Complement receptor 4 mediates the clearance of extracellular tau fibrils by microglia.

Tauopathies exhibit a characteristic accumulation of misfolded tau aggregates in the brain. Tau pathology shows disease-specific spatiotemporal propagation through intercellular transmission, which is closely correlated with the progression of clinical manifestations. Therefore, identifying molecular mechanisms that prevent tau propagation is critical for developing therapeutic strategies for tauopathies. The various innate immune receptors, such as complement receptor 3 (CR3) and complement receptor 4 (CR4), have been reported to play a critical role in the clearance of various extracellular toxic molecules by microglia. However, their role in tau clearance has not been studied yet. In the present study, we investigated the role of CR3 and CR4 in regulating extracellular tau clearance. We found that CR4 selectively binds to tau fibrils but not to tau monomers, whereas CR3 does not bind to either of them. Inhibiting CR4, but not CR3, significantly reduces the uptake of tau fibrils by BV2 cells and primary microglia. By contrast, inhibiting CR4 has no effect on the uptake of tau monomers by BV2 cells. Furthermore, inhibiting CR4 suppresses the clearance of extracellular tau fibrils, leading to more seed-competent tau fibrils remaining in the extracellular space relative to control samples. We also provide evidence that the expression of CR4 is upregulated in the brains of human Alzheimer's disease patients and the PS19 mouse model of tauopathy. Taken together, our data strongly support that CR4 is a previously undescribed receptor for the clearance of tau fibrils in microglia and may represent a novel therapeutic target for tauopathy.

Antimicrobial activity of ceftazidime-avibactam against KPC-2-producing Enterobacterales: a cross-combination and dose-escalation titration study with relebactam and vaborbactam.

With the introduction of ceftazidime-avibactam worldwide, the antimicrobial activity of new ß-lactam/ß-lactamase inhibitors (BL/BLIs) needs to be investigated. From January 2020 to June 2023, Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales were collected. With a broth microdilution test of new BL/BLIs, cross-activity test with nine combinations of BLs and new BLIs and dose-escalation titration test for non-susceptible isolates were conducted to investigate inhibitory activities of new BLIs. A total of 188 isolates was collected and most isolates (186/188, 98.9%) carried the KPC-2 gene exclusively, while two isolates (1.1%) co-harbored NDM-1. Among the 186 KPC-2-producing isolates, 184 (98.9%) were susceptible to ceftazidime-avibactam, 173 (93.0%) to imipenem-relebactam, and 184 (98.9%) to meropenem-vaborbactam. All isolates non-susceptible to imipenem-relebactam or meropenem-vaborbactam became susceptible when avibactam replaced relebactam or vaborbactam, with 7 of 11 (63.6%) imipenem-relebactam non-susceptible isolates and both (100.0%) of the meropenem-vaborbactam non-susceptible isolates. When the minimum inhibitory concentrations (MICs) of BLs were compared using log2 scales, combinations with avibactam showed statistically significant efficacy in lowering MICs compared to relebactam and vaborbactam (all P < 0.05). In the dose-escalation test of new BLIs, increasing dose of all new BLIs corresponded to increased susceptibility to BLs. Ceftazidime-avibactam exhibited excellent susceptibility against KPC-2-producing Enterobacterales unless co-harboring metallo-ß-lactamase. The cross-combination test against non-susceptible isolates suggests that the inhibitory activity of avibactam was superior to those of relebactam or vaborbactam. Increasing the dose of new BLIs produced increased susceptibility to BLs, suggesting that high-concentration regimen need to be developed. IMPORTANCE: This study investigated 188 Klebsiella pneumoniae carbapenemase (KPC)-2-producing Enterobacterales collected from January 2020 to June 2023 in a tertiary care hospital of Korea. Most isolates were susceptible to ceftazidime-avibactam (98.9%) and meropenem-vaborbactam (98.9%), while susceptibility to imipenem-relebactam was lower (93.0%). The cross-combination test using nine combinations of the individual ß-lactams (BLs) and new ß-lactamase inhibitors (BLIs) showed that the inhibitory activity of avibactam was significantly superior to relebactam or vaborbactam when the Log2 MIC of BLs were compared for each combination with BLIs (all P < 0.05). The dose-escalation test of new BLIs demonstrated that increasing doses of new BLIs corresponded to increased susceptibility to BLs. Taken together, this study illustrates the excellent activity of ceftazidime-avibactam against KPC-2-producing Enterobacterales and suggests further investigation into high-concentration regimens for potentially non-susceptible clinical isolates.

V advancement eversion flap for fingertip injury: Preventing ischemia and hook-nail deformity.

Introduction: Traumatic fingertip amputation is the most common type of upper extremity injuries. The V-Y advancement flap is a reliable method for reconstructing fingertip defects, but it is associated with complications such as hook-nail deformity and suture site ischemia. Here, we describe our modifications to V-Y advancement flap technique, termed as "V advancement eversion flap" and review the outcomes of this procedure in 21 patients with fingertip amputation. Methods: This was a retrospective review of 21 consecutive patients with fingertip injury who were treated surgically using the V advancement eversion flap technique at a single trauma center between 2006 and 2019. We analyzed the age, injury location and mechanism, Allen classification, injury geometry, and objective and subjective clinical outcomes. Results: Twenty-three fingertip amputations with defect sizes greater than 1.0 cm2 from the tip to lunula were included in this study. The mean age of the patients was 43.6 years (range, 24-65 years). The average follow-up period was 20 months (range, 12-37 months). The average wound healing time (apparent epithelization) was 29.4 days (range, 14-41 days). At the final follow-up, all flaps had healed uneventfully without noticeable hook-nail deformity. In the static two-point discrimination test, the mean value was 4.61 mm in the injured finger. Patient ratings of the outcomes were "excellent" in 18 and "good" in 5 cases. Conclusion: The V advancement eversion flap technique, when properly designed and executed in fingertip amputation cases, can minimize morbidity and result in successful wound healing without flap necrosis and hook-nail deformity.

Anatomical Exploration of the KI1 Acupoint: Implications for Medial and Lateral Plantar Nerve Stimulation.

Background and Objectives: This study aims to identify the precise anatomical location and therapeutic mechanisms of the KI1 acupoint (Yongquan) in relation to foot muscles and nerves, known for treating neurological disorders and pain. Materials and Methods: Dissection of six cadavers at Chungnam National University College of Medicine examined KI1's relation to the foot's four-layer structure. Results: The KI1 acupoint was located in the superficial and deep layers of the plantar foot, adjacent to significant nerves like the medial and lateral plantar nerves. Differences in the acupoint's exact location between genders were noted, reflecting variances in foot morphology. KI1 acupuncture was found to stimulate the muscle spindles and nerve fibers essential for balance and bipedal locomotion. This stimulation may enhance sensory feedback, potentially improving cognitive functions and balance control. Conclusions: This anatomical insight into KI1 acupuncture underpins its potential in neurological therapies and pain management.

The Dimensional Conceptualization of Personality Disorders: Personality Organization, Personality Functioning, and Personality Disorders.

Over the past several decades, significant criticism of the categorical classification system for personality disorders has highlighted the need to transition to a dimensional classification system. This study reviewed key issues involved in the potential conversion of the diagnostic system of personality disorders from a categorical to a dimensional model. The result suggests that Kernberg's concept of personality organization can be used to indicate the overall severity of personality pathology.

Associations of toll-like receptor polymorphisms with systemic lupus erythematosus: A meta-analysis.

Objective: The objective of this study was to examine whether polymorphisms in toll-like receptors 7 and 4 (TLR7 and 4) contribute to vulnerability to systemic lupus erythematosus (SLE). Methods: We searched MEDLINE, Embase, and Web of Science for relevant articles and performed a meta-analysis to investigate the relationship between TLR7 rs179008, rs3853839, rs1790010, TLR4 rs4986791, and rs798690 polymorphisms and SLE. Results: Eighteen studies and 16 papers including 8022 patients with SLE and 9822 healthy controls were retrieved. Meta-analysis revealed that the TLR7 rs179008 T variant was not associated with SLE (OR = 1.008, 95% CI = 0.849-1.394, P = 0.504). Ethnic classification revealed no association between the TLR7 rs179008 T gene and SLE in either European or Latin American groups. Additionally, homozygous comparison, recessive, and dominant models revealed no association between the TLR7 rs179008 variant and SLE. In contrast, a significant association between SLE and the TLR7 rsrs3853839 GG + GA allele (OR = 2.135, 95% CI = 1.502-3.035, <0.001; OR = 23.20, 95% CI = 14.13-38.08, <0.001) was observed in the Arab and Asian groups. The T variant of TLR7 rsrs179010 was also associated with SLE in Asians (OR = 1.177, 95% CI = 1.048-1.321, P = 0.006). In contrast, the TLR4 rs4986791 variant was not associated with SLE in Europeans when allele, homozygous comparison, recessive, and dominant models were used. Furthermore, no association between the TLR4 rs4986790 variant and SLE risk in Europeans was found using any genomic model. Conclusions: Meta-analysis revealed that the TLR7 rs3853839 variant is associated with SLE risk in Asians and Arabs and that TLR7 rs179010 is associated with SLE in Asians. However, TLR7 rs179008, TLR4 rs4986791, and TLR rs798690 polymorphisms were not associated with SLE risk.

Effect of Thrombin-Containing Local Hemostatics on Postoperative Spinal Epidural Hematoma in Biportal Endoscopic Spinal Surgery.

STUDY DESIGN: Retrospective case-control study. PURPOSE: This study aimed to investigate the preventive effect of thrombin-containing local hemostatics (TCLH) on postoperative spinal epidural hematoma (POSEH) in biportal endoscopic spinal surgery (BESS). This study compared the incidence of morphometric and symptomatic POSEH with or without TCLH in BESS. OVERVIEW OF LITERATURE: POSEH is reported not uncommon in BESS when compared with conventional spine surgery (CSS). TCLH achieves hemostasis with a high success rate in CSS. However, few studies have examined the effect of TCLH on BESS. METHODS: Patients with and without TCLH were assigned to groups A and B, respectively. POSEH between the two groups was compared morphometrically and symptomatically. The risk factors for symptomatic and morphometric POSEH in BESS were identified. RESULTS: The morphometric POSEH was greater in group B, and the difference was significant (p =0.019). The incidence of symptomatic POSEH was lower in group A with 4.6% (5/109) than in group B with 9.5% (9/95); however, the rate was not significantly different (p =0.136). The morphometric POSEH was classified into two small (hG1 and hG2) and large (hG3 and hG4) and were compared between groups A and B, and the difference was significant (p =0.02). In the multivariable logistic regression, nonuse of TCLH (p =0.004) and preoperative diagnosis of stenosis (p =0.016) were variables found to be significant risk factors of morphometric POSEH. CONCLUSIONS: Severe compression of the thecal sac by POSEH is more common in patients without TCLH. The risk of hematoma formation was higher when bilateral decompression was needed and the cut bone surface was more exposed.

Clinical features and change in incidence of acute acquired comitant esotropia: a 15-year single-centre study in South Korea.

BACKGROUND/OBJECTIVES: We investigated the clinical features and change in incidence of AACE in South Korea. SUBJECTS/METHODS: We reviewed the medical records of AACE patients who visited the Strabismus Clinic of at a tertiary referral hospital from 2007 to 2021. Clinical features were retrieved, including age at onset, angle of deviation, refractive errors, neuroimaging findings, and treatment outcomes. For each year, the proportion of new AACE patients among all new patients who visited the clinic, and the ratio of new AACE patients to new intermittent exotropia (IXT) patients, were analysed to estimate the incidence of AACE. RESULTS: Overall, 59 patients were included in the study. The mean age of the patients was 24.7 ± 9.3 years; the incidence of AACE was highest in teenagers and young adults. No patients had a history of visual occlusion, recent physical or psychological stress, or uncorrected myopia, unlike to classic AACE; moreover, no patients exhibited abnormalities in neuroimaging. There was a significantly increasing trend in the proportion of new AACE patients among all new patients (linear regression analysis, R2 = 0.778, p < 0.001). There was also a significantly increasing trend in the ratio of new AACE patients to new IXT patients (R2 = 0.803, p < 0.001). CONCLUSIONS: A new type of AACE, distinct from the classic types, is increasingly common in South Korea; this increasing incidence also appears to be a global phenomenon. Large-scale investigations are needed to define the exact clinical features, incidence, and pathophysiology of this new type of AACE.

Association between systemic sclerosis and venous thromboembolism, pulmonary embolism, and deep vein thrombosis: a meta-analysis.

OBJECTIVE: This study aimed to analyze the published data pertaining to the correlation between venous thromboembolism (VTE) and systemic sclerosis (SSc). METHODS: We conducted manual searches and explored MEDLINE, EMBASE, and Cochrane databases to review papers reporting the risk of VTE in patients with SSc. A meta-analysis was performed exploring the relative risks (RRs) of deep vein thrombosis (DVT), pulmonary embolism (PE), and VTE in these individuals. RESULTS: Six trials that included 41,105 patients with SSc were eligible for inclusion. A meta-analysis of the six included studies revealed a statistically significant correlation (RR 2.372, 95% confidence interval [CI] = 1.608-3.500, p < 0.001) between the risk of VTE and SSc. Regional subgroup study revealed a strong correlation between SSc and VTE risk in Americans, Europeans, and Asians. Additionally, a significant correlation between SSc and PE risk was observed (RR 3.154, 95% CI = 1.320-7.539, p = 0.010). Finally, the meta-analysis revealed a substantial correlation (RR 5.190, 95% CI = 1.513-17.01, p = 0.009) between the risk of DVT and SSc. CONCLUSION: This meta-analysis showed that SSc is linked to an increased risk of DVT, PE, and VTE. This finding underscores the importance of close monitoring for the emergence of these conditions in patients with SSc.

A meta-analysis of the association between the ATIC 347 C/G polymorphism and methotrexate responsiveness and toxicity in rheumatoid arthritis.

OBJECTIVES: The purpose of this study was to determine whether the 347 C/G polymorphism in the 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) gene predicts the responsiveness to or toxicity of methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHOD: To identify relevant publications, we searched the Medline, Embase, Cochrane, and Web of Science databases. We performed a meta-analysis of studies on the relationship between the ATIC 347 C/G polymorphism and MTX toxicity or non-responsiveness in patients with RA. RESULTS: Thirteen studies consisting of 3,185 patients with RA satisfied our inclusion criteria. The analysis included 10 studies on MTX responsiveness and seven studies on MTX toxicity in patients with RA in connection with ATIC 347C/G polymorphism. According to our meta-analysis, the ATIC 347 GG genotype and failure to respond to MTX treatment were significantly associated (OR = 0.741, 95% CI = 0.591-0.929, p=0.009). According to stratification by ethnicity, this genotype was significantly associated with non-responsiveness to MTX in Europeans (OR=0.548, 95% CI=0.377-0.796, p=0.002) but not in Asian populations (OR=0.882, 95% CI=0.665-1.1172, p=0.388). However, analyses employing allelic, dominant, and homozygous contrast models failed to detect any relationship between the polymorphism and the failure to respond to MXT. However, the ATIC 347GG genotype and MTX toxicity were not associated (OR=1.278, 95% CI=0.937-1.745, p=0.121). Asian and European populations showed no evidence of a relationship between the ATIC 347GG genotype and MTX toxicity (OR=1.252, 95% CI=0.905-1.732, p=0.175 and OR =1.617, 95% CI=0.549-4.765, p=0.383, respectively). CONCLUSIONS: This meta-analysis revealed that ATIC 347 C/G polymorphism was related to non-responsiveness to MTX in European populations with RA. However, no significant correlation was found with MTX toxicity.

APP-C31: An Intracellular Promoter of Both Metal-Free and Metal-Bound Amyloid-ß40 Aggregation and Toxicity in Alzheimer's Disease.

Intracellular C-terminal cleavage of the amyloid precursor protein (APP) is elevated in the brains of Alzheimer's disease (AD) patients and produces a peptide labeled APP-C31 that is suspected to be involved in the pathology of AD. But details about the role of APP-C31 in the development of the disease are not known. Here, this work reports that APP-C31 directly interacts with the N-terminal and self-recognition regions of amyloid-ß40 (Aß40 ) to form transient adducts, which facilitates the aggregation of both metal-free and metal-bound Aß40 peptides and aggravates their toxicity. Specifically, APP-C31 increases the perinuclear and intranuclear generation of large Aß40 deposits and, consequently, damages the nucleus leading to apoptosis. The Aß40 -induced degeneration of neurites and inflammation are also intensified by APP-C31 in human neurons and murine brains. This study demonstrates a new function of APP-C31 as an intracellular promoter of Aß40 amyloidogenesis in both metal-free and metal-present environments, and may offer an interesting alternative target for developing treatments for AD that have not been considered thus far.

Relative efficacy and safety of calcineurin inhibitor, mycophenolate mofetil, and azathioprine as maintenance therapies for lupus nephritis: a network meta-analysis.

OBJECTIVE: This study aimed to assess the relative efficacy and safety of calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), and azathioprine (AZA) as maintenance therapies for lupus nephritis. METHODS: Randomized controlled trials (RCTs) examining the efficacy and safety of CNI, MMF, and AZA as maintenance therapies in patients with lupus nephritis were included. We performed a Bayesian random-effects network meta-analysis to combine the direct and indirect evidence from RCTs. RESULTS: Ten RCTs comprising 884 patients were included in the study. Although the difference was not statistically significant, MMF showed a trend toward a lower relapse rate compared with AZA (odds ratio [OR] 0.72, 95% credible interval [CrI] 0.45-1.22). Similarly, tacrolimus showed a trend toward a lower relapse rate compared with AZA (OR 0.85, 95% CrI 0.34-2.00). Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that MMF had the highest probability of being the best treatment based on the relapse rate, followed by CNI and AZA. The incidence of leukopenia in the MMF and CNI groups was significantly lower than that in the AZA group (OR 0.12, 95% CrI 0.04-0.34; OR 0.16, 95% CrI 0.04-0.50; respectively). Fewer patients with infections were observed in the MMF group than in the AZA group, although the difference was not statistically significant. The analysis of withdrawals due to adverse events showed a similar pattern. CONCLUSION: Lower relapse rates combined with a more favorable safety profile suggest that CNI and MMF are superior to AZA as maintenance treatments in lupus nephritis patients.

Comparison of the efficacy and safety of olokizumab at different dosages in patients with active rheumatoid arthritis: a network meta-analysis of randomized controlled trials.

OBJECTIVE: This study aimed to assess the relative efficacy and safety of olokizumab at different dosages in patients with active rheumatoid arthritis (RA). METHODS: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of olokizumab administered intravenously to RA patients at 64 mg/kg every 2 or 4 weeks (Q2 or Q4W). RESULTS: Five RCTs comprising 2609 patients met the inclusion criteria. Both olokizumab Q2 and Q4W treatments achieved a significant American College of Rheumatology 20% response (ACR20) compared with the placebo (odds ratio [OR] 3.21, 95% credible interval [CrI] 2.53-4.09; OR 3.05, 95% CrI 2.43-3.86). However, olokizumab Q2W was associated with the most favorable surface using the cumulative ranking curve (SUCRA) for the ACR20 response rate. The ranking probability based on the SUCRA indicated that olokizumab Q2W had the highest probability of being considered the best treatment option for achieving the ACR20 response rate, followed by olokizumab Q4W, adalimumab, and placebo. The ACR50 and 70 response rates showed a similar distribution pattern to the ACR20 response rate, except that olokizumab Q4W had a higher-ranking probability than olokizumab Q2W for ACR50. The SUCRA rating likelihood of adverse events (AEs) and withdrawal due to AEs showed that a placebo was likely to be the best intervention. CONCLUSION: Both olokizumab Q2 and Q4W were efficacious and well-tolerated treatments for active RA.

Role of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as potential biomarkers in Behçet's disease: a meta-analysis.

AIM: The mean platelet volume (MPV), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) have attracted interest as possible indicators of inflammation and disease activity in various diseases. This meta-analysis assessed the association between NLR, MPV, PLR, and Behçet's disease (BD) and their correlation with disease activity and thrombosis. METHODS: A thorough search of the Medline, Embase, and Cochrane databases was performed to identify relevant studies. Studies comparing NLR, MPV, and PLR between patients with BD and healthy controls, as well as studies examining these measures in connection with disease activity and thrombosis in BD satisfied the inclusion criteria. The standardized mean difference (SMD) and 95% confidence interval (CI) were used to calculate the effect sizes. RESULTS: This meta-analysis included 24 articles. The findings revealed no discernible differences in MPV between the BD and control groups (p = 0.992). NLR was substantially higher in the BD group than in the control group (p < 0.001). PLR was higher in the BD group than in the control group (p = 0.030), indicating that BD is associated with a larger PLR. Patients with active and inactive BD did not vary significantly in terms of disease activity according to the MPV. Comparing MPV between patients with BD with and without thrombosis showed no discernible changes. However, individuals with active BD had a considerably higher NLR and PLR than those with inactive BD (p = 0.003 and p = 0.005, respectively). The statistical significance threshold for the association between NLR, PLR, and thrombosis in patients with BD was not met. CONCLUSION: NLR and PLR can be regarded as general markers of inflammation according to the results of this meta-analysis.

Standardized mortality ratios in systemic sclerosis: a meta-analysis assessing overall and sex- and disease subtype-specific differences.

OBJECTIVE: This study aims to evaluate the overall and sex- and illness subtype-specific standardized mortality ratios (SMRs) in patients with systemic sclerosis (SSc). METHODS: We searched and examined studies that compared the overall and sex- and illness subtype-specific SMRs in patients with SSc to those in the general population using MEDLINE, EMBASE, and Cochrane databases (until May 2023). We then conducted a meta-analysis of the overall and sex- and illness subtype-specific SMRs in patients with SSc. RESULTS: Overall, 29 studies including 30,673 patients with SSc and 5582 deaths met the inclusion criteria. Patients with SSc had a higher overall SMR than that in the general population (SMR: 2.742, 95% confidence interval [CI]: 2.224-3.38091, p < 0.001). The SMR significantly increased in populations from Europe, North America, Asia, and Oceania according to regional stratification. A sex-specific meta-analysis revealed a substantial increase in the SMR in both men and women (SMR: 3.598, 95% CI: 3.097-4.180, p < 0.001; SMR: 2.833, 95% CI: 2.4384-3.292, p < 0.001, respectively) and the mortality rate was higher in men compared to women. A substantial increase in the SMR in diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) was observed in a disease subtype-specific meta-analysis. In addition, the SMR in the dcSSc group was higher than that in the lcSSc group (SMR: 4.726, 95% CI: 3.795-5.885, p < 0.001; SMR: 1.987, 95% CI: 1.586-2.489, p < 0.001, respectively). CONCLUSION: Our findings demonstrated that the mortality rate in patients with SSc was 2.74-times greater than that in the general population. The mortality rate was higher in men compared to women. Additionally, compared to patients with lcSSc, those with dcSSc showed much higher fatality rates.

Investigating the Cardiovascular Benefits of Dapagliflozin: Vasodilatory Effect on Isolated Rat Coronary Arteries.

Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is an antidiabetic medication that reduces blood glucose. Although it is well known that dapagliflozin has additional benefits beyond glycemic control, such as reducing blood pressure and lowering the risk of cardiovascular events, no sufficient research data are available on the direct effect of dapagliflozin on cardiovascular function. Thus, in this study, we investigated the direct vascular effect of dapagliflozin on isolated rat coronary arteries. The left descending coronary arteries of 13-week-old male Sprague Dawley rats were cut into segments 2-3 mm long and mounted in a multi-wire myography system to measure isometric tension. Dapagliflozin effectively reduced blood vessel constriction induced by U-46619 (500 nM) in coronary arteries regardless of the endothelium. Treatment with an eNOS inhibitor (L-NNA, 100 µM), sGC inhibitor (ODQ, 5 µM), or COX inhibitor (indomethacin, 3 µM) did not affect the vasodilation induced by dapagliflozin. The application of a Ca2+-activated K+ channel (KCa) blocker (TEA, 2 mM), voltage-dependent K+ channel (KV) blocker (4-AP, 2 mM), ATP-sensitive K+ channel blocker (KATP) glibenclamide (3 µM), and inward-rectifier K+ channel (KIR) blocker (BaCl2, 30 µM) did not affect the dapagliflozin-induced vasodilation either. The treatment with dapagliflozin decreased contractile responses induced by the addition of Ca2+, which suggested that the extracellular Ca2+ influx was inhibited by dapagliflozin. Treatment with dapagliflozin decreased the phosphorylation level of the 20 kDa myosin light chain (MLC20) in vascular smooth muscle cells. In the present study, we found that dapagliflozin has a significant vasodilatory effect on rat coronary arteries. Our findings suggest a novel pharmacologic approach for the treatment of cardiovascular diseases in diabetic patients through the modulation of Ca2+ homeostasis via dapagliflozin administration.

Use of Three-Column Reconstruction and Free Vascularized Fibular Grafts for the Repair of Large Tibial Defects after Tumor Resection.

Background: This study aimed to evaluate the clinical outcomes of three-column reconstruction of the lower leg using a single-barrel contralateral vascularized fibular graft (VFG), medial locking plate, and the ipsilateral fibula for the repair of large tibial defects after tumor resection. Methods: In this retrospective study, we reviewed 12 patients who underwent three-column reconstruction using a single-barrel contralateral VFG, medial locking plate, and the ipsilateral fibula between June 1996 and May 2020. These patients had large tibial bone defects following tumor resection. The mean age of the patients was 26.3 years (range, 11-63 years), and 7 of them were women. The mean follow-up period was 104.8 months (range, 26-284 months). The mean size of the tibial bone defect after tumor resection was 17.8 cm (range, 11-26.8 cm). The clinical and radiological outcomes were evaluated at the final follow-up. Results: All patients survived beyond the final follow-up without recurrence of the primary bone tumor. The mean time from reconstruction to bony union at both host-graft junctions was 12.9 months (range, 4-36 months). The mean Musculoskeletal Tumor Society score was 82.3% (range, 60%-97%). All tibial defects were reconstructed with adequate bone healing. There were 4 cases of stress fracture and graft failure; these were resolved by using longer plates and more screws. All patients were ambulatory without assistance and showed no permanent complications. Conclusions: Large tibial defects that occur after tumoral resection can be effectively reconstructed by three-column reconstruction using a medial locking plate, an inlay single-barrel VFG harvested from the contralateral side, and the intact ipsilateral fibula. This technique permits early weight-bearing before fibular hypertrophy and bony union.

Chromosome-level genome assembly of chub mackerel (Scomber japonicus) from the Indo-Pacific Ocean.

Chub mackerels (Scomber japonicus) are a migratory marine fish widely distributed in the Indo-Pacific Ocean. They are globally consumed for their high Omega-3 content, but their population is declining due to global warming. Here, we generated the first chromosome-level genome assembly of chub mackerel (fScoJap1) using the Vertebrate Genomes Project assembly pipeline with PacBio HiFi genomic sequencing and Arima Hi-C chromosome contact data. The final assembly is 828.68 Mb with 24 chromosomes, nearly all containing telomeric repeats at their ends. We annotated 31,656 genes and discovered that approximately 2.19% of the genome contained DNA transposon elements repressed within duplicated genes. Analyzing 5-methylcytosine (5mC) modifications using HiFi reads, we observed open/close chromatin patterns at gene promoters, including the FADS2 gene involved in Omega-3 production. This chromosome-level reference genome provides unprecedented opportunities for advancing our knowledge of chub mackerels in biology, industry, and conservation.

Risk factors and clinical outcomes of cytomegalovirus diseases in hematologic malignancy patients without hematopoietic stem-cell transplantation.

PURPOSE: This study aims to evaluate the risk factors and prognosis for CMV diseases in hematologic malignancy patients without hematopoietic stem-cell transplantation (HSCT). METHODS: We performed a case-control study (1:2) between 2012 and 2022. Adults with pathologic-confirmed CMV diseases (n=60) among hematologic malignancy patients were matched and compared to whom without CMV disease. RESULTS: Lymphoma was the most common underlying malignancy, and gastrointestinal tract involvement was the most common CMV disease. In the case group, high-dose steroid administration and transfusion within one month before diagnosis were higher (p<0.001). Steroid administration (aOR=5.78; 95% confidence interval: 1.25-26.68, p=0.024), red blood cell transfusion within one month (aOR=14.63; 2.75-77.76, p=0.002), low BMI (aOR=13.46, 2.07-87.45, p=0.006), and hypoalbuminemia (aOR=26.48, 5.93-118.17, p<0.001) were independent risk factors associated with CMV disease. The 30-day mortality was higher in the case group and CMV disease was significantly associated with all-cause mortality (aOR=14.41, 3.23-64.31, p<0.001). CONCLUSION: In hematologic malignancy patients without HSCT, risk factors for CMV organ disease included high-dose steroid administration and RBC transfusion within one month, low BMI, and hypoalbuminemia. Overall mortality was significantly higher with CMV disease, and CMV disease occurrence was a significant risk factor for mortality.

Mucosal distribution of somatostatin-secreting gastric Delta cells in children with gastrointestinal reflux diseases.

Introduction: Gastric delta cells (D-cells) secrete somatostatin, which is the primary paracrine suppressor of acid secretion. The number and distribution of D-cells were investigated in children exhibiting endoscopic findings of duodenogastric and gastroesophageal reflux. This study aimed to determine whether the number of D-cells in the gastric body differs from that in the gastric antrum in children using endoscopic findings. Methods: We retrospectively used immunohistochemical assessments to determine the number of D-cells in the gastric body and antrum in 102 children who presented with abdominal symptoms. The number and distribution of D-cells were investigated according to symptoms, endoscopic findings of gastroesophageal reflux and duodenogastric reflux, and Helicobacter pylori infection status. Results: The average age of the patients was 13.3 ± 3.3 years, and the male-to-female ratio was 1:1.68. The mean number of D-cells per high-power field in the antrum and body did not significantly differ by symptoms. However, these values were significantly lower in the gastric body than in the antrum for all symptoms (p < 0.05). Children with reflux had a higher mean number of D-cells (9.6 ± 8.8) in the gastric body than did those without reflux (4.3 ± 3.4) (p = 0.007). Furthermore, the number of D-cells in the gastric body was marginally significantly lower in Helicobacter pylori-positive children (4.9 ± 6.5) than in Helicobacter pylori-negative children (8.5 ± 8.2) (p = 0.053). Conclusion: The number of D-cells in the gastric body decreased in Helicobacter pylori-positive children but significantly increased in children with duodenogastric reflux. Therefore, somatostatin peptide secretion by D-cells may be a major pathophysiological pathway in gastrointestinal reflux disease.