scientific attention as potential therapeutic candidates for fCI. This study investigated the therapeutic effects of the hot water extract of Petalonia binghamiae (wPB), a brown alga, in in vitro and in vivo models of fCI. The neuroprotective efficacy of wPB was evaluated in an in vitro excitotoxicity model established using HT-22 cells challenged with glutamate. Afterward, C57/BL6 mice were administered wPB for 7 days (10 or 100 mg/kg, intragastric) and subjected to middle cerebral artery occlusion and reperfusion (MCAO/R) operation, which was used as an in vivo fCI model. wPB co-incubation significantly inhibited cell death, oxidative stress, and apoptosis, as well as stimulated the expression of heme oxygenase-1 (HO-1), an antioxidant enzyme, and the nuclear translocation of its upstream regulator, nuclear factor erythroid 2-related factor 2 (Nrf2) in HT-22 cells challenged with glutamate-induced excitotoxicity. Pretreatment with either dose of wPB significantly attenuated infarction volume, neuronal death, and sensorimotor deficits in an in vivo fCI model. Furthermore, the attenuation of oxidative stress and apoptosis in the ischemic lesion accompanied the wPB-associated protection. This study suggests that wPB can counteract fCI via an antioxidative effect, upregulating the Nrf2/HO-1 pathway.

Changes in smoking status, amount of smoking and their relation to the risk of microvascular complications in men with diabetes mellitus.

BACKGROUND: Smoking is a definite risk factor for macrovascular complications in diabetes mellitus (DM). However, the effect of smoking on microvascular complications is inconclusive. METHOD: Study participants were 26,673 diabetic men who received health check-up both in 2003-2004 and 2009, excluding women. Assessing smoking status (never, quitting and current) at 2003-2004 and 2009, changes in smoking status were categorised into 7 groups (never - never, never - quitting, never - current, quitting-quitting, quitting-current, current-quitting and current-current). Smoking amount was categorised into never, light (0-10 pack years), moderate (10-20 pack years), and heavy smoking (>20 pack years) based on 2009 data. They were followed-up until 2013 to identify incident microvascular complications. We calculated the adjusted hazard ratios (HR) and 95% confidence interval (CI) (adjusted HR [95% CI]) for incident microvascular complications according to changes in smoking status and smoking amount. RESULTS: Current-quitting (1.271 [1.050-1.538]), current-current (1.243 [1.070-1.444]) and heavy smoking (1.238 [1.078-1.422]) were associated with an increased risk of overall microvascular complications. The risk of nephropathy increased in current-current smoking (1.429 [1.098-1.860]) and heavy smoking (1.357 [1.061-1.734]). An increased risk of neuropathy was observed in current-quitting smoking (1.360 [1.076-1.719]), current-current smoking (1.237 [1.025-1.492]) and heavy smoking (1.246 [1.048-1.481]). However, we couldn't see the interpretable findings for the association between smoking and retinopathy. CONCLUSIONS: Lasting and heavy smoking increases the risk of microvascular complications, including nephropathy and neuropathy. Quitting smoking and reducing smoking amount are imperative in preventing microvascular complications in DM patients.

Efficacy and drug retention of tofacitinib in rheumatoid arthritis: from the nationwide Korean College of Rheumatology Biologics registry.

OBJECTIVES: Janus kinase inhibitors are expected to change the management patterns and prognosis of chronic rheumatic diseases. This study aimed to evaluate the efficacy, drug retention, and adverse events of tofacitinib, a Janus kinase inhibitor, for rheumatoid arthritis (RA) using a Korean nationwide database. METHODS: Data of patients with RA receiving tofacitinib were extracted from the Korean College of Rheumatology Biologics and Targeted Therapy registry, including clinical characteristics and disease activity markers for RA. Outcomes of clinical efficacy, drug survival rate, and safety profiles were compared between biologic disease-modifying anti-rheumatic drug (bDMARD)-naive and -failure patients. Mann-Whitney U-test, logistic regression analysis, Kaplan-Meier analysis, and log-rank test were used in data analysis. RESULTS: Three hundred patients with RA received tofacitinib therapy (16.3% male; mean age 55.4±11.9 years); 91 patients were bDMARD-naive. Baseline disease activity markers and proportions of patients who were taking conventional synthetic DMARDs were not different between bDMARD-naive and bDMARD-failure patients. American College of Rheumatology responses and disease activity score-28 did not differ between bDMARD-failure and -naive patients at the 1-year follow-up. The drug retention rate of tofacitinib did not differ between bDMARD-failure (155 per 2.4 years) and -naive patients (89 per 1.9 years) (log-rank test, p=0.202). In logistic regression, the positivity of RF and ACPA were associated with reduced drug retention (p=0.01 and 0.02, respectively). Totally 83 (27.7%) of patients had adverse, and 14 (4.7%) patients had herpes zoster infection. CONCLUSIONS: Nationwide real-world data showed that tofacitinib therapy is effective in patients with RA independent of previous use of a bDMARD. The drug retention of tofacitinib did not differ between bDMARD-failure and -naive patients, and RF or ACPA positivity may be associated with reduced discontinuation of tofacitinib.