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While the impact of respiratory virus infections has been well researched in some respiratory diseases, no clinical studies have discussed the subject of who would be more likely to develop respiratory virus infections among patients with various respiratory illnesses who come from different backgrounds. This study aimed to identify respiratory diseases that are frequently associated with respiratory virus infections along with the characteristics of patients who develop such infections in clinical settings. Tested specimens were obtained from the lower respiratory tract by bronchoscopy to provide more accurate data. Data of bronchoscopies at Ryukyu University Hospital between August 2012 and September 2016 were reviewed, and patients who underwent multiplex polymerase chain reaction (PCR) tests for detecting respiratory viruses in bronchoscopy specimens were retrospectively recruited for descriptive statistics. Differences among patients' primary pulmonary diseases and backgrounds were compared between the PCR-positive and -negative patients, and multivariate statistical analysis was performed to analyze factors associated with a positive PCR test result. Overall, 756 bronchoscopies were performed during the study period and PCR tests were performed for 177 patients. Of them, 27 tested positive for respiratory viruses, mainly parainfluenza virus and rhinovirus, and out of those, 7 were hospitalized for >1 month. Overall, all patients did not experience typical upper respiratory infection symptoms. In positive patients, 13 and 7 had diagnoses of interstitial lung disease and bacterial pneumonia, respectively. The diagnoses of 3 bacterial pneumonia cases were changed to viral pneumonia after receiving their PCR-positive tests. Respiratory virus infections were confirmed in 14 patients on immunosuppressant therapy and 4 on maintenance dialysis. Multivariate analysis revealed that immunosuppressant therapy and maintenance dialysis were independently associated with respiratory virus infections. Viruses were commonly detected in patients with interstitial lung diseases and bacterial pneumonia, while few patients were diagnosed with pure viral pneumonia. These illnesses were considered to be induced by respiratory infections. Immunosuppressant therapy and maintenance dialysis were associated with respiratory virus infections. Multiplex PCR testing is an essential diagnostic tool for respiratory virus infections in immunocompromised patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Our aim is to make an ideal embryo culture medium close to human oviduct fluid (HOF) components, and to evaluate the quality of this medium with embryo quality and clinical outcomes in assisted reproductive technology (ART) by a prospective randomized controlled trial (RCT)., Methods: Study I: HOF was collected laparoscopically from patients ( n  = 28) with normal pelvic findings. According to HOF analysis results, the new medium "HiGROW OVIT ® " (OVIT) was designed. Study II: Embryos (2 pronuclei (2PN) = 9633) were assigned from 1435 patients. The blastulation rate (BR), good BR (gBR), utilized (transferred/cryo-preserved) BR (uBR), pregnancy rate (PR), and miscarriage rate (MR) were compared between the OVIT and control groups by RCT., Results: The novel medium 'OVIT' was produced according to 31 HOF components. The concentrations of essential amino acids (e-AAs) were lower in OVIT than in current media, yet the opposite was true for ne-AA concentrations. gBR and uBR were higher in the OVIT group than in the control group. In the older female group, gBT and uBR were significantly higher in the OVIT group., Conclusions: The novel medium 'OVIT' was produced according to HOF data. The OVIT had significantly better embryo quality and clinical outcomes than the current media., Competing Interests: Takafumi Utsunomiya has nothing to disclose. The remaining authors have nothing to disclose., (© 2022 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

A 84-year-old female noticed erythema over her whole body for several months and was referred to our department for evaluation of her skin eruption. A physical examination revealed millet-sized erythematous papules and macules all over her body, a high body temperature, and a decreased level of consciousness. A laboratory examination showed an elevated white blood cell count (8200/μl), atypical lymphocytes (3%) and sIL-2R (4030U / ml). Computed Tomography showed systemic lymphadenopathy. A lymph node biopsy taken from the left inguinal lymph node revealed destruction of the lymph nodes, enlargement of the high endothelial venules, and atypical lymphocyte infiltration. Based on the clinical findings and laboratory examination, we diagnosed angioimmunoblastic Tcell lymphoma (AITL). AITL is a relatively rare peripheral T-cell lymphoma with severe systemic symptoms such as fever and lymph node swelling. While approximately half of all cases experience skin symptoms, which are one of the initial symptoms, it is difficult to determine the diagnosis due to the various clinical features or many non-specific rashes. We should keep in mind a differential diagnosis of lymphoma in cases of the presence of persistent eruption, systemic symptoms, and the existence of atypical lymphocytes in peripheral blood.

This case pertains to a 72-year-old man who visited the emergency department with a complaint of upper abdominal pain. On examination, we suspected gastric perforation due to gastric cancer and decided to perform emergency surgery. We performed laparoscopic omentoplasty and collected #4d lymph nodes that were enlarged on CT. The pathological diagnosis was lymph node metastasis. Based on CT findings, we determined it was Bulky N. For initial management, we performed 3 preoperative chemotherapy(SOX therapy)courses and staging laparoscopy. On surgery, extensive disseminated nodules on the abdominal wall, stomach wall, and liver surface were found, and ascites cytology revealed positive findings. Therefore, we did not perform primary lesion resection. Although the disseminated nodule did not pathologically show tumor cells, CY1 was found, resulting to a diagnosis of unresectable gastric cancer. Since the tumor was HER2 3+, we initiated SOX/trastuzumab therapy. After 16 courses, staging laparoscopy was performed as the lymph nodes had shrunk significantly. The results showed no tumor cells in ascites and the disseminated nodules, and laparoscopic total gastrectomy was subsequently performed. Pathological findings showed no tumor cells in the primary lesion or lymph nodes; therefore, a diagnosis of pathological complete response was made. Currently, the patient is alive without recurrence for 6 months after surgery.

We report a case of recurrence on umbilical port site and ileum close to anastomotic portion after laparoscopic ileocecal resection for cecal cancer. A 62-year-old woman was diagnosed as cecal cancer and performed ileocecal resection with D3 lymphadenectomy. One year and half after surgery, recurrence on umbilical port site and ileum close to anastomotic portion was detected with computed tomography and positron emission tomography. Chemotherapy(CAPOX plus Bmab)was performed. As a result of partial response, we performed resection of umbilical portion and anastomotic portion. Adjuvant chemotherapy was not performed. Neither recurrence or metastasis have been detected until 10 months after surgery.

Although rapid antigen tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is convenient, some articles have demonstrated their low sensitivity indicating false-negative results should always be considered. Here, we raise the issue of false-positive on rapid antigen tests for SARS-CoV-2 with the first case of acute HIV infection who repeatedly positive for the rapid antigen test. A 39-year-old man was admitted to our hospital complaining of high-grade fever, dry cough, general fatigue, and anorexia. The rapid antigen test performed on a nasopharyngeal swab sample was positive, therefore the patient was separated in an isolated room apart from the COVID-19 ward while awaiting the confirmatory RT-PCR result. However, the RT-PCR for SARS-CoV-2 performed on nasopharyngeal swabs was repeatedly negative (three times), while the antigen test was repeatedly positive (three times in total). This patient was eventually diagnosed with acute human immunodeficiency virus (HIV) infection based on a high titer of HIV-RNA and absence of plasma HIV-1/2 antibodies. Physicians should consider the possibility of false-positive results in addition to false-negative results when using a rapid antigen test for SARS-CoV-2, and keep in mind that nucleic acid amplification tests are needed to confirm the diagnosis., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: A multicenter investigation of neonate exposure to potentially harmful excipients (PHEs) in neonatal intensive care units (NICUs) in Japan has not been conducted., Methods: A multicenter nationwide observational study was conducted. Neonate patient demographic data and information on all medicines prescribed and administered during hospitalization on 1 day between November 2019 and March 2021 were extracted from the medical records. Nine PHEs, paraben, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol, benzalkonium chloride, and aspartame, were selected. PHEs were identified from the package insert and the Interview Form. The quantitative daily exposure was calculated if quantitative data were available for each product containing the PHE., Results: Prescription data was collected from 22 NICUs in Japan. In total, 343 neonates received 2360 prescriptions for 426 products containing 228 active pharmaceutical ingredients. PHEs were found in 52 (12.2%) products in 646 (27.4%) prescriptions for 282 (82.2%) neonates. Benzyl alcohol, sodium benzoates, and parabens were the most common PHEs in parenteral, enteral, and topical formulations, respectively. Quantitative analysis showed that 10 (10%), 38 (42.2%), 37 (94.9%), and 9 (39.1%) neonates received doses exceeding the acceptable daily intake of benzyl alcohol, polysorbate 80, propylene glycol, and sorbitol, respectively. However, due to the lack of quantitative information for all enteral and topical products, accurate daily PHE exposure could not be quantified., Conclusions: Neonates admitted to NICUs in Japan were exposed to PHEs, and several of the most commonly prescribed medicines in daily clinical practice in NICUs contained PHEs. Neonate PHE exposure could be reduced by replacing these medicines with available PHE-free alternatives.

Background: Normal bronchial epithelium has been described in terms of transparency and smoothness. No studies have compared bronchoscopic and pathological findings in the identification of bronchial epithelium., Objectives: This study aimed to classify bronchoscopic findings for peripheral pulmonary tumour (PPT) for accurate bronchoscopic diagnosis accounting for the presences of bronchial epithelium and bronchial stenosis using an ultrathin bronchoscope., Methods: We performed endocytoscopy using narrow-band imaging (NBI) of specimens immediately after lobectomy to investigate the normal bronchial epithelium under the physiological saline injection technique (PSIT) prior to classification of PPT. A retrospective study to classify bronchoscopic findings included 46 patients diagnosed with malignancy by bronchoscopy for PPT., Results: We recognized a "light blue line" (LBL) with NBI under PSIT, corresponding to strong reflection of short-wavelength light by cilia on the epithelial surface in an ex vivo endocytoscopic study. Bronchoscopic findings of PPT were classified morphologically into stenotic type (ST) and non-stenotic type (NonST). Tumours were also classified as exposed type (ET) and non-exposed type (NonET) based on the presence of epithelium. Most ST and NonET lesions (74%) were adenocarcinoma. Among squamous cell carcinoma, 55% were categorized as ST and ET. All NonST and NonET cases were adenocarcinoma. A significant difference in the presence of LBL was seen between ET and NonET., Conclusions: Our simple classification based on the appearance of stenosis and LBL in PPT may facilitate pathological diagnosis., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Aim: Alzheimer's disease causes loss of appetite, resulting in bodyweight reduction. This, in turn, causes progression of cognitive dysfunction and physical complications that hasten death. Earlier care for loss of appetite is essential in Alzheimer's disease management. Rivastigmine is a therapeutic agent for Alzheimer's disease that has dual inhibition effects on acetylcholine esterase and butyrylcholine esterase. Butyrylcholine esterase is known to degrade the gastric hormone, ghrelin, which regulates appetite; therefore, we considered that rivastigmine might have an effect on appetite. The present study aimed to evaluate the hypothesis that rivastigmine improves appetite in Alzheimer's disease patients., Methods: Rivastigmine was given to mild-to-moderate Alzheimer's disease patients for 16 weeks. We evaluated the effects of rivastigmine on food intake, bodyweight, motivation (estimated by the vitality index), cognition function (estimated by the Hasegawa Dementia Scale-Revised), plasma butyrylcholine esterase activity, active ghrelin and inactive ghrelin., Results: Plasma butyrylcholine esterase activity significantly decreased over time (percent change: -18.9 ± 27.0%, P < 0.05 at week 8; percent change: -33.4 ± 45.4%, P < 0.05 at week 16). Negative correlations were detected between percent changes in butyrylcholine esterase activity and active ghrelin (r s  = -0.62, P = 0.033) or active/inactive ghrelin ratio (r s  = -0.73, P = 0.007). Furthermore, motivation (including appetite) improved significantly (percent change: 17.9 ± 18.6%, P < 0.05 at week 16)., Conclusions: The present study suggests that rivastigmine might improve appetite in mild-to-moderate Alzheimer's disease patients by suppressing degradation of plasma active ghrelin through the inhibition of plasma butyrylcholine esterase. Geriatr Gerontol Int 2018; 18: 886-891., (© 2018 Japan Geriatrics Society.)

Objective The purpose was to evaluate the association between bite instability and comorbidities, comprehensive geriatric evaluations, or disabilities in elderly people. Methods A dentist examined the oral function, such as the bite stability, number of teeth, and the use of dentures, in 119 patients (93 women, mean age: 86.7±7.8) in 2 nursing homes for the elderly. The association between the oral function and the prevalence of diseases, including hypertension, diabetes mellitus, and dementia, was analyzed. Results The median number of teeth was 0 [0, 4]. The patients were divided into a bite-stable group (n=78, 66%) and bite-unstable group (n=41, 34%). The prevalence of hypertension was significantly higher in the bite-stable group than in the bite-unstable group (83% vs. 63%, respectively; p=0.0149), whereas the prevalence of diabetes mellitus was significantly lower in the bite-stable group than in the bite-unstable group (10% vs. 27%, respectively; p=0.0190). The prevalence of a cognitive function decline was significantly lower in the bite-stable group as well (59% vs. 83%, p=0.0082). According to the simplified comprehensive geriatric assessment 7, the bite-stable group scored significantly higher for instrumental activities of daily living (ADL) than the bite-unstable group (54% vs. 24%, respectively; p=0.0021). A multivariate logistic regression analysis demonstrated that bite instability was independently correlated with hypertension, diabetes mellitus, and instrumental activities of daily living. Conclusion Bite instability was independently associated with a decreased prevalence of hypertension or increased prevalence of diabetes mellitus and low levels of instrumental ADL in the elderly.

We report a case of appendicitis with an abscess that was treated with single-incision laparoscopic ileocecal resection with D2 lymphadenectomy because of intraoperative suspicion of appendiceal cancer. A 73-year-old woman was admitted to the hospital because of right lower abdominal pain. She was diagnosed with appendicitis with an abscess. Although single-incision laparoscopic appendectomy was planned, appendiceal cancer was suspected from intraoperative findings. Therefore, we performed single-incision laparoscopic ileocecal resection with D2 lymphadenectomy. The pathological result was moderately differentiated adenocarcinoma in the appendix. Because of the high risk of fStage II appendiceal cancer, adjuvant chemotherapy was administered. Neither recurrence nor metastasis have been detected 7 months after surgery.

A 78-year-old woman was diagnosed with a gastrointestinal stromal tumor(GIST)of the stomach, gradually increasing from 5 years prior. The tumor was suspected to invade the pancreatic body tail and spleen, as observed with computed tomography. Because the patient refused to undergo resection, we administered imatinib mesylate for 6 years. Since early rectal cancer was revealed, the patient was referred for resection and underwent laparoscopic low anterior resection and partial gastrectomy. Histopathologically, the tumor was replaced by tissues with myxomatous changes, and no viable tumor cells were detected. This was a rare case of GIST, resected after long-term chemotherapy by imatinib mesylate, and pathological complete response was achieved.

Glioblastoma (GBM) is an ideal candidate disease for signal transduction targeted therapy because the majority of these tumors harbor genetic alterations that result in aberrant activation of growth factor signaling pathways. Loss of heterozygosity of chromosome 10, mutations in the tumor suppressor gene PTEN, and PI3K mutations are molecular hallmarks of GBM and indicate poor prognostic outcomes in many cancers. Consequently, inhibiting the PI3K pathway may provide therapeutic benefit in these cancers. PI3K inhibitors generally block proliferation rather than induce apoptosis. To restore the sensitivity of GBM to apoptosis induction, targeted agents have been combined with conventional therapy. However, the molecular heterogeneity and infiltrative nature of GBM make it resistant to traditional single agent therapy. Our objectives were to test a dual PI3K/mTOR inhibitor that may cross the blood-brain barrier (BBB) and provide the rationale for using this inhibitor in combination regimens to chemotherapy-induced synergism in GBM. Here we report the preclinical potential of a novel, orally bioavailable PI3K/mTOR dual inhibitor, DS7423 (hereafter DS), in in-vitro and in-vivo studies. DS was tested in mice, and DS plasma and brain concentrations were determined. DS crossed the BBB and led to potent suppression of PI3K pathway biomarkers in the brain. The physiologically relevant concentration of DS was tested in 9 glioma cell lines and 22 glioma-initiating cell (GIC) lines. DS inhibited the growth of glioma tumor cell lines and GICs at mean 50% inhibitory concentration values of less than 250 nmol/L. We found that PI3K mutations and PTEN alterations were associated with cellular response to DS treatment; with preferential inhibition of cell growth in PI3KCA-mutant and PTEN altered cell lines. DS showed efficacy and survival benefit in the U87 and GSC11 orthotopic models of GBM. Furthermore, administration of DS enhanced the antitumor efficacy of temozolomide against GBM in U87 glioma models, which shows that PI3K/mTOR inhibitors may enhance alkylating agent-mediated cytotoxicity, providing a novel regimen for the treatment of GBM. Our present findings establish that DS can specifically be used in patients who have PI3K pathway activation and/or loss of PTEN function. Further studies are warranted to determine the potential of DS for glioma treatment.

A 40-year-old man presented to our department with chief complaints of nausea and abdominal pain, and was diagnosed with small intestine ileus. After hospitalization, he underwent intestinal tract decompression using an ileus tube. A small bowel tumor was suspected as the cause of the intestinal obstruction. We then performed laparoscopic surgery for diagnosis and resection. In the intraoperative findings, stenosis near the small intestine tumor could be confirmed. The patient therefore underwent laparoscopic resection of a segment of the small intestine. Following rapid intraoperative pathological examination, the tumor was identified as well-differentiated adenocarcinoma with metastasis of the intermediate mesenteric lymph nodes. We then performed dissection of the main lymph nodes using small laparotomy incisions. Adjuvant chemotherapy with XELOX(130mg/m2 L-OHP on day 1 and 2,000 mg/m2 capecitabine on days 1-14)was administered for 6 months. Currently the patient is in relapse-free survival.

A 74-year-old woman presented to our emergency department with a chief complaint of appetite loss, and already diagnosed dehydration and heart failure. After hospitalization, the signs of heart failure were improved with liquid supplementation and electrolyte revision. At admission, computed tomography incidentally detected a rectal tumor. She underwent colonography, which revealed a huge villous tumor in the rectum. Based on the result of the initial biopsy, it was classified as a group 4 tumor, but additional biopsy of specimens obtained from 6 places led to a diagnosis of group 5 tumor. Then, we performed laparoscopic super-low anterior resection and made an ileal stoma. The electrolyte imbalance was improved and did not recur after the operation. In this case, the electrolyte imbalance caused by the huge villous tumor was electrolyte depletion syndrome (EDS).

Although there have been several studies regarding heart failure with preserved ejection fraction (HFpEF), investigations of the risk factors for readmission of Japanese patients with HFpEF remain scarce. Therefore, our goal was to identify the risk factors for readmission of Japanese patients with heart failure (HF), particularly those with HFpEF. We analyzed 310 patients who were hospitalized for the first time with HF. Preserved EF was defined EF ≥50 %, and reduced EF (rEF) was EF <50 %. The study endpoint was readmission for HF after discharge. Medical history, vital signs, electrocardiograms, chest radiographs, blood tests and echocardiograms were compared between patients with HFpEF and with HFrEF. Among the 142 patients who had HFpEF, 43 reached the endpoint within 1 year. Multivariate analysis revealed depression (HR: 7.185), high brain natriuretic peptide (BNP) levels at discharge (HR: 1.003), and dilated inferior vena cava (HR: 1.100) as independent risk factors for readmission. In contrast, 39 of the 168 patients with HFrEF reached the endpoint. Risk factors for readmission of HFrEF patients were low sodium (HR: 0.856), high blood urea nitrogen (HR: 1.045), high BNP levels at discharge (HR: 1.003) and absence of beta-blocker prescription (HR: 0.395). In conclusion, our study suggests that the predictors of HF readmission differ between HFpEF and HFrEF patients.

We describe the design, syntheses, and structure-activity relationships of novel zwitterionic compounds as nonthiazolidinedion-based peroxisome proliferator-activated receptor (PPAR) α/γ dual agonists. In our previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a sufficient glucose-lowering effect in db/db mice. However, this compound possessed an issue, i.e., the 1,3,4-oxadiazole ring was not stable in acidic conditions. Thus, we carried out further optimization to improve the stability while maintaining the other favorable profile features including potent PPARα/γ dual agonistic activity. We addressed the issue by changing the oxadiazole ring to a bioisostere amide group. These amide derivatives were stable in acidic conditions and decreased plasma glucose and plasma triglyceride levels significantly without marked weight gain.

A 60-year-old man had visited our hospital a few times due to vomiting since July 2008. In January 2009, because he was no longer able to eat, he was hospitalized to receive close examination. Single balloon enteroscopy revealed jejunal adenocarcinoma. After examination of the whole body, as there was no distant metastasis, jejunum partial resection was performed in February 2009. One dissemination nodule was recognized on the serosa near the main tumor. We obtained the final pathological diagnosis as Stage IV. From April 2009, adjuvant chemotherapy with combination of oxaliplatin, 5-fluorouracil and Leucovorin (mFOLFOX6) was performed 8 times. In April 2009, a small metastatic lesion appeared in the upper lobe of the right lung. We started administering combination of irinotecan, 5-fluorouracil and Leucovorin (FOLFIRI) from January 2010, but stopped because of side effects after the second cycle. Administration of capecitabine was started in March 2010. The metastatic lesion had diminished for a time but was found to be enlarged in March 2011. Thus, a partial right lung resection was performed in April 2012. After lung resection, systemic chemotherapy was not performed. The patient remains alive without a recurrence 3 years after lung resection and over 5 years after detection of the small intestinal adenocarcinoma.

Duplication cysts of the esophagogastric junction are an extremely rare disease entity. Computed tomography showed a cystic lesion in the wall of the esophagogastric junction ofa 75-year-old man. The cystic tumor gradually increased in size from 40 mm to 60 mm in diameter within 6 months. On the basis of magnetic resonance cholangiopancreatography and positron emission tomography, it was described as a cystic pathological alteration enclosing a solid lesion. The pre-operative diagnosis was a gastrointestinal stromal tumor in the stomach cardia, and we performed proximal gastrectomy under laparotomy. Histological findings showed gastric mucosa in the internal mucosa of the cyst and an adenocarcinoma inside the cyst. We diagnosed the cystic tumor as a duplication cyst of the esophagogastric junction with adenocarcinoma. It is important to carefully choose the procedure to be used for resection of cystic tumors adjacent to the alimentary canal.

Background: Although vascular endothelial growth factor (VEGF) is elevated in patients with acute myocardial infarction (AMI), the clinical significance of its elevation remains unclear. The present study was designed to determine the relationship between VEGF and left ventricular dimension in patients with AMI., Methods and Results: Plasma VEGF levels were examined by enzyme-linked immunosorbent assay daily for one week and then weekly for four weeks in 38 patients with AMI (65.4 ± 1.7 years). Left ventriculography was performed at 14 days, 6 months, and 2 years after the onset of AMI. Plasma VEGF levels were significantly elevated and reached a peak on day 6. Peak plasma VEGF levels positively correlated with both end-diastolic and end-systolic volume indices at 14 days after the onset of AMI. When patients with AMI were divided into two groups according to plasma VEGF levels on admission, left ventricular volume indices were higher in the high VEGF group than in the low VEGF group at the subacute phase of AMI (14 days). These differences were no longer present in the chronic phase of AMI., Conclusion: Plasma VEGF levels were increased in patients with AMI, and peak levels were associated with left ventricular volume indices in the subacute phase, suggesting an important role of endogenous VEGF in the left ventricular dimension in patients with AMI., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

A 55-year-old man was admitted to our hospital because of abdominal distension. Computed tomography revealed an abscess in the anterior abdominal wall and invasion of the large intestine. Biopsy of the large intestine revealed adenocarcinoma. Immunohistochemically, the antigen expression profile of the tumor was positive for cytokeratin 7, cytokeratin 903 (34βE12), and cytokeratin 20. We diagnosed the tumor as urachal cancer and performed surgery. Examination of the resected specimen showed that the tumor was located in the transverse colon. Finally, the patient was diagnosed as having transverse colon cancer with urachal abscess.

A 60-year-old man was diagnosed as having type 3 advanced gastric cancer in the gastric antrum and multiple liver metastases( S2, S3, S4, and S7)( cT3[ SS] N0M0H1, Stage IV). The patient received combined neoadjuvant chemotherapy with S-1 and cisplatin( CDDP). S-1( 80 mg/body/day) was administered orally for 3 weeks followed by 2 drug-free weeks as a course, and CDDP (60 mg/m2) was administered by intravenous infusion on day 8. The gastric tumor reduced in size and the liver metastases improved after 5 courses of treatment. Distal gastrectomy, D2 lymph node dissection, and partial liver resection( 4 sites) were performed. S-1 alone was continued as adjuvant chemotherapy; no recurrence was detected in 2 years and 2 months after surgery. Although there is insufficient evidence to support the benefit of surgical resection in patients with advanced gastric cancer with liver metastases, chemotherapy combined with surgical resection would improve the survival time without deterioration of quality of life of these patients. This case suggests that neoadjuvant chemotherapy is effective against advanced gastric cancer even with multiple liver metastases.

A 69-year-old man with a history of distal gastrectomy for early gastric cancer consulted our department concerning a possible diagnosis of sigmoid colon cancer. After detailed examination, he was diagnosed with type 3 advanced sigmoid colon cancer with colonic stenosis and large type 3 gastric cancer in the residual stomach with gross infiltration of the adjacent organs. The patient first underwent sigmoidectomy and then received a regimen of neoadjuvant combination chemotherapy with S-1, cisplatin( CDDP), and Lentinan( LNT)( S-1 80 mg/m2, CDDP 60 mg/m2, and LNT 2 mg/body twice weekly for 2 weeks) for gastric cancer( cT4b[ SI, liver, pancreas], N2M0H0, Stage IIIC). After 2 courses of treatment, the gastric tumor had reduced in size but had penetrated the transverse colon. We performed total resection of the gastric remnant, D2 lymph node dissection, and en bloc resection of the transverse colon, partial liver, pancreas body and tail, partial diaphragm, and pericardium. S-1/CDDP (a total of 11 courses) followed by single-agent S-1 therapy was continued as adjuvant chemotherapy. With a follow-up time of 3 years and 10 months, no recurrence was noted following total resection of the gastric remnant.

A 68-year-old woman was admitted to our hospital because of back pain and syncope. Transthoracic echocardiography revealed pericardial effusion, a collapsed right ventricle, a giant aneurysm connected to the coronary sinus, a dilated left main trunk coronary artery, and a dilated left circumflex artery (LCx). Furthermore, there was a coronary artery fistula arising from the LCx that drained into the coronary sinus. We diagnosed cardiac tamponade due to rupture of the coronary artery fistula or giant aneurysm, and successful emergency surgery was performed. Rupture of coronary artery aneurysm or coronary artery fistula is very rare. Transthoracic two-dimensional echocardiography was very useful in our case for the diagnosis of cardiac tamponade, giant coronary aneurysm, and coronary artery fistula.

An 85-year-old woman complaining of nausea was admitted to our hospital after being found to have complete atrioventricular block. We diagnosed the patient with infective endocarditis after observing vegetation on transesophageal echocardiography (TEE) and detecting Pseudomonas aeruginosa in a blood culture. The patient had no history of intravenous drug use, instrumentation or valvular disease. Although sensitive antibiotics were administered intravenously, the second TEE performed on the 10th day demonstrated increased vegetation. The patient developed septic shock and died on the 14th day. To our knowledge, this is the first report of infective endocarditis caused by community-acquired Pseudomonas aeruginosa in Japan.

We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl)amino]methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 μg/mL; JP2, 462 μg/mL). Furthermore, this compound showed good oral bioavailability (F=54%) in monkeys., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Anemia is a common complication of chronic kidney disease (CKD), and a few studies suggest that both CKD and anemia have a marked impact on the prognosis of patients with cardiovascular disease. We retrospectively analyzed the prevalence of CKD and anemia in 312 patients with acute myocardial infarction (AMI). The patients were divided into four groups according to the presence of CKD and anemia. Chronic kidney disease was defined as estimated glomerular filtration rate <60 ml/min/1.73 m(2), and anemia was defined according to the World Health Organization definition. Of 312 AMI patients, 166 (53.2%) had CKD and 87 (27.8%) had anemia. A powerful relationship was observed between both CKD and anemia and major adverse cardiac and cerebrovascular events (MACCE) or death by any cause. After adjustment for comorbidities, the hazard ratio (HR) for MACCE was significantly higher in the anemia-only group (HR 5.42, 95% confidence interval (CI) 1.38-21.27, P = 0.015), the CKD-only group (HR 6.4, 95% CI 2.09-19.58, P = 0.001), and the CKD and anemia group (HR 11.61, 95% CI 3.65-36.89, P < 0.001). With respect to death by any cause, the HR was significantly higher in the CKD-only group (HR 2.68, 95% CI 1.02-7.02, P = 0.045) and the CKD and anemia group (HR 4.40, 95% CI 1.56-12.43, P = 0.005). One-half of the patients with AMI had CKD as well. Furthermore, when anemia coexisted with CKD, these conditions had a multiplicative amplification effect on the risk of MACCE and death by any cause in patients with AMI.

A 50-year-old man visited a physician due to continued right hypochondrium pain for a period of about two months. He was diagnosed with cholecystitis and was referred to our hospital. On arrival, he presented with mild tenderness in the right upper quadrant. Abdominal computed tomography (CT) showed small gallstones and a thickened gallbladder wall. At the same time, a low-density area expanding from the gallbladder bed was revealed. Magnetic resonance cholangiopancreatography (MRCP) showed a smooth stricture of the common hepatic duct. We suspected chronic cholecystitis and inflammatory change in the liver because of cholecystitis. However, malignant diseases could not be excluded, and conservative treatment with antibiotics was therefore performed. On post-hospitalization day 26, cholecystectomy was performed. Rapid diagnosis of a surgical wedged biopsy specimen of the liver showed infiltration of the hepatic sinusoids by atypical lymphocytes. Malignant lymphoma was highly suspected. After further examination, we obtained the diagnosis of primary hepatic CD5+diffuse large B-cell lymphoma. Cyclophosphamide+doxorubicin+vincristine+prednisolone(CHOP) with rituximab therapy was performed. Complete remission was achieved after 8 courses of therapy. However, tumor recurrence in the floor of the mouth occurred one year after the operation. Salvage chemotherapy is now being performed.

We present a case of a 61-year-old woman who underwent endoscopic mucosal resection (EMR) for early-stage colorectal cancer. However, because the condition of the horizontal margin of the resected tumor was unknown, she further underwent local transanal excision. Lower gastrointestinal endoscopy performed 1 year later showed protruding lesions both on the scar tissue and in the vicinity. Biopsy revealed malignant melanoma. She then underwent laparoscopic abdominoperineal resection and colostomy. This was an extremely rare case of adenocarcinoma complicated by malignant melanoma after resection.

For the purpose of obtaining orally potent VLA-4 inhibitors, we have carried out structural modification of the (N'-phenylureido)phenyl group in compound 1, where the group was found to be attributed to poor pharmacokinetic profile in our previous research. Through modification, we have identified several compounds with both potent in vitro activity and improved oral exposure. In particular, compound 7e with 7-fluoro-2-(1-methyl-1H-indol-3-yl)-1,3-benzoxazolyl group as a novel replacement of the (N'-phenylureido)phenyl group significantly inhibited eosinophil infiltration into bronchoalveolar lavage fluid at 15mg/kg in an Ascaris-antigen-induced murine bronchial inflammatory model, and its efficacy was comparable to that of the anti-mouse α(4) antibody (R1-2)., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate of very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1). The synthesis employs a reductive etherification as a key reaction using (2S,4S)-1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4-triethylsilyloxycyclohexanecarboxilic acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from commercially available starting material.

Imatinib is a standard treatment for unresectable gastrointestinal stromal tumor (GIST). We described the case of a 66- year-old woman with bulky GIST of which a diameter was 25 cm. Therefore, we decided the tumor was unresectable. After 2-year administration of imatinib, the diameter of tumor was reduced to 6 cm. After 3-year administration of imatinib, the diameter of tumor was increased to 8 cm. The patient did not have any distant metastasis. He underwent a resection of the tumor. The historical examination showed that c-kit and CD34 were positive. The number of mitosis was 12/50 HPF. Conversion chemotherapy for bulky GIST may contribute to a curative resection.

Background: Diabetes mellitus (DM) is a risk factor of poor prognosis in patients with heart failure (HF). The prevalence and prognostic impact of the pre-diabetic state, however, are not well understood., Methods and Results: One hundred and thirty-six consecutive patients admitted due to HF were included in this prospective study. The 75-g oral glucose tolerance test (OGTT) was performed in all patients without known DM, and patients were classified into normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and DM groups. Forty-two of the 136 patients had previously been diagnosed with diabetes. Of the remaining 94 patients without known diabetes, 35 (37.2%) patients were classified as NGT, 9 (9.6%) as having IFG, 37 (39.4%) were classified as having IGT, and 13 (13.8%) were newly diagnosed with DM. During follow-up, patients with DM or IGT had significantly lower major adverse cardiac and cerebrovascular event (MACCE)-free rates than NGT patients (P=0.006, P=0.036, respectively). IFG, however, was not significantly related to increased MACCE risk. The presence of IGT (hazard ratio [HR], 4.51; P=0.011) and DM (HR, 4.74; P=0.005) were independent predictors of MACCE even after multivariate analysis., Conclusions: IGT and DM contribute to adverse prognosis in patients with HF. It is feasible to perform diabetes screening using OGTT in patients with HF for risk stratification.

A 60-year-old woman was admitted to our hospital because of upper abdominal discomfort and body weight loss. Abdominal CT showed multiple liver tumors with early enhancement and delayed washout. There were no abnormal findings in other organs. IVR-CT showed hypervascular masses, but it is not a typical tumor staining of HCC. To obtain the diagnosis, we performed laparoscopic partial liver resection in the left lateral segment. Histological examination suggested a primary hepatic carcinoid a tumor. But primary hepatic carcinoid tumor is comparatively rare, so we underwent further examinations. Two months later after the liver resection, the tumor of pancreatic tail was detected by CT and MRI. We could obtain the diagnosis of pancreatic endocrine tumor by EUS-FNA. We conducted a distal pancreatectomy with splenectomy and partial colonic resection. She had no symptom related to neuroendocrinology. The final diagnosis was non-functional endocrine carcinoma of pancreas. After that, we added extended right hepatic lobectomy with radiofrequency ablation in left lobe. The woman remains alive without a recurrence after the surgery.

Background: Optimal treatment strategies for restenosis of sirolimus-eluting stents (SES) have not been adequately addressed yet., Methods and Results: During the 3-year follow-up of 12 824 patients enrolled in the j-Cypher registry, 1456 lesions in 1298 patients underwent target-lesion revascularization (TLR). Excluding 362 lesions undergoing TLR for stent thrombosis or TLR using treatment modalities other than SES or balloon angioplasty (BA), 1094 lesions with SES-associated restenosis in 990 patients treated with either SES (537 lesions) or BA (557 lesions) constituted the study population for the analysis of recurrent TLR and stent thrombosis after the first TLR. Excluding 24 patients with both SES- and BA-treated lesions, 966 patients constituted the analysis set for the mortality outcome. Cumulative incidence of recurrent TLR in the SES-treated restenosis lesions was significantly lower than that in the BA-treated restenosis lesions (23.8% versus 37.7% at 2 years after the first TLR; P<0.0001). Among 33 baseline variables evaluated, only hemodialysis was identified to be the independent risk factor for recurrent TLR by a multivariable logistic regression analysis. After adjusting for confounders, repeated SES implantation was associated with a strong treatment effect in preventing recurrent TLR over BA (odds ratio, 0.44; 95% confidence interval, 0.32 to 0.61; P<0.0001). The 2-year mortality and stent thrombosis rates between the SES- and the BA-treated groups were 10.4% versus 10.8% (P=0.4) and 0.6% versus 0.6%, respectively., Conclusions: Repeated implantation of SES for SES-associated restenosis is more effective in preventing recurrent TLR than treatment with BA, without evidence of safety concerns.

Background and Purpose: The mechanisms of anti-inflammatory actions of statins, 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, remain unclear. We investigated the effects of statins on interleukin (IL)-6-induced monocyte chemo-attractant protein (MCP)-1 expression and monocyte chemotaxis., Experimental Approach: Cultures of human aortic endothelial cells (HAECs) were stimulated with IL-6 in the absence and presence of statins. Gene expression and protein secretion of MCP-1, phosphorylation of Janus kinase (JAK) and the signal transducers and activators of transcription (STAT) pathway, and human monocyte migration were examined., Key Results: IL-6 plus its soluble receptor sIL-6R (IL-6/sIL-6R) promoted THP-1 monocyte migration, and increased gene expression and protein secretion of MCP-1, more than IL-6 alone or sIL-6R alone. Various statins inhibited IL-6/sIL-6R-promoted monocyte migration and MCP-1 expression in HAECs. Co-incubation of mevalonate and geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, reversed the inhibitory effects of statins on MCP-1 expression. Geranylgeranyl transferase inhibitor, but not farnesyl transferase inhibitor, suppressed IL-6/sIL-6R-stimulated MCP-1 expression. IL-6/sIL-6R rapidly phosphorylated JAK1, JAK2, TYK2, STAT1 and STAT3, which were inhibited by statins. Transfection of STAT3 small interfering RNA (siRNA), but not STAT1 siRNA, attenuated the ability of IL-6/sIL-6R to enhance THP-1 monocyte migration. In addition, statins blocked IL-6/sIL-6R-induced translocation of STAT3 to the nucleus., Conclusions and Implications: Statins suppressed IL-6/sIL-6R-induced monocyte chemotaxis and MCP-1 expression in HAECs by inhibiting JAK/STAT signalling cascades, explaining why statins have anti-inflammatory properties beyond cholesterol reduction.

We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.

A 60-year-old man who had serious chest and arm pain died suddenly during hospitalization. He suffered from coronary vasospastic angina complicated by a fatal acute fulminant-type of myocarditis associated with Churg-Strauss syndrome (CSS). The diagnosis at autopsy was acute progressive eosinophilic myocarditis associated with CSS.

We report a case of ovarian metastasis after complete response of colon cancer. A 55-year-old woman underwent a sigmoidectomy for sigmoid colon cancer with hepatic metastasis and para-aorta lymph node metastasis. After the operation, the patient was given chemotherapy with bevacizumab+mFOLFOX6. Nine months after the operation, the patient was judged to have achieved complete response. Thirteen months after the operation, right ovarian tumor was found and bilateral oophrectomy, hysterectomy and omentectomy were performed. Histopathologically the ovarian tumor was metastasized from colonic cancer. After the second operation, the patient was given chemotherapy with bevacizumab+FOLFIRI. At present, the patient remains disease-free for 6 months after the ovarian operation.

Skeletal muscle metastasis of carcinoma is comparatively rare. We report a case of metastasis to the quadriceps femoris muscle after the operation for rectal carcinoma. A 70-year-old man underwent rectal amputation in May 2007 due to rectal carcinoma. In May 2008, he noticed a painful tumor in the right femoral region. We obtained the diagnosis of recurrent rectal carcinoma by open biopsy. Simultaneously, lung metastasis was revealed by a close examination. Metastatic tumor resection was performed before chemotherapy, because it was important to preserve his performance status. From June 2008, chemotherapy was started. A year after the second operation, lung metastatic lesions were gradually progressed. At present, new skeletal muscle metastasis is not found. He is receiving chemotherapy in outpatient care. The resection of skeletal muscle metastasis made a contribution to his quality of life.

During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-(2-methylphenylamino)benzoxazole moiety which mimics the diphenylurea structure. However, this modification resulted in a significant decrease (3, IC(50)=19 nM) in VLA-4 inhibitory activity compared to 1 (IC(50)=1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic acid moiety in compound 3. As a result, our efforts have led to the discovery of trans-4-substituted cyclohexanecarboxylic acid derivative 11b (IC(50)=2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties (CL=3.3 ml/min/kg, F=51%) in rats.

Optimization of benzoic acid derivatives by introducing substituents into the diphenyl urea moiety led to the identification of compound 20l as a potent VLA-4 antagonist. Compound 20l inhibited eosinophil infiltration into bronchial alveolar lavage fluid in a murine asthma model by oral dosing and its efficacy was comparable to anti-mouse alpha4 antibody (R1-2). Furthermore, this compound significantly blocked bronchial hyper-responsiveness in the model.

Intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) play critical roles in mediating monocyte adhesion to the vascular endothelium and monocyte migration into the subendothelial regions of the vessels. Inasmuch as cardiotrophin-1 (CT-1), an IL-6-type cytokine, was expressed in human atherosclerotic plaque, we examined whether CT-1 induces monocyte adhesion and migration by stimulating gene and protein expressions of ICAM-1 and MCP-1 in human aortic endothelial cells (HAECs). Immunocytochemistry revealed that CT-1 increased intensity of ICAM-1 and MCP-1 immunoreactivity in HAECs. Adhesion assay and chemotaxis assay revealed that CT-1 increased human monocytic THP-1 cell adhesion to HAECs and promoted chemotaxis in THP-1 cells, which were attenuated by anti-ICAM-1 and anti-MCP-1 antibody, respectively. Western blot analysis showed that CT-1 increased phosphorylation of ERK1/2 MAP kinase, p38 MAP kinase, and Akt and that their inhibitors, PD-98059, SB-203580, and LY-294002, respectively, inhibited phosphorylation. RNase protection assay and ELISA demonstrated that CT-1 increased gene and protein expressions of ICAM-1 and MCP-1. EMSA revealed that CT-1 enhanced NF-kappaB DNA-binding activity. CT-1-mediated upregulation of ICAM-1 and MCP-1 was suppressed by PD-98059, SB-203580, LY-294002, and parthenolide. The present study demonstrates that CT-1 promotes monocyte adhesion and migration by stimulating ICAM-1 and MCP-1 through mechanisms that involve ERK1/2 MAP kinase, p38 MAP kinase, phosphatidylinositol 3-kinase, and NF-kappaB pathways and suggests that CT-1 plays an important role in the pathophysiology of vascular inflammation and atherosclerosis.

To ascertain an optimum condition for detecting micronuclei in the liver caused by numerical aberration inducers, either carbendazim (125-1000mg/kg, p.o.), colchicine (0.375-1.5mg/kg, i.v.), cytochalasin B (2.5-20mg/kg, i.v.), diazepam (3.13-25mg/kg, i.v.), noscapine (7.8-62.5mg/kg, i.v.), paclitaxel (1-100mg/kg, i.v.) or trichlorfon (18.75-150mg/kg, i.v.) was administered once to male Slc:ddY mice 1 day before or after partial hepatectomy (PH, Day 1). Five days after PH (on Day 6), hepatic micronuclei were determined in conjunction with classifications of the main nuclei and relative liver weights as a proliferative indicator or a dysfunction marker of cell division. Additionally, hepatocyte proliferation index (HPI) was calculated by using mono-, bi- and multinucleated cell counts. Treatment of mice with six compounds, except for colchicine, after PH showed higher incidence of micronucleated hepatocytes (MNH) than that before PH, and also increases in binucleated and multinucleated cells. Especially for carbendazim, diazepam, noscapine and trichlorfon, the dosing after PH was essential for the detecting numerical aberration. Colchicine evidently increased HPI and decreased relative liver weights without MNH induction on Day 6. On Day 8 when HPI and relative liver weights almost returned to the basal range, a significant increase in MNH was noted. This implied that the strong inhibition of colchicine on hepatocyte proliferation may obstruct the induction of MNH on Day 6. In conclusion, to detect the potential numerical aberration, exposure of mice to test chemicals should be performed 1 day after PH, during which enhanced proliferation of hepatocytes was seen, and it would be better to analyze the liver specimens on Day 6 or more post-PH.

Objectives: Soluble glycoprotein 130 (sgp130), a circulating form of receptor subunit for the interleukin (IL) -6 cytokine family, modulates the biological actions of its ligands as an inhibitory regulator. The role of sgpl30 in cardiovascular diseases such as acute coronary syndrome remains unknown., Methods: Plasma levels of sgp130 were examined by enzyme-linked immunosorbent assay in 33 patients with acute myocardial infarction (AMI; mean age 67 +/- 2 years, 21 males and 12 females), who were admitted to our hospital within 24 hr of onset of AMI and survived for 4 weeks., Results: Plasma sgp130 levels were significantly higher at admission (260.5 +/- 7.3 ng/ml), and were significantly lower from day 2 to day 5 (202.4 +/- 5.1 ng/ml at day 3) as compared with normal control subjects (n = 38, 227.1 +/- 5.6 ng/ml). The lowest sgp130 levels inversely correlated with white blood cell count at admission (r = -0.42, p < 0.05) and with peak C-reactive protein levels (r = -0.43, p < 0.05). Additional in vitro study revealed that incubation of AMI plasma with exogenous IL-6 plus soluble IL-6 receptor resulted in a decrease in plasma sgp130 levels, suggesting the possible reason for reduced plasma sgp130 levels in AMI., Conclusions: The present study indicates that plasma sgp130 levels were modulated during the time course of AMI and inversely associated with inflammation in AMI.

Dystrophin is a cytoskeletal protein localized to the sarcolemma of skeletal and cardiac muscle, and neurons. We have recently demonstrated that a significant cardiac damage including myocytes injury, inflammation, and fibrosis, was found in dystrophin-deficient myocardium during pressure overload [Kamogawa et al., 2001: Cardiovasc Res 50:509-515]. However, little is known about how the cardiac sarcolemmal cytoskeleton produces qualitative and quantitative changes in response to pressure overload. Accordingly, we investigated dystrophin gene expression and protein accumulation during cardiac hypertrophy. Cardiac hypertrophy was produced by banding of the abdominal aorta of rats. Total RNA from the left ventricle of the heart was used for a quantitative reverse transcription-polymerase chain reaction (RT-PCR). Dystrophin mRNA expression significantly increased by 33 +/- 18% at 1 day (P < 0.05) and 45 +/- 19% at 2 days (P < 0.01) after banding, while G3PDH mRNA showed no significant change. RT-PCR for dystrophin tissue-specific exon 1 revealed that only muscle type promoter, but not non-muscle type promoter (brain and Purkinje-cell type), was activated immediately after banding. Immunohistochemistry for dystrophin showed intense cellular membrane staining with an increase in the perimeter of the myocytes by 14% at 3 days (46.3 microm, P < 0.01) and 19% at 7 days (51.2 microm, P < 0.01) after banding. Western blotting also showed dystrophin protein increased by 14 +/- 6% at 2 days (P < 0.05) and by 32 +/- 10% at 3 days (P < 0.01) after aortic banding. In conclusion, upregulation of dystrophin mRNA expression and protein accumulation occurs in response to cardiac hypertrophy. These data and the vulnerability of dystrophin-deficient myocardium to pressure overload suggest that dystrophin could play an important role in maintaining the integrity of the sarcolemma., (Copyright 2003 Wiley-Liss, Inc.)

We herein report that experimental murine amyloid A (AA) deposition is accelerated by oral administration of semipurified amyloid fibrils extracted from different species. Three groups of mice were treated with semipurified murine AA amyloid fibrils, semipurified bovine AA amyloid fibrils or semipurified human light chain-derived (A(lambda)) amyloid fibrils for 10 days. After 3 weeks, each mouse was subjected to inflammatory stimulation by subcutaneous injection with a mixture of complete Freund's adjuvant supplemented with Mycobacterium butyricum. The mice were killed on the third day after the inflammatory stimulation, and the spleen, liver, kidney and gastrointestinal tract were examined for amyloid deposits. Amyloid deposits were detected in 14 out of 15 mice treated with murine AA amyloid fibrils, 12 out of 15 mice treated with bovine AA amyloid fibrils and 11 out of 15 mice treated with human A(lambda) amyloid fibrils. No amyloid deposits were detected in control mice receiving the inflammatory stimulant alone or in amyloid fibril-treated mice without inflammatory stimulation. Our results suggest that AA amyloid deposition is accelerated by oral administration of semipurified amyloid fibrils when there is a concurrent inflammatory stimulation.

RAW264 cells, reported to be originated from Abelson-virus-induced B lymphomas, are widely used as a murine monocyte cell line. We found that RAW264 show enhanced expression of murine N-MYC. Murine cDNA clones associated with N-MYC were separated from (lambda)gt11 cDNA library constructed by using mRNA from the macrophage cell line, RAW264 cells. Sequencing analysis of the longest cDNA clone N-MYCL showed that the length of the coding region was 18 bases shorter than that of the predicted full length N-MYC cDNA, and the 3' untranslated region had the 5' long terminal repeat (LTR) sequence of the Moloney-like proviral sequence, suggesting the expression of N-MYC by insertion of the proviral sequence. This suggests that expression of N-MYC plays a role in the establishment of macrophage cell line RAW264. Integration of LTR and overexpression of the N-MYC gene might have existed in the parental lymphoma cells, playing a role in the development of lymphoma or in the establishment of macrophage cell line., (Copyright 2003 S. Karger AG, Basel)

Objective: Dystrophin provides mechanical reinforcement to the membranes of myocytes. Dystrophin abnormalities are known to cause cardiomyopathy and skeletal muscle disorders; however, the pathogenesis of these abnormalities remains unclear. Dystrophin-deficient skeletal muscle is vulnerable to stresses such as stretch and hypo-osmotic shock. We investigated whether the myocardium of dystrophin-deficient (mdx) mice shows increased vulnerability to acute pressure overload in vivo., Methods and Results: Abdominal aortic banding was performed in 12-week-old mdx and control mice. The aortic pressure was measured by cannulation of the right carotid artery at the time of sacrifice. Systolic pressures in mdx mice at 0, 1, 2, 7 and 14 days after aortic banding were 100 +/- 11, 119 +/- 7, 123 +/- 4, 134 +/- 11 and 130 +/- 10 mmHg, respectively. Microscopic analysis revealed focal lesions in the left ventricular wall in banded mdx mice. These lesions consisted of damaged myocytes and inflammatory cells, and also of fibrosis at a late stage. Similar lesions were not observed in non-banded or banded control mice. The proportion of areas of lesions to total left ventricular area increased over time: 1.0 +/- 0.6% in mdx mice without aortic banding (sham, n = 6), and 1.7+/-1.4% 1 day (n = 6, vs. sham, NS), 2.6 +/- 1.9% 2 days (n = 7, vs. sham, P < 0.05), 6.3+ /- 6.5% 7 days (n = 13, vs. sham, P < 0.05) and 9.9 +/- 8.3% 14 days after aortic banding (n=15, vs. sham, P < 0.01). Furthermore, linear regression analysis revealed a significant correlation between percentage of lesion area and systolic pressure in mdx mice (P < 0.05)., Conclusion: Dystrophin-deficient myocardium is more vulnerable than normal myocardium to pressure overload in vivo. This result has two clinical implications: (1) the patients with dystrophynopathy, such as the Duchenne and the Becker types of muscular dystrophy and X-linked type of dilated cardiomyopathy, who develop arterial hypertension should be treated aggressively, and (2) they should avoid stresses that elevate blood pressure.