Left sinus of Valsalva aneurysm causing acute myocardial infarction with compression of the left main coronary trunk.

Sinus of Valsalva aneurysm (SVA) is a rare cardiac anomaly that commonly originates from the right or noncoronary sinuses and rarely from the left sinus. SVA is usually diagnosed in the setting of clinical sequelae of a rupture. We herein report a case of an unruptured left SVA presenting as acute myocardial infarction. A 54-year-old woman with a history of radical operation for patent ductus arteriosus in childhood was transferred to our hospital. An electrocardiogram indicated extensive myocardial ischemia with ST elevation. Urgent coronary angiography was performed but was unable to identify the left coronary artery. Subsequent aortography and computed tomography revealed a large SVA originating from the left sinus and compressing the left coronary artery. The patient died after approximately one month of intensive care, including mechanical circulatory support and coronary artery bypass grafting. Autopsy confirmed that the left main coronary trunk was stretched and compressed by the SVA and revealed unexpected atherosclerosis in the left anterior descending artery. Although a left SVA is an extremely rare anomaly, it occasionally provokes fatal myocardial infarction. Since an SVA might hinder performing percutaneous coronary intervention, cardiac surgery should be considered when myocardial ischemia is recognized. Learning objective: We herein report a case of an unruptured left sinus of Valsalva aneurysm (SVA) with acute myocardial infarction. Urgent percutaneous coronary intervention (PCI) was unsuccessful, as the left coronary artery was compressed by the SVA. The patient died after intensive care, including coronary artery bypass grafting (CABG). SVA, especially from the left sinus, is extremely rare but occasionally provokes myocardial infarction by compressing the coronary arteries. Because SVA might hinder PCI, CABG should be considered when myocardial ischemia is recognized.

Severe mitral regurgitation in chronic adult T-cell leukemia/lymphoma with granulomatous valvular inflammation.

Adult T-cell leukemia/lymphoma (ATLL) is a mature peripheral T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-1) infection. Besides the oncogenic property, HTLV-1 causes HTLV-1-associated myelopathy/tropical spastic paraparesis and certain inflammatory diseases via a complex host immune response to latent virus infection. Cardiac involvement of ATLL is rare, with the majority of cases being disclosed in postmortem autopsy in patients with advanced subtypes. We herein report the case of a 64-year-old female patient with indolent chronic ATLL with severe mitral regurgitation. Although the condition of ATLL was stable, dyspnea on exertion gradually progressed over the course of three years and echocardiography revealed marked thickening of the mitral valve. Finally, the patient experienced hemodynamic collapse with atrial fibrillation and underwent surgical valve replacement. The removed mitral valve was grossly edematous and swollen. A histological examination revealed a granulomatous reaction mimicking the active phase of rheumatic valvulitis, with the infiltration of ATLL cells that were immunohistochemically positive for CD3, CD4, FoxP3, HLA-DRα, and CCR4. The postoperative course was uneventful, with the exception that Sjögren's syndrome was noted. The history of rheumatic fever was unclear, and such unique valvular pathology was presumably related to autoimmune mechanisms associated with HTLV-1 infection. Learning objective: We report a case of chronic adult T-cell leukemia/lymphoma (ATLL) with isolated valvular infiltration with a unique histology of granulomatous reaction. Human T-cell leukemia virus type I infection may accelerate autoimmune reactions and cardiac inflammation, irrespective of indolent clinical subtype. Among ATLL cases, possible progression of valvular insufficiency and heart failure in patients with cardiac symptoms should be carefully evaluated.

A Successful Case of Switching Treatment from Ketamine to Methadone for Complex Neuropathic Pain.

Background: Methadone is frequently used for the management of complex pain at the end of life by palliative care specialists. It is also used in low doses as an add-on therapy to chronic opioid treatment of cancer-related pain, usually with good effect, and without any reported severe adverse effects. However, there are few reports of switching from ketamine to methadone. Case: We report a case of a patient with rectal cancer and intractable pain. Switching from ketamine to methadone to maintain analgesia was successfully carried out without impacting activities of daily living. Established measurement tools, such as numerical rating scale, Douleur Neuropathique, Functional Independence Measure, and Barthel Index, were used. Conclusion: Switching from ketamine to methadone may be beneficial in relieving refractory cancer-related neuropathic pain without decreasing functioning.

Incidental Gallbladder Cancer on Cholecystectomy: Strategy for Re-resection of Presumed Benign Diseases from a Retrospective Multicenter Study by the Yokohama Clinical Oncology Group.

BACKGROUND/AIM: Current expert consensus recommends re-resection for incidental gallbladder cancer (IGBC) of pT1b-3. This study examined whether this consensus was reasonably applicable to patients with IGBC in one Japanese region. PATIENTS AND METHODS: This was a multicenter, retrospective analysis of cholecystectomies for presumed benign diseases between January 2000 and December 2009. RESULTS: IGBC was diagnosed in 70 (1.0%) out of 6,775 patients undergoing cholecystectomy. Five-year disease-specific cumulative survival was 100% in 19 patients with pT1a, 80.0% in five with pT1b, 49.5% in 33 with pT2, and 23.1% in 13 with pT3. Re-resection was not performed for the 24 patients with pT1a/1b disease, whereas 24 out of 46 patients with pT2/3 underwent re-resection. Regardless of re-resection, independent factors associated with a poor prognosis on multivariate analysis were grade 2 or poorer disease and bile spillage at prior cholecystectomy. In the 24 patients with pT2/3 re-resection, 11 patients without either of these two factors had significantly better 5-year disease-specific cumulative survival than the 13 patients with one or two independent factors associated with a poor prognosis (72.7% vs. 30.8%, p=0.009). CONCLUSION: This Japanese regional study suggests that indication of re-resection for IGBC should not be determined by pT-factor alone and that much more attention should be paid to pathological and intraoperative findings at prior cholecystectomy.

A long-term survivor keeping in a complete response without treatment after pemetrexed maintenance therapy for advanced non-squamous non-small cell lung cancer.

Pemetrexed has significant efficacy for some non-squamous non-small cell lung cancer cases, as demonstrated in the current case. For those patients, pemetrexed administration should be carefully considered.

Utility of 99 mTc-Pyrophosphate Scintigraphy in Diagnosing Transthyretin Cardiac Amyloidosis in Real-World Practice.

Background: Amyloid transthyretin (ATTR) cardiac amyloidosis has now been recognized as one of the major causes of heart failure, especially in elderly patients. The purpose of the present study was to validate the usefulness of technetium-99 m (99 mTc)-pyrophosphate (99 mTc-PYP) scintigraphy in the screening diagnosis for ATTR amyloidosis in daily clinical practice. Methods and Results: Ninety-eight patients underwent 99 mTc-PYP scintigraphy in the previous 3 years (PYP positive/negative, 18/80), of whom 29 underwent concomitant endomyocardial biopsy (ATTR positive/negative, 9/20). The sensitivity and specificity of 99 mTc-PYP scintigraphy for the diagnosis of biopsy-proven ATTR amyloidosis were 0.889 and 0.950, respectively. Age, gender, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level, or electrocardiogram findings did not differ significantly between PYP-positive and PYP-negative patients. Left ventricular (LV) wall thickness was significantly greater in PYP-positive than in PYP-negative patients, but LV ejection fraction or prevalence of atrial fibrillation was similar between groups. In the PYP-positive patients, higher uptake of PYP correlated with younger age and lower NT-proBNP. Conclusions: 99 mTc-PYP scintigraphy was useful, with high sensitivity and specificity in the screening diagnosis for ATTR cardiac amyloidosis, which is difficult to diagnose on clinical characteristics alone. 99 mTc-PYP scintigraphy should be considered to elucidate the underlying causes of heart failure, especially in elderly patients based on the higher prevalence of ATTR cardiac amyloidosis in this population.

CORRIGENDUM: Utility of 99 mTc-Pyrophosphate Scintigraphy in Diagnosing Transthyretin Cardiac Amyloidosis in Real-World Practice.

[This corrects the article DOI: 10.1253/circrep.CR-19-0015.].

Accumulation of gold nano-rods in the failing heart of transgenic mice with the cardiac-specific expression of TNF-α.

Gold nano-rods, rod-shaped gold nanoparticles, act as contrast agents for in vivo bioimaging, drug delivery vehicles and thermal converters for photothermal therapy. Pro-inflammatory cytokines play critical roles in the development of heart failure. We examined the delivery of GNRs into the failing heart of a transgenic (TG) mouse model of inflammatory cardiomyopathy with the cardiac-specific overexpression of TNF-α. We modified GNRs with polyethylene glycol (PEG) to avoid cytotoxicity and reduce the rapid clearance of nanoparticles from blood. PEG-modified GNRs (4.5 mM as gold atoms, 200 µL) were administered intravenously to TG (n = 7) and wild-type (WT) mice (n = 5). These were killed 24 h later, and the heart, lung, liver, kidney and spleen were excised. A quantitative analysis of gold was performed using inductively coupled plasma mass or optical emission spectrometry. The amount of gold (ng) in the TG heart (3.24 ± 1.56 ng/mg heart weight) was significantly greater than that in the WT heart (1.01 ± 0.19; p < 0.05). No significant differences were observed among the other organs of TG and WT mice. The amount of gold in the TG heart was significantly and positively correlated with the ratio of the ventricular weight to body weight, which is known to be an index of ventricular hypertrophy. In conclusion, PEG-modified GNRs accumulated in the inflammatory TG heart in proportion with the severity of ventricular hypertrophy.

Predictive factors for bile leakage after hepatectomy for hepatic tumors: a retrospective multicenter study with 631 cases at Yokohama Clinical Oncology Group (YCOG).

BACKGROUND: International Study Group of Liver Surgery (ISGLS) proposed the standardized definition for bile leakage (BL) after hepatectomy (Hx) at 2011 to precisely perceive incidence and predictive factors of this critical condition. METHODS: We conducted a multicenter retrospective study using the ISGLS definition of BL after Hx. RESULTS: Perioperative data regarding 631 patients undergoing elective Hx for hepatic tumors without biliary reconstruction performed between January 2009 and December 2011 were analyzed. BL was observed in 30 patients (4.8%). (Grade A, 8 (1.3%); B, 21(3.3%); C, 1 (0.2%)). Five independent predictors (diagnosis of liver metastases, prolonged operation, high risk procedures defined as Hx with broad exposure of the hilar Glissonean sheath, low platelet count and high serum total bilirubin on postoperative day 1) for grade B/C BL were elucidated by the multivariate analysis. When the study cohorts were divided into groups by number of accompanying these predictors, the more the accompanying independent predictors, the higher the incidence of BL. Notably, incidence of BL exceeded 40% in patients with four or more of these predictors. CONCLUSIONS: Risk stratification for BL after Hx can be achievable using independent predictors clarified in this study. However, proper management for high risk patients remains to be elucidated.

Heat Shock Protein 90 Ensures Efficient Mumps Virus Replication by Assisting with Viral Polymerase Complex Formation.

Paramyxoviral RNAs are synthesized by a viral RNA-dependent RNA polymerase (RdRp) consisting of the large (L) protein and its cofactor phosphoprotein (P protein). The L protein is a multifunctional protein that catalyzes RNA synthesis, mRNA capping, and mRNA polyadenylation. Growing evidence shows that the stability of several paramyxovirus L proteins is regulated by heat shock protein 90 (Hsp90). In this study, we demonstrated that Hsp90 activity was important for mumps virus (MuV) replication. The Hsp90 activity was required for L-protein stability and activity because an Hsp90-specific inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), destabilized the MuV L protein and suppressed viral RNA synthesis. However, once the L protein formed a mature polymerase complex with the P protein, Hsp90 activity was no longer required for the stability and activity of the L protein. When the Hsp90 activity was inhibited, the MuV L protein was degraded through the CHIP (C terminus of Hsp70-interacting protein)-mediated proteasomal pathway. High concentrations of 17-AAG showed strong cytotoxicity to certain cell types, but combined use of an Hsp70 inhibitor, VER155008, potentiated degradation of the L protein, allowing a sufficient reduction of 17-AAG concentration to block MuV replication with minimum cytotoxicity. Regulation of the L protein by Hsp90 and Hsp70 chaperones was also demonstrated for another paramyxovirus, the measles virus. Collectively, our data show that the Hsp90/Hsp70 chaperone machinery assists in the maturation of the paramyxovirus L protein and thereby in the formation of a mature RdRp complex and efficient viral replication.IMPORTANCE Heat shock protein 90 (Hsp90) is nearly universally required for viral protein homeostasis. Here, we report that Hsp90 activity is required for efficient propagation of mumps virus (MuV). Hsp90 functions in the maintenance of the catalytic subunit of viral polymerase, the large (L) protein, prior to formation of a mature polymerase complex with the polymerase cofactor of L, phosphoprotein. Hsp70 collaborates with Hsp90 to regulate biogenesis of the MuV L protein. The functions of these chaperones on the viral polymerase may be common among paramyxoviruses because the L protein of measles virus is also similarly regulated. Our data provide important insights into the molecular mechanisms of paramyxovirus polymerase maturation as well as a basis for the development of novel antiviral drugs.

Differential Expression of Cardiac Troponin T and I in a Patient with Isolated Skeletal Muscular Sarcoidosis.

A 49-year-old female was referred to our hospital due to high serum creatine kinase (CK) (2,605 IU/L) and serum cardiac troponin T (cTnT) (0.342 ng/mL) levels. She had no other complaints and further examinations suggested no signs of cardiac disease. Additionally, the serum cardiac troponin I (cTnI) levels were normal. She reported having gradually felt difficulty in walking upstairs. A biopsy indicated skeletal muscle sarcoidosis with positive staining for cTnT. Steroid therapy immediately resolved her muscular symptoms with a normalization of the serum CK levels. Since the serum levels of cTnI were normal, the concomitant measurement of cTnT/cTnI might be useful to diagnose skeletal muscular disease biochemically in such cases.

Mumps Virus Induces Protein-Kinase-R-Dependent Stress Granules, Partly Suppressing Type III Interferon Production.

Stress granules (SGs) are cytoplasmic granular aggregations that are induced by cellular stress, including viral infection. SGs have opposing antiviral and proviral roles, which depend on virus species. The exact function of SGs during viral infection is not fully understood. Here, we showed that mumps virus (MuV) induced SGs depending on activation of protein kinase R (PKR). MuV infection strongly induced interferon (IFN)-λ1, 2 and 3, and IFN-ß through activation of IFN regulatory factor 3 (IRF3) via retinoic acid inducible gene-I (RIG-I) and the mitochondrial antiviral signaling (MAVS) pathway. MuV-induced IFNs were strongly upregulated in PKR-knockdown cells. MuV-induced SG formation was suppressed by knockdown of PKR and SG marker proteins, Ras-GTPase-activating protein SH3-domain-binding protein 1 and T-cell-restricted intracellular antigen-1, and significantly increased the levels of MuV-induced IFN-λ1. However, viral titer was not altered by suppression of SG formation. PKR was required for induction of SGs by MuV infection and regulated type III IFN (IFN-λ1) mRNA stability. MuV-induced SGs partly suppressed type III IFN production by MuV; however, the limited suppression was not sufficient to inhibit MuV replication in cell culture. Our results provide insight into the relationship between SGs and IFN production induced by MuV infection.

Cross-Neutralization between Human and African Bat Mumps Viruses.

Recently, a new paramyxovirus closely related to human mumps virus (MuV) was detected in bats. We generated recombinant MuVs carrying either or both of the fusion and hemagglutinin-neuraminidase bat virus glycoproteins. These viruses showed replication kinetics similar to human MuV in cultured cells and were neutralized efficiently by serum from healthy humans.

Mumps Virus Is Released from the Apical Surface of Polarized Epithelial Cells, and the Release Is Facilitated by a Rab11-Mediated Transport System.

UNLABELLED: Mumps virus (MuV) is an airborne virus that causes a systemic infection in patients. In vivo, the epithelium is a major replication site of MuV, and thus, the mode of MuV infection of epithelial cells is a subject of interest. Our data in the present study showed that MuV entered polarized epithelial cells via both the apical and basolateral surfaces, while progeny viruses were predominantly released from the apical surface. In polarized cells, intracellular transport of viral ribonucleoprotein (vRNP) complexes was dependent on Rab11-positive endosomes, and vRNP complexes were transported to the apical membrane. Expression of a dominant negative form of Rab11 (Rab11S25N) reduced the progeny virus release in polarized cells but not in nonpolarized cells. Although in this way these effects were correlated with cell polarity, Rab11S25N did not modulate the direction of virus release from the apical surface. Therefore, our data suggested that Rab11 is not a regulator of selective apical release of MuV, although it acts as an activator of virus release from polarized epithelial cells. In addition, our data and previous studies on Sendai virus, respiratory syncytial virus, and measles virus suggested that selective apical release from epithelial cells is used by many paramyxoviruses, even though they cause either a systemic infection or a local respiratory infection. IMPORTANCE: Mumps virus (MuV) is the etiological agent of mumps and causes a systemic infection. However, the precise mechanism by which MuV breaks through the epithelial barriers and achieves a systemic infection remains unclear. In the present study, we show that the entry of MuV is bipolar, while the release is predominantly from the apical surface in polarized epithelial cells. In addition, the release of progeny virus was facilitated by a Rab11-positive recycling endosome and microtubule network. Our data provide important insights into the mechanism of transmission and pathogenesis of MuV.

γ-H2AX induced by linear alkylbenzene sulfonates is due to deoxyribonuclease-1 translocation to the nucleus via actin disruption.

Phosphorylation of histone H2AX (γ-H2AX) occurs following formation of DNA double strand breaks (DSBs). Other types of DNA damage also generate DSBs through DNA replication and repair, leading to the production of γ-H2AX. In the present study, we demonstrated that linear alkylbenzene sulfonates (LAS), the most widely used and non-genotoxic anionic surfactants, could generate γ-H2AX via a novel pathway. Breast adenocarcinoma MCF-7 cells were treated with five kinds of LAS with alkyl chains ranging from 10 to 14 carbon units (C10-C14LAS). The generation of DSBs and subsequent production of γ-H2AX increased in a manner that depended on the number of carbon units in LAS. γ-H2AX could also be generated with non-cytotoxic doses of LAS and was independent of the cell cycle, indicating the non-apoptotic and DNA replication-independent formation of DSBs. The generation of γ-H2AX could be attenuated by EGTA and ZnCl2, deoxyribonuclease-1 (DNase I) inhibitors, as well as by the knockdown of DNase I. LAS weakened the interaction between DNase I and actin, and the enhanced release of DNase I was dependent on the number of carbon units in LAS. DNase I released by the LAS treatment translocated to the nucleus, in which DNase I attacked DNA and generated γ-H2AX. These results suggested that the LAS-induced generation of γ-H2AX could be attributed to the translocation of DNase I to the nucleus through the disruption of actin, and not to LAS-induced DNA damage.

Thrombomodulin improves rat survival after extensive hepatectomy.

BACKGROUND: Recombinant human soluble thrombomodulin (rTM) protects against disseminated intravascular coagulopathy by inhibiting coagulation, inflammation, and apoptosis. This study tests the hypothesis that rTM is hepatoprotective after extensive hepatectomy (Hx) and investigates the mechanisms underlying this effect. MATERIALS AND METHODS: Experiment 1: rats (15 per group) were injected with rTM (1.0 or 2.0 mg/kg) or saline just before 95% Hx and their 7-d survival assessed. Experiment 2: rats were assigned to either a treated (2.0 mg/kg rTM just before Hx) or control group (n = 5 per group). Five rats per group were euthanized immediately after surgery, and at 1, 3, 6, 12, and 24 h postoperatively; serum and liver remnant samples were collected for biochemical and histologic analysis, as well as reverse-transcription polymerase chain reaction and Western blotting. RESULTS: All saline-injected rats died within 52 h of Hx, whereas injection of 2.0 mg/kg rTM prolonged survival (P = 0.003). rTM increased the number of Ki67-positive cells and reduced the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. The number of myeloperoxidase-positive cells and the expression of high-mobility group box 1 protein did not differ. Reverse-transcription polymerase chain reaction revealed that rTM significantly enhanced protease-activated receptor-1 and sphingosine kinase 1 messenger RNA expression and significantly reduced plasminogen activator inhibitor-1 and Bax messenger RNA expression. Immunohistochemistry and Western blotting demonstrated that protease-activated receptor-1 expression 24 h after Hx was significantly higher in rTM-treated than in control rats. CONCLUSIONS: rTM may improve survival after extensive Hx by inhibiting apoptosis and promoting liver regeneration.

Hydroxychloroquine-inhibited dengue virus is associated with host defense machinery.

Hydroxychloroquine (HCQ) is an antimalarial drug also used in treating autoimmune diseases. Its antiviral activity was demonstrated in restricting HIV infection in vitro; however, the clinical implications remain controversial. Infection with dengue virus (DENV) is a global public health problem, and we lack an antiviral drug for DENV. Here, we evaluated the anti-DENV potential of treatment with HCQ. Immunofluorescence assays demonstrated that HCQ could inhibit DENV serotype 1-4 infection in vitro. RT-qPCR analysis of HCQ-treated cells showed induced expression of interferon (IFN)-related antiviral proteins and certain inflammatory cytokines. Mechanistic study suggested that HCQ activated the innate immune signaling pathways of IFN-ß, AP-1, and NFκB. Knocking down mitochondrial antiviral signaling protein (MAVS), inhibiting TANK binding kinase 1 (TBK1)/inhibitor-κB kinase ɛ (IKKɛ), and blocking type I IFN receptor reduced the efficiency of HCQ against DENV-2 infection. Furthermore, HCQ significantly induced cellular production of reactive oxygen species (ROS), which was involved in the host defense system. Suppression of ROS production attenuated the innate immune activation and anti-DENV-2 effect of HCQ. In summary, HCQ triggers the host defense machinery by inducing ROS- and MAVS-mediated innate immune activation against DENV infection and may be a candidate drug for DENV infection.

Phosphorylation of histone H2AX generated by linear alkylbenzene sulfonates and its suppression by UVB exposure.

We previously demonstrated that the nonionic surfactants, nonylphenol polyethoxylates (NPEOs) induced the phosphorylation of histone H2AX (γ-H2AX), accompanied by DNA double-strand breaks (DSBs), and that exposure to ultraviolet (UV) degraded NPEOs, which sometimes enhanced their DNA-damaging ability. In this study, we showed that linear alkylbenzene sulfonates (LAS), general anion surfactants, also generated DSBs with γ-H2AX, and this ability was attenuated by UVB exposure. In the human breast adenocarcinoma cell line, MCF-7, γ-H2AX was generated in a dose-dependent manner immediately after cells were treated with LAS, and this was attributed to the formation of DSBs and was independent of cell cycle phases. The ability to generate γ-H2AX was markedly reduced in LAS exposed to UVB. HPLC analysis revealed that LAS were a mixture of various alkyl chain lengths, the peaks of which were detected at individual retention times. UVB evenly decreased all peaks of LAS, without migration of peaks to other retention times, which indicated that UVB may degrade the benzene ring of LAS, but did not shorten the alkyl chains. UVB is an important environmental factor in the degradation of LAS exhibiting the ability to induce DSBs, the most serious type of DNA damage.