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Background: Right-sided infective endocarditis is uncommon. This is primarily seen in patients with intravenous drug use, pacemaker or central venous lines, or congenital heart disease. The vast majority of cases involve the tricuspid valve. Isolated pulmonary valve endocarditis is extremely rare. We report the first case of a pulmonary valve nonbacterial thrombotic endocarditis caused by right ventricular outlflow tract (RVOT) obstruction in association with a large sinus of Valsalva aneurysm.Case Presentation: A 60-year-old man with a six-week history of fever, initially treated as pneumonia and sinusitis with levofloxacin, was admitted to the hospital with a new onset of a heart murmur. An echocardiogram showed thickening of the pulmonary valve suggestive of valve vegetation. A dilated aortic root and sinus of Valsalva aneurysm measuring at least 6.4 cm were also identified. The patient was empirically treated for infective endocarditis with vancomycin and gentamycin for 28 days. Four months later, the patient underwent resection of a large aortic root aneurysm and exploration of the pulmonary valve. During the surgery, vegetation of the pulmonary valve was confirmed. Microscopic pathological examination revealed fibrinous debris with acute inflammation and organizing fibrosis with chronic inflammation, compatible with a vegetation. Special stains were negative for bacteria and fungi.Conclusion: This is the first case report of a pulmonary valve nonbacterial endocarditis caused by RVOT obstruction in association with a sinus of Valsalva aneurysm. We speculate that jets created by the RVOT obstruction and large sinus of Valsalva aneurysm hitting against endothelium of the pulmonary valve is the etiology of this rare nonbacterial thrombotic endocarditis. [ABSTRACT FROM AUTHOR]

Cellular therapies with cardiomyocytes produced from induced pluripotent stem cells (iPSC-CMs) offer a potential route to cardiac regeneration as a treatment for chronic ischemic heart disease. Here, we report successful long-term engraftment and in vivo maturation of autologous iPSC-CMs in two rhesus macaques with small, subclinical chronic myocardial infarctions, all without immunosuppression. Longitudinal positron emission tomography imaging using the sodium/iodide symporter (NIS) reporter gene revealed stable grafts for over 6 and 12 months, with no teratoma formation. Histological analyses suggested capability of the transplanted iPSC-CMs to mature and integrate with endogenous myocardium, with no sign of immune cell infiltration or rejection. By contrast, allogeneic iPSC-CMs were rejected within 8 weeks of transplantation. This study provides the longest-term safety and maturation data to date in any large animal model, addresses concerns regarding neoantigen immunoreactivity of autologous iPSC therapies, and suggests that autologous iPSC-CMs would similarly engraft and mature in human hearts., Competing Interests: Declaration of interests Some of these experiments were performed while D.S.N. and C.E.M. were employees of, and K. Nakamura was an advisor to, Sana Biotechnology. D.S.N. and C.E.M. are equity holders in Sana Biotechnology., (Published by Elsevier Inc.)

Oligodendrocytes produce lipid-rich myelin sheaths that provide metabolic support to the underlying axon and facilitate saltatory conduction. Oligodendrocyte mitochondria supply the bulk of energy and carbon-chain backbones required for lipid synthesis. The sparsity of mitochondria in the myelin sheath suggests that tight regulation of mitochondrial trafficking is crucial for their efficient distribution in the cell. In particular, retention of mitochondria at axoglial junctions would support local lipid synthesis and membrane remodeling during myelination. How mitochondrial docking in oligodendrocytes is regulated is not known. Our findings indicate that syntaphilin (SNPH), a mitochondrial docking protein that has been characterized in neurons, is expressed by oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes in vitro and present in the myelin sheath in vivo. We have previously reported that bath application of netrin-1 promotes the elaboration of myelin basic protein-positive membranes, and that localized presentation of a netrin-1 coated microbead results in rapid accumulation of mitochondria at the site of oligodendrocyte-bead adhesion. Here we show that netrin-1 increases the redistribution of SNPH to oligodendrocyte processes during the expansion of myelin basic protein-positive membranes and that SNPH clusters at the oligodendrocyte plasma membrane at sites of adhesion with netrin-1-coated beads where mitochondria are retained. These findings suggest roles for SNPH in oligodendrocytes regulating netrin-1-mediated mitochondrial docking and myelin membrane expansion., (© 2023 The Authors. GLIA published by Wiley Periodicals LLC.)

Competing Interests: None

Heart failure remains a significant cause of morbidity and mortality following myocardial infarction. Cardiac remuscularization with transplantation of human pluripotent stem cell-derived cardiomyocytes is a promising preclinical therapy to restore function. Recent large animal data, however, have revealed a significant risk of engraftment arrhythmia (EA). Although transient, the risk posed by EA presents a barrier to clinical translation. We hypothesized that clinically approved antiarrhythmic drugs can prevent EA-related mortality as well as suppress tachycardia and arrhythmia burden. This study uses a porcine model to provide proof-of-concept evidence that a combination of amiodarone and ivabradine can effectively suppress EA. None of the nine treated subjects experienced the primary endpoint of cardiac death, unstable EA, or heart failure compared with five out of eight (62.5%) in the control cohort (hazard ratio = 0.00; 95% confidence interval: 0-0.297; p = 0.002). Pharmacologic treatment of EA may be a viable strategy to improve safety and allow further clinical development of cardiac remuscularization therapy., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Mitochondria are dynamic organelles that produce energy and molecular precursors that are essential for myelin synthesis. Unlike in neurons, mitochondria in oligodendrocytes increase intracellular movement in response to glutamatergic activation and are more susceptible to oxidative stress than in astrocytes or microglia. The signaling pathways that regulate these cell type-specific mitochondrial responses in oligodendrocytes are not understood. Here, we visualized mitochondria migrating through thin cytoplasmic channels crossing myelin basic protein-positive compacted membranes and localized within paranodal loop cytoplasm. We hypothesized that local extracellular enrichment of netrin-1 might regulate the recruitment and function of paranodal proteins and organelles, including mitochondria. We identified rapid recruitment of mitochondria and paranodal proteins, including neurofascin 155 (NF155) and the netrin receptor deleted in colorectal carcinoma (DCC), to sites of contact between oligodendrocytes and netrin-1-coated microbeads in vitro. We provide evidence that Src-family kinase activation and Rho-associated protein kinase (ROCK) inhibition downstream of netrin-1 induces mitochondrial elongation, hyperpolarization of the mitochondrial inner membrane, and increases glycolysis. Our findings identify a signaling mechanism in oligodendrocytes that is sufficient to locally recruit paranodal proteins and regulate the subcellular localization, morphology, and function of mitochondria., (© 2020 Wiley Periodicals LLC.)

Osteoarthritis (OA) is a prevalent disease characterized by chronic joint degeneration and low-grade localized inflammation. There is no available treatment to delay OA progression. We report that in human primary articular chondrocytes, erythromycin, a well-known macrolide antibiotic, had the ability to inhibit pro-inflammatory cytokine Interleukin 1β (IL-1β)-induced catabolic gene expression and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Furthermore, erythromycin inhibited monosodium iodoacetate (MIA)-induced joint inflammation and cartilage matrix destruction in mice, an arthritis model that reflects the inflammatory and cartilage matrix loss aspects of OA. EM900, an erythromycin-derivative lacking antibiotic function, had the same activity as erythromycin in vitro and in vivo, indicating distinct anti-inflammatory and antibiotic properties. Using an antibody against erythromycin, we found erythromycin was present on chondrocytes in a dose-dependent manner. The association of erythromycin with chondrocytes was diminished in ghrelin receptor null chondrocytes, and administration of the ghrelin ligand prevented the association of erythromycin with chondrocytes. Importantly, the anti-inflammatory activity of erythromycin was diminished in ghrelin receptor null chondrocytes. Moreover, erythromycin could not exert its chondroprotective effect in ghrelin receptor null mice, and the loss of ghrelin receptor further augmented joint damage upon MIA-injection. Therefore, our study identified a novel pharmacological mechanism for how erythromycin exerts its chondroprotective effect. This mechanism entails ghrelin receptor signaling, which is necessary for alleviating inflammation and joint destruction., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Poly-d-lysine (PDL) and poly-l-lysine are standard surfaces for culturing neural cells; however, both are relatively unstable, costly, and the coated surface typically must be prepared immediately before use. Here, polyelectrolyte multilayers (PEMs) are employed as highly stable, relatively inexpensive, alternative substrates to support primary neural cell culture. Initial findings identify specific silk-based PEMs that significantly outperform the capacity of PDL to promote neuronal survival and process extension. Based on these results, a library of PEM variants, including commercial and bio-sourced polyelectrolytes, is generated and three silk-based PEMs that substantially outperform PDL as a substrate for primary neurons in cell culture are identified. Further, testing these PEM variants as substrates for primary oligodendrocyte progenitors demonstrates that one silk-based PEM functions significantly better than PDL. These findings reveal specificity of cellular responses, indicating that PEMs may be tuned to optimally support different neural cell types., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Postnatal bone growth involves a dramatic increase in length and girth. Intriguingly, this period of growth is independent of growth hormone and the underlying mechanism is poorly understood. Recently, an IGF2 mutation was identified in humans with early postnatal growth restriction. Here, we show that IGF2 is essential for longitudinal and appositional murine postnatal bone development, which involves proper timing of chondrocyte maturation and perichondrial cell differentiation and survival. Importantly, the Igf2 null mouse model does not represent a simple delay of growth but instead uncoordinated growth plate development. Furthermore, biochemical and two-photon imaging analyses identified elevated and imbalanced glucose metabolism in the Igf2 null mouse. Attenuation of glycolysis rescued the mutant phenotype of premature cartilage maturation, thereby indicating that IGF2 controls bone growth by regulating glucose metabolism in chondrocytes. This work links glucose metabolism with cartilage development and provides insight into the fundamental understanding of human growth abnormalities., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Background: Inflammation is a major cause of cartilage destruction and leads to the imbalance of metabolic activities in the arthritic joint. Pigment epithelium-derived factor (PEDF) has been reported to have both pro- and anti-inflammatory activities in various cell types and to be upregulated in the arthritic joint, but its role in joint destruction is unclear. Our aim was to investigate the role of PEDF in cartilage degeneration under inflammatory conditions., Methods: PEDF was ectopically expressed in primary human articular chondrocytes, and catabolic gene expression and protein secretion in response to the pro-inflammatory cytokine interleukin 1 beta (IL-1β) were evaluated. Metatarsal bones from PEDF-deficient and wild type mice were cultured in the presence or absence of IL-1β. Cartilage matrix integrity and matrix metalloproteinases MMP-1, MMP-3, and MMP-13 were evaluated. PEDF-deficient and wild type mice were evaluated in the monosodium iodoacetate (MIA) inflammatory joint destruction animal model to determine the role of PEDF in inflammatory arthritis in vivo. Student's t-tests and Mann-Whitney tests were employed where appropriate, for parametric and non-parametric data, respectively., Results: We showed that PEDF protein levels were higher in human osteoarthritis samples compared to normal samples. We demonstrated that ectopic PEDF expression in primary human articular chondrocytes exacerbated catabolic gene expression in the presence of IL-1β. In whole bone organ cultures, IL-1β induced MMP-1, MMP-3 and MMP-13 protein production, and caused significant cartilage matrix loss. Interestingly, Toluidine Blue staining showed that PEDF-deficient bones from 29 week old animals, but not 10 week old animals, had reduced matrix loss in response to IL-1β compared to their wild type counterparts. In addition, PEDF-deficiency in 29 week old animals preserved matrix integrity and protected against cell loss in the MIA joint destruction model in vivo., Conclusion: We conclude that PEDF exacerbates cartilage degeneration in an age-dependent manner under an inflammatory setting. This is the first study identifying a specific role for PEDF in joint inflammation and highlights the multi-faceted activities of PEDF.

Background: Angiogenesis is an essential process in endometriosis disease progression. Earlier, we demonstrated that anti-angiogenic peptide, ABT-898 prevents neoangiogenesis of human endometriotic lesions in a xenograft mouse model. Since angiogenesis is essential for normal ovarian and uterine function, we evaluated effects of ABT-898 on normal female reproductive processes in mice., Methods: Cycling female C57BL/6N mice were dosed with ABT-898 (100 mg/kg) or 5 % dextrose control for 21 consecutive days to cover multiple estrous cycles (average estrous cycle 4 to 5 days in mice). Pregnant female mice were dosed with ABT-898 (100 mg/kg) or control on alternate days over the course of gestation, beginning at gestation day 7.5 to 17.5 (gestation length 21 days). Histological analysis along with CD31 and Vimentin immunohistochemistry were performed on ovaries and uteri obtained from treated and control mice. To understand the influence of ABT-898 on systemic angiogenic factors, a Pro Mouse Cytokine 9-plex assay was performed on plasma samples obtained from mice prior to treatment, during the second week of ABAT-898 or control treatment and on the last day of treatment., Results: ABT-898 did not affect the number of estrous cycles over the 21 day treatment compared to control. Histological analysis of ovaries found no difference in the number of primordial, primary, secondary, and antral follicles between ABT-898 treated and control groups. Similarly, no difference was observed in the microvessel density between ABT-898 treated and control uteri, ovarian follicles or corpus luteum when assessed using CD31 or vimentin immunohistochemistry. Electron microscopy revealed similar capillary structure and appearance in both ABT-898 treated and control uteri. Although peripheral blood angiogenic cytokine profiles (IL-15, IL-18, M-CSF, b-FGF, PDGF-bb, MIG, MIP-2, LIF and VEGF) changed over the course of the intervention, there was no significant difference between ABT-898 and control groups at any of the studied time points. Treatment with ABT-898 during pregnancy had no effect on litter size at birth, pup weight at birth or pup weight at weaning., Conclusion: Our findings suggest that ABT-898 may not alter angiogenesis dependent reproductive processes in female mice. However, an extensive reproductive toxicology screening is required to substantiate use of ABT-898 in future.

Myelin injury in multiple sclerosis (MS) has been attributed both to "outside-in" primary immune mediated and "inside-out" metabolic stress of oligodendrocyte (OL) related mechanisms. Subsequent remyelination is dependent on recruitment and differentiation of oligodendrocyte progenitor cells (OPCs). RNS60 is a physically-modified saline containing charge-stabilized nanobubbles generated by subjecting normal saline to Taylor-Couette-Poiseuille (TCP) flow under elevated oxygen pressure. Administration of RNS60 has been shown to reduce the severity of EAE by dampening the immune response and myelin loss. Additionally, RNS60 has been demonstrated to enhance mitochondrial ATP synthesis in neurons. Here, we used post-natal rat derived OLs and OPCs to assess the impact of RNS60 on the response of OLs to metabolic stress in vitro (glucose-nutrient deprivation, referred to as 'NG') and on OPC differentiation capacity. Under the NG condition, our findings indicate that RNS60 decreases caspases 3/7 activation. Respirometric analyses revealed that RNS60 increased spare glycolytic capacity (SGC) under normal culture conditions. However, RNS60 enhanced OL spare respiratory capacity (SRC) when a metabolic stress was present. Furthermore, we show that RNS60 promotes OPC differentiation under physiological conditions. Our findings provide evidence for the potential therapeutic efficacy of RNS60 through the promotion of OL survival and OPC differentiation.

Endometriosis is a gynecological disease defined by the growth of endometrium outside of the uterus. Although endometriosis contributes to 50% of female infertility cases, medical treatments are incompatible with pregnancy. Angiogenesis, the growth of blood vessels from existing vasculature, plays a crucial role in endometriotic lesion growth and survival. Previously, we demonstrated the effectiveness of thrombospondin-1 analog, ABT-898 (Abbott Laboratories) to inhibit endometriotic lesion vascularization in mice. We have now evaluated the trans-generational implications of ABT-898 treatment before and during mouse pregnancy. We hypothesized that ABT-898 would target lesion vasculature without affecting pregnancy, offspring development, or ovarian and uterine vascularity in mice. Endometriosis was induced using human endometrium in β-estradiol-primed BALB/c-Rag-2-/-Il2rγ-/- mice receiving intraperitoneal injections of ABT-898 (25 mg/kg) or 5% dextrose control for 21 days. Ultrasound assessment of lesion vascularization revealed a reduction in blood flow supplying treated lesions. Excised ABT-898 treated lesions stained for CD31+ endothelial cells exhibited a decrease in microvessel density. Following confirmation of estrous cycling, mice were bred and treated with ABT-898 on gestation days 7, 9, 11, 13, 15, 17, and 19. ABT-898 did not affect estrous cycling or pregnancy parameters including litter size across generations and offspring weight gain. Quantification of angiogenic cytokine plasma levels revealed no significant differences between treatment groups. Vimentin staining of the uterus and ovary revealed no observable effects of ABT-898. Similarly, no obvious histological anomalies were observed in the kidney, liver, ovary, or uterus following ABT-898 treatment. These results suggest that ABT-898 effectively inhibit endometriotic lesion vascularization without affecting trans-generational pregnancy outcomes in mice.

Objective: A major hurdle in osteoarthritis (OA) research is the lack of sensitive detection and monitoring methods. It is hypothesized that proteases, such as matrix metalloproteinases (MMPs), are up-regulated in the early stages of OA development. This study was undertaken to investigate if a near-infrared (NIR) fluorescent probe activated by MMPs could visualize in vivo OA progression beginning in the early stages of the disease., Methods: Using an MMP-activatable NIR fluorescent probe (MMPSense 680), we assessed the up-regulation of MMP activity in vitro by incubating human chondrocytes with the proinflammatory cytokine interleukin-1β (IL-1β). MMP activity was then evaluated in vivo serially in a mouse model of chronic, injury-induced OA. To track MMP activity over time, mice were imaged 1-8 weeks after OA-inducing surgery. Imaging results were correlated with histologic findings., Results: In vitro studies confirmed that NIR fluorescence imaging identified enhanced MMP activity in IL-1β-treated human chondrocytes. In vivo imaging showed significantly higher fluorescence intensity in OA knees compared to sham-operated (control) knees of the same mice. Additionally, the total emitted fluorescence intensity steadily increased over the entire course of OA progression that was examined. NIR fluorescence imaging results correlated with histologic findings, which showed an increase in articular cartilage structural damage over time., Conclusion: Imaging of MMP activity in a mouse model of OA provides sensitive and consistent visualization of OA progression, beginning in the early stages of OA. In addition to facilitating the preclinical study of OA modulators, this approach has the potential for future translation to humans., (Copyright © 2015 by the American College of Rheumatology.)

Endometriosis is a gynecological disease characterized by the growth of endometrium outside of the uterine cavity. It is often associated with dysmenorrhea, dyspareunia, pelvic pain and infertility. One of the key requirements for endometriotic lesions to survive is development of a blood supply to support their growth. Indeed, dense vascularization is characteristic feature of endometriotic lesions. This has led to the idea that suppression of blood vessel growth (anti-angiogenic therapy) may be a successful therapeutic approach for endometriosis. Potential effectiveness of anti-angiogenic therapies has been assessed in some animal models but there are no reports of human clinical trials. Without understanding the specific mechanism by which endometriosis lesions establish a new blood supply, short-term animal experiments will have limited value for translation into human medicine. Further, it is crucial to use appropriate animal models to assess efficacy of anti-angiogenic compounds. Syngeneic and autologous rodent models, where endometrial fragments are auto-transplanted into the peritoneal cavity are commonly used in anti-angiogenic therapy studies. Another approach is xenograft models where human endometrium is engrafted into immunodeficient mice. Here we review the animal models and experimental techniques used to evaluate anti-angiogenic therapies for endometriosis. We also review our own work on the role of stromal cell derived factor-1 in the recruitment of endothelial progenitor cells in endometriotic lesion angiogenesis, and the effects of the anti-angiogenic peptide ABT-898, a thrombospondin-1 mimetic, on endometriotic lesion growth and vascular development., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Endometriosis is a common cause of pelvic pain and infertility in women, and a common indication for hysterectomy, yet the disease remains poorly diagnosed and ineffectively treated. Because endometriotic lesions require new blood supply for survival, inhibiting angiogenesis could provide a novel therapeutic strategy. ABT-898 mimics the antiangiogenic properties of thrombospondin-1, so we hypothesized that ABT-898 will prevent neovascularization of human endometriotic lesions and that ABT-898 treatment will not affect reproductive outcomes in a mouse model. Endometriosis was induced in BALB/c-Rag2(-/-)Il2rg(-/-) mice by surgical implantation of human endometrial fragments in the peritoneal cavity. Mice received daily injections of ABT-898 for 21 days. Flow cytometry was performed to measure circulating endothelial progenitor cells in peripheral blood. Cytokines were measured in plasma samples. Half of the ABT-898-treated and control mice were euthanized to assess neovascularization of endometriotic lesions, using CD31(+) immunofluorescence. The remaining mice were mated and euthanized at gestation day 12. Endometriotic lesions increased circulating endothelial progenitor cells 13 days after engraftment, relative to baseline. Endometriotic lesions from ABT-898-treated mice exhibited reduced neovascularization, compared with controls, and lesions had fewer CD31(+) microvessels. Chronic treatment with ABT-898 did not lead to any fetal anomalies or affect litter size at gestation day 12, compared with controls. Our results suggest that ABT-898 inhibits neovascularization of human endometriotic lesions without affecting mouse fecundity., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Sudden cardiac death is the major cause of death in the United States today, claiming over 400,000 victims each year, or one per minute. In the majority of cases, the underlying mechanism is malignant ventricular tachyarrhythmia, with the common substrate being abnormal myocardium from ischemic heart disease or congestive cardiomyopathy.

Four cases of thoracic air gun injuries in children are presented. Potentially lethal injuries with penetration of the heart and lung occurred. All of the children were treated with surgical removal of the pellet, two from the ventricular myocardium, one from the right atrial appendage, and one from the right middle lobe of the lung. All of the patients survived and had an uneventful recovery. The need for regulating the use of air guns by children has been alluded to, in addition to the need for public education regarding the potential danger of air gun injuries.