Search

Reports documenting the mid-term patency of spiral saphenous vein grafts for superior vena cava syndrome in patients with advanced thoracic malignancy are, so far, scarce. The present report describes a 69-year-old man who suffered superior vena cava syndrome due to malignant invasion by advanced lung cancer. Since the huge mass in the anterior mediastinum was unresectable, a bypass from the left innominate vein to the right atrium using an autologous spiral saphenous vein graft was surgically created. Postoperatively, the patient received chemoradiotherapy and maintenance anticoagulant therapy, resulting in survival for 4 years without graft occlusion or recurrence of superior vena cava syndrome.

Introduction: This study investigated whether our urinary podocyte detection method using podocalyxin (PDX) and Wilms tumor 1 (WT1) immunoenzyme staining combined with liquid-based cytology can serve as a noninvasive routine laboratory test for glomerular disease., Methods: The presence of PDX- and WT1-positive cells was investigated in 79 patients with glomerular disease and 51 patients with nonglomerular disease., Results: The frequencies and numbers of PDX- and WT1-positive cells were significantly higher in the glomerular disease group than in the nonglomerular disease group. The best cutoffs for PDX- and WT1-positive cell counts for identifying patients with glomerular disease were 3.5 (sensitivity = 67.1% and specificity = 100%) and 1.2 cells/10 mL (sensitivity = 43.0% and specificity = 100%), respectively., Conclusion: Because our urinary podocyte detection method using PDX immunoenzyme staining can be standardized and it detected glomerular disease with high accuracy, it can likely serve as a noninvasive routine laboratory test for various glomerular diseases., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Current detergent or ether-disrupted split vaccines (SVs) for influenza do not always induce adequate immune responses, especially in young children. This contrasts with the whole virus particle vaccines (WPVs) originally used against influenza that were immunogenic in both adults and children but were replaced by SV in the 1970s due to concerns with reactogenicity. In this study, we re-evaluated the immunogenicity of WPV and SV, prepared from the same batch of purified influenza virus, in cynomolgus macaques and confirmed that WPV is superior to SV in priming potency. In addition, we compared the ability of WPV and SV to induce innate immune responses, including the maturation of dendritic cells (DCs) in vitro. WPV stimulated greater production of inflammatory cytokines and type-I interferon in immune cells from mice and macaques compared to SV. Since these innate responses are likely triggered by the activation of pattern recognition receptors (PRRs) by viral RNA, the quantity and quality of viral RNA in each vaccine were assessed. Although the quantity of viral RNA was similar in the two vaccines, the amount of viral RNA of a length that can be recognized by PRRs was over 100-fold greater in WPV than in SV. More importantly, 1000-fold more viral RNA was delivered to DCs by WPV than by SV when exposed to preparations containing the same amount of HA protein. Furthermore, WPV induced up-regulation of the DC maturation marker CD86 on murine DCs, while SV did not. The present results suggest that the activation of antigen-presenting DCs, by PRR-recognizable viral RNA contained in WPV is responsible for the effective priming potency of WPV observed in naïve mice and macaques. WPV is thus recommended as an alternative option for seasonal influenza vaccines, especially for children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The influence of pelvic tilt mobility, which can be reproduced in computer-simulation models, is an important subject to be addressed in the understanding of femoroacetabular impingement (FAI) pathophysiology., Purpose: To use computer-simulation models of FAI cases to evaluate the optimum improvement in hip range of motion (ROM) achieved by decreasing the anterior pelvic tilt and compare the results with the improvement in ROM achieved after cam resection surgery., Study Design: Controlled laboratory study., Methods: The pre- and postoperative computed tomography (CT) images from 28 patients with FAI treated with arthroscopic cam resection were evaluated. Using a dynamic computer-simulation program, 3-dimensional models with a 5° and a 10° decrease in anterior pelvic tilt from the supine functional pelvic plane (baseline) were created from the preoperative CT scans. Similar models were constructed for hips before (at baseline) and after cam resection. Improvements from baseline in maximum internal rotation at 45°, 70°, and 90° of flexion were assessed for the 5° change in pelvic tilt, 10° change in pelvic tilt, and cam resection models, and the results were compared for all conditions., Results: The combination of a 10° change in pelvic tilt and cam resection showed the largest ROM improvement from baseline ( P < .001). Improvement in internal rotation in the cam resection model was significantly higher compared with the 5° pelvic tilt change model ( P < .001), while there was no significant difference between the cam resection model and the 10° pelvic tilt change model., Conclusion: Decreasing anterior pelvic tilt by 10° in the preoperative computer simulation model resulted in an equivalent effect to cam resection, while a 5° change in pelvic tilt was inferior to cam resection in terms of ROM improvement., Clinical Relevance: Enough of a decrease in anterior pelvic tilt may contribute to ROM improvement that is as effective as that of cam resection surgery., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This study was funded by a grant-in-aid for scientific research (grant 18K09073). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

The gatekeeping adenylation (A) domain of the non-ribosomal peptide synthetase (NRPS) selectively incorporates specific proteinogenic/non-proteinogenic amino acid into a growing peptide chain. The EntE of the enterobactin NRPS is a discrete aryl acid A-domain with 2,3-dihydroxybenzoic acid (DHB) substrate specificity. Reprogrammed EntE N235G variant possesses an enlarged substrate recognition site, and is capable of accepting non-native aryl acids. Biochemical characterization of this unique substrate recognition site should provide a better understanding of activi-site microenvironments. Here, we synthesized a non-hydrolysable adenylate analogue with 2-aminobenzoic acid (2-ABA), 3-aminobenzoic acid (3-ABA), and 4-aminobenzoic acid (4-ABA) and used them to calculate the apparent inhibition constants (K i app. ). Dose-response experiments using 3-ABA-sulfamoyladenosine (AMS) provided K i app. values of 596 nM for wild-type EntE and 2.4 nM for the N235G variants. These results suggest that 3-amino group of benzoic acid plays an important role in substrate recognition by the N235G variant. These findings would help designing aryl acid substrates with substituents at the 2- and 3-positions.

Rituximab (RTX) is an effective treatment for refractory nephrotic syndrome (NS), but may produce human anti-chimeric antibodies (HACA) which can cause severe infusion reaction or rituximab-induced serum sickness (RISS). RISS presents with a fever, rash, and arthralgia, which typically occurs 7-21 days after RTX infusion. On the other hand, Kawasaki disease (KD) also presents with fever and rash. There have been no reports of KD developed after RTX infusion. A 6-year-old girl with frequently relapsing NS was admitted to our hospital for fever and rash on day 7 after receiving RTX. Although it was suggestive of RISS at first, she also had conjunctival hyperemia, swelling, and erythema of the hands and feet, and a right coronary artery abnormality on echocardiography. Her symptoms met the diagnostic criteria of KD. We administered intravenous immunoglobulin (IVIg) (2 g/kg), and her symptoms resolved within a few days. The HACA titer determined using the serum collected at admission was very high. This is the first report of KD with a clinical course similar to RISS. It should be noted that a careful follow-up of coronary arteries should be performed in patients suspected of RISS.

Background: Cytomegalovirus (CMV) infection is one of the major factors that affect morbidity and mortality in kidney transplant (KTx) patients. The rate of CMV seropositivity in children before KTx is lower than that in adults; therefore, pediatric KTx patients have a higher risk of CMV infection. In Japanese pediatric KTx patients, preemptive therapy for CMV infection is a main conventional therapy. This study investigated whether this preemptive treatment would affect kidney function at 2 years post-KTx., Methods: A total of 163 patients, that is approximately half of the Japanese pediatric KTx patients nationwide, were recruited to participate in our study. We compared the values of the sequential estimated glomerular filtration rate (eGFR) at two years post-KTx and other influencing factors in CMV viremia, CMV disease, and no-infection groups., Results: Cytomegalovirus infection after KTx occurred in 75 patients (46.0%), 38.7% of whom developed CMV disease. The sequential eGFR values post-KTx did not differ significantly between the three groups. CMV infection was not significantly correlated with other factors, other infections (including Epstein-Barr [EB] virus infection), acute rejection (AR), or adverse events. Only prolonged duration of total hospitalization was significantly associated with CMV infection (P = .002). In the multivariate analysis, younger age, CMV infection, and adverse effects were independently significantly related to prolonged total hospitalization., Conclusion: Preemptive therapy for CMV infection evidenced by viremia and disease did not significantly influence kidney function in Japanese pediatric KTx patients at two years after the operation., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The present report describes a case of mega-aortic syndrome accompanied with severe aortic regurgitation in a 75-year-old man who underwent a two-stage hybrid repair. Intraoperative pathologic findings at the first repair, consisting of Bentall operation and total arch replacement with a Lupiae graft, aided the identification of the giant cell aortitis. Despite complicating hemorrhagic stroke, steroid therapy was initiated and endovascular repair was subsequently completed. Over more than 2 years of follow-up, the patient continued steroid therapy and is doing well without any reintervention., Competing Interests: Disclosure StatementAll authors have no conflict of interest., (Copyright © 2020 Annals of Vascular Diseases.)

Graphene is an ideal candidate to use in various applications as a component in semiconductor devices with excellent properties, such as its atomic thickness, optical transparency, chemical stability, and high electrical and thermal conductivities. The high gas sensitivities of graphene functionalized with metal, metal oxides, and other groups have been improved through intensive research. However, the development of a metal-free graphene gas sensor and clarification of its mechanism still remain a challenge. In this study, H 2 , CO 2 , NH 3 , and He gas sensing performances are demonstrated using two- to multilayered graphene, directly fabricated on a quartz substrate. The sheet resistances of more than 100 graphene layers were considerably changed from 3% to 6% by He gas injection, caused by its piezoresistive property. The anomalous resistance changes by piezoresistivity is a result of electron transfer path changes associated with graphene assemble structure changes by insertion of He gas between graphene crystal units and pressing graphene units. The sheet resistances of the synthesized graphene were found to dramatically change through physical adsorption and chemisorption. The chemisorption of NH 3 gas on functional oxygen groups at graphene edges was responsible for the chemiresistive behavior of the material. The gas sensing and piezoresistive mechanisms of graphene determined in this work sheds light on the development of a graphene gas sensor.

A wet type solution blow spinning system with a water-mist coagulation chamber was developed to spin fine regenerated cellulose fibers from the non-volatile ionic liquid solvent 1-ethyl-3-methylimidazolium diethyl phosphate. The molecular weight distribution of cellulose, and the rheological properties and spinnability of its spinning solution were evaluated. Scanning electron microscope observations indicated that the fine water mist/vapor was important for efficient coagulation of the stretched solution jets. Under optimized spinning parameters, a non-woven fabric was obtained consisting of fine fibers with an average diameter of 0.98 ± 0.62 μm. The tensile strength of the samples was greatly influenced by the fabric structure formed upon regeneration of cellulose from solution. X-ray diffraction and polarized optical microscopy measurements revealed that the prepared cellulosic non-woven fabric was highly crystalline and had a well-defined molecular orientation, respectively, which might have contributed to the increased tensile strength., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Adenylation (A) domains act as the gatekeepers of non-ribosomal peptide synthetases (NRPSs), ensuring the activation and thioesterification of the correct amino acid/aryl acid building blocks. Aryl acid building blocks are most commonly observed in iron-chelating siderophores, but are not limited to them. Very little is known about the reprogramming of aryl acid A-domains. We show that a single asparagine-to-glycine mutation in an aryl acid A-domain leads to an enzyme that tolerates a wide range of non-native aryl acids. The engineered catalyst is capable of activating non-native aryl acids functionalized with nitro, cyano, bromo, and iodo groups, even though no enzymatic activity of wild-type enzyme was observed toward these substrates. Co-crystal structures with non-hydrolysable aryl-AMP analogues revealed the origins of this expansion of substrate promiscuity, highlighting an enlargement of the substrate binding pocket of the enzyme. Our findings may be exploited to produce diversified aryl acid containing natural products and serve as a template for further directed evolution in combinatorial biosynthesis., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In contrast to current ether- or detergent-disrupted "split" vaccines (SVs) for influenza, inactivated whole influenza virus particle vaccines (WPVs) retain the original virus structure and components and as such may confer similar immunity to natural infection. In a collaboration between academia and industry, the potential of WPV as a new seasonal influenza vaccine was investigated. Each of the four seasonal influenza vaccine manufacturers in Japan prepared WPVs and SVs from the same batches of purified influenza virus. Both mice and monkeys vaccinated with the WPVs exhibited superior immune responses to those vaccinated with the corresponding SVs. Vaccination with A/California/07/2009 (H1N1) WPV enabled mice to survive a lethal challenge dose of homologous virus whereas those vaccinated with SV succumbed to infection within 6 days. Furthermore, mice vaccinated with WPV induced substantial numbers of multifunctional CD8 + T cells, important for control of antigenically drifted influenza virus strains. In addition, cytokines and chemokines were detected at early time points in the sera of mice vaccinated with WPV but not in those animals vaccinated with SV. These results indicate that WPVs induce enhanced innate and adaptive immune responses compared to equivalent doses of SVs. Notably, WPV at one fifth of the dose of SV was able to induce potent immunity with limited production of IL-6, one of the pyrogenic cytokines. We thus propose that WPVs with balanced immunogenicity and safety may set a new global standard for seasonal influenza vaccines., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Water soluble spin-crossover (SCO) iron(II) nanoparticles (NPs) were synthesized by the polyethylene glycol (PEG) coating of [Fe(Htrz) 3-3× (NH 2 trz) 3× ](BF 4 ) 2 (x = 0, 0.1, 0.5 and 1). The NPs with x = 0.1 show gradual SCO behavior over 280-330 K in water. The relaxation times, T1 and T2, were determined and the thermally-responsive T2 values making these NPs a candidate for use as a MRI contrast agent.

The tumor suppressor protein RECK has been implicated in the regulation of matrix metalloproteinases (MMPs), NOTCH-signaling and WNT7-signaling. It remains unclear, however, how broad the spectrum of RECK targets extends. To find novel RECK binding partners, we took the unbiased approach of yeast two-hybrid screening. This approach detected ADAMTS10 as a RECK-interactor. ADAMTS10 has been characterized as a metalloproteinase involved in fibrillin-rich microfibril biogenesis, and its mutations have been implicated in the connective tissue disorder Weill-Marchesani syndrome. Experiments in vitro using recombinant proteins expressed in mammalian cells indicated that RECK indeed binds ADAMTS10 directly, that RECK protects ADAMTS10 from fragmentation following chemical activation and that ADAMTS10 interferes with the activity of RECK to inhibit MT1-MMP. In cultured cells, RECK increases the amount of ADAMTS10 associated with the cells. Hence, the present study has uncovered novel interactions between two molecules of known clinical importance, RECK and ADAMTS10.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Acute kidney injury (AKI) is a syndrome which has a broad range of etiologic factors depending on different clinical settings. Because AKI has significant impacts on prognosis in any clinical settings, early detection and intervention is necessary to improve the outcomes of AKI patients. This clinical guideline for AKI was developed by a multidisciplinary approach with nephrology, intensive care medicine, blood purification, and pediatrics. Of note, clinical practice for AKI management which was widely performed in Japan was also evaluated with comprehensive literature search.

Objective: Arima syndrome (AS) is a rare disease and its clinical features mimic those of Joubert syndrome or Joubert syndrome-related diseases (JSRD). Recently, we clarified the AS diagnostic criteria and its severe phenotype. However, genetic evidence of AS remains unknown. We explored causative genes of AS and compared the clinical and genetic features of AS with the other JSRD., Patients and Methods: We performed genetic analyses of 4 AS patients of 3 families with combination of whole-exome sequencing and Sanger sequencing. Furthermore, we studied cell biology with the cultured fibroblasts of 3 AS patients., Results: All patients had a specific homozygous variant (c.6012-12T>A, p.Arg2004Serfs*7) or compound heterozygous variants (c.1711+1G>A; c.6012-12T>A, p.Gly570Aspfs*19;Arg2004Serfs*7) in centrosomal protein 290 kDa (CEP290) gene. These unique variants lead to abnormal splicing and premature termination. Morphological analysis of cultured fibroblasts from AS patients revealed a marked decrease of the CEP290-positive cell number with significantly longer cilium and naked and protruded ciliary axoneme without ciliary membrane into the cytoplasm., Conclusion: AS resulted in cilia dysfunction from centrosome disruption. The unique variant of CEP290 could be strongly linked to AS pathology. Here, we provided AS specific genetic evidence, which steers the structure and functions of centrosome that is responsible for normal ciliogenesis. This is the first report that has demonstrated the molecular basis of Arima syndrome., (Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Trastuzumab following anthracycline causes cardiotoxicity in up to 28% of patients. Although the cardiotoxicity is often irreversible once cardiac dysfunction is detected, the early predictor has not been established yet., Methods: We prospectively observed breast cancer patients treated with anthracycline or trastuzumab at Tonan Hospital. All patients underwent echocardiography and blood sampling at baseline, and every three months during chemotherapy. Cardiotoxicity was defined as a decline in left ventricular ejection fraction >10% points., Results: Of 40 patients, 34 patients (85%) were treated with anthracycline (epirubicin), 18 (45%) with trastuzumab, and 12 (30%) with both agents. Cardiotoxicity was observed in four patients (10%), who were all treated with both agents. The absolute levels of high-sensitive troponin T (hs-TnT) were increased in all four patients with cardiotoxicity, and all the highest points were observed before or at the time of detection of cardiotoxicity. The highest level of hs-TnT was not significantly different in patients with and without cardiotoxicity. "Hs-TnT increment from baseline to the highest value" and "hs-TnT integration value above baseline" were significantly greater in patients with cardiotoxicity (0.039 vs. 0.007 ng/mL, P = 0.046, 0.113 vs. 0.022 ng months/mL, P = 0.013, respectively). The integration value had 100% sensitivity and specificity with a cutoff level at 0.070 ng months/mL., Conclusions: Hs-TnT assay may be able to predict anthracycline- and trastuzumab-induced cardiotoxicity in breast cancer patients, and the hs-TnT increment or hs-TnT integration value above baseline was more reliable than the absolute value.

Background: Although Asian population was recognized to have a lower risk of venous thromboembolism (VTE), its increasing prevalence and incidence remain unclear in patients with malignancies. We attempted to predict VTE development using activation markers of coagulation and fibrinolysis., Methods: We enrolled patients with malignancy admitted to Tonan Hospital between April and December 2014 to receive a new-for-them chemotherapy regimen. All patients were examined for VTE by computed tomography and whole-leg compression ultrasonography before chemotherapy and three months later. We also examined plasma levels of thrombin-antithrombin complex (TAT) and plasmin α2-plasmin inhibitor complex (PIC) before chemotherapy. The cut off values of TAT and PIC were set at 2.1 ng/mL and 1.8 μg/mL, respectively., Results: Of 97 patients, the majority (67%) had distant metastases. The most common malignancies were colorectal (26%), breast (23%), and stomach (19%) cancer. VTE was detected in 29 patients (31%); all were asymptomatic. VTE was newly developed in 12 patients in the three-month observation period, which means the incidence was 49 per 1000 person-years. Non-increased PIC with increased TAT was the only significant risk factor for both VTE prevalence and incidence in multivariate analysis, and the odds ratios were 3.0 (95% confidence interval, 1.1-8.2; P = 0.034) and 9.4 (95% confidence interval, 1.7-51.9; P = 0.011), respectively., Conclusions: The prevalence and incidence of VTE were high in hospitalized Japanese patients receiving chemotherapy for malignancies. Non-increased PIC with increased levels of TAT may be an independent risk factor for VTE development.

Background: There is discordance regarding the effect of symptom status before aortic valve replacement (AVR) on long-term outcome after AVR in severe aortic stenosis (AS).Methods and Results:The CURRENT AS registry is a multicenter retrospective registry enrolling 3,815 consecutive patients with severe AS. Among 1,196 patients managed with the initial AVR strategy, long-term clinical outcomes were compared between the symptomatic patients (n=905), and asymptomatic patients (n=291). Median follow-up interval was 1337 days with a 91% follow-up rate at 2 years. AVR was performed in 886 patients (98%) in the symptomatic group and in 287 patients (99%) in the asymptomatic group. Symptomatic patients were older and more often had comorbidities than asymptomatic patients with similar echocardiographic AS severity. The cumulative 5-year incidences of all-cause death and heart failure (HF) hospitalization were significantly higher in symptomatic patients than in asymptomatic patients (25.6% vs. 15.4%, P=0.001, and 14.2% vs. 3.8%, P<0.001, respectively). On landmark analysis at 30 days after AVR, the differences in mortality and HF hospitalization between the 2 groups were mainly observed beyond 30 days., Conclusions: When managed with the initial AVR strategy, the long-term outcomes of symptomatic severe AS were worse than those of asymptomatic severe AS. Early AVR strategy might be recommended in some selected asymptomatic severe AS patients with reasonable operative risk.

Human intestinal absorption and drug metabolism vary to a large extent among individuals. For example, CYP3A4 activity has large individual variation that cannot be attributed to only genetic differences. Various flavonoids in vegetables, such as kaempferol and quercetin, possess inhibitory effects, and some vegetable and fruit juices have also been found to inhibit CYP3A4 activity. Therefore, differences in daily intake of flavonoid-containing vegetables may induce individual variation in intestinal bioavailability. To identify a vegetable that strongly inhibits CYP3A4, we investigated the effects of juices, prepared from individual vegetables, on CYP3A4 activity using recombinant CYP3A4 and LS180 cells in this study. Nine vegetable juices (cabbage, Japanese radish, onion, tomato, eggplant, carrot, Chinese cabbage, green pepper, and lettuce), were prepared and recombinant CYP3A4 and LS180 cells were used for evaluation of CYP3A4 activity. Metabolism to 6β-hydroxytestosterone by recombinant CYP3A4 was strongly inhibited by cabbage, onion, and green pepper juices, and cabbage and green pepper juices significantly inhibited CYP3A4 activity in a preincubation time-dependent manner. In addition, CYP3A4 activity in LS180 cells was significantly inhibited by cabbage and onion juices. In conclusion, this study showed that juices prepared from some individual vegetables could significantly inhibit CYP3A4 activity. Therefore, variation in the daily intake of vegetables such as cabbage and onion may be one of the factors responsible for individual differences in intestinal bioavailability.

Combination chemotherapy consisting of systemic and intraperitoneal agents against peritoneal metastases from several types of cancer has shown promising results. We herein report a case in which combination therapy with intravenous and intraperitoneal paclitaxel with S-1 converted an unresectable pancreatic cancer with peritoneal metastases into a resectable one. The patient was a 65-year old woman with recurrent pancreatitis for 5 months. Endoscopic ultrasonography-guided fine-needle aspiration revealed minute epithelial masses composed of cells with irregular nuclei in the pancreatic body. The patient underwent abdominal surgery, but no excision was performed, as two peritoneal metastases in the bursa omentalis were detected. Combination therapy was initiated, consisting of intravenous and intraperitoneal paclitaxel with S-1 as a single-center clinical trial. The regimen consisted with 2-week administration of S-1 (80 mg per day) followed by 1 week of rest, intravenous paclitaxel 50 mg/m 2 , and intraperitoneal paclitaxel 20 mg/m 2 by a peritoneal access device on days 1 and 8. Over the seven cycles of the chemotherapy, the primary lesion did not change in size, and peritoneal lavage cytology remained negative. After confirming the disappearance of the peritoneal lesions by exploratory laparoscopy, the patient underwent distal pancreatectomy combined with resection of the transverse mesocolon and stomach wall. Thus, the 2-way chemotherapy of intravenous and intraperitoneal paclitaxel with S-1 was well-tolerated and was able to convert pancreatic cancer with peritoneal metastases to resectable disease.

Intravenous and intraperitoneal paclitaxel with S-1 is showing promising results in gastric cancer with peritoneal metastases. We herein report a successful conversion of unresectable to resectable disease using combination chemotherapy with trastuzumab. The patient was a 39-year-old woman with human epidermal growth factor receptor 2-positive gastric cancer with peritoneal, pulmonary and bilateral ovarian metastases. After 6 cycles of S-1 plus cisplatin with trastuzumab, followed by 15 cycles of intravenous and intraperitoneal paclitaxel with S-1 and trastuzumab, the pulmonary and peritoneal metastases exhibited complete response and no evidence of malignancy was found on diagnostic laparoscopy. We performed metastasectomy of the bilateral sizeable ovaries, followed by total gastrectomy. The patient had no recurrence for 16 months after the gastrectomy. Therefore, satisfactory response to systemic and intraperitoneal chemotherapy may convert unresectable to resectable disease, and primary tumor resection with ovarian metastasectomy may prolong survival. This combination chemotherapy has the potential of becoming a conversion therapy for gastric cancer with peritoneal metastases, even if ascites and ovarian metastases are extensive.

Background: Paraneoplastic erythrocytosis can be brought on by ectopic erythropoietin production usually in kidney, brain, and liver tumor with increase of serum erythropoietin level. We report here a paraneoplastic erythrocytosis of colon cancer with serum erythropoietin within the normal reference, which required an immunohistologic test for erythropoietin-antibody to be diagnosed., Case Report: Our case report was of a 75-year-old woman with erythrocytosis. Her hemoglobin and serum erythropoietin levels were 191 g/dL and 12.6 IU/L (reference range, 9.1-32.8), respectively. Colonoscopy revealed an advanced sigmoid colon tumor 20 mm in diameter. She underwent colectomy, and immunohistochemical examination showed the colon adenocarcinoma was focally positive for erythropoietin-antibody. One month after the surgery, her hemoglobin level decreased to 117 g/L., Conclusions: Colon cancer can cause paraneoplastic erythrocytosis, and it is important to consider not simply the absolute serum erythropoietin level but also the serum erythropoietin level relative to simultaneously measured hemoglobin level. We should include paraneoplastic erythrocytosis as a differential diagnosis in cases of high hemoglobin level unexplained by other diseases.

A 15-year-old girl was found to be hypertensive (230-270/140-170 mm Hg) without any subjective symptoms. Magnetic resonance imaging confirmed the presence of a well-defined 22 mm hypodense lesion in the lower pole of the left kidney, located close to the renal hilum. Plasma rennin activity was elevated (75 ng/mL/h), and reninoma was diagnosed. Retroperitoneoscopy-assisted nephron-sparing surgery was planned. The retroperitoneum was accessed through a 4 cm left pararectal upper abdominal incision. Following blunt dissection, the abdominal wall was elevated with a lifting bar and lifting retractor, inserted below the 12th rib in the anterior axillary line to create sufficient working space in the retroperitoneal cavity without the need for pneumoperitoneum. Three 5 mm trocars were introduced above the superior iliac crest for the camera and the assistant. Gerota's fascia was opened and the kidney exposed. The surgeon dissected the left kidney through the minilaparotomy incision under both direct vision and using the magnified view on the monitor, which was particularly effective for the lateral and posterior sides of the kidney. The posterior peritoneum was incised intentionally next to the diaphragm to allow further mobilization of the kidney. Diathermy was used to remove the tumor and a layer of surrounding normal parenchymal tissue at least 0.5 cm thick. The histopathologic diagnosis was reninoma. Ischemia time was 14 minutes. Postoperatively, both plasma rennin activity and blood pressure were normal (1.9 ng/mL/h and 90-110/70-80 mm Hg, respectively). After follow-up of 12 months, there is no evidence of recurrence.

Clinicians generally suspect pulmonary tumor embolism (PTE) with uncontrolled carcinomas which often spread to lungs. We, however, experienced an autopsy case of diffuse microscopic PTE despite controlled liver metastases of transitional cell carcinoma (TCC). A 66-year-old man with progressing respiratory symptoms showed almost normal chest findings on computed tomography. Although liver metastases were successfully shrunk by chemotherapy, the patient died from aggressive respiratory failure. An autopsy revealed small pulmonary vessels showing diffuse tumor emboli. TCC can cause PTE even if liver metastases are controlled. We must therefore be aware that PTE can manifest as respiratory symptoms without any computed tomography findings.

Background: Although palonosetron (PALO) and NK1 receptor antagonist both reduce chemotherapy-induced nausea and vomiting, no comparison trial in moderately emetogenic chemotherapy (MEC) had been reported. The purpose of this study was to find out which drug combinations are preferable for patients receiving MEC., Methods: Chemotherapy-naive patients receiving MEC were randomized to two groups; group A first received PALO therapy [PALO plus 1-day dexamethasone (DEX)], and group B first received fosaprepitant (FAPR) therapy [FAPR, granisetron (GRAN), and DEX]. Patients were re-allocated to the other therapy, respectively, for the second cycle of chemotherapy. We administered intravenous PALO (0.75 mg) and DEX (9.9 mg) to the PALO therapy group, and FAPR (150 mg), DEX (4.95 mg), and GRAN (3 mg) to the FAPR therapy group, on Day 1. Complete response (CR) was the primary endpoint; complete control (CC), total control (CT), and the therapy chosen by the patients for their third and following cycles of antiemetic therapy were the secondary endpoints. We evaluated CR, CC, and TC in the acute phase, in the delayed phase, and over the whole period., Results: A total of 35 patients and 70 cycles of therapy was evaluable for analysis. No significant difference was found at all evaluation points. Overall CR rates for PALO and FAPR therapy were 74 vs 69 % (P = 0.567), CC rates 66 vs 69 % (P = 0.521), and TC rates 46 vs 60 % (P = 0.235), respectively. Patients also showed no clear preference for their third and following cycles of chemotherapy, choosing both regimens almost equally often (PALO 10 vs FAPR 13)., Conclusions: PALO and 1-day DEX is almost equivalent to FAPR, GRAN, and DEX for MEC.

A 74-year-old woman with advanced gastric cancer was admitted to our hospital. A central venous (CV) port catheter was implanted into the right subclavian vein for preoperative chemotherapy and parenteral nutritional management. On the 35th day after implantation, she complained of diarrhea, fever and dyspnea. The chest radiograph showed a right-sided massive pleural effusion. As the patient progressively fell into severe respiratory distress, endotracheal intubation was performed for management of respiration by mechanical ventilation. Initially, given the patient's symptoms, she was diagnosed with septic shock. Therefore, after placement of a CV catheter through the right femoral vein, in consideration of the possibility of a port infection, she was treated with thoracentesis and infusion of antibiotics. The patient gradually recovered, and again received parenteral nutrition through the CV port catheter. After the infusion was administered, she complained of dyspnea. A CT scan of the chest revealed a right pleural effusion and displacement of the tip of the CV port catheter out of the wall of the superior vena cava. We diagnosed delayed vascular injury (DVI), and the CV port catheter was removed. She soon recovered with conservative treatment. We speculated that the initial respiratory symptoms such as the pleural effusion were caused by DVI. DVI should therefore be recognized as a complication related to implanted CV port catheters.

A common strategy to identify tumor suppressor genes has been positional cloning, taking advantages of chromosomal abnormalities, linkage to polymorphic markers, etc. We have been taking another approach, based on shotgun cloning with cDNA-expression library, to isolate genes suppressing an aspect of transformed phenotypes. Genes identified in such an artificial system, however, require subsequent validation for their clinical relevance through independent approaches, such as finding mutations and altered expression in human cancers. Whether the parental genes act as oncogenes or tumor suppressors needs to be deduced from available annotations and/or new experimental data. Once validated, such genes, being isolated by virtue of their biological activities, are likely to be useful in developing new strategies for tumor prognosis, tumor stratification, and drug discovery.

By combination of differential scanning calorimetry (DSC) and fluorescence spectroscopy of 6-propionyl-2-(dimethylamino)naphthalene (Prodan), we elucidated the thermotropic phase behavior of hydrogenated soybean phosphatidylcholine (HSPC)-cholesterol binary liposome membrane which has similar lipid composition to Doxil®, the widely used liposome product in treatment of various tumors. We found that the characteristic points at cholesterol mole fraction (Xch)=0.023 and 0.077 correspond to the hexagonal lattice, in which cholesterol molecules are considered to be regularly distributed in all regions of HSPC lipid bilayer with 1 : 42 and 1 : 12 units, respectively, as static averaged structures. Apparent endothermic peak disappeared at Xch=0.40 in the DSC thermograms, indicating the existence of single liquid ordered phase at Xch>0.40. In addition, fluorescence measurements of Prodan and its lauroyl derivative in poly(ethylene glycol) (PEG)-modified liposomes indicated that PEG modification has a negligible effect on the phase behavior of HSPC-cholesterol binary liposome membrane. These results may provide useful information in developing novel liposome products whose stability and encapsulated drug release are controlled.

Protein crystals form in supersaturated solutions via a nucleation and growth mechanism. The amyloid fibrils of denatured proteins also form via a nucleation and growth mechanism. This similarity suggests that, although protein crystals and amyloid fibrils are distinct in their morphologies, both processes can be controlled in a similar manner. It has been established that ultrasonication markedly accelerates the formation of amyloid fibrils and simultaneously breaks them down into fragmented fibrils. In this study, we investigated the effects of ultrasonication on the crystallization of hen egg white lysozyme and glucose isomerase from Streptomyces rubiginosus. Protein crystallization was monitored by light scattering, tryptophan fluorescence, and light transmittance. Repeated ultrasonic irradiations caused the crystallization of lysozyme and glucose isomerase after cycles of irradiations. The size of the ultrasonication-induced crystals was small and homogeneous, and their numbers were larger than those obtained under quiescent conditions. Switching off ultrasonic irradiation when light scattering or tryptophan fluorescence began to change resulted in the formation of larger crystals due to the suppression of the further nucleation and fractures in preformed crystals. The results indicate that protein crystallization and amyloid fibrillation are explained on the basis of a common phase diagram in which ultrasonication accelerates the formation of crystals or crystal-like amyloid fibrils as well as fragmentation of preformed crystals or fibrils., (© 2013.)

In a previous study, Vanabin2, a member of a family of V(IV)-binding proteins, or Vanabins, was shown to act as a V(V)-reductase. The current study assesses the ability of Vanabin2 to reduce various transition metal ions in vitro. An NADPH-coupled oxidation assay yielded no evidence of reduction activity with the hexavalent transition metal anions, Mo(VI)O4(2-) and W(VI)O4(2-), or with three divalent cations, Mn(II), Ni(II), and Co(II). Although Cu(II) is readily reduced by glutathione and is gradually oxidized in air, this process was not affected by the presence of Vanabin2. In the experiments conducted thus far, Vanabin2 acts only as a V(V)-reductase. This high selectivity may account for the metal ion selectivity of vanadium accumulation in ascidians.

The cases are reported of mitral valve repair with symmetrical papillary muscle approximation from heads to bases close to cardiac apex for functional mitral regurgitation (FMR). The two papillary heads attaching the chordae to both leaflets from the posteromedial papillary muscle were approximated parallel to the solitary head of the anterolateral papillary muscle. This procedure permits an even reduction of lateral shift of the papillary muscle, resulting in an elimination of mitral tethering, and provides a satisfactory and durable mitral valve repair with good outcomes in patients with idiopathic dilated cardiomyopathy and FMR.

Amyloid fibrils and amorphous aggregates are two types of aberrant aggregates associated with protein misfolding diseases. Although they differ in morphology, the two forms are often treated indiscriminately. β(2)-microglobulin (β2m), a protein responsible for dialysis-related amyloidosis, forms amyloid fibrils or amorphous aggregates depending on the NaCl concentration at pH 2.5. We compared the kinetics of their formation, which was monitored by measuring thioflavin T fluorescence, light scattering, and 8-anilino-1-naphthalenesulfonate fluorescence. Thioflavin T fluorescence specifically monitors amyloid fibrillation, whereas light scattering and 8-anilino-1-naphthalenesulfonate fluorescence monitor both amyloid fibrillation and amorphous aggregation. The amyloid fibrils formed via a nucleation-dependent mechanism in a supersaturated solution, analogous to crystallization. The lag phase of fibrillation was reduced upon agitation with stirring or ultrasonic irradiation, and disappeared by seeding with preformed fibrils. In contrast, the glass-like amorphous aggregates formed rapidly without a lag phase. Neither agitation nor seeding accelerated the amorphous aggregation. Thus, by monitoring the kinetics, we can distinguish between crystal-like amyloid fibrils and glass-like amorphous aggregates. Solubility and supersaturation will be key factors for further understanding the aberrant aggregation of proteins.

A 38-year-old man was diagnosed with acute type A aortic dissection and severe aortic regurgitation, and taken immediately to the operating room for repair of the ascending aorta using the Bentall procedure. The presence of the anomalous right coronary artery was revealed at the time of the procedure, and was repaired with single coronary button technique. Some case reports have described anomalous coronary artery in association with acute myocardiac infarction or angina pectoris. This report describes a case of anomalous coronary artery diagnosed during an emergency operation for aortic dissection.

The membrane-anchored metalloproteinase-regulator RECK has been characterized as a tumor suppressor. Here we report that mice with reduced Reck-expression show limb abnormalities including right-dominant, forelimb-specific defects in postaxial skeletal elements. The forelimb buds of low-Reck mutants have an altered dorsal ectoderm with reduced Wnt7a and Igf2 expression, and hypotrophy in two signaling centers (i.e., ZPA and AER) that are essential for limb outgrowth and patterning. Reck is abundantly expressed in the anterior mesenchyme in normal limb buds; mesenchyme-specific Reck inactivation recapitulates the low-Reck phenotype; and some teratogens downregulate Reck in mesenchymal cells. Our findings illustrate a role for Reck in the mesenchymal-epithelial interactions essential for mammalian development.

Closure of patent ductus arteriosus (PDA) in the elderly is a high-risk procedure due to the fragility of the aorta and aneurysmal changes in the ductus. Stent grafting has emerged as a method for treating aortic disease. We describe a case in which this endovascular technique was successfully performed for closure of a PDA with aneurismal change in a high-risk patient. This approach may comprise the armamentarium for treating this pathology in adults.

Background: Ventricular septal rupture (VSR) is an infrequent but life-threatening situation. Although outcomes have improved with the introduction of infarction exclusion, we have experienced difficulty in determining the optimal patch size and shape for obtaining good outcomes. Therefore, we modified the infarction exclusion technique. Herein, we review our experience on the basis of early closure of VSR with and without use of the infarction exclusion technique., Methods: We retrospectively analyzed the hospital records of 33 patients who underwent surgical treatment for VSR. We employed Dagget's method from 1982 to 1995, and then introduced the infarction exclusion technique in 1995. We have developed two modifications: the two-sheet single-patch technique and the three-sheet double-patch technique., Results: Overall hospital mortality was 41.9% and that of the infarction exclusion group was significantly lower than the hospital mortality rate of the noninfarction exclusion group (21% and 63%, respectively, p = 0.0266). Late mortality of survivors was low in all groups during the observation period. The three-sheet double-patch group showed no residual shunt. This difference in outcomes between the single-patch and double-patch groups was statistically significant (p = 0.0174)., Conclusions: The two-sheet method facilitates the restoration of ventricular geometry. A double-patch using the three-sheet method may be useful for reducing residual shunt., (© 2012 Wiley Periodicals, Inc.)

Cell-penetrating peptides are arginine- and lysine-rich cationic peptides that can readily enter cells not only by themselves but also carrying other macromolecular cargos. In fact, we have reported that polycationic polymer such as poly-l-lysine (PLL) and poly-l-arginine (PLA) translocate through negatively charged phospholipid liposome membranes. In this work, we made a comparative study of the interaction of PLL or PLA with lipid membranes consisting of negatively charged phospholipids to understand the role of basic amino acid residue (i.e. arginine and lysine) in the membrane-penetrating activity of polypeptides. PLA and PLL translocated into giant unilamellar vesicle composed of soybean phospholipids. ζ-potential and turbidity measurements demonstrated the electrostatic binding of PLL and PLA to large unilamellar vesicle (LUV). Fluorescence studies using membrane probes revealed that the binding of PLA and PLL to LUV affects the hydration and packing of the membrane interface region, in which the membrane insertion of PLA appeared to be greater than PLL. Differential scanning calorimetry showed that the enthalpy of the gel to liquid-crystalline phase transition for dipalmitoyl phosphatidylglycerol vesicle was greatly reduced by binding of PLL and PLA, in which the reduction is much larger in PLA than in PLL. Circular dichroism measurements in 2,2,2-trifluoroethanol/water mixture or in the presence of LUV indicated that the propensity of PLA to form α-helical structure is greater than PLL. Consistently, attenuated total reflection-Fourier transform infrared spectroscopy revealed that there is greater α-helical structure in PLA bound to LUV compared to PLL, which has much less ordered structure. Furthermore, isothermal titration calorimetry measurements demonstrated that the contribution of enthalpy to the energetics of binding to LUV is two-fold larger in PLA than in PLL. These results suggest that the stronger interaction of arginine residue with negatively charged phospholipid membranes compared to lysine residue appears to facilitate the conformational change in cationic polypeptide and its insertion into lipid membrane interior., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

APOBEC1 (A1) is a cytidine deaminase involved in the regulation of lipids in the small intestine. Herpes simplex virus 1 (HSV-1) is a ubiquitous pathogen that is capable of infecting neurons in the brain, causing encephalitis. Here, we show that A1 is induced during encephalitis in neurons of rats infected with HSV-1. In cells stably expressing A1, HSV-1 infection resulted in significantly reduced virus replication compared to that in control cells. Infectivity could be restored to levels comparable to those observed for control cells if A1 expression was silenced by specific A1 short hairpin RNAs (shRNA). Moreover, cytidine deaminase activity appeared to be essential for this inhibition and led to an impaired accumulation of viral mRNA transcripts and DNA copy numbers. The sequencing of viral gene UL54 DNA, extracted from infected A1-expressing cells, revealed G-to-A and C-to-T transitions, indicating that A1 associates with HSV-1 DNA. Taken together, our results demonstrate a model in which A1 induction during encephalitis in neurons may aid in thwarting HSV-1 infection.

Recent good results of cardiovascular surgery have led to expansion of its indication to elderly patients and patients with serious complications. Such patients may have serious respiratory complications after cardiac surgery and need to undergo tracheostomy relatively early in the postoperative period. Although the full sternotomy approach is the standard in almost all cardiac surgeries, superficial and deep sternal infections are rather common after early tracheostomy in full sternotomy patients. The lower partial sternotomy approach is a safer and more useful procedure in patients who will need tracheostomy in the early period after cardiac surgery. We report on 2 patients who were successfully tracheostomized within a week after cardiac surgery, with a review of the literature.

CHOP (cyclophosphamide, adriamycin, vincristine, and prednisolone) plus rituximab is a standard chemotherapy used to treat patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL). However, among elderly patients, this regimen has not been completely satisfactory in its efficacy and safety. We report our clinical experience in 8 collaborative institutions to determine if the VNCOP-B (etoposide, mitoxantrone, cyclophosphamide, vincristine, prednisolone, and bleomycin) combination therapy plus rituximab was effective and safe to treat elderly patients with aggressive B-NHL. Between September 2004 and December 2007, 23 previously untreated patients, median age 73 years, 50.0% classified as high-intermediate/high-risk on the standard International Prognostic Index (IPI) entered this trial. Complete remission rate was 90.5%, with a 100% overall response rate (RR) at the end of induction therapy; overall survival (OS) rate at 3 years was 76.4% (median follow-up 744 days), with an 82.6% 3-year progression-free survival (PFS) rate (median follow-up 744 days). The most common grade 3/4 toxicities were hematologic, including neutropenia in 75.0% of the patients despite prophylactic administration of granulocyte colony-stimulating factor (G-CSF), febrile neutropenia in 30.0%, respectively. There was no treatment-related mortality (TRM). Rituximab not only combined with chemotherapy but also given sequentially improved survival. R-VNCOP-B could be another option for elderly patients who are not considered to tolerate in receiving R-CHOP., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Median full-sternotomy carries a risk of sternal infection and lethal mediastinitis in cardiac surgery. We performed open-heart surgery through partial median sternotomy in 5 patients with tracheostomy. Coronary artery bypass grafting (CABG) was performed in 3 patients, aortic valve replacement in 1, and mitral valve replacement in 1. No operative deaths or complications related to wound infection occurred. Partial sternotomy represents a safe alternative in cardiac surgery in patients with tracheostoma.

Tumors of the pulmonary artery (PA) are rare and their prognosis is poor. Proper diagnosis is often delayed or made post mortem despite diagnostic advances. Although the only treatment of choice is radical surgical resection, local recurrences are soon recognized after the operation. There is no standard regimen of perioperative additional therapy, and its effectiveness is still unknown. We report a case of an 80-year-old male whose PA was almost completely obstructed by the intimal sarcoma. It was resected and reconstructed with autologous pericardial roll. His postoperative course was uneventful.

Background: Developmental angiogenesis proceeds through multiple morphogenetic events including sprouting, intussusception, and pruning. Mice lacking the membrane-anchored metalloproteinase regulator Reck die in utero around embryonic day 10.5 with halted vascular development; however, the mechanisms by which this phenotype arises remain unclear., Results: We found that Reck is abundantly expressed in the cells associated with blood vessels undergoing angiogenesis or remodelling in the uteri of pregnant female mice. Some of the Reck-positive vessels show morphological features consistent with non-sprouting angiogenesis. Treatment with a vector expressing a small hairpin RNA against Reck severely disrupts the formation of blood vessels with a compact, round lumen. Similar defects were found in the vasculature of Reck-deficient or Reck conditional knockout embryos., Conclusions: Our findings implicate Reck in vascular remodeling, possibly through non-sprouting angiogenesis, in both maternal and embyonic tissues.

The membrane-anchored matrix metalloproteinase-regulator RECK is often downregulated in various types of cancers; the levels of residual RECK in resected tumors often correlate with better prognosis. Forced expression of RECK in cancer cells suppresses tumor angiogenesis, invasion, and metastasis in xenograft models. RECK is therefore a promising marker for benignancy and a potential effector in cancer therapy. We established a cell line containing two transgene systems: (1) the secreted alkaline phosphatase (SEAP) gene fused to Reck promoter and (2) the HRAS(12V) oncogene driven by the Tet-off promoter system. This cell line exhibits transformed phenotype in regular medium and flat morphology with increased SEAP activity in the presence of doxycycline, allowing the assessment of RECK-inducing activity of chemicals in the contexts of both transformed and untransformed cells. Our pilot experiments with 880 known bioactive compounds detected 34 compounds that activate RECK promoter; among these, 10 were authentic anticancer drugs. Four selected compounds up-regulated endogenous RECK protein in several human cancer cell lines. The top-ranking compound, disulfiram, strongly suppressed spontaneous lung-metastasis of human fibrosarcoma cells in nude mice. Our data demonstrate the value of this screen in discovering effective cancer therapeutics.