Myocardial fibrosis and calcification are attenuated by microRNA-129-5p targeting Asporin and Sox9 in cardiac fibroblasts.

Myocardial fibrosis and calcification associate with adverse outcomes in nonischemic heart failure. Cardiac fibroblasts (CF) transition into myofibroblasts (MF) and osteogenic fibroblasts (OF) to promote myocardial fibrosis and calcification. However, common upstream mechanisms regulating both CF-to-MF transition and CF-to-OF transition remain unknown. microRNAs are promising targets to modulate CF plasticity. Our bioinformatics revealed downregulation of miR-129-5p and upregulation of its targets small leucine-rich proteoglycan Asporin (ASPN) and transcription factor SOX9 as common in mouse and human heart failure (HF). We experimentally confirmed decreased miR-129-5p and enhanced SOX9 and ASPN expression in CF in human hearts with myocardial fibrosis and calcification. miR-129-5p repressed both CF-to-MF and CF-to-OF transition in primary CF, as did knockdown of SOX9 and ASPN. Sox9 and Aspn are direct targets of miR-129-5p that inhibit downstream ß-catenin expression. Chronic Angiotensin II infusion downregulated miR-129-5p in CF in WT and TCF21-lineage CF reporter mice, and it was restored by miR-129-5p mimic. Importantly, miR-129-5p mimic not only attenuated progression of myocardial fibrosis, calcification marker expression, and SOX9 and ASPN expression in CF but also restored diastolic and systolic function. Together, we demonstrate miR-129-5p/ASPN and miR-129-5p/SOX9 as potentially novel dysregulated axes in CF-to-MF and CF-to-OF transition in myocardial fibrosis and calcification and the therapeutic relevance of miR-129-5p.

Finding MRI features to obviate the need of repeat spinal biopsies in clinically suspected persistent or recurrent spinal osteomyelitis.

Purpose: The aim of this study was to determine magnetic resonance imaging (MRI) features that could help differen-tiate the bone destruction due to persistent/recurrent spine infection from worsening bone destruction due to mechanical factors, which could help obviate the need for repeat spine biopsy. Material and methods: A retrospective study was performed on selected subjects who were more than 18 years of age, were diagnosed with infectious spondylodiscitis, underwent at least 2 spinal interventions for the diagnosis at the same level, and had MRI prior to each image-guided intervention. Both MRI studies were analysed for vertebral body changes, paravertebral collections, epidural thickening and collections, bone marrow signal changes, loss of vertebral body height, abnormal signal in intervertebral disc, and loss of disc height. Results: We observed that worsening of changes in paravertebral and epidural soft tissue were statistically more significant predictors of recurrent/persistent spine infection (p< 0.05). However, worsening destruction of vertebral body and intervertebral disc, abnormal vertebral marrow signal changes, and abnormal signal in intervertebral disc did not necessarily indicate worsening infection or recurrence. Conclusions: In patients of infectious spondylitis with suspected recurrence, the most common and pronounced MRI findings of worsening osseous changes can be deceiving and can result in negative repeat spinal biopsy. Changes in paraspinal and epidural soft tissues are more helpful in identifying the cause of worsening bone destruction. Correlation with clinical examination, inflammatory markers, and observing soft tissue changes on follow-up MRI is a more reliable way to identify patients who may benefit from repeat spine biopsy.

Dual energy CT in musculoskeletal applications beyond crystal imaging: bone marrow maps and metal artifact reduction.

Dual energy CT (DECT) is becoming increasingly popular and valuable in the domain of musculoskeletal imaging. Gout maps and crystal detection have been predominant indications for about a decade. Other important indications of bone marrow maps and metal artifact reduction are also frequent with added advantages of detection and characterization of bone marrow lesions similar to MR imaging and diagnosis of hardware related complications, respectively. This article discusses technical considerations and physics of DECT imaging and its role in musculoskeletal indications apart from crystal imaging with respective case examples and review of the related literature. DECT pitfalls in these domains are also highlighted and the reader can gain knowledge of above concepts for prudent use of DECT in their musculoskeletal and general practices.

Adult Wilms tumor: An unusual case report with dedicated literature review.

Wilms tumor is the most common primary renal malignancy in pediatric age group, however, is rare in adults accounting for 0.5% of all adult renal malignancies. The histopathology is similar in both age groups, however the prognosis in adults is poor with tumor being at advanced stage at presentation with increased incidence of metastasis. Due to rare occurrence in adults and lack of differentiating clinical and imaging features its diagnosis is delayed or often misdiagnosed as adult renal cell cancer. Pre surgical or early post-surgical chemotherapy has shown significantly better surgical outcome and survival rate, however, delayed or misdiagnosis precludes or delays the chemotherapy. Lack of standardized treatment guidelines for adults also adds to the poor prognosis. Presurgical biopsy of renal masses in young adults can be suggested for early diagnosis as well as inclusion of presurgical chemotherapy for overall better outcome.

Tunneled and routine peripherally inserted central catheters placement in adult and pediatric population: review, technical feasibility, and troubleshooting.

Vascular access procedures are crucial for the management of various critically ill pediatric and adult patients. Venous access is commonly performed in the form routine as well as tunneled peripherally inserted central catheters (PICC). These venous accesses are commonly used in emergency, surgical as well as ICU settings, for various infusions, total parenteral nutrition, long term intravenous antibiotics, frequent blood draws, etc. PICC insertion is guided using ultrasound and fluoroscopic guidance, which decreases the risk of complications that are otherwise seen with central venous accesses like triple lumen catheters, etc. PICC insertion and care is very simple and can be performed by specially trained PICC nurses and that helps in decreasing the overall cost of healthcare. This review article is written with educational intent for the readers to discuss indications, contraindications, procedure techniques, imaging, care of routine as well as tunneled PICC.

Solid pseudopapillary Tumor of the Pancreas: Radiological and surgical review.

Solid Pseudopapillary Neoplasms of the pancreas are rare pancreatic tumors with low-grade malignant potential, typically affecting young females. In this review, we discuss the surgical anatomy; the imaging characteristics, and image reporting essentials for proper surgical planning along with the atypical features which should caution the physician regarding the risk of malignancy. We also discuss the common surgical procedures and organ preservation surgeries along with a comprehensive review of the literature.

Traumatic vertebral artery injury: a review of the screening criteria, imaging spectrum, mimics, and pitfalls.

PURPOSE: Traumatic vertebral artery injury (TVAI) can have a varied clinical presentation and appearance on imaging. In this review, we present the screening criteria, spectrum of imaging features, grading, and imaging pitfalls of TVAI. Our review focuses on the imaging of TVAI on computed tomography angiography (CTA), magnetic resonance angiography (MRA), and cases of TVAI mimics. IMAGING: The imaging spectrum on CTA can range from either focal or long segment luminal stenosis (the most common findings), smooth or tapered narrowing of lumen, string of pearls appearance, concentric intramural haematoma, intimal flap (the most definite sign), and double lumen of the artery. On time-of-flight MRA, the most common findings include loss of flow void within the vessel due to slow flow, thrombosis or occlusion, and hyperintense signal within the vessel wall due to intramural haematoma on T1 fat-saturated images. CONCLUSION: The reader should be aware of the screening criteria, common and uncommon findings, variant anatomy, artifacts, and mimics of TVAI when evaluating cases of craniocervical trauma, to be competent in calling in or ruling out injury.

Estrogen rescues heart failure through estrogen receptor Beta activation.

BACKGROUND: Recently, we showed that exogenous treatment with estrogen (E2) rescues pre-existing advanced heart failure (HF) in mice. Since most of the biological actions of E2 are mediated through the classical estrogen receptors alpha (ERα) and/or beta (ERß), and both these receptors are present in the heart, we examined the role of ERα and ERß in the rescue action of E2 against HF. METHODS: Severe HF was induced in male mice by transverse aortic constriction-induced pressure overload. Once the ejection fraction (EF) reached ~ 35%, mice were treated with selective agonists for ERα (PPT, 850 µg/kg/day), ERß (DPN, 850 µg/kg/day), or E2 (30 µg/kg/day) together with an ERß-antagonist (PHTPP, 850 µg/kg/day) for 10 days. RESULTS: EF of HF mice was significantly improved to 45.3 ± 2.1% with diarylpropionitrile (DPN) treatment, but not with PPT (31.1 ± 2.3%). E2 failed to rescue HF in the presence of PHTPP, as there was no significant improvement in the EF at the end of the 10-day treatment (32.5 ± 5.2%). The improvement of heart function in HF mice treated with ERß agonist DPN was also associated with reduced cardiac fibrosis and increased cardiac angiogenesis, while the ERα agonist PPT had no significant effect on either cardiac fibrosis or angiogenesis. Furthermore, DPN improved hemodynamic parameters in HF mice, whereas PPT had no significant effect. CONCLUSIONS: E2 treatment rescues pre-existing severe HF mainly through ERß. Rescue of HF by ERß activation is also associated with stimulation of cardiac angiogenesis, suppression of fibrosis, and restoration of hemodynamic parameters.

microRNAs in Neurodegeneration: Current Findings and Potential Impacts.

Significant advancements have been made in unraveling and understanding the non-coding elements of the human genome. New insights into the structure and function of noncoding RNAs have emerged. Their relevance in the context of both physiological cellular homeostasis and human diseases is getting appreciated. As a result, exploration of noncoding RNAs, in particular microRNAs (miRs), as therapeutic agents or targets of therapeutic strategies is under way. This review summarizes and discusses in depth the current literature on the role of miRs in neurodegenerative diseases.

Presymptomatic change in microRNAs modulates Tau pathology.

MicroRNAs (miRs) are 18~23 nucleotides long non-coding RNAs that regulate gene expression. To explore whether miR alterations in tauopathy contribute to pathological conditions, we first determined which hippocampal miRs are altered at the presymptomatic and symptomatic stages of tauopathy using rTg4510 mice (Tau mice), a well-characterized tauopathy model. miR-RNA pairing analysis using QIAGEN Ingenuity Pathway Analysis (IPA) revealed 401 genes that can be regulated by 71 miRs altered in Tau hippocampi at the presymptomatic stage. Among several miRs confirmed with real-time qPCR, miR142 (-3p and -5p) in Tau hippocampi were significantly upregulated by two-weeks of age and onward. Transcriptome studies by RNAseq and IPA revealed several overlapping biological and disease associated pathways affected by either Tau or miR142 overexpression, including Signal Transducer and Activator of Transcription 3 (Stat3) and Tumor Necrosis Factor Receptor 2 (Tnfr2) signaling pathways. Similar to what was observed in Tau brains, overexpressing miR142 in wildtype cortical neurons augments mRNA levels of Glial Fibrillary Acidic Protein (Gfap) and Colony Stimulating Factor 1 (Csf1), accompanied by a significant increase in microglia and reactive astrocyte numbers. Taken together, our study suggests that miR alterations by Tau overexpression may contribute to the neuroinflammation observed in Tau brains.

A case of pulmonary arteriovenous malformation: role of interventional radiology in diagnosis and treatment.

Pulmonary arterio-venous malformations (PAVMs) are abnormal pulmonary arteries and pulmonary veins communicating directly without interposition of a capillary bed and about 80-90% of patients with PAVMs eventually may present with hereditary hemorrhagic telangiectasia (HHT), remaining ones are sporadic cases. On the other hand, about 15-35% of HHT patients may present with PAVMs. The PAVMs have a tendency to grow and increase in size over time and various factors like puberty, pregnancy and pulmonary arterial hypertension (PAH) affect growth. This condition needs early diagnosis, aggressive management and vigilant follow up. Our article aims to review pulmonary AVMs as a rare cause of strokes in young patients. We will discuss the clinical presentation, diagnosis, complications, the therapeutic options and the follow up.

Immunomodulation: A definitive role of microRNA-142.

Majority of microRNAs are evolutionarily conserved in vertebrates. This is suggestive of their similar roles in regulation of gene networks. In addition to their conserved mature sequences and regulatory roles, a few microRNAs show very cell or tissue specific expression. These microRNAs are highly enriched in some cell types or organs. One such microRNA is microRNA-142 (miR-142). The classical stem-loop structure of miR142 encodes for two species of mature microRNAs; miR142-5p and miR142-3p. MiR-142 is abundant in cells of hematopoietic origin, and therefore, aptly plays a role in lineage differentiation of hematopoietic cells. Interestingly, over the years, miR-142 has gained considerable attention for its quintessential role in regulating immune response. This mini-review discusses the important functional roles of miR-142 in inflammatory and immune response in different physiological and disease setting.

Caudal Regression Syndrome: A Case Series of a Rare Congenital Anomaly.

BACKGROUND: Caudal regression syndrome is a rare, neural tube defect characterized by an abnormal development of the caudal aspect of the vertebral column and the spinal cord., It results in neurological deficits ranging from bladder and bowel involvement to severe sensory and motor deficits in the lower limbs. Maternal diabetes, genetic factors and some teratogens have been shown to be associated with its pathogenesis. Caudal regression syndrome is usually diagnosed initially by antenatal ultrasound with more definitive diagnosis made by antenatal or postnatal MRI. In this case series, we report four cases of caudal regression syndrome in different age groups including prenatal, infant and adult. CASE REPORT: We are presenting multimodal imaging findings of 4 cases of caudal regression syndrome in 4 different age groups including fetus, infant, early childhood and adult. The pathogenesis, associated risk factors, complications, treatment options and prognosis of caudal regression syndrome are discussed as well. CONCLUSIONS: Caudal regression syndrome is a rare entity, characterized by sacrococcygeal dysgenesis with an abrupt termination of a blunt-ending spinal cord. Ultrasound and fetal MRI can be used to make a prenatal diagnosis, while MRI is the imaging modality of choice in adults. Early detection and prompt treatment is very important to decrease the risk of complications, and thus, to improve the prognosis.

Pott puffy tumor.

Pott puffy tumor is osteomyelitis of the frontal bone with associated subperiosteal abscess causing swelling and edema over the forehead and scalp. It is a complication of frontal sinusitis or trauma. We present the case of an 8-year-old girl with frontal swelling. Imaging evaluation showed frontal osteomyelitis as a complication of frontal sinusitis with associated epidural and subperiosteal abscess. The patient was treated surgically and recovered well. This case highlights the need for high clinical suspicion and early diagnosis and management to prevent life-threatening complications. Unfortunately, in our case the patient had to undergo surgery for this complication, which could have been prevented by earlier diagnosis.

Role of oxidized lipids in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by interplay of many cellular, molecular, and genetic events that lead to excessive proliferation of pulmonary cells, including smooth muscle and endothelial cells; inflammation; and extracellular matrix remodeling. Abnormal vascular changes and structural remodeling associated with PAH culminate in vasoconstriction and obstruction of pulmonary arteries, contributing to increased pulmonary vascular resistance, pulmonary hypertension, and right ventricular failure. The complex molecular mechanisms involved in the pathobiology of PAH are the limiting factors in the development of potential therapeutic interventions for PAH. Over the years, our group and others have demonstrated the critical implication of lipids in the pathogenesis of PAH. This review specifically focuses on the current understanding of the role of oxidized lipids, lipid metabolism, peroxidation, and oxidative stress in the progression of PAH. This review also discusses the relevance of apolipoprotein A-I mimetic peptides and microRNA-193, which are known to regulate the levels of oxidized lipids, as potential therapeutics in PAH.

Rescue of Pressure Overload-Induced Heart Failure by Estrogen Therapy.

BACKGROUND: Estrogen pretreatment has been shown to attenuate the development of heart hypertrophy, but it is not known whether estrogen could also rescue heart failure (HF). Furthermore, the heart has all the machinery to locally biosynthesize estrogen via aromatase, but the role of local cardiac estrogen synthesis in HF has not yet been studied. Here we hypothesized that cardiac estrogen is reduced in HF and examined whether exogenous estrogen therapy can rescue HF. METHODS AND RESULTS: HF was induced by transaortic constriction in mice, and once mice reached an ejection fraction (EF) of ≈35%, they were treated with estrogen for 10 days. Cardiac structure and function, angiogenesis, and fibrosis were assessed, and estrogen was measured in plasma and in heart. Cardiac estrogen concentrations (6.18±1.12 pg/160 mg heart in HF versus 17.79±1.28 pg/mL in control) and aromatase transcripts (0.19±0.04, normalized to control, P<0.05) were significantly reduced in HF. Estrogen therapy increased cardiac estrogen 3-fold and restored aromatase transcripts. Estrogen also rescued HF by restoring ejection fraction to 53.1±1.3% (P<0.001) and improving cardiac hemodynamics both in male and female mice. Estrogen therapy stimulated angiogenesis as capillary density increased from 0.66±0.07 in HF to 2.83±0.14 (P<0.001, normalized to control) and reversed the fibrotic scarring observed in HF (45.5±2.8% in HF versus 5.3±1.0%, P<0.001). Stimulation of angiogenesis by estrogen seems to be one of the key mechanisms, since in the presence of an angiogenesis inhibitor estrogen failed to rescue HF (ejection fraction=29.3±2.1%, P<0.001 versus E2). CONCLUSIONS: Estrogen rescues pre-existing HF by restoring cardiac estrogen and aromatase, stimulating angiogenesis, and suppressing fibrosis.

Role of miR206 in genistein-induced rescue of pulmonary hypertension in monocrotaline model.

Pulmonary hypertension (PH) is a progressive lung disease associated with proliferation of smooth muscle cells and constriction of lung microvasculature, leading to increased pulmonary arterial pressure, right ventricular failure, and death. We have previously shown that genistein rescues preexisting established PH by significantly improving lung and heart function. (Matori H, Umar S, Nadadur RD, Sharma S, Partow-Navid R, Afkhami M, Amjedi M, Eghbali M. Hypertension 60: 425-430, 2012). Here, we have examined the role of microRNAs (miRs) in the rescue action of genistein in monocrotaline (MCT)-induced PH in rats. Our miR microarray analysis on the lung samples from control, PH, and genistein-rescue group revealed that miR206, which was robustly upregulated to ∼11-fold by PH, was completely normalized to control levels by genistein treatment. Next, we examined whether knockdown of miR206 could reverse preexisting established PH. PH was induced in male rats by 60 mg/kg of MCT, and rats received three intratracheal doses of either miR206 antagomir (10 mg/kg body wt) or scrambled miR control at days 17, 21, and 26. Knockdown of miR206 resulted in significant improvement in the cardiopulmonary function, as right ventricular pressure was significantly reduced to 38.6 ± 3.61 mmHg from 61.2 ± 5.4 mmHg in PH, and right ventricular hypertrophy index was decreased to 0.35 ± 0.04 from 0.59 ± 0.037 in PH. Knockdown of miR206 reversed PH-induced pulmonary vascular remodeling in vivo and was associated with restoration of PH-induced loss of capillaries in the lungs and induction of vascular endothelial growth factor A expression. In conclusion, miR206 antagomir therapy improves cardiopulmonary function and structure and rescues preexisting severe PH in MCT rat model possibly by stimulating angiogenesis in the lung.

Involvement of Opioid Receptors in the Lipid Rescue of Bupivacaine-Induced Cardiotoxicity.

BACKGROUND: Lipid emulsion (LE) has been successfully used for resuscitation of local anesthetic cardiotoxicity caused by bupivacaine overdose. Opioid receptors have been shown to play a key role in cardio protection. We explored whether this rescue action of LE is mediated through opioid receptors. METHODS: Asystole was induced by bupivacaine (10 mg/kg over 20 seconds, IV) in young male Sprague-Dawley rats, and resuscitation with LE (intralipid 20%; 5 mL/kg bolus and 0.5 mL/kg/min maintenance) was started immediately. The rats were pretreated 2 minutes before inducing asystole with nonselective opioid receptor antagonists such as naloxone and naloxone methiodide, as well as highly selective opioid receptor antagonists for subtype κ, δ, and µ or phosphate buffer solution as a control. Heart rates and ejection fractions were measured using echocardiography. RESULTS: LE rescue of bupivacaine cardiotoxicity was prevented by high-dose (1 mg/kg) naloxone but not by lower doses of naloxone (1, 5, and 10 µg/kg), by naloxone methiodide (which does not cross the blood-brain barrier), and by a selective δ- and κ-opioid receptor antagonists at a higher (10 mg/kg) dose. Successful LE rescue was not affected by highly selective µ-opioid receptor antagonists. δ-Opioid receptor antagonist (10 mg/kg) pretreatment also resulted in reduced phosphorylation level of cardiac glycogen synthase kinase-3ß in rats that were not resuscitated by LE compared with control. CONCLUSIONS: Our data highlight the involvement of peripheral δ- and κ-opioid receptors in the rescue action of LE.

Apolipoprotein A-I mimetic peptide 4F rescues pulmonary hypertension by inducing microRNA-193-3p.

BACKGROUND: Pulmonary arterial hypertension is a chronic lung disease associated with severe pulmonary vascular changes. A pathogenic role of oxidized lipids such as hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids is well established in vascular disease. Apolipoprotein A-I mimetic peptides, including 4F, have been reported to reduce levels of these oxidized lipids and improve vascular disease. However, the role of oxidized lipids in the progression of pulmonary arterial hypertension and the therapeutic action of 4F in pulmonary arterial hypertension are not well established. METHODS AND RESULTS: We studied 2 different rodent models of pulmonary hypertension (PH): a monocrotaline rat model and a hypoxia mouse model. Plasma levels of hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids were significantly elevated in PH. 4F treatment reduced these levels and rescued preexisting PH in both models. MicroRNA analysis revealed that microRNA-193-3p (miR193) was significantly downregulated in the lung tissue and serum from both patients with pulmonary arterial hypertension and rodents with PH. In vivo miR193 overexpression in the lungs rescued preexisting PH and resulted in downregulation of lipoxygenases and insulin-like growth factor-1 receptor. 4F restored PH-induced miR193 expression via transcription factor retinoid X receptor α. CONCLUSIONS: These studies establish the importance of microRNAs as downstream effectors of an apolipoprotein A-I mimetic peptide in the rescue of PH and suggest that treatment with apolipoprotein A-I mimetic peptides or miR193 may have therapeutic value.

Influence of sex differences on microRNA gene regulation in disease.

Sexual dimorphism is observed in most human diseases. The difference in the physiology and genetics between sexes can contribute tremendously to the disease prevalence, severity, and outcome. Both hormonal and genetic differences between males and females can lead to differences in gene expression patterns that can influence disease risk and course. MicroRNAs have emerged as potential regulatory molecules in all organisms. They can have a broad effect on every aspect of physiology, including embryogenesis, metabolism, and growth and development. Numerous microRNAs have been identified and elucidated to play a key role in cardiovascular diseases, as well as in neurological and autoimmune disorders. This is especially important as microRNA-based tools can be exploited as beneficial therapies for disease treatment and prevention. Sex steroid hormones as well as X-linked genes can have a considerable influence on the regulation of microRNAs. However, there are very few studies highlighting the role of microRNAs in sex biased diseases. This review attempts to summarize differentially regulated microRNAs in males versus females in different diseases and calls for more attention in this underexplored area that should set the basis for more effective therapeutic strategies for sexually dimorphic diseases.