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This case demonstrates the importance of considering septic pulmonary embolism (SPE) on the differential for chest pain in the pediatric population, especially in patients with a history of skin and soft tissue infection. The adolescent patient in this report, with a history of axillary hidradenitis suppurativa complicated by methicillin-resistant Staphylococcus aureus (MRSA) superinfection and recent completion of a 3-month course of doxycycline, presented with isolated focal chest pain in the absence of other infectious or respiratory signs or symptoms. Initial pulmonary imaging revealed multiple bilateral wedge-shaped nodules. Three specialty teams were consulted in the patient's evaluation, resulting in biopsy of a suspicious lesion that confirmed the diagnosis of MRSA SPE. Following a course of targeted antibiotic therapy, the patient's chest pain resolved and imaging findings improved. Insights gleaned from the workup of this patient are useful in formulating a framework for recognition of SPE in children presenting with chest pain, and also highlight the importance of considering insidious SPE presentation in the setting of antibiotic pretreatment., (© 2020 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer. SIGNIFICANCE: This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia., (©2020 American Association for Cancer Research.)

As the drug development pipeline for Duchenne muscular dystrophy (DMD) rapidly advances, clinical trial outcomes need to be optimized. Effective assessment of disease burden, natural history progression, and response to therapy in clinical trials for Duchenne muscular dystrophy are critical factors for clinical trial success. By choosing optimal biomarkers to better assess therapeutic efficacy, study costs and sample size requirements can be reduced. Currently, functional measures continue to serve as the primary outcome for the majority of DMD clinical trials. Quantitative measures of muscle health, including magnetic resonance imaging and spectroscopy, electrical impedance myography, and ultrasound, sensitively identify diseased muscle, disease progression, and response to a therapeutic intervention. Furthermore, such non-invasive techniques have the potential to identify disease pathology prior to onset of clinical symptoms. Despite robust supportive evidence, non-invasive quantitative techniques are still not frequently utilized in clinical trials for Duchenne muscular dystrophy. Non-invasive quantitative techniques have demonstrated the ability to quantify disease progression and potential response to therapeutic intervention, and should be used as a supplement to current standard functional measures. Such methods have the potential to significantly accelerate the development and approval of therapies for DMD.

Lack of sarcolemma-localized neuronal nitric oxide synthase mu (nNOSμ) contributes to muscle damage and fatigue in dystrophic muscle. In this study, we examined the effects of compensating for lack of nNOSμ with a phosphodiesterase type 5 (PDE5) inhibitor in mdx mice following downhill running and endurance training. Dystrophic mice ( mdx ) were treated with sildenafil citrate and compared with untreated mdx and wild-type mice after an acute bout of downhill running and during a progressive low-intensity treadmill running program (5 days/wk, 4 wk). Magnetic resonance imaging (MRI) and spectroscopy (MRS) transverse relaxation time constant (T 2 ) of hindlimb and forelimb muscles were measured as a marker of muscle damage after downhill running and throughout training. The MRI blood oxygenation level dependence (BOLD) response and 31 phosphorus MRS ( 31 P-MRS) data were acquired after stimulated muscle contractions. After downhill running, the increase in T 2 was attenuated ( P < 0.05) in treated mdx and wild-type mice compared with untreated mdx . During training, resting T 2 values did not change in wild-type and mdx mice from baseline values; however, the running distance completed during training was greater ( P < 0.05) in treated mdx (>90% of target distance) and wild-type (100%) than untreated mdx (60%). The post-contractile BOLD response was greater ( P < 0.05) in treated mdx that trained than untreated mdx , with no differences in muscle oxidative capacity, as measured by 31 P-MRS. Our findings indicate that PDE5 inhibition reduces muscle damage after a single bout of downhill running and improves performance during endurance training in dystrophic mice, possibly because of enhanced microvascular function. NEW & NOTEWORTHY This study examined the combined effects of PDE5 inhibition and exercise in dystrophic muscle using high-resolution magnetic resonance imaging and spectroscopy. Our findings demonstrated that sildenafil citrate reduces muscle damage after a single bout of downhill running, improves endurance-training performance, and enhances microvascular function in dystrophic muscle. Collectively, the results support the combination of exercise and PDE5 inhibition as a therapeutic approach in muscular dystrophies lacking nNOSμ.

Background: Duchenne muscular dystrophy (DMD) causes progressive pathologic changes to muscle secondary to a cascade of inflammation, lipid deposition, and fibrosis. Clinically, this manifests as progressive weakness, functional loss, and premature mortality. Though insult to whole muscle groups is well established, less is known about the relationship between intramuscular pathology and function., Objective: Differences of intramuscular heterogeneity across muscle length were assessed using an ordinal MRI grading scale in lower leg muscles of boys with DMD and correlated to patient's functional status., Methods: Cross sectional T 1 weighted MRI images with fat suppression were obtained from ambulatory boys with DMD. Six muscles (tibialis anterior, extensor digitorum longus, peroneus, soleus, medial and lateral gastrocnemii) were graded using an ordinal grading scale over 5 slice sections along the lower leg length. The scores from each slice were combined and results were compared to global motor function and age., Results: Statistically greater differences of involvement were observed at the proximal ends of muscle compared to the midbellies. Multi-slice assessment correlated significantly to age and the Vignos functional scale, whereas single-slice assessment correlated to the Vignos functional scale only. Lastly, differential disease involvement of whole muscle groups and intramuscular heterogeneity were observed amongst similar age subjects., Conclusion: A multi-slice ordinal MRI grading scale revealed that muscles are not uniformly affected, with more advanced disease visible near the tendons in a primarily ambulatory population with DMD. A geographically comprehensive evaluation of the heterogeneously affected muscle in boys with DMD may more accurately assess disease involvement.

Recently, the first magnetic resonance microscopy (MRM) images at the cellular level in isolated mammalian brain tissues were obtained using microsurface coils. These methods can elucidate the cellular origins of MR signals and describe how these signals change over the course of disease progression and therapy. In this work, we explore the capability of these microimaging techniques to visualize mouse muscle fibers and their nuclei. Isolated myofibers expressing lacZ were imaged with and without a stain for β-galactosidase activity (S-Gal + ferric ammonium citrate) that produces both optical and MR contrast. We found that MRM can be used to image single myofibers with 6-μm resolution. The ability to image single myofibers will serve as a valuable tool to study MR properties attributed to healthy and myopathic cells. The ability to image nuclei tagged with MR/Optical gene markers may also find wide use in cell lineage MRI studies.

Assessment of muscle pathology is a key outcome measure to measure the success of clinical trials studying muscular dystrophies; however, few robust minimally invasive measures exist. Indocyanine green (ICG)-enhanced near-infrared (NIR) optical imaging offers an objective, minimally invasive, and longitudinal modality that can quantify pathology within muscle by imaging uptake of ICG into the damaged muscles. Dystrophic mice lacking dystrophin (mdx) or gamma-sarcoglycan (Sgcg -/- ) were compared to control mice by NIR optical imaging and magnetic resonance imaging (MRI). We determined that optical imaging could be used to differentiate control and dystrophic mice, visualize eccentric muscle induced by downhill treadmill running, and restore the membrane integrity in Sgcg -/- mice following adeno-associated virus (AAV) delivery of recombinant human SGCG (desAAV8hSGCG). We conclude that NIR optical imaging is comparable to MRI and can be used to detect muscle damage in dystrophic muscle as compared to unaffected controls, monitor worsening of muscle pathology in muscular dystrophy, and assess regression of pathology following therapeutic intervention in muscular dystrophies.

Muscle damage is currently assessed through methods such as muscle biopsy, serum biomarkers, functional testing, and imaging procedures, each with its own inherent limitations, and a pressing need for a safe, repeatable, inexpensive, and noninvasive modality to assess the state of muscle health remains. Our aim was to develop and assess near-infrared (NIR) optical imaging as a novel noninvasive method of detecting and quantifying muscle damage. An immobilization-reambulation model was used for inducing muscle damage and recovery in the lower hindlimbs in mice. Confirmation of muscle damage was obtained using in vivo indocyanine green-enhanced NIR optical imaging, magnetic resonance imaging, and ex vivo tissue analysis. The soleus of the immobilized-reambulated hindlimb was found to have a greater amount of muscle damage compared to that in the contralateral nonimmobilized limb, confirmed by in vivo indocyanine green-enhanced NIR optical imaging (3.86-fold increase in radiant efficiency), magnetic resonance imaging (1.41-fold increase in T2), and an ex vivo spectrophotometric assay of indocyanine green uptake (1.87-fold increase in normalized absorbance). Contrast-enhanced NIR optical imaging provides a sensitive, rapid, and noninvasive screening method that can be used for imaging and quantifying muscle damage and recovery in vivo., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Aims: Under pressure overload, initial adaptive hypertrophy of the heart is followed by cardiomyocyte elongation, reduced contractile force, and failure. The mechanisms governing the transition to failure are not fully understood. Pressure overload reduced cardiac myosin light chain kinase (cMLCK) by ∼80% within 1 week and persists. Knockdown of cMLCK in cardiomyocytes resulted in reduced cardiac contractility and sarcomere disorganization. Thus, we hypothesized that acute reduction of cMLCK may be causative for reduced contractility and cardiomyocyte remodelling during the transition from compensated to decompensated cardiac hypertrophy., Methods and Results: To mimic acute cMLCK reduction in adult hearts, the floxed-Mylk3 gene that encodes cMLCK was inducibly ablated in Mylk3(flox/flox)/merCremer mice (Mylk3-KO), and compared with two control mice (Mylk3(flox/flox) and Mylk3(+/+)/merCremer) following tamoxifen injection (50 mg/kg/day, 2 consecutive days). In Mylk3-KO mice, reduction of cMLCK protein was evident by 4 days, with a decline to below the level of detection by 6 days. By 7 days, these mice exhibited heart failure, with reduction of fractional shortening compared with those in two control groups (19.8 vs. 28.0% and 27.7%). Severely convoluted cardiomyocytes with sarcomeric disorganization, wavy fibres, and cell death were demonstrated in Mylk3-KO mice. The cardiomyocytes were also unable to thicken adaptively to pressure overload., Conclusion: Our results, using a new mouse model mimicking an acute reduction of cMLCK, suggest that cMLCK plays a pivotal role in the transition from compensated to decompensated hypertrophy via sarcomeric disorganization., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Objectives: We sought to develop a new bioactive gas-delivery method by the use of echogenic liposomes (ELIP) as the gas carrier., Background: Nitric oxide (NO) is a bioactive gas with potent therapeutic effects. The bioavailability of NO by systemic delivery is low with potential systemic effects., Methods: Liposomes containing phospholipids and cholesterol were prepared by the use of a new method, freezing under pressure. The encapsulation and release profile of NO from NO-containing ELIP (NO-ELIP) or a mixture of NO/argon (NO/Ar-ELIP) was studied. The uptake of NO from NO-ELIP by cultured vascular smooth muscle cells (VSMCs) both in the absence and presence of hemoglobin was determined. The effect of NO-ELIP delivery to attenuate intimal hyperplasia in a balloon-injured artery was determined., Results: Coencapsulation of NO with Ar enabled us to adjust the amount of encapsulated NO. A total of 10 microl of gas can be encapsulated into 1 mg of liposomes. The release profile of NO from NO-ELIP demonstrated an initial rapid release followed by a slower release during the course of 8 h. Sixty-eight percent of cells remained viable when incubated with 80 microg/ml of NO/Ar-ELIP for 4 h. The delivery agent of NO to VSMCs by the use of NO/Ar-ELIP was 7-fold greater than unencapsulated NO. We discovered that NO/Ar-ELIP remained an effective delivery agent of NO to VSMCs even in the presence of hemoglobin. Local NO-ELIP administration to balloon-injured carotid arteries attenuated the development of intimal hyperplasia and reduced arterial wall thickening by 41 +/- 9%., Conclusions: Liposomes can protect and deliver a bioactive gas to target tissues with the potential for both visualization of gas delivery and controlled therapeutic gas release.