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While cell therapies hold remarkable promise for replacing injured cells and repairing damaged tissues, cell replacement is not the only means by which these therapies can achieve therapeutic effect. For example, recent publications show that treatment with varieties of adult, multipotent stem cells can improve outcomes in patients with neurological conditions such as traumatic brain injury and hearing loss without directly replacing damaged or lost cells. As the immune system plays a central role in injury response and tissue repair, we here suggest that multipotent stem cell therapies achieve therapeutic effect by altering the immune response to injury, thereby limiting damage due to inflammation and possibly promoting repair. These findings argue for a broader understanding of the mechanisms by which cell therapies can benefit patients., Injury to the central nervous system and ear lead to immediate neuron and hair cell loss (green), respectively. Neuron/hair cell loss continues over subsequent months, exacerbating neurological impairments. Recent studies indicate this could result from chronic inflammation and unresolved proinflammatory signals (red). Treatment with mesenchymal progenitor cells (blue) improves neuron/hair cell survival, potentially via anti‐inflammatory mechanisms.

The authors report a 27-year-old woman with a remote left femoral osteosarcoma and amputation above the left knee who presented with a large right ventricular mass. Initial evaluation with thoracic CT was inconclusive regarding thrombus versus tumor, but metastatic osteosarcoma was suggested by findings at transthoracic echocardiography, cardiac CT, and cardiac MRI. The patient underwent tumor debulking, and osteosarcoma was confirmed with pathologic examination. She responded to chemotherapy, which resulted in reduction in size of the residual right ventricular tumor and of a few pulmonary metastases. Following induction chemotherapy, patient remains well undergoing maintenance therapy with an oral tyrosine kinase inhibitor. Keywords: CT, Echocardiography, MR Imaging, Intraoperative, Cardiac, Heart, Right Ventricle, Imaging Sequences, Metastases, Oncology Supplemental material is available for this article. © RSNA, 2021

Patients with restrictive cardiomyopathy due to Fabry disease are often deemed ineligible for left ventricular assist device (LVAD) support due to the risk of suction events with a small LV cavity. We describe the first case series of LVAD support for Fabry disease. LVAD therapy can improve survival, quality of life, and provide clinical stability to start enzyme replacement therapy. Precautions at the time of surgery include rapid treatment of fever to avoid Fabry crises, involvement of a multidisciplinary team, and early initiation of rehabilitation. We describe LVAD support for both bridging and destination therapy.

Ultraviolet radiation‐induced DNA mutations are a primary environmental driver of melanoma. The reason for this very high level of unrepaired DNA lesions leading to these mutations is still poorly understood. The primary DNA repair mechanism for UV‐induced lesions, that is, the nucleotide excision repair pathway, appears intact in most melanomas. We have previously reported a postreplication repair mechanism that is commonly defective in melanoma cell lines. Here we have used a genome‐wide approach to identify the components of this postreplication repair mechanism. We have used differential transcript polysome loading to identify transcripts that are associated with UV response, and then functionally assessed these to identify novel components of this repair and cell cycle checkpoint network. We have identified multiple interaction nodes, including global genomic nucleotide excision repair and homologous recombination repair, and previously unexpected MASTL pathway, as components of the response. Finally, we have used bioinformatics to assess the contribution of dysregulated expression of these pathways to the UV signature mutation load of a large melanoma cohort. We show that dysregulation of the pathway, especially the DNA damage repair components, are significant contributors to UV mutation load, and that dysregulation of the MASTL pathway appears to be a significant contributor to high UV signature mutation load., The UV‐G2 checkpoint is triggered by UV‐induced DNA lesions not repaired by NER during G1 phase. Global genomic NER (GG‐NER) pathway repairs these lesions during G2 phase, and homologous recombination repair (HRR) repairs the single‐stranded gaps. The MASTL pathway controls exit from the checkpoint arrest. These are all under AKT‐dependent translational control.

Objective— Smooth muscle cells (SMCs) are the most abundant cells in human atherosclerotic lesions and are suggested to contribute at least 50% of atheroma foam cells. In mice, SMCs contribute fewer total lesional cells. The purpose of this study was to determine the contribution of SMCs to total foam cells in apolipoprotein E-deficient (ApoE −/− ) mice, and the utility of these mice to model human SMC foam cell biology and interventions. Approach and Results— Using flow cytometry, foam cells in the aortic arch of ApoE −/− mice were characterized based on the expression of leukocyte-specific markers. Nonleukocyte foam cells increased from 37% of total foam cells in 27-week-old to 75% in 57-week-old male ApoE −/− mice fed a chow diet and were ≈70% in male and female ApoE −/− mice following 6 weeks of Western diet feeding. A similar contribution to total foam cells by SMCs was found using SMC-lineage tracing ApoE −/− mice fed the Western diet for 6 or 12 weeks. Nonleukocyte foam cells contributed a similar percentage of total atheroma cholesterol and exhibited lower expression of the cholesterol exporter ABCA1 (ATP-binding cassette transporter A1) when compared with leukocyte-derived foam cells. Conclusions— Consistent with previous studies of human atheromas, we present evidence that SMCs contribute the majority of atheroma foam cells in ApoE −/− mice fed a Western diet and a chow diet for longer periods. Reduced expression of ABCA1, also seen in human intimal SMCs, suggests a common mechanism for formation of SMC foam cells across species, and represents a novel target to enhance atherosclerosis regression.

Introduction Iatrogenic embolization following cardiac investigative procedures may result from hydrophilic polymer emboli (HPE) from catheter valve and vessel wall calcifications, and air embolism from open heart surgery. This retrospective clinical pathologic analysis was undertaken to ascertain the frequency and extent of these potentially fatal complications. Methods This retrospective clinical pathologic autopsy analysis with premortem diagnostic imaging correlation identified 110 individuals who had undergone endovascular procedures between 2010 and 2016 within 90 days of death and followed by hospital autopsy. Clinical outcomes, radiologic studies, and autopsy materials were reviewed. Results Iatrogenic emboli were assessed as causing death in 9/110 autopsy cases (8.2%) and 9/34 (26.5%) cases with proven iatrogenic emboli. Iatrogenic emboli caused strokes in 10/110 (9.1%) autopsy cases including calcified emboli (CE, n=6), HPE (n=2), cardiac valvular tissue (n=1), and air embolism (n=1). Seven cases of calcified emboli complicating endovascular procedures were identified: four of the CE were thought to be the cause of death due to fatal strokes (n=2) and fatal myocardial (n=1) and colonic infarction (n=1). The CE likely originated from calcified aortic valves and atherosclerotic aortic plaques. Histologic evidence of HPE was found in 23% (25/110) of cases; 54% (26/48) showed evidence of infarction in postprocedural imaging, with radiologic evidence of infarction in 32% (8/25) of cases with HPE histology. Endovascular aortic repair was associated with the greatest density/distribution of HPE. HPE material showed degradation with time and was often associated with an inflammatory response. HPE directly contributed to death in three cases. One fatal air embolism followed open heart surgery, and one cardiac tissue embolus resulted in a major stroke. Conclusions We advocate for greater awareness of these underrecognized and occasionally fatal complications of endovascular procedures. Targeted postprocedural imaging has a role in the identification of iatrogenic embolic infarcts.

Objectives This study investigated processes causing leaflet thickening and structural valve degeneration (SVD). Background Although transcatheter aortic valve replacement (TAVR) has changed the treatment of aortic stenosis, concerns remain regarding SVD, potentially related to valve thrombosis and thickening, based on studies using computed tomography (CT). Detailed histological analyses are provided to help attain insights into these processes. Methods Explanted transcatheter heart valves (THVs) were evaluated for thrombosis, fibrosis, and calcification for quantification of leaflet thickness. Immunohistochemical and microscopy approaches were used to investigate SVD-associated mechanisms. Results THVs (n = 23) were obtained from 22 patients (median 81 years of age; 50% male) from 0 to 2,583 days post TAVR. Maximal leaflet thickness increased relative to implant duration (ρ = 0.427; p = 0.027). THVs explanted after >2 years were thicker than those explanted after Conclusions There is a time-dependent degeneration of THVs consisting of thrombus formation, endothelial hyperplasia, fibrosis, tissue remodeling, proteinase expression, and calcification. Future investigation is needed to further understand these mechanisms contributing to leaflet thickening and SVD.

OBJECTIVE To evaluate surgical findings and hearing results for patient's undergoing the described surgical approach for congenitally absent or dysplastic oval window (OW). STUDY DESIGN The Institutional Review Board approved retrospective review of patients with conductive hearing loss (CHL) operated on from 1992 to 2016. SETTING Academic tertiary center. PATIENTS Patients with CHL, an intact tympanic membrane (TM), and without history of chronic infection underwent middle ear exploration. Eleven patients and 13 ears underwent an oval window drill-out (OWD) procedure. INTERVENTION Eleven patients presented, all with dysplastic or congenitally absent oval window (CAOW). CHL was identified using audiometry and tuning forks, many patients also had preoperative computed tomography temporal bones. A transcanal approach was used and an OWD was performed with a variety of prostheses placed. MAIN OUTCOME MEASURE Audiometric studies before and after intervention were compared with 12 month and long-term follow-up (1-22 yr). RESULTS Preoperative air-bone gaps ranged from 40 to 60 dB and averaged 55.1 dB. Postoperative air-bone gaps ranged from 0 to 60 dB and averaged 24.1 dB. The preoperative pure-tone average (PTA) ranged from 55 to 99 dB and averaged 71.3 dB. Postoperative PTA ranged from 21 to 108 dB and averaged 49.6 dB. CONCLUSION Dysplastic and CAOW are uncommon congenital major ear anomalies. OWD is a viable treatment option, though careful counseling is critical, as significant complications are possible, especially with facial nerve (FN) abnormalities. This series demonstrates successful closure of the air-bone gap for many patients with this technique.

Marfan syndrome (MFS) is a genetic disorder that results in accelerated aortic root widening and aneurysm. However, management of MFS patients with blood pressure (BP)‐lowering medications, such as angiotensin II (AngII) receptor blocker (ARB) losartan, continues to pose challenges due to their questionable efficacy at attenuating the rate of aortic root widening in patients. Herein we investigate the anti‐aortic root widening effects of a sub‐BP‐lowering dose valsartan, an ARB previously linked to non‐BP lowering anti‐remodeling effects. Despite absence of BP‐lowering effects, valsartan attenuated MFS aortic root widening by 75.9%, which was similar to a hypotensive dose of losartan (79.4%) when assessed by ultrasound echocardiography. Medial thickening, elastic fiber fragmentation, and phospho‐ERK signaling were also inhibited to a similar degree with both treatments. Valsartan and losartan decreased vascular contractility ex vivo between 60% and 80%, in a nitric oxide (NO)‐sensitive fashion. Valsartan increased acetylcholine (Ach)‐induced vessel relaxation and phospho‐eNOS levels in the aortic vessel supporting BP‐independent activation of protective endothelial function, which is critical to ARB‐mediated aortic root stability. This study supports the concept of achieving aortic root stability with valsartan in absence of BP‐lowering effects, which may help address efficacy and compliance issues with losartan‐based MFS patient management., Inhibition of Marfan aortic root remodeling and widening with blood pressure lowering medications losartan and valsartan. However, valsartan was used at sub‐blood pressure lowering dose, therefore implying blood pressure independence.

The top two causes of death worldwide, are ischemic heart disease and stroke; in essence, both are manifestations of vascular pathology. Additionally, aortic aneurysms and related pathologies are associated with significant mortality and morbidity. Biomaterials and devices for the heart are discussed in the previous chapter. This chapter focuses on the biomaterials and devices used to manage vascular disease. Vascular pathology results in disease primarily via one of two principal mechanisms: (1) Narrowing (stenosis) or complete obstruction of vessel lumens, either progressively (e.g., by intimal hyperplasia or atherosclerosis, see below) or precipitously (e.g., by either thrombosis directly or fragmentation of thrombus with downstream vessel blockage, called embolism); and (2) weakening of vessel walls, leading to dilation or rupture. Thus, the vasculature has been a longstanding and important target for both open surgical procedures and endovascular interventions using biomaterials and associated devices to open blood vessels that are clogged and to strengthen or otherwise repair weak or defective vessels. The devices that have facilitated these procedures are highly specialized to the anatomic site and functional role of the segment of vascular bed targeted, and the specific pathological processes the procedures and devices are intended to manage. In this chapter, we discuss devices used for vascular repair and replacement (including vascular grafts and endovascular stents and stent grafts), filters to prevent pulmonary embolism, catheters and other vascular devices.

BACKGROUND AND OBJECTIVES Sensorineural hearing loss (SNHL) in children is associated with neurocognitive morbidity. The cause of SNHL is a loss of hair cells in the organ of Corti. There are currently no reparative treatments for SNHL. Numerous studies suggest that cord blood mononuclear cells (human umbilical cord blood, hUCB) allow at least partial restoration of SNHL by enabling repair of a damaged organ of Corti. Our objective is to determine if hUCB is a safe treatment for moderate to severe acquired SNHL in children. Subjects and. METHODS Eleven children aged 6 months to 6 years with moderate to severe acquired SNHL were treated with intravenous autologous hUCB. The cell dose ranged from 8 to 30 million cells/kg body weight. Safety was assessed by measuring systemic hemodynamics during hUCB infusion. Infusion-related toxicity was evaluated by measuring neurologic, hepatic, renal and pulmonary function before and after infusion. Auditory function, auditory verbal language assessments and MRI with diffusion tensor imaging (DTI) were obtained before and after treatment. RESULTS All patients survived, and there were no adverse events. No infusionrelated changes in hemodynamics occurred. No infusion-related toxicity was recorded. Five subjects experienced a reduction in auditory brainstem response (ABR) thresholds. Four of those 5 subjects also experienced an improvement in cochlear nerve latencies. Comparison of MRI with DTI sequences obtained before and after treatment revealed increased fractional anisotropy in the primary auditory cortex in three of five subjects with reduced ABR thresholds. Statistically significant (p

Marfan syndrome (MFS) is a genetic disorder that frequently leads to aortic root dissection and aneurysm. Despite promising preclinical and pilot clinical data, a recent large-scale study using antihypertensive angiotensin II (AngII) receptor type 1 (ATR1) blocker losartan has failed to meet expectations at preventing MFS-associated aortic root dilation, casting doubts about optimal therapy. To study the deleterious role of normal ATR1 signaling in aortic root widening, we generated MFS mice lacking ATR1a expression in an attempt to preserve protective ATR2 signaling. Despite being hypotensive and resistant to AngII vasopressor effects, MFS/ATR1a-null mice showed unabated aortic root enlargement and remained fully responsive to losartan, confirming that blood pressure lowering is of minor therapeutic value in MFS and that losartan's antiremodeling properties may be ATR1 independent. Having shown that MFS causes endothelial dysfunction and that losartan can activate endothelial function in mice and patients, we found that nitric oxide synthase (NOS) inhibition renders losartan therapeutically inactive, whereas multiple transgenic and pharmacologic models of endothelial NOS activation block aortic root dilation by correcting extracellular signal–regulated kinase signaling. In vitro , losartan can increase endothelial NO release in the absence of AngII and correct MFS NO levels in vivo . Our data suggest that increased protective endothelial function, rather than ATR1 inhibition or blood pressure lowering, might be of therapeutic significance in preventing aortic root disease in MFS.

Giant cell arteritis (GCA) is the most common vasculitis in adults affecting large and medium-sized arteries. IL-6 and T cell accumulation within the arterial wall contribute to the pathogenesis of GCA, and blockade of IL-6 activity is efficacious in its treatment. We examined the relationship between levels of IL-6 expression and immunological processes that control the expansion of T cells in GCA-positive temporal artery biopsies. CD4 T cells accumulated in clusters within the media and deep intima of all GCA lesions. There was a significant positive correlation between the expression of IL-6 mRNA and increased frequency of proliferating CD4 T cells. The expansion of T cells can be inhibited by T regs but IL-6 expression was not correlated with differences in T reg accumulation. Increased IL-6 levels were also significantly correlated with lower frequencies of CD4 T cells undergoing apoptotic cell death. In conclusion, IL-6 may contribute to the accumulation of CD4 T cells in GCA by supporting their proliferation and survival within the arterial wall through mechanisms that are independent of effects on local T reg expansion.

We present a case of myocarditis in a 26-year-old pregnant woman at 29 weeks gestation. Despite optimal medical therapy, she experienced a cardiac arrest 10 days postadmission. An interdisciplinary team facilitated emergency delivery of her baby by perimortem (ie, during maternal cardiac arrest) Caesarean section and initiation of emergency mechanical circulatory support. A cardiac biopsy revealed a mixed eosinophilic and histiocytic infiltrate. After a course of steroid therapy, she experienced full recovery. Both the patient and the infant are alive and well. The case highlights the success of modern interdisciplinary care, as well as ongoing gaps in our knowledge of myocarditis.

The American Academy of Otolaryngology-Head and Neck Surgery Foundation has published a supplement to this issue of Otolaryngology-Head and Neck Surgery featuring the "Clinical Practice Guideline: Benign Paroxysmal Positional Vertigo (Update)." To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 14 recommendations developed emphasize diagnostic accuracy and efficiency, reducing the inappropriate use of vestibular suppressant medications, decreasing the inappropriate use of ancillary testing, and increasing the appropriate therapeutic repositioning maneuvers. An updated guideline is needed due to new clinical trials, new systematic reviews, and the lack of consumer participation in the initial guideline development group.

OBJECTIVE To compare the clinical and laboratory features of IgG4-related disease (IgG4-RD) and lymphocyte-variant hypereosinophilic syndrome (L-HES), two rare diseases that often present with lymphadenopathy, gastrointestinal symptoms, eosinophilia, and elevated immunoglobulins/IgE. METHOD Comparative case series of 31 patients with IgG4-RD and 13 patients with L-HES. RESULTS Peripheral blood eosinophilia was present in eight of 31 patients with IgG4-RD compared to 13 of 13 patients with L-HES (median eosinophils 0.4 vs 7.0 giga/L, P=.001) and 12 of 20 patients with IgG4-RD had increased serum IgE compared to eight of 13 patients with L-HES, P=.930. Twenty-seven of 30 patients with IgG4-RD had elevated serum IgG4 compared to five of 12 patients with L-HES (median IgG4 9.6 g/L vs 0.80 g/L, P=.002). Flow cytometry demonstrated an aberrant T-cell phenotype in 7 of 23 patients with IgG4-RD and 13 of 13 patients with L-HES (P

Background: Cutaneous polyarteritis nodosa (CPAN) is a small-to-medium vessel vasculitis limited to the skin. As it is a rare condition, there is little data available to guide treatment. Previous articles have suggested that colchicine and dapsone be used in mild disease and glucocorticoids in acute flares, with DMARDs such as methotrexate or azathioprine being reserved for moderate to severe disease, or steroid-refractory disease. Objectives: Our objective was to review therapeutic regimens used to treat CPAN and to evaluate patient response. Methods: A retrospective chart review including records from January 2003 to June 2017 was performed to identify patients with both histologic and clinical features of CPAN. We extracted information regarding patient age, clinical presentation, biopsy results, and response to treatment. Results: Thirteen patients were identified who had clinical features of CPAN that were supported by histologic findings on biopsy. The majority of patients were female (92.3%). The average age at diagnosis was 44.9 years and mean duration of follow up was 53 months. All patients had involvement of the lower limbs with the most common cutaneous manifestation being subcutaneous nodules (92.3%), followed by papules (46.2%) and livedo reticularis (30.8%). Eight out of thirteen patients (61.5%) received steroids and three did not experience clinical benefit. Another patient did not respond to prednisone and hydroxychloroquine, but had significant improvement of her symptoms on prednisone and methotrexate. Seven out of nine patients (77.8%) who were treated with methotrexate had a favourable response. Three of those patients responded to methotrexate after failing other therapies such as dapsone, azathioprine, and prednisone. Conclusion: In this case series, we found that most patients had a favorable response to methotrexate and thus the role of methotrexate in treating CPAN merits further investigation. As CPAN often has a chronic relapsing and remitting course, initiating methotrexate at the same time as steroid therapy may lower overall lifetime exposure to steroids. References [1] Daoud MS, Hutton KP, Gibson LE. Cutaneous periarteritis nodosa: a clinicopathological study of 79 cases. Br J Dermatol. 1997May;136(5):706–13. [2] Ross K, Contreras J, aung-Din D, Lien M. Asymptomatic cutaneous polyarteritis nodosa: treatment options and therapeutic guidelines. Cutis. 2017Aug;100(2):125–8. [3] Maillard H, Szczesniak S, Martin L, Garot D, Machet MC, Machet L, et al. [Cutaneous periarteritis nodosa: diagnostic and therapeutic aspects of 9 cases]. Ann Dermatol Venereol. 1999Feb;126(2):125–9. [4] Khoo BP, Ng SK. Cutaneous polyarteritis nodosa: a case report and literature review. Ann acad Med Singapore. 1998Nov;27(6):868–72. [5] Schartz NEC, alaoui S, Vignon-Pennamen MD, Cordoliani F, Fermand JP, Morel P, et al. Successful treatment in two cases of steroid-dependent cutaneous polyarteritis nodosa with low-dose methotrexate. Dermatology. 2001;203(4):336–8. Disclosure of interests: Mohan Stewart: None declared, ada Lo: None declared, Kamran Shojania: None declared, Sheila au: None declared, Jan Dutz: None declared, Michael Seidman: None declared, Jon Chan Grant/research support from: Janssen, UCB, Novartis, Pfizer, Celgene, Consultant for: amgen, Celgene, Eli Lilly, Janssen, amgen, abbvie, Novartis, Pfizer, UCB, Sandoz, Merck

The Envoy Esteem and the Carina system are the 2 totally implantable hearing devices. The Esteem is designed for patients with bilateral moderate to severe sensorineural hearing loss who have an unaided speech discrimination score of greater than and equal to 40%. The Carina system is designed for patients with moderate to severe sensorineural hearing loss or those with mixed hearing loss. The Esteem offers a technologically advanced method to provide improvements in hearing and is available in the United States, whereas the Carina system is currently not available in the United States.

Background Polyarteritis nodosa is a small vessel to medium vessel vasculitis that frequently presents with multi-organ involvement, but can sometimes be limited to single organs such as the testes. Patients often require treatment with glucocorticoids, plus or minus additional immunosuppressive therapy depending on the severity of the disease. We describe a rare case of polyarteritis nodosa involving the right testis and urinary bladder without other systemic features of vasculitis. Case presentation A previously healthy 54-year-old First Nations Canadian man presented with intermittent gross hematuria. He underwent surgical excision of his right testis for cryptorchidism and a transurethral resection of a bladder mass. Histology showed an active medium vessel vasculitis in both organs. On extensive clinical, laboratory, and radiographic review, he had no systemic features of vasculitis. On 2-year follow-up, he has not required any systemic therapy and has not developed further symptoms. Conclusion Single organ polyarteritis nodosa can sometimes be managed with surgical excision of the involved organ alone. Although our patient had two organs involved, we extrapolated the results of our literature search to guide his care. This case highlights the potential for surgical excision to cure polyarteritis nodosa despite the involvement of two organs in the absence of symptoms and signs of systemic vasculitis.

The long-term audiological consequences of mild traumatic brain injury (mTBI) include hearing loss, tinnitus, hyperacusis, and central auditory dysfunction, and are becoming a topic of heightened regard in the medical community. Tinnitus and hearing loss are two of the most common audiological disabilities reported in the US military population. While there is currently no cure for tinnitus, a variety of treatment options exist to help patients manage their symptoms. Mechanisms underlying tinnitus, hearing loss, and hyperacusis are unknown, although proposed theories suggest a tonotopic reorganization and hyperexcitability of the auditory cortex are involved. Further research regarding behavioral, alternative, and surgical therapies is critical for helping patients who suffer from hearing disorders following brain injury.

Deficiency of FANCD2/FANCI-associated nuclease 1 (FAN1) in humans leads to karyomegalic interstitial nephritis (KIN), a rare hereditary kidney disease characterized by chronic renal fibrosis, tubular degeneration, and characteristic polyploid nuclei in multiple tissues. The mechanism of how FAN1 protects cells is largely unknown but is thought to involve FAN1's function in DNA interstrand cross-link (ICL) repair. Here, we describe a Fan1-deficient mouse and show that FAN1 is required for cellular and organismal resistance to ICLs. We show that the ubiquitin-binding zinc finger (UBZ) domain of FAN1, which is needed for interaction with FANCD2, is not required for the initial rapid recruitment of FAN1 to ICLs or for its role in DNA ICL resistance. Epistasis analyses reveal that FAN1 has cross-link repair activities that are independent of the Fanconi anemia proteins and that this activity is redundant with the 5′–3′ exonuclease SNM1A. Karyomegaly becomes prominent in kidneys and livers of Fan1-deficient mice with age, and mice develop liver dysfunction. Treatment of Fan1-deficient mice with ICL-inducing agents results in pronounced thymic and bone marrow hypocellularity and the disappearance of c-kit+ cells. Our results provide insight into the mechanism of FAN1 in ICL repair and demonstrate that the Fan1 mouse model effectively recapitulates the pathological features of human FAN1 deficiency.

Cardiac fibrosis is observed across diverse etiologies of heart failure. Granzyme B (GzmB) is a serine protease involved in cell-mediated cytotoxicity in conjunction with the pore-forming protein, perforin. Recent evidence suggests that GzmB also contributes to matrix remodeling and fibrosis through an extracellular, perforin-independent process. However, the role of GzmB in the onset and progression of cardiac fibrosis remains elusive. The present study investigated the role of GzmB in the pathogenesis of cardiac fibrosis. GzmB was elevated in fibrotic human hearts and in angiotensin II–induced murine cardiac fibrosis. Genetic deficiency of GzmB reduced angiotensin II–induced cardiac hypertrophy and fibrosis, independently of perforin. GzmB deficiency also reduced microhemorrhage, inflammation, and fibroblast accumulation in vivo . In vitro , GzmB cleaved the endothelial junction protein, vascular endothelial (VE)-cadherin, resulting in the disruption of endothelial barrier function. Together, these results suggest a perforin-independent, extracellular role for GzmB in the pathogenesis of cardiac fibrosis.

Objective To evaluate racial differences in the survival of elderly myeloma patients in the pre- and post-novel agent era. Materials and Methods We conducted this study to compare five-year relative survival rates (RS) of elderly patients with multiple myeloma in pre-novel (1991–2002) and post-novel (2007–2011) agent era based on ethnicity utilizing the Surveillance, Epidemiology, and End Results (SEER-18) database. Results The database comprised of 23,318 patients (13,179 in the pre- and 10,139 in the post-novel agent era). The 5-year RS was significantly better in the post-novel agent era (36.3–39.6 vs. 24.2–25.9, Z-score = 16.4, p = 0.0001). There was significant survival benefit in post-novel agent era for both males and females and also for Caucasians and African Americans ( Conclusions The survival benefit in the period 2007–2011 is likely due to the introduction of novel agents. A lack of survival benefit for the very elderly African-American is a concerning finding. We therefore recommend further study to explore the causes of this racial disparity.

IgG4-related disease is a fibro-inflammatory condition that can affect nearly any organ system. Common presentations include major salivary and lacrimal gland enlargement, orbital disease, autoimmune pancreatitis, retroperitoneal fibrosis and tubulointerstitial nephritis. This review focuses on the hematologic manifestations of IgG4-related disease, including lymphadenopathy, eosinophilia, and polyclonal hypergammaglobulinemia. The disease can easily be missed by unsuspecting hematologists, as patients may present with clinical problems that mimic disorders such as multicentric Castleman disease, lymphoma, plasma cell neoplasms and hypereosinophilic syndromes. When IgG4-related disease is suspected, serum protein electrophoresis and IgG subclasses are helpful as initial tests but a firm histological diagnosis is essential both to confirm the diagnosis and to rule out mimickers. The central histopathological features are a dense, polyclonal, lymphoplasmacytic infiltrate enriched with IgG4-positive plasma cells (with an IgG4/IgG ratio >40%), storiform fibrosis, and obliterative phlebitis. Importantly for hematologists, the latter two features are seen in all tissues except bone marrow and lymph nodes, making these two sites suboptimal for histological confirmation. Many patients follow an indolent course and respond well to treatment, but a significant proportion may have highly morbid or fatal complications such as periaortitis, severe retroperitoneal fibrosis or pachymeningitis. Corticosteroids are effective but cause new or worsening diabetes in about 40% of patients. Initial response rates to rituximab are high but durable remissions are rare. More intensive lymphoma chemotherapy regimens may be required in rare cases of severe, refractory disease, and targeted therapy against plasmablasts, IgE and other disease biomarkers warrant further exploration.

The American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF) has published a supplement to this issue featuring the new Clinical Practice Guideline: Allergic Rhinitis. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 14 recommendations developed address the evaluation of patients with allergic rhinitis, including performing and interpretation of diagnostic testing and assessment and documentation of chronic conditions and comorbidities. It will then focus on the recommendations to guide the evaluation and treatment of patients with allergic rhinitis, to determine the most appropriate interventions to improve symptoms and quality of life for patients with allergic rhinitis.

BACKGROUND: Microvascular angina (MVA) is an incompletely understood clinical entity. Computational analysis of coronary Computed Tomography Angiography (CTA) has shown an association between low coronary lumen volume to myocardial mass (V/M) ratio and lower Fractional Flow Reserve values, independent of plaque measures. We hypothesized that low V/M ratio may be present in patients with MVA.METHODS: A retrospective case-control analysis was performed using patients fulfilling guideline criteria for MVA with controls matched for age, gender, coronary risk factors and atherosclerotic plaque burden. V/M was extracted off site (Heartflow Inc; Redwood City, CA) employing allometric scaling laws that allow the definition of the coronary circulation beyond the epicardium. FFRCT values were calculated in the major epicardial coronary arteries for each group.RESULTS: A total of 30 patients with MVA and 32 matched controls were included in the study. Mean total coronary lumen volume (2302 mm(3) ± 109 vs 2978 mm(3) ± 134, p < 0.001) and mean myocardial mass (90.4 g ± 13.7 vs 100.4 g ± 20.1, p = 0.029) were lower in MVA patients compared to controls. Mean V/M ratio was significantly lower in MVA compared to controls (25.6 mm(3)/g ± 5.9 vs 30.0 mm(3)/g ± 6.5, p = 0.007; c-statistic 0.69). V/M ratio did not differ significantly between subclasses of angina severity (p = 0.747). No difference in mean nadir FFRCT values was found between MVA and control groups in the LAD (0.86 ± 0.07 vs 0.83 ± 0.07, p = 0.154), LCX (0.90 ± 0.05 vs 0.90 ± 0.06, p = 0.240) and RCA (0.90 ± 0.04 vs 0.90 ± 0.03, p = 0.773) vessels.CONCLUSION: Patients with microvascular angina demonstrate a significantly lower coronary CTA-derived coronary volume/myocardial mass ratio than asymptomatic controls.

The objective is to perform a systematic review and meta-analysis of the literature on the long-term results of hearing preservation after vestibular schwannoma resection.Ovid/Medline, PubMed, Embase, and the Cochrane library from January 1980 to January 2015.Inclusion criteria: age ≥18 years, minimum 10 patients in the treatment group, hearing preserving microsurgery, no previous radiation treatment, serviceable hearing at immediate postop follow-up, hearing outcomes reported using Gardner Robinson or the American Academy of Otolaryngology-Head and Neck Surgeons hearing grading scales, and average follow-up of 5 years. Preoperative, immediate postoperative, and last follow-up audiograms were required. Exclusion criteria included neurofibromatosis type 2 patients and surgery for salvage therapy or decompression.Quality evaluated using Methodological Index for Non-Randomized Studies.Meta-analysis was performed using R v3.2.2, Metafor package v 1.9-7. Cohen's D was used to determine effect size. Ten reports had at least 5-year follow-up and used standardized hearing grading scales. The systematic review found that if hearing was preserved at Class A or B at early postop visit, the chance of preserving hearing at 5 years was excellent. Those who maintained speech discrimination score ≥ 89% at the early postoperative follow-up had better long-term hearing preservation. The meta-analysis reveals that only preoperative and postoperative pure-tone average was associated with long-term hearing preservation.Long-term (5 yr) hearing durability rates are generally very good. Most studies do not report patient and tumor characteristics, therefore precluding combining studies for meta-analysis. Only preoperative and postoperative postoperative pure-tone average was associated with long-term hearing durability.

Background Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia, which are caused by WAS mutations affecting Wiskott-Aldrich syndrome protein (WASp) expression or activity, manifest in immunodeficiency, autoimmunity, genomic instability, and lymphoid and other cancers. WASp supports filamentous actin formation in the cytoplasm and gene transcription in the nucleus. Although the genetic basis for XLT/WAS has been clarified, the relationships between mutant forms of WASp and the diverse features of these disorders remain ill-defined. Objective We sought to define how dysfunctional gene transcription is causally linked to the degree of T H cell deficiency and genomic instability in the XLT/WAS clinical spectrum. Methods In human T H 1- or T H 2-skewing cell culture systems, cotranscriptional R-loops (RNA/DNA duplex and displaced single-stranded DNA) and DNA double-strand breaks (DSBs) were monitored in multiple samples from patients with XLT and WAS and in normal T cells depleted of WASp. Results WASp deficiency provokes increased R-loops and R-loop–mediated DSBs in T H 1 cells relative to T H 2 cells. Mechanistically, chromatin occupancy of serine 2-unphosphorylated RNA polymerase II is increased, and that of topoisomerase 1, an R-loop preventing factor, is decreased at R-loop–enriched regions of IFNG and TBX21 (T H 1 genes) in T H 1 cells. These aberrations accompany increased unspliced (intron-retained) and decreased spliced mRNA of IFNG and TBX21 but not IL13 (T H 2 gene). Significantly, increased cellular load of R-loops and DSBs, which are normalized on RNaseH1-mediated suppression of ectopic R-loops, inversely correlates with disease severity scores. Conclusion Transcriptional R-loop imbalance is a novel molecular defect causative in T H 1 immunodeficiency and genomic instability in patients with WAS. The study proposes that cellular R-loop load could be used as a potential biomarker for monitoring symptom severity and prognostic outcome in the XLT-WAS clinical spectrum and could be targeted therapeutically.

Aims The aim of this study was to examine the short- and medium-term outcomes of transcatheter aortic valve replacement (TAVR) with the self-expanding and repositionable Portico valve (St. Jude Medical, St. Paul, MN, USA). Methods and results A total of 57 patients underwent TAVR with the Portico valve between March 2012 and August 2014, representing the first-in-human experience and the entire early experience in Canada. Patients were followed up at 30 days and one year with repeat echocardiography and clinical review. Patients were 80.8±7.3 years of age, and the Society of Thoracic Surgeons predicted risk of mortality was 7.7±5.7%. All patients had a valve implanted and four patients (7%) required a second valve. At 30 days, there were two deaths (3.5%), three disabling strokes (5.3%), and new pacemakers in five (8.8%) patients. Echocardiography revealed moderate/severe aortic regurgitation in two patients (3.6%). At one year, survival was 84.2% and echocardiographic findings were unchanged. Conclusions Transcatheter aortic valve replacement with the repositionable Portico valve provides satisfactory short- and medium-term haemodynamic and clinical results.

Decorin (DCN) is a small-leucine rich proteoglycan that mediates collagen fibrillogenesis, organization, and tensile strength. Adventitial DCN is reduced in abdominal aortic aneurysm (AAA) resulting in vessel wall instability thereby predisposing the vessel to rupture. Recombinant DCN fusion protein CAR-DCN was engineered with an extended C-terminus comprised of CAR homing peptide that recognizes inflamed blood vessels and penetrates deep into the vessel wall. In the present study, the role of systemically-administered CAR-DCN in AAA progression and rupture was assessed in a murine model. Apolipoprotein E knockout (ApoE-KO) mice were infused with angiotensin II (AngII) for 28 days to induce AAA formation. CAR-DCN or vehicle was administrated systemically until day 15. Mortality due to AAA rupture was significantly reduced in CAR-DCN-treated mice compared to controls. Although the prevalence of AAA was similar between vehicle and CAR-DCN groups, the severity of AAA in the CAR-DCN group was significantly reduced. Histological analysis revealed that CAR-DCN treatment significantly increased DCN and collagen levels within the aortic wall as compared to vehicle controls. Taken together, these results suggest that CAR-DCN treatment attenuates the formation and rupture of Ang II-induced AAA in mice by reinforcing the aortic wall.

Dilated cardiomyopathy is characterized by substantial locus, allelic, and clinical heterogeneity that necessitates testing of many genes across clinically overlapping diseases. Few studies have sequenced sufficient individuals; thus, the contributions of individual genes and the pathogenic variant spectrum are still poorly defined. We analyzed 766 dilated cardiomyopathy patients tested over 5 years in our molecular diagnostics laboratory. Patients were tested using gene panels of increasing size from 5 to 46 genes, including 121 cases tested with a multiple-cardiomyopathy next-generation panel covering 46 genes. All variants were reassessed using our current clinical-grade scoring system to eliminate false-positive disease associations that afflict many older analyses. Up to 37% of dilated cardiomyopathy cases carry a clinically relevant variant in one of 20 genes, titin (TTN) being the largest contributor (up to 14%). Desmoplakin (DSP), an arrhythmogenic right ventricular cardiomyopathy gene, contributed 2.4%, illustrating the utility of multidisease testing. The clinical sensitivity increased from 10 to 37% as gene panel sizes increased. However, the number of inconclusive cases also increased from 4.6 to 51%. Our data illustrate the utility of broad gene panels for genetically and clinically heterogeneous diseases but also highlight challenges as molecular diagnostics moves toward genome-wide testing. Genet Med 16 8, 601–608.

While transcatheter aortic valve replacement (TAVR) has drastically changed the treatment of aortic stenosis, concerns remain regarding structural valve degeneration (SVD) potentially related to valve thrombosis and thickening. Therefore, we aimed to investigate processes causing leaflet thickening

Summary: Eukaryotic replisomes are driven by the mini chromosome maintenance (MCM [M]) helicase complex, an offset ring locked around the template for leading strand synthesis by CDC45 (C) and GINS (G) proteins. Although the CDC45 MCM GINS (CMG) structure implies that interstrand crosslinks (ICLs) are absolute blocks to replisomes, recent studies indicate that cells can restart DNA synthesis on the side of the ICL distal to the initial encounter. Here, we report that restart requires ATR and is promoted by FANCD2 and phosphorylated FANCM. Following introduction of genomic ICLs and dependent on ATR and FANCD2 but not on the Fanconi anemia core proteins or FAAP24, FANCM binds the replisome complex, with concomitant release of the GINS proteins. In situ analysis of replisomes proximal to ICLs confirms the ATR-dependent release of GINS proteins while CDC45 is retained on the remodeled replisome. The results demonstrate the plasticity of CMG composition in response to replication stress. : Replication of the mammalian genome is driven by the replisome complex, which unwinds DNA and must overcome many impediments. Zhang et al. find that the encounter of the CMG with a strong block triggers a change in replisome composition that is important for restart of replication past the obstruction. Keywords: replication traverse, interstrand crosslink, ICL, ATR, FANCM, FANCD2, CMG, GINS

Although perhaps not always as dramatic as seen on television’s House, medical diagnostics are a pillar of modern clinical practice and the basis on which all treatment decisions are made. As treatments becomemore sophisticated, it becomes necessary for diagnostics to become more precise to enable the correct choice of treatment. This concept has been broadly embraced by the oncology community, with refined classifications of neoplasms and molecular characterization of therapeutically targetable alterations becoming the norm as we move toward what is commonly called “personalized medicine.” Such exquisite precision, however, is not limited to cancer; immune therapies have seen dramatic leaps forward in recent years as well, and as such, diagnostics need to catch up. Although many inflammatory conditions can be diagnosed noninvasively or using a simple blood draw, tissue biopsy is sometimes required. On the occasion that a patient undergoes an invasive diagnostic procedure, it becomes that much more important for the evaluating pathologist to provide meaningful and useful guidance for clinical colleagues. Biopsies to evaluate suspected myocarditis, however, often leave clinicians, and patients, wanting, because untargeted right ventricular endomyocardial biopsies have a low clinical sensitivity for myocarditis. As such, new tools are needed to aid in diagnosis. Magnetic resonance imaging and positron emission tomography have been used to improve the sensitivity of endomyocardial biopsy by allowing targeting of sites with active inflammation. However, radiology cannot reliably distinguish between ischemic events and myocarditis, nor can it identify the type or aetiology of the myocarditis. In this issue, Emmens et al. present another possible strategy to reduce invasiveness and improve diagnostic yield. They show that most cases of lymphocytic myocarditis are associated with a concomitant increase in the number of lymphocytes present in the quadriceps muscle, and that the number of lymphocytes in quadriceps muscle tissue (studied at autopsy in this study) might have a diagnostic sensitivity for myocarditis

FANCJ mutations are linked to Fanconi anemia (FA) and increase breast cancer risk. FANCJ encodes a DNA helicase implicated in homologous recombination (HR) repair of double-strand breaks (DSBs) and interstrand cross-links (ICLs), but its mechanism of action is not well understood. Here we show with live-cell imaging that FANCJ recruitment to laser-induced DSBs but not psoralen-induced ICLs is dependent on nuclease-active MRE11. FANCJ interacts directly with MRE11 and inhibits its exonuclease activity in a specific manner, suggesting that FANCJ regulates the MRE11 nuclease to facilitate DSB processing and appropriate end resection. Cells deficient in FANCJ and MRE11 show increased ionizing radiation (IR) resistance, reduced numbers of γH2AX and RAD51 foci, and elevated numbers of DNA-dependent protein kinase catalytic subunit foci, suggesting that HR is compromised and the nonhomologous end-joining (NHEJ) pathway is elicited to help cells cope with IR-induced strand breaks. Interplay between FANCJ and MRE11 ensures a normal response to IR-induced DSBs, whereas FANCJ involvement in ICL repair is regulated by MLH1 and the FA pathway. Our findings are discussed in light of the current model for HR repair.

Background Short-term changes in preoperative nutrition can have profound effects on surgery-related outcomes such as ischemia/reperfusion injury in preclinical models. Dietary interventions that lend protection against stress in animal models (eg, fasting, dietary restriction [DR]) impact adipose tissue quality/quantity. Adipose tissue holds high surgical relevance because of its anatomic location and large tissue volume, and it is ubiquitously traumatized during surgery. Yet the response of adipose tissue to trauma under clinically relevant circumstances including dietary status remains poorly defined. We hypothesized that preoperative diet alters the adipose tissue response to surgical trauma. Methods A novel mouse model of adipose tissue surgical trauma was employed. Dietary conditions (diet-induced obesity [DIO], preoperative DR) were modulated before application of surgical adipose tissue trauma in the context of clinically common scenarios (different ages, simulated bacterial wound contamination). Local/distant adipose tissue phenotypic responses were measured as represented by gene expression of inflammatory, tissue remodeling/growth, and metabolic markers. Results Surgical trauma had a profound effect on adipose tissue phenotype at the site of trauma. Milder but significant distal effects on non-traumatized adipose tissue were also observed. DIO exacerbated the inflammatory aspects of this response, and preoperative DR tended to reverse these changes. Age and lipopolysaccharide (LPS)-simulated bacterial contamination also impacted the adipose tissue response to trauma, with young adult animals and LPS treatment exacerbating the proinflammatory response. Conclusion Surgical trauma dramatically impacts both local and distal adipose tissue biology. Short-term preoperative DR may offer a strategy to attenuate this response.

Cardiopulmonary resuscitation (CPR) is an inherently traumatic procedure. Successful resuscitations are often complicated by iatrogenic injuries to structures of the neck, thorax, or abdomen. Rib and sternal fractures are the most frequently induced injuries. However, rare and life-threatening trauma to vital organs such as the heart may also occur during CPR. We describe a novel case of CPR-associated right ventricular rupture in a woman with acute-on-chronic pulmonary embolism and no known pre-existing cardiac disease. We propose that chest compressions in the setting of elevated right ventricular pressure resulted in cardiac rupture, in this case.

Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites. This correlates with increased DNA damage, synergistic tumor cytotoxicity, blunting of self-renewal, and strong anti-tumor responses, in vivo in unfavorable AML subtypes and BRCA wild-type breast cancer cells. Our combinatorial approach introduces a strategy to enhance efficacy of PARPis in treating cancer.

Cockayne syndrome (CS) is a premature aging disorder characterized by photosensitivity, impaired development and multisystem progressive degeneration, and consists of two strict complementation groups, A and B. Using a yeast two-hybrid approach, we identified the 5'-3' exonuclease SNM1A as one of four strong interacting partners of CSB. This direct interaction was confirmed using purified recombinant proteins-with CSB able to modulate the exonuclease activity of SNM1A on oligonucleotide substrates in vitro-and the two proteins were shown to exist in a common complex in human cell extracts. CSB and SNM1A were also found, using fluorescently tagged proteins in combination with confocal microscopy and laser microirradiation, to be recruited to localized trioxsalen-induced ICL damage in human cells, with accumulation being suppressed by transcription inhibition. Moreover, SNM1A recruitment was significantly reduced in CSB-deficient cells, suggesting coordination between the two proteins in vivo. CSB-deficient neural cells exhibited increased sensitivity to DNA crosslinking agents, particularly, in a non-cycling, differentiated state, as well as delayed ICL processing as revealed by a modified Comet assay and γ-H2AX foci persistence. The results indicate that CSB coordinates the resolution of ICLs, possibly in a transcription-associated repair mechanism involving SNM1A, and that defects in the process could contribute to the post-mitotic degenerative pathologies associated with CS.

Fanconi Anemia (FA) is a rare autosomal genetic disorder characterized by progressive bone marrow failure (BMF), endocrine dysfunction, cancer, and other clinical features commonly associated with normal aging. The anemia stems directly from an accelerated decline of the hematopoietic stem cell compartment. Although FA is a complex heterogeneous disease linked to mutations in 19 currently identified genes, there has been much progress in understanding the molecular pathology involved. FA is broadly considered a DNA repair disorder and the FA gene products, together with other DNA repair factors, have been implicated in interstrand cross-link (ICL) repair. However, in addition to the defective DNA damage response, altered epigenetic regulation, and telomere defects, FA is also marked by elevated levels of inflammatory mediators in circulation, a hallmark of faster decline in not only other hereditary aging disorders but also normal aging. In this review, we offer a perspective of FA as a monogenic accelerated aging disorder, citing the latest evidence for its multi-factorial deficiencies underlying its unique clinical and cellular features.

Viral pathogens are well known to cause injury, inflammation, tissue destruction, and remodeling of heart muscle. Indeed, viruses are among the most common inciting agents to cause a condition termed acute myocarditis. This condition may also be provoked by bacteria, other pathogens, as well as toxins and autoimmune diseases, each of which could mimic the appearance of viral myocarditis. The reason for this phenotypic mimicry is that myocarditis is a process characterized pathologically by an inflammatory infiltrate of the myocardium with death or degeneration of adjacent myocytes, not typical of the ischemic damage associated with atherosclerotic coronary artery disease. The inflammation and damage may involve myocytes, interstitium, vascular elements, and pericardium. The inflammatory process affects cardiac function adversely, causing either ventricular dysfunction, arrhythmias, or both. The acute process may persist and manifest as chronic low-grade tissue inflammation and fibrosis associated with cardiomyopathy and frank heart failure.

Despite advances in technology, ventricular assist devices still experience a number of complications limiting their long-term use. We present a 73-year-old woman implanted with a left ventricular assist device (LVAD) five years prior due to end-stage dilated cardiomyopathy, who died several weeks after admission to the hospital. Post-mortem examination revealed a large obstructing pannus in the LVAD inflow. As a result of increased LVAD use, complications such as infection, device thrombosis and pannus must be promptly recognized and managed appropriately to ensure the greatest chance of patient survival. Keywords: Mechanical circulatory support, Ventricular assist device, Heart failure, Pannus, Destination therapy