The Neuroprotective Effect of Therapeutic Hypothermia in Cognitive Impairment of an Ischemia/Reperfusion Injury Mouse Model.

Background and Objectives: Therapeutic hypothermia (TH) shows promise as an approach with neuroprotective effects, capable of reducing secondary brain damage and intracranial pressure following successful mechanical thrombectomy in the acute phase. However, its effect on cognitive impairment remains unclear. This study investigated whether TH can improve cognitive impairment in a mouse model of transient middle cerebral artery occlusion followed by reperfusion (tMCAO/R). Materials and Methods: Nine-week-old C57BL/6N mice (male) were randomly assigned to three groups: sham, tMCAO/R, and tMCAO/R with TH. Cognitive function was assessed 1 month after model induction using the Y-maze test, and regional cerebral glucose metabolism was measured through positron emission tomography with fluorine-18 fluorodeoxyglucose. Results: tMCAO/R induced cognitive impairment, which showed improvement with TH. The TH group exhibited a significant recovery in cerebral glucose metabolism in the thalamus compared to the tMCAO/R group. Conclusions: These findings indicate that TH may hold promise as a therapeutic strategy for alleviating ischemia/reperfusion-induced cognitive impairment.

Transcatheter Treatment of Mitral Valve Regurgitation in the Setting of Concomitant Coronary or Multivalvular Heart Disease: A Focused Review.

Treatment for mixed valve disease has historically been limited, often surgery being the only option. With the recent advancement of transcatheter therapies, percutaneous approaches are quickly becoming viable therapeutic considerations in inoperable or high-risk patients, also offering the option for a staged or same-session treatment. Guidelines are primarily focused on single-valve disease. However, patients often present with multiple pathologies. This review summarizes the data and literature on transcatheter treatment of patients with mitral regurgitation who concomitantly have aortic stenosis or regurgitation, tricuspid regurgitation, or ischemic cardiomyopathy. Pathophysiology, hemodynamics, available therapies as well as order and timing of interventions are discussed.

TNF in Human Tuberculosis: A Double-Edged Sword.

TNF, a pleiotropic proinflammatory cytokine, is important for protective immunity and immunopathology during Mycobacterium tuberculosis (Mtb) infection, which causes tuberculosis (TB) in humans. TNF is produced primarily by phagocytes in the lungs during the early stages of Mtb infection and performs diverse physiological and pathological functions by binding to its receptors in a context-dependent manner. TNF is essential for granuloma formation, chronic infection prevention, and macrophage recruitment to and activation at the site of infection. In animal models, TNF, in cooperation with chemokines, contributes to the initiation, maintenance, and clearance of mycobacteria in granulomas. Although anti-TNF therapy is effective against immune diseases such as rheumatoid arthritis, it carries the risk of reactivating TB. Furthermore, TNF-associated inflammation contributes to cachexia in patients with TB. This review focuses on the multifaceted role of TNF in the pathogenesis and prevention of TB and underscores the importance of investigating the functions of TNF and its receptors in the establishment of protective immunity against and in the pathology of TB. Such investigations will facilitate the development of therapeutic strategies that target TNF signaling, which makes beneficial and detrimental contributions to the pathogenesis of TB.

Body Mass Index, Adverse Pregnancy Outcomes, and Cardiovascular Disease Risk.

BACKGROUND: Obesity is a well-established risk factor for both adverse pregnancy outcomes (APOs) and cardiovascular disease (CVD). However, it is not known whether APOs are mediators or markers of the obesity-CVD relationship. This study examined the association between body mass index, APOs, and postpartum CVD risk factors. METHODS: The sample included adults from the nuMoM2b (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be) Heart Health Study who were enrolled in their first trimester (6 weeks-13 weeks 6 days gestation) from 8 United States sites. Participants had a follow-up visit at 3.7 years postpartum. APOs, which included hypertensive disorders of pregnancy, preterm birth, small-for-gestational-age birth, and gestational diabetes, were centrally adjudicated. Mediation analyses estimated the association between early pregnancy body mass index and postpartum CVD risk factors (hypertension, hyperlipidemia, and diabetes) and the proportion mediated by each APO adjusted for demographics and baseline health behaviors, psychosocial stressors, and CVD risk factor levels. RESULTS: Among 4216 participants enrolled, mean±SD maternal age was 27±6 years. Early pregnancy prevalence of overweight was 25%, and obesity was 22%. Hypertensive disorders of pregnancy occurred in 15%, preterm birth in 8%, small-for-gestational-age birth in 11%, and gestational diabetes in 4%. Early pregnancy obesity, compared with normal body mass index, was associated with significantly higher incidence of postpartum hypertension (adjusted odds ratio, 1.14 [95% CI, 1.10-1.18]), hyperlipidemia (1.11 [95% CI, 1.08-1.14]), and diabetes (1.03 [95% CI, 1.01-1.04]) even after adjustment for baseline CVD risk factor levels. APOs were associated with higher incidence of postpartum hypertension (1.97 [95% CI, 1.61-2.40]) and hyperlipidemia (1.31 [95% CI, 1.03-1.67]). Hypertensive disorders of pregnancy mediated a small proportion of the association between obesity and incident hypertension (13% [11%-15%]) and did not mediate associations with incident hyperlipidemia or diabetes. There was no significant mediation by preterm birth or small-for-gestational-age birth. CONCLUSIONS: There was heterogeneity across APO subtypes in their association with postpartum CVD risk factors and mediation of the association between early pregnancy obesity and postpartum CVD risk factors. However, only a small or nonsignificant proportion of the association between obesity and CVD risk factors was mediated by any of the APOs, suggesting APOs are a marker of prepregnancy CVD risk and not a predominant cause of postpartum CVD risk.

Correction: Genetic and chemical markers for authentication of three Artemisia species: A. capillaris, A. gmelinii, and A. fukudo.

[This corrects the article DOI: 10.1371/journal.pone.0264576.].

LED Lights Influenced Phytochemical Contents and Biological Activities in Kale (Brassica oleracea L. var. acephala) Microgreens.

Light-emitting diodes (LEDs) are regarded as an effective artificial light source for producing sprouts, microgreens, and baby leaves. Thus, this study aimed to investigate the influence of different LED lights (white, red, and blue) on the biosynthesis of secondary metabolites (glucosinolates, carotenoids, and phenolics) and the biological effects on kale microgreens. Microgreens irradiated with white LEDs showed higher levels of carotenoids, including lutein, 13-cis-ß-carotene, α-carotene, ß-carotene, and 9-cis-ß-carotene, than those irradiated with red or blue LEDs. These findings were consistent with higher expression levels of carotenoid biosynthetic genes (BoPDS and BoZDS) in white-irradiated kale microgreens. Similarly, microgreens irradiated with white and blue LEDs showed slightly higher levels of glucosinolates, including glucoiberin, progoitrin, sinigrin, and glucobrassicanapin, than those irradiated with red LEDs. These results agree with the high expression levels of BoMYB28-2, BoMYB28-3, and BoMYB29 in white- and blue-irradiated kale microgreens. In contrast, kale microgreens irradiated with blue LEDs contained higher levels of phenolic compounds (gallic acid, catechin, ferulic acid, sinapic acid, and quercetin). According to the total phenolic content (TPC) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) inhibition assays, the extracts of kale microgreens irradiated with blue LEDs had slightly higher antioxidant activities, and the DPPH inhibition percentage had a positive correlation with TPC in the microgreens. Furthermore, the extracts of kale microgreens irradiated with blue LEDs exhibited stronger antibacterial properties against normal pathogens and multidrug-resistant pathogens than those irradiated with white and red LEDs. These results indicate that white-LED lights are suitable for carotenoid production, whereas blue-LED lights are efficient in increasing the accumulation of phenolics and their biological activities in kale microgreens.

The result of prospective evaluation of 3-dimensional printing-aided extensive thoracoabdominal aorta repair.

Objectives: Paraplegia is a distressing complication after open thoracoabdominal aortic aneurysm (TAAA) repair, and revascularization of T8-L2-level segmental arteries is considered pivotal to prevent paraplegia. We employed 3-dimensional (3D) printing to efficiently revascularize segmental/visceral arteries and prospectively evaluated its safety and efficacy. Methods: From January 1, 2020, to June 30, 2022, we prospectively enrolled patients of extent I, II, or III TAAA repair. Guidance models were 3D-printed based on preoperative computed tomography, and multibranched aortic grafts were manually constructed upon this model before surgery. The composite outcome of operative mortality, permanent stroke, and permanent spinal cord deficit (SCD) was compared with the historical control group (n = 77, in 2015-2020), subjected to similar TAAA repair without 3D printing. Results: A total of 38 patients (58.6 ± 13.2 years) underwent open TAAA repair with the aid of 3D printing. Extent I, II, and III repairs were performed in 14 (36.8%), 17 (44.7%), and 7 (18.4%), respectively. Concomitant arch repair and bi-iliac reconstruction were performed in 7 (18.4%) and 6 patients (15.8%), respectively. Mean pump time was 107.7 ± 55.5 minutes. Operative mortality, permanent stroke, and permanent SCD each occurred in 1 patient (2.6%), and the incidence of the composite outcome was 7.9% (3/38). In the control group, mean pump time was 166.0 ± 83.9 minutes, significantly longer than the 3D-printing group (P < .001), and operative mortality, permanent stroke, permanent SCD, and the composite outcome occurred in 7 (9.1%), 9 (11.7%), 8 (10.4%), and 19 (24.7%), respectively. Conclusions: Open repairs of extensive TAAA with 3D printing showed favorable safety and efficacy, which need further validation by larger studies.

The 2022 FASEB Virtual Catalyst Conference on the Cardiac Interatrial Septum and Stroke Risk, December 7, 2022.

There is emerging evidence that the cardiac interatrial septum has an important role as a thromboembolic source for ischemic strokes. There is little consensus on treatment of patients with different cardiac interatrial morphologies or pathologies who have had stroke. In this paper, we summarize the important background, diagnostic, and treatment considerations for this patient population as presented during the Federation of American Societies for Experimental Biology (FASEB) Virtual Catalytic Conference on the Cardiac Interatrial Septum and Stroke Risk, held on December 7, 2022. During this conference, many aspects of the cardiac interatrial septum were discussed. Among these were the embryogenesis of the interatrial septum and development of anatomic variants such as patent foramen ovale and left atrial septal pouch. Also addressed were various mechanisms of injury such as shunting physiologies and the consequences that can result from anatomic variants, as well as imaging considerations in echocardiography, computed tomography, and magnetic resonance imaging. Treatment options including anticoagulation and closure were addressed, as well as an in-depth discussion on whether the left atrial septal pouch is a stroke risk factor. These issues were discussed and debated by multiple experts from neurology, cardiology, and radiology.

The effects of music therapy on labor pain, childbirth experience, and self-esteem during epidural labor analgesia in primiparas: a non-randomized experimental study.

PURPOSE: This non-randomized study was performed to evaluate the effects of music therapy on labor pain, the childbirth experience, and self-esteem in women during vaginal delivery. METHODS: In total, 136 primiparous women over 37 weeks of gestation receiving epidural analgesia during vaginal delivery were recruited via convenience sampling. To minimize diffusion effects, data from the control group (n=71) were collected first (April 2020 to March 2021), followed by data from the music group (n=65; April 2021 to May 2022). Participants in the music group listened to classical music during labor, while the control group was offered usual care (no music). Labor pain was measured using a numeric rating scale (NRS), and self-esteem and childbirth experience were collected using self-report questionnaires. Data were analyzed using the independent t-test, chi-square test and Cronbach's α coefficients. RESULTS: The overall pain level (NRS) at baseline was 0 in both groups. Mothers in the music therapy group had lower levels of latent pain (t=1.95, p=.005), active pain (t=3.69, p<.001) and transition-phase pain (t=7.07, p<.001) than the control group. A significant difference was observed between the two groups, and the music therapy group expressed more positive perceptions of the childbirth experience (t=-1.36, p=.018). For self-esteem, the experimental group's score was slightly higher, but without a statistically significant difference from the control group. CONCLUSION: Using music therapy during labor decreased labor pain and improved the childbirth experience. Music therapy can be clinically recommended as a non-pharmacological, safe, and easy method for nursing care in labor. Clinical trail number: KCT008561.

Resistance of hypervirulent Klebsiella pneumoniae to cathepsin B-mediated pyroptosis in murine macrophages.

Introduction: Hypervirulent Klebsiella pneumoniae (hvKp) has emerged as a clinically significant global pathogen in the last decade. However, the host immune responses of the macrophages during hvKp infection are largely unknown. In the present study, we aimed to compare the cytotoxic effects of hvKp and classical K. pneumoniae (cKp) in murine macrophages. Results: We found that the activation of caspase-1 -dependent pyroptosis was higher in cKp-infected macrophages compared with that in hvKp-infected macrophages. In Caspase-1 deficiency macrophages, pyroptosis diminished during infection. Both hvKp and cKp strains led to nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3) inflammasome formation and lysosomal cathepsin B activation, thus resulting in pyroptosis. Compared with the cKp strain, the hvKp strain inhibited these phenomena in murine macrophages. Conclusion: HvKp infection resulted in different levels of pyroptosis via the activation of cathepsin B-NLRP3-caspase-1 in murine macrophages. Therefore, the manipulation of pyroptotic cell death is a potential target for host response during hvKp infection in macrophages.

Licochalcone A Exerts Anti-Cancer Activity by Inhibiting STAT3 in SKOV3 Human Ovarian Cancer Cells.

Licochalcone A (LicA), a major active component of licorice, has been reported to exhibit various pharmacological actions. The purpose of this study was to investigate the anticancer activity of LicA and detail its molecular mechanisms against ovarian cancer. SKOV3 human ovarian cancer cells were used in this study. Cell viability was measured using a cell counting kit-8 assay. The percentages of apoptotic cells and cell cycle arrest were determined by flow cytometry and Muse flow cytometry. The expression levels of proteins regulating cell apoptosis, cell cycle, and the signal transducer and activator of transcription 3 (STAT3) signaling pathways were examined using Western blotting analysis. The results indicated that LicA treatment inhibited the cell viability of SKOV3 cells and induced G2/M phase arrest. Furthermore, LicA induced an increase in ROS levels, a reduction in mitochondrial membrane potential, and apoptosis accompanied by an increase in cleaved caspases and cytoplasmic cytochrome c. Additionally, LicA caused a dramatic decrease in STAT3 protein levels, but not mRNA levels, in SKOV3 cells. Treatment with LicA also reduced phosphorylation of the mammalian target of rapamycin and eukaryotic translation initiation factor 4E-binding protein in SKOV3 cells. The anti-cancer effects of LicA on SKOV3 cells might be mediated by reduced STAT3 translation and activation.

Dimethyl itaconate is effective in host-directed antimicrobial responses against mycobacterial infections through multifaceted innate immune pathways.

BACKGROUND: Itaconate, a crucial immunometabolite, plays a critical role in linking immune and metabolic functions to influence host defense and inflammation. Due to its polar structure, the esterified cell-permeable derivatives of itaconate are being developed to provide therapeutic opportunities in infectious and inflammatory diseases. Yet, it remains largely uncharacterized whether itaconate derivatives have potentials in promoting host-directed therapeutics (HDT) against mycobacterial infections. Here, we report dimethyl itaconate (DMI) as the promising candidate for HDT against both Mycobacterium tuberculosis (Mtb) and nontuberculous mycobacteria by orchestrating multiple innate immune programs. RESULTS: DMI per se has low bactericidal activity against Mtb, M. bovis Bacillus Calmette-Guérin (BCG), and M. avium (Mav). However, DMI robustly activated intracellular elimination of multiple mycobacterial strains (Mtb, BCG, Mav, and even to multidrug-resistant Mtb) in macrophages and in vivo. DMI significantly suppressed the production of interleukin-6 and -10, whereas it enhanced autophagy and phagosomal maturation, during Mtb infection. DMI-mediated autophagy partly contributed to antimicrobial host defenses in macrophages. Moreover, DMI significantly downregulated the activation of signal transducer and activator of transcription 3 signaling during infection with Mtb, BCG, and Mav. CONCLUSION: Together, DMI has potent anti-mycobacterial activities in macrophages and in vivo through promoting multifaceted ways for innate host defenses. DMI may bring light to new candidate for HDT against Mtb and nontuberculous mycobacteria, both of which infections are often intractable with antibiotic resistance.

Low-Molecular-Weight ß-1,3-1,6-Glucan Derived from Aureobasidium pullulans Exhibits Anticancer Activity by Inducing Apoptosis in Colorectal Cancer Cells.

ß-glucan, a plant polysaccharide, mainly exists in plant cell walls of oats, barley, and wheat. It is attracting attention due to its high potential for use as functional foods and pharmaceuticals. We have previously reported that low-molecular-weight Aureobasidium pullulans-fermented ß-D-glucan (LMW-AP-FBG) could inhibit inflammatory responses by inhibiting mitogen-activated protein kinases and nuclear factor-κB signaling pathways. Bases on previous results, the objective of the present study was to investigate the therapeutic potential of LMW-AP-FBG in BALB/c mice intracutaneously transplanted with CT-26 colon cancer cells onto their backs. Daily intraperitoneal injections of LMW-AP-FBG (5 mg/kg) for two weeks significantly suppressed tumor growth in mice bearing CT-26 tumors by reducing tumor proliferation and inducing apoptosis as compared to phosphate buffer-treated control mice. In addition, LMW-AP-FBG treatment reduced the viability of CT-26 cells in a dose-dependent manner by inducing apoptosis with loss of mitochondrial transmembrane potential and increased activated caspases. Taken together, LMW-AP-FBG exhibits anticancer properties both in vivo and in vitro.

Chemical mimetics of the N-degron pathway alleviate systemic inflammation by activating mitophagy and immunometabolic remodeling.

The Arg/N-degron pathway, which is involved in the degradation of proteins bearing an N-terminal signal peptide, is connected to p62/SQSTM1-mediated autophagy. However, the impact of the molecular link between the N-degron and autophagy pathways is largely unknown in the context of systemic inflammation. Here, we show that chemical mimetics of the N-degron Nt-Arg pathway (p62 ligands) decreased mortality in sepsis and inhibited pathological inflammation by activating mitophagy and immunometabolic remodeling. The p62 ligands alleviated systemic inflammation in a mouse model of lipopolysaccharide (LPS)-induced septic shock and in the cecal ligation and puncture model of sepsis. In macrophages, the p62 ligand attenuated the production of proinflammatory cytokines and chemokines in response to various innate immune stimuli. Mechanistically, the p62 ligand augmented LPS-induced mitophagy and inhibited the production of mitochondrial reactive oxygen species in macrophages. The p62 ligand-mediated anti-inflammatory, antioxidative, and mitophagy-activating effects depended on p62. In parallel, the p62 ligand significantly downregulated the LPS-induced upregulation of aerobic glycolysis and lactate production. Together, our findings demonstrate that p62 ligands play a critical role in the regulation of inflammatory responses by orchestrating mitophagy and immunometabolic remodeling.

Recommendations for the Use of Echocardiography in the Evaluation of Rheumatic Heart Disease: A Report from the American Society of Echocardiography.

Acute rheumatic fever and its chronic sequela, rheumatic heart disease (RHD), pose major health problems globally, and remain the most common cardiovascular disease in children and young people worldwide. Echocardiography is the most important diagnostic tool in recognizing this preventable and treatable disease and plays an invaluable role in detecting the presence of subclinical disease needing prompt therapy or follow-up assessment. This document provides recommendations for the comprehensive use of echocardiography in the diagnosis and therapeutic intervention of RHD. Echocardiographic diagnosis of RHD is made when typical findings of valvular and subvalvular abnormalities are seen, including commissural fusion, leaflet thickening, and restricted leaflet mobility, with varying degrees of calcification. The mitral valve is predominantly affected, most often leading to mitral stenosis. Mixed valve disease and associated cardiopulmonary pathology are common. The severity of valvular lesions and hemodynamic effects on the cardiac chambers and pulmonary artery pressures should be rigorously examined. It is essential to take advantage of all available modalities of echocardiography to obtain accurate anatomic and hemodynamic details of the affected valve lesion(s) for diagnostic and strategic pre-treatment planning. Intraprocedural echocardiographic guidance is critical during catheter-based or surgical treatment of RHD, as is echocardiographic surveillance for post-intervention complications or disease progression. The role of echocardiography is indispensable in the entire spectrum of RHD management.

Limpet teeth microstructure unites auxeticity with extreme strength and high stiffness.

Materials displaying negative Poisson's ratio, referred to as auxeticity, have been found in nature and created in engineering through various structural mechanisms. However, uniting auxeticity with high strength and high stiffness has been challenging. Here, combining in situ nanomechanical testing with microstructure-based modeling, we show that the leading part of limpet teeth successfully achieves this combination of properties through a unique microstructure consisting of an amorphous hydrated silica matrix embedded with bundles of single-crystal iron oxide hydroxide nanorods arranged in a pseudo-cholesteric pattern. During deformation, this microstructure allows local coordinated displacement and rotation of the nanorods, enabling auxetic behavior while maintaining one of the highest strengths among natural materials. These findings lay a foundation for designing biomimetic auxetic materials with extreme strength and high stiffness.

Allostatic Load and Adverse Pregnancy Outcomes.

OBJECTIVE: To assess the association between allostatic load, as an estimate of chronic stress, and adverse pregnancy outcomes. METHODS: This was a secondary analysis of nuMoM2b (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be), a prospective observational cohort study. Our primary exposure was dichotomous high allostatic load in the first trimester, defined as 4 or more of 12 biomarkers in the "worst" quartile. The primary outcome was a composite adverse pregnancy outcome: hypertensive disorders of pregnancy (HDP), preterm birth, small for gestational age (SGA), and stillbirth. Secondary outcomes included components of the composite. Multivariable logistic regression was used to test the association between high allostatic load and adverse pregnancy outcomes, adjusted for potential confounders. Mediation and moderation analyses were conducted to assess the role of allostatic load along the causal pathway between racial disparities and adverse pregnancy outcomes. RESULTS: Among 4,266 individuals, 34.7% had a high allostatic load. Composite adverse pregnancy outcome occurred in 1,171 (27.5%): 14.0% HDP, 8.6% preterm birth (48.0% spontaneous and 52.2% indicated), 11.0% SGA, and 0.3% stillbirth. After adjustment for maternal age, gravidity, smoking, bleeding in the first trimester, and health insurance, high allostatic load was significantly associated with a composite adverse pregnancy outcome (adjusted odds ratio [aOR] 1.5, 95% CI 1.3, 1.7) and HDP (aOR 2.5, 95% CI 2.0-2.9), but not preterm birth or SGA. High allostatic load partially mediated the association between self-reported race and adverse pregnancy outcomes. The association between allostatic load and HDP differed by self-reported race, but not for a composite adverse pregnancy outcome, preterm birth, or SGA. CONCLUSION: High allostatic load in the first trimester is associated with adverse pregnancy outcomes, particularly HDP. Allostatic load was a partial mediator between race and adverse pregnancy outcomes. The association between allostatic load and HDP differed by self-reported race.

Clinical features and management of snake bites in 70 dogs in Korea.

BACKGROUND: Snakebites remain a devastating and life-threatening environmental hazard. While the management of snakebites has been well described in humans, few clinical data and guidelines exist for dogs, especially in Korea. OBJECTIVES: This retrospective study evaluated the clinical features of 70 dogs with snakebite wounds in Korea. METHODS: The medical records of 72 dogs that presented to three animal hospitals from June 2008 to July 2021 were reviewed; among these, 70 dogs that met the inclusion criteria were enrolled. Their signalment, history, clinical signs, physical examination, blood analysis, treatment, and prognosis were also evaluated. RESULTS: Of 70 dog owners, 35 (50%) witnessed the bite, with a mean time between bite and hospital presentation of 9.7 ± 4.1 h in 58 dogs. Blood smears were evaluated in 45 dogs, of which 28 (62%) showed echinocytosis. Anemia and acute kidney injury were found in 21 (29%) and 2 dogs (3%), respectively. A total of 37 dogs (53%) were hospitalized, 5 (7%) of which died. CONCLUSIONS: The most significant finding was the high prevalence of echinocytosis. The data from this retrospective study could inform the management of dogs bitten by snakes in Korea.