The Present Status and the Recent Development of the Treatment for Inflammatory Bowel Diseases: Desirable Effect of Extracorporeal Immunomodulation

Abstract: The immunological and genetic pathogeneses of inflammatory bowel disease (IBD) have been well elucidated in the recent years. The pharmacologic treatment of IBDs accordingly becomes to focus upon the individual pathologic step (targeting therapy), whereas the therapeutic action is not yet a pinpoint one. It has been known recently that new drugs such as biological immunomodulating agents and anti‐inflammatory cytokines have better short‐term effects in some respects than the conventional drugs, and they might alter the treatment strategy of IBDs in the near future. The limitation of pharmacologic treatments mainly results from adverse effects of the drugs, i.e. infection susceptibility, oncogenesis, teratogenesis and so forth. The extracorporeal therapy such as leukocytapheresis and photopheresis is reportedly effective for IBDs probably through immunomodulation such as decrease in circulating activated T‐lymphocytes and activated granulocytes that play a central role in the pathogenesis of IBD. It can be said that these extracorporeal treatment methods have advantage of rapid action and lack of serious adverse effects to drug therapy.     

Integrins play a critical role in mechanical stress-induced p38 MAPK activation

Mechanical stress activates various hypertrophic responses, including activation of mitogen-activated protein kinases (MAPKs) in cardiac myocytes. Stretch activated extracellular signal-regulated kinases partly through secreted humoral growth factors, including angiotensin II, whereas stretch-induced activation of c-Jun NH(2)-terminal kinases and p38 MAPK was independent of angiotensin II. In this study, we examined the role of integrin signaling in stretch-induced activation of p38 MAPK in cardiomyocytes of neonatal rats. Overexpression of the tumor suppressor PTEN, which inhibits outside-in integrin signaling, strongly suppressed stretch-induced activation of p38 MAPK. Overexpression of focal adhesion kinase (FAK) antagonized the effects of PTEN, and both tyrosine residues at 397 and 925 of FAK were necessary for its effects. Stretch induced tyrosine phosphorylation and activation of FAK and Src. Stretch-induced activation of p38 MAPK was abolished by overexpression of FAT and CSK, which are inhibitors of the FAK and Src families, respectively, and was suppressed by overexpression of a dominant-negative mutant of Ras. Mechanical stretch-induced increase in protein synthesis was suppressed by SB202190, a p38 MAPK inhibitor. These results suggest that mechanical stress activates p38 MAPK and induces cardiac hypertrophy through the integrin-FAK-Src-Ras pathway in cardiac myocytes.     

Critical roles of VEGF-C-VEGF receptor 3 in reconnection of the collecting lymph vessels in mice

Molecular mechanisms of reconnection of collecting lymph vessels were analyzed by using murine popliteal prenodal lymph vessels. At 1 and 2 weeks after being divided by cutting the lymph vessel, lymphatic reconnection was frequently observed accompanied by mesh-like lymphatic channels. Electron microscopic study also showed a monolayer of endothelial cells in the newly developed lymph vessels. Smooth muscle markers were immunofluorescently demonstrated in the wall of the new vessels. At 1 week after the procedure of cutting, augmented expressions of VEGF receptors 1, 2 and 3 were found immunohistochemically at the site of the reconnected lymph vessels. The expression of mRNA for VEGF receptor 3 was enhanced at 5 days and 1 week in small pieces of the tissues containing the reconnected lymph vessels, compared with that in the corresponding tissues obtained with sham operated ones. The administration of VEGF-C at the cutting site of the collecting lymph vessel significantly increased the rate of the reconnected lymph vessels, whereas additional treatment with Flt4/Fc chimera protein significantly reduced the rate of the reconnected ones. These results suggest that activation of VEGF-C-VEGF receptor 3 has critical roles in reconnection of the collecting lymph vessels in adult mice.     

Reversible respiratory failure due to rhabdomyolysis associated with cytomegalovirus infection

A 58-year-old woman presented with muscle weakness, whole body myalgia, and dyspnea. On admission, neurological examination showed proximal muscle weakness in the extremities. The weakness gradually extended to the bulbar and respiratory muscles, necessitating an artificial ventilator. Serum CK level was markedly increased (33,774 IU/L; normal <150 IU/L) and myoglobinuria was noted in urinalysis. There was no sign of renal failure. Nerve conduction study was normal, but needle EMG showed myopathic changes in the weak muscles. Serological studies for virus titers showed more than a four-fold increase of cytomegalovirus (CMV) antibody titer during the disease course. The IgM anti-GM2 antibody was also elevated in the acute phase and decreased in the recovery phase. The muscle weakness and respiratory failure gradually improved after intravenous methylprednisolone administration, and the serum CK level was normalized in several days. CMV infection was thought to have played a central role in the rhabdomyolysis, leading to critical but reversible respiratory muscle paralysis.     

Right atrial abnormalities in a patient with arrhythmogenic right ventricular cardiomyopathy without ventricular tachycardia

We describe a 59-year-old woman with sick sinus syndrome (SSS) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Diagnosis of SSS was made because she had frequent episodes of sinus arrest with prolonged ventricular asystole. Cardiac images showed a dilated right atrium (RA) and a right ventricle (RV). Electroanatomical mapping of the RA showed extensive scarring with no recordable electrical potentials. Although she had frequent premature ventricular contractions, neither spontaneous ventricular tachycardia (VT) nor induced VT was observed. Microscopic examination of the RV indicated fibrofatty myocardium. Atrial arrhythmias associated with SSS may be the cause of symptoms in some cases of ARVC.     

Detection of circulating tumor cells in patients with pancreatic cancer: a preliminary result

Background/Purpose

It has been reported that circulating tumor cells (CTCs) can be used to predict survival in metastatic breast cancer. In this preliminary study, we examined the level of CTCs in pancreatic cancer (PC) patients to elucidate whether we could predict survival in PC.

Methods

The eligible subjects, at Tokyo Medical University Hospital, were 26 patients with PC, 11 with chronic pancreatitis, and 10 healthy volunteers. Three PC patients underwent surgery, 18 patients (who were stage IV) were treated with gemcitabine (GEM), and 5 patients received best supportive care (BSC).

Results

The CTC count was 1/7.5 ml blood or higher (defined as positive) in 11 of the 26 patients (42%; mean, 16.9/7.5 ml blood; range, 1-105/7.5 ml blood). Gemcitabine was administered to 6 of the 11 CTC-positive patients (3.8 courses on average). The treatment was continued for more than three courses in 2 patients, in both of whom the CTC count was only 1/7.5 ml blood. Operation was performed in 1 of the 11 CTC-positive patients. The remaining 4 patients of the 11 CTC-positive patients received only BSC. CTC was negative in 15 patients with PC (stage II, 1; stage III, 1; stage IVa, 7; and stage IVb, 6) and in the subjects with benign conditions. The median survival times (MSTs) of the CTC-positive and-negative patients were 110.5 and 375.8 days (P < 0.001). When the analysis was limited to the 14 stage-IVb patients, the MSTs of the CTC-positive and-negative patients were 52.5 and 308.3 days (P < 0.01).

Conclusions

The present study demonstrated that the detection of CTCs in peripheral blood may be useful to predict prognosis in patients with PC.     

Flowcharts for the management of biliary tract and ampullary carcinomas

No strategies for the diagnosis and treatment of biliary tract carcinoma have been clearly described. We developed flowcharts for the diagnosis and treatment of biliary tract carcinoma on the basis of the best clinical evidence. Risk factors for bile duct carcinoma are a dilated type of pancreaticobiliary maljunction (PBM) and primary sclerosing cholangitis. A nondilated type of PBM is a risk factor for gallbladder carcinoma. Symptoms that may indicate biliary tract carcinoma are jaundice and pain in the upper right area of the abdomen. The first step of diagnosis is to carry out blood biochemistry tests and ultrasonography (US) of the abdomen. The second step of diagnosis is to find the local extension of the carcinoma by means of computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), percutaneous transhepatic cholangiography (PTC), and endoscopic retrograde cholangiopancreatography (ERCP). Because resection is the only way to completely cure biliary tract carcinoma, the indications for resection are determined first. In patients with resectable disease, the indications for biliary drainage or portal vein embolization (PVE) are checked. In those with nonresectable disease, biliary stenting, chemotherapy, radiotherapy, and/or best supportive care is selected.     

Potential of dendritic-cell immunotherapy for relapse after allogeneic hematopoietic stem cell transplantation, shown by WT1 peptide- and keyhole-limpet-hemocyanin-pulsed, donor-derived dendritic-cell vaccine for acute myeloid leukemia

Induction of leukemia-specific immune responses is a promising treatment for acute myeloid leukemia. A 58-year-old woman received Wilms' tumor 1 (WT1) peptide- and keyhole limpet hemocyanin (KLH)-pulsed, donor-derived dendritic cell (DC) vaccination for AML relapse after allogeneic stem cell transplantation. The vaccination induced immune responses to the naive antigen KLH, whereas definitive immune responses to WT1 were not detected. Leukemia gradually progressed despite of vaccination. This study indicates that DC vaccination can induce an antigen-specific immune response in a patient after allogeneic stem cell transplantation, thus representing a viable strategy to induce antigen-specific immune responses in such patients.     

Pitavastatin, an HMG-CoA reductase inhibitor, exerts eNOS-independent protective actions against angiotensin II induced cardiovascular remodeling and renal insufficiency

Angiotensin II (Ang II) plays a pivotal role in cardiovascular remodeling leading to hypertension, myocardial infarction, and stroke. Pitavastatin, an HMG-CoA reductase inihibitor, is known to have pleiotropic actions against the development of cardiovascular remodeling. The objectives of this study were to clarify the beneficial effects as well as the mechanism of action of pitavastatin against Ang II-induced organ damage. C57BL6/J mice at 10 weeks of age were infused with Ang II for 2 weeks and were simultaneously administered pitavastatin or a vehicle. Pitavastatin treatment improved Ang II-induced left ventricular hypertrophy and diastolic dysfunction and attenuated enhancement of cardiac fibrosis, cardiomyocyte hypertrophy, coronary perivascular fibrosis, and medial thickening. Ang II-induced oxidative stress, cardiac TGFbeta-1 expression, and Smad 2/3 phosphorylation were all attenuated by pitavastatin treatment. Pitavastatin also reduced Ang II-induced cardiac remodeling and diastolic dysfunction in eNOS-/- mice as in wild-type mice. In eNOS-/- mice, the Ang II-induced cardiac oxidative stress and TGF-beta-Smad 2/3 signaling pathway were enhanced, and pitavastatin treatment attenuated the enhanced oxidative stress and the signaling pathway. Moreover, pitavastatin treatment reduced the high mortality rate and improved renal insufficiency in Ang II-treated eNOS-/- mice, with suppression of glomerular oxidative stress and TGF-beta-Smad 2/3 signaling pathway. In conclusion, pitavastatin exerts eNOS-independent protective actions against Ang II-induced cardiovascular remodeling and renal insufficiency through inhibition of the TGF-beta-Smad 2/3 signaling pathway by suppression of oxidative stress.     

Overview of Regular Dialysis Treatment in Japan as of 31 December 2006

A statistical survey of dialysis patients for the year 2006 was carried out for 4051 medical facilities across Japan, and responses were received from 3985 (98.37%) facilities. There were 264 473 dialysis patients (including 9003 peritoneal dialysis patients) in Japan at the end of 2006, which showed an increase of 6708 (2.6%) from the end of 2005. The number of patients per million population was 2069.9. The crude mortality rate during 2006 was 9.2%. The mean age of the patients who began dialysis (in 2006) was 66.4 years, and the mean age of the entire dialysis population was 64.4 years. The primary renal diseases of the patients who began dialysis were diabetic nephropathy (42.9%), chronic glomerulonephritis (25.6%), and nephrosclerosis (9.4%). Of the 3488 facilities that participated in the survey on the dialysate water quality, 2873 facilities (82.4%) measured the endotoxin concentration in the dialysate; and 1197 facilities (37.1%) out of 3228 measured the bacterial count in the dialysate. The mean hemoglobin concentration in the dialysis population at the end of 2006 was 10.23 ± 1.33 g/dL, which was equal to that at the end of 2005 (10.23 ± 1.37 g/dL). The mean concentration of serum creatinine in 15 853 patients who started dialysis during 2006 was 8.37 ± 3.58 mg/dL. The estimated glomerular filtration rate, which was calculated with formula modified for the Japanese population from the Modification of Diet in Renal Disease (MDRD) Study equation, was 5.46 ± 6.60 mL/min/1.73 m².