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.

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.

Orphan Nuclear Receptor ERRα Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate TLR-Induced Inflammation.

The orphan nuclear receptor estrogen-related receptor α (ERRα; NR3B1) is a key metabolic regulator, but its function in regulating inflammation remains largely unknown. Here, we demonstrate that ERRα negatively regulates Toll-like receptor (TLR)-induced inflammation by promoting Tnfaip3 transcription and fine-tuning of metabolic reprogramming in macrophages. ERRα-deficient (Esrra(-/-)) mice showed increased susceptibility to endotoxin-induced septic shock, leading to more severe pro-inflammatory responses than control mice. ERRα regulated macrophage inflammatory responses by directly binding the promoter region of Tnfaip3, a deubiquitinating enzyme in TLR signaling. In addition, Esrra(-/-) macrophages showed an increased glycolysis, but impaired mitochondrial respiratory function and biogenesis. Further, ERRα was required for the regulation of NF-κB signaling by controlling p65 acetylation via maintenance of NAD(+) levels and sirtuin 1 activation. These findings unravel a previously unappreciated role for ERRα as a negative regulator of TLR-induced inflammatory responses through inducing Tnfaip3 transcription and controlling the metabolic reprogramming.

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.

Usefulness of three-dimensional computed tomography for patellofemoral measurement.

PURPOSE: This study aimed to establish the normal values for knee patellofemoral alignment as measured using 3-dimensional computed tomography (3D CT), to standardize the technique, and to show the inter- and intra-observer reliability of this measurement. METHODS: The present study included 62 asymptomatic volunteers (124 knees). 3D CT scanning was performed with each volunteer in the supine position with 15° of knee flexion, and consistent 3D axial images of the patellofemoral joint were obtained with alignment in the desired stereographic baseline direction in anterior-posterior, lateral, and axial rotations. Two independent observers measured patellofemoral alignment parameters, including the sulcus angle, congruence angle, lateral patellofemoral angle, condyle-patellar angle, and lateral trochlear inclination angle. RESULTS: Based on 3D CT measurement, the mean values of the parameters were 145.9° ± 9.2° for the sulcus angle, 12.6° ± 22.6° for the congruence angle, 9.2° ± 4.6° for the lateral patellofemoral angle, 14.1° ± 6.4° for the condyle-patellar (lateral facets) angle, - 8.5° ± 8.4° for condyle-patellar (patellar axis) angle, and 16.5° ± 6.3° for the lateral trochlear inclination angle. A statistically significant difference was observed between men and women in the sulcus and condyle-patellar (patellar axis) angles (p = 0.045, 0.011, respectively). All parameters showed excellent inter- and intra-observer reliability. CONCLUSION: The normal values and ranges for patellofemoral alignment parameters were evaluated using 3D CT. The results of this study provide reference information that may facilitate diagnosis and treatment planning of patellofemoral disorders in skeletally mature non-pathologic patients. LEVEL OF EVIDENCE: II.

Postoperative Angular Changes According to Weightbearing in Patients With Moderate to Severe Hallux Valgus.

Hallux valgus is a progressive angular deformity of the big toe, the degree of which is aggravated in weightbearing stance. Hallux valgus and intermetatarsal angles on postoperative weightbearing images are usually larger than those of intraoperative fluoroscopic and immediate postoperative non-weightbearing images. Here, we hypothesized that various angular parameters of hallux valgus would increase postoperatively with weightbearing. A total of 66 feet (58 patients) of moderate to severe hallux valgus were reviewed on consecutive plain foot anteroposterior radiographs. The changes of hallux valgus, intermetatarsal, hallux valgus interphalangeal, and distal metatarsal articular angles were compared. Hallux valgus and intermetatarsal angles were significantly increased with weightbearing postoperatively (p < .001). Hallux valgus interphalangeal and distal metatarsal articular angles did not show significant changes with weightbearing (p > .5). Hallux valgus and intermetatarsal angles were increased with weightbearing after hallux valgus surgery. Mean angular changes were 5.3 and 2.7 degrees, respectively. These values should be considered in the preoperative planning and intraoperative correction processes.

Effect of Morphological Characteristics and Biomineralization of 3D-Printed Gelatin/Hyaluronic Acid/Hydroxyapatite Composite Scaffolds on Bone Tissue Regeneration.

The use of porous three-dimensional (3D) composite scaffolds has attracted great attention in bone tissue engineering applications because they closely simulate the major features of the natural extracellular matrix (ECM) of bone. This study aimed to prepare biomimetic composite scaffolds via a simple 3D printing of gelatin/hyaluronic acid (HA)/hydroxyapatite (HAp) and subsequent biomineralization for improved bone tissue regeneration. The resulting scaffolds exhibited uniform structure and homogeneous pore distribution. In addition, the microstructures of the composite scaffolds showed an ECM-mimetic structure with a wrinkled internal surface and a porous hierarchical architecture. The results of bioactivity assays proved that the morphological characteristics and biomineralization of the composite scaffolds influenced cell proliferation and osteogenic differentiation. In particular, the biomineralized gelatin/HA/HAp composite scaffolds with double-layer staggered orthogonal (GEHA20-ZZS) and double-layer alternative structure (GEHA20-45S) showed higher bioactivity than other scaffolds. According to these results, biomineralization has a great influence on the biological activity of cells. Hence, the biomineralized composite scaffolds can be used as new bone scaffolds in bone regeneration.

A female with typical fragile-X phenotype caused by maternal isodisomy of the entire X chromosome.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability, especially in males. Females with FXS tend to be relatively mildly affected because of compensation by a second X chromosome with a normal FMR1 gene. In most cases, FXS is caused by an expansion of the CGG repeats (>200 triplets, full mutation, FM) in the 5'-untranslated region of the FMR1 gene. Premutation alleles (PM, 55-200 repeats), usually lack the clinical features of FXS, are highly unstable when transmitted to offspring and can give rise to FM, especially in female meiosis. We describe a 3-year-old girl with typical FXS, with only a fully expanded FMR1 allele (288 CGG repeats) due to uniparental isodisomy of X chromosome, inherited from mother carrying a premutation allele. The patient's FMR1 methylation region is completely methylated due to full mutation of CGG repeat. This unusual and rare case indicates the importance of a detailed genomic approach to explain nontraditional Mendelian inheritance pattern.

Focused Ion Beam-Induced Displacive Phase Transformation From Austenite to Martensite during Fabrication of Quenched and Partitioned Steel Micro-Pillar.

We report evidence of a displacive phase transformation from retained austenite to martensite during preparation of quenched and partitioned steel micro-pillars by using a focused ion beam (FIB) technique. The BCC phase produced by the FIB damage was identified as martensite. The invariant-plane strain surface relief associated with the martensitic transformation was observed in the retained austenite phase immediately after a FIB scan of the surface with the Ga+ ion beam. Use of a low acceleration voltage appears to lower the probability of the phase transformation, while a decrease of the acceleration voltage will result in an increase of the total milling time required to prepare a micro-pillar. This report addresses challenges related to the preparation of austenite micro-pillars by a conventional FIB technique.

Feasibility evaluation of non-invasive cardiac function technology during echocardiography-based cardiac stress testing.

Evaluation of cardiac function during periods of stress is of key importance for the perioperative setting. Non-invasive hemodynamic monitors provide markers of cardiac function. This pilot study sought to evaluate the ability of a non-invasive hemodynamic monitor to detect cardiac stress during formal stress echocardiography testing. The primary goal was to compare the change in hemodynamic values during the pre/during/post phases of stress echocardiography testing in patients who had results negative versus positive for myocardial ischemia. Adult patients scheduled for outpatient cardiac stress testing were screened. Only patients scheduled for stress-echocardiography testing were consented. Patients with history of arrhythmias were excluded. During the testing, patients wore a cuff-based hemodynamic sensor (Nexfin system, Edwards Lifesciences). Data from the hemodynamic sensor were compared to the findings of the stress study. A total of 37 patients were enrolled, with 31 patients included for analysis. Five patients had stress studies positive for coronary ischemia. Comparison of the hemodynamic variables between patients who had a positive stress study versus negative showed a significant reduction in the percentage change in dP/dt and stroke volume from baseline (p < 0.05). This pilot study indicates that patients who have abnormal stress echocardiograms also have significantly reduced values from a noninvasive hemodynamic monitor. Further evaluation of the clinical utility of this technology, to assist in the care of patients at risk for cardiac ischemia, should be carried out.

PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism.

The role of peroxisome proliferator-activated receptor α (PPAR-α) in innate host defense is largely unknown. In this study, we show that PPAR-α is essential for antimycobacterial responses via activation of transcription factor EB (TFEB) transcription and inhibition of lipid body formation. PPAR-α deficiency resulted in an increased bacterial load and exaggerated inflammatory responses during mycobacterial infection. PPAR-α agonists promoted autophagy, lysosomal biogenesis, phagosomal maturation, and antimicrobial defense against Mycobacterium tuberculosis or M. bovis bacillus Calmette-Guérin. PPAR-α agonists regulated multiple genes involved in autophagy and lysosomal biogenesis, including Lamp2, Rab7, and Tfeb in bone marrow-derived macrophages. Silencing of TFEB reduced phagosomal maturation and antimicrobial responses, but increased macrophage inflammatory responses during mycobacterial infection. Moreover, PPAR-α activation promoted lipid catabolism and fatty acid ß-oxidation in macrophages during mycobacterial infection. Taken together, our data indicate that PPAR-α mediates antimicrobial responses to mycobacterial infection by inducing TFEB and lipid catabolism.

MicroRNA in innate immunity and autophagy during mycobacterial infection.

The fine-tuning of innate immune responses is an important aspect of host defenses against mycobacteria. MicroRNAs (miRNAs), small non-coding RNAs, play essential roles in regulating multiple biological pathways including innate host defenses against various infections. Accumulating evidence shows that many miRNAs regulate the complex interplay between mycobacterial survival strategies and host innate immune pathways. Recent studies have contributed to understanding the role of miRNAs, the levels of which can be modulated by mycobacterial infection, in tuning host autophagy to control bacterial survival and innate effector function. Despite considerable efforts devoted to miRNA profiling over the past decade, further work is needed to improve the selection of appropriate biomarkers for tuberculosis. Understanding the roles and mechanisms of miRNAs in regulating innate immune signaling and autophagy may provide insights into new therapeutic modalities for host-directed anti-mycobacterial therapies. Here, we present a comprehensive review of the recent literature regarding miRNA profiling in tuberculosis and the roles of miRNAs in modulating innate immune responses and autophagy defenses against mycobacterial infections.

Synthesis and in vitro evaluation of homoisoflavonoids as potent inhibitors of nitric oxide production in RAW-264.7 cells.

Syntheses of natural homoisoflavonoids, (±)-portulacanones A-C (4, 8 and 9), portulacanone D (6), isolated from Portulaca oleracea L. (POL) and their derivatives (3, 5 and 7) have been achieved for the first time along with the synthesis of known derivatives (1 and 2) and their in vitro inhibitory effect against NO production in LPS-induced RAW-264.7 macrophages was evaluated as an indicator of anti-inflammatory activity. All the compounds tested had a concentration-dependent inhibitory effect on NO production by RAW-264.7 macrophages without obvious cytotoxicity. Compounds 3 (97.2% at 10 µM; IC50 = 1.26 µM) followed by 6 (portulacanone D) (92.5% at 10 µM; IC50 = 2.09 µM), 1 (91.4% at 10 µM; IC50 = 1.75 µM) and 7 (83.0% at 10 µM; IC50 = 2.91 µM) were the most potent from the series. This finding was further correlated with the suppressed expression of iNOS induced by LPS. Our promising preliminary results may provide the basis for the assessment of compound 3 as a lead structure for a NO production-targeted anti-inflammatory drug development and also could support the usefulness of POL as a folklore medicinal plant in the treatment of inflammatory diseases.

AMP-Activated Protein Kinase and Host Defense against Infection.

5'-AMP-activated protein kinase (AMPK) plays diverse roles in various physiological and pathological conditions. AMPK is involved in energy metabolism, which is perturbed by infectious stimuli. Indeed, various pathogens modulate AMPK activity, which affects host defenses against infection. In some viral infections, including hepatitis B and C viral infections, AMPK activation is beneficial, but in others such as dengue virus, Ebola virus, and human cytomegaloviral infections, AMPK plays a detrimental role. AMPK-targeting agents or small molecules enhance the antiviral response and contribute to the control of microbial and parasitic infections. In addition, this review focuses on the double-edged role of AMPK in innate and adaptive immune responses to infection. Understanding how AMPK regulates host defenses will enable development of more effective host-directed therapeutic strategies against infectious diseases.

The effects of a home-based sensorimotor program on executive and motor functions in children with ADHD: a case series.

[Purpose] The purpose of this study was to learn about the effects of a home-oriented program based on sensorimotor activities on executive and motor functions in children with ADHD. [Participants and Methods] In this study, a home-based sensorimotor program was conducted for two male children diagnosed with ADHD. The participants performed the program with their parents four times a week, for forty minutes each time, over a 12-week period. The participants'executive functions and gross motor skills were evaluated using the Children's Color Trails Test (CCTT) and the Bruininks-Oseretsky Test of Motor Proficiency-2 (BOT-2). [Results] After participating in the home-based sensorimotor program, the participants showed improvements in both their executive and motor functions. [Conclusion] This study confirmed that a home-based sensorimotor program was effective in improving executive and motor functions in children with ADHD. This conclusion suggests the need to develop various exercise programs that can relieve the symptoms of ADHD in children and improve their abilities to adapt at home or school.

The effects of a client-centered leisure activity program on satisfaction, self-esteem, and depression in elderly residents of a long-term care facility.

[Purpose] This study aimed to examine the effects of a client-centered leisure activity program on satisfaction, upper limb function, self-esteem, and depression in elderly residents of a long-term care facility. [Subjects and Methods] This study included 12 elderly subjects, aged 65 or older, residing in a nursing home. The subjects were divided into an experimental and a control group. Subjects in the control group received leisure activities already provided by the facility. The experimental group participated in a client-centered leisure activity program. The subjects conducted individual activities three times per week, 30 minutes per session. The group activity was conducted three times per week for eight weeks. Each subject's performance of and satisfaction with the leisure activity programs, upper limb function, self-esteem, and depression were measured before and after the intervention. [Results] After participating in a program, significant improvements were seen in both the Canadian Occupational Performance Measure and upper limb function in the experimental group. Also after the intervention, the subjects' self-esteem significantly increased and their depression significantly decreased. [Conclusion] A client-centered leisure activity program motivates elderly people residing in a long-term care facility and induces their voluntary participation. Such customized programs are therefore effective for enhancing physical and psychological functioning in this population.

Negative regulators and their mechanisms in NLRP3 inflammasome activation and signaling.

Inflammasomes are cytosolic multiprotein complexes that cause the release of biologically active interleukin-1ß. The best-characterized inflammasome is the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 or Nod-like receptor protein 3) inflammasome. The NLRP3 inflammasome forms an assembly consisting of the ASC (apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain) adaptor protein and the effector, caspase-1 (cysteine-dependent aspartate-directed protease-1). Numerous agents and ligands derived from pathogens, modified self-cells and the environment induce NLRP3 inflammasome complex formation. NLRP3 inflammasome activation is tightly controlled at the transcriptional and post-translational levels to prevent unwanted excessive inflammation. Recent studies have highlighted the roles and mechanisms of several negative regulators that inhibit the assembly of NLRP3 inflammasome complexes and suppress inflammatory responses. The identification and characterization of new players in the regulation of NLRP3 inflammasome may lead to the development of inflammasome-targeting therapeutics against various inflammatory diseases related to NLRP3 inflammasome-associated pathogenesis.

MicroRNA-125a Inhibits Autophagy Activation and Antimicrobial Responses during Mycobacterial Infection.

MicroRNAs (miRNAs) are small noncoding nucleotides that play critical roles in the regulation of diverse biological functions, including the response of host immune cells. Autophagy plays a key role in activating the antimicrobial host defense against Mycobacterium tuberculosis. Although the pathways associated with autophagy must be tightly regulated at a posttranscriptional level, the contribution of miRNAs and whether they specifically influence the activation of macrophage autophagy during M. tuberculosis infection are largely unknown. In this study, we demonstrate that M. tuberculosis infection of macrophages leads to increased expression of miRNA-125a-3p (miR-125a), which targets UV radiation resistance-associated gene (UVRAG), to inhibit autophagy activation and antimicrobial responses to M. tuberculosis. Forced expression of miR-125a significantly blocked M. tuberculosis-induced activation of autophagy and phagosomal maturation in macrophages, and inhibitors of miR-125a counteracted these effects. Both TLR2 and MyD88 were required for biogenesis of miR-125a during M. tuberculosis infection. Notably, activation of the AMP-activated protein kinase significantly inhibited the expression of miR-125a in M. tuberculosis-infected macrophages. Moreover, either overexpression of miR-125a or silencing of UVRAG significantly attenuated the antimicrobial effects of macrophages against M. tuberculosis. Taken together, these data indicate that miR-125a regulates the innate host defense by inhibiting the activation of autophagy and antimicrobial effects against M. tuberculosis through targeting UVRAG.

Antiangiogenic Effects of Ziyuglycoside II, a Major Active Compound of Sanguisorba officinalis L.

Ziyuglycoside II, a major bioactive compound of Sanguisorba officinalis L., displays anticancer potential against several human cancer cells. However, little information concerning its antiangiogenic properties and possible mechanisms is available. The aim of this study was to investigate the inhibitory effects of ziyuglycoside II on angiogenesis. Ziyuglycoside II inhibited the proliferation, migration, and tubule formation of human umbilical vein endothelial cells, as well as the number of microvessels growing from the aortic rings. The underlying antiangiogenic mechanism of ziyuglycoside II correlated with blocking vascular endothelial growth factor receptor-2 and the fibroblast growth factor receptor-1 mediated signaling pathway. Moreover, an in vivo Matrigel plug assay in mice showed a significant decrease in vascularization and hemoglobin content in the plugs from ziyuglycoside II-treated mice compared with control mice. Overall, these results suggest that ziyuglycoside II inhibits various attributes of angiogenesis, which might contribute to its reported antitumor effects. Copyright © 2017 John Wiley & Sons, Ltd.

The effect of a VR exercise program on falls and depression in the elderly with mild depression in the local community.

[Purpose] The purpose of this study is to explore the effect of a VR exercise program on falls and depression in the elderly with mild depression who reside in the local community. [Subjects and Methods] This study was performed by targeting 15 elderly subjects with mild depression who resided in the local community. The targeted subjects voluntarily selected 3 VR exercise programs (each lasting 10 minutes) among 4 activities, and a resting time of 5 minutes was given for an interval after each activity. The VR exercise program was performed for total 12 weeks (36 times), 3 times a week, 45 minutes per session. [Results] After exercise, scores of static balance test (anteroposterior), Falls Efficacy Scale, and the Activities-specific Balance Confidence Scale in the test subjects were improved and depression and internal stress scores were significantly decreased after the intervention. [Conclusion] It can be concluded that the VR exercise program exerts a positive effect not only on the physical factor but also on the mental factor of the elderly subjects with mild depression who reside in the local community. It is expected that based on the VR exercise program, diversified home programs for the elderly should be developed in the future.