Treatment with the angiogenesis inhibitor endostatin: a novel therapy in rheumatoid arthritis

OBJECTIVE: An endostatin that inhibits angiogenesis dependent tumor growth is being tested as an antitumor agent. The neoangiogenesis condition of cancer is essentially identical to that of rheumatoid arthritis (RA). Thus antiangiogenic treatment has potential for treatment of RA. We investigated the effects of human recombinant endostatin on human RA synovial tissue by use of a novel model of RA, in which human RA tissue is grafted into SCID mice (SCID-HuRAg). METHODS: Ten or 50 mg/kg of human recombinant endostatin was administered by percutaneous direct intrasynovial injection in each of 7 SCID-HuRAg mice. We examined the volume of the grafted tissue mass and the histological changes 7 days after endostatin administration. Six control mice received phosphate buffered saline in the same manner. RESULTS: The grafted synovial volume of SCID-HuRAg mice was significantly decreased by endostatin administration. The number of inflammatory cells (macrophages and lymphocytes) was also significantly reduced in a dose dependent manner. The number of vessels that were counted by von Willebrand factor VIII and type IV collagen positive cells was decreased, although apoptotic cells were increased in RA synovia. CONCLUSION: The results suggest that antiangiogenesis treatment using endostatin represents a potential new therapeutic strategy for RA.     

Double cancer (lung and colon cancer) that showed complete remission with irinotecan and cisplatin combined chemotherapy

We report a rare case of double (colon and lung) cancer which showed complete remission with chemotherapy with irinotecan (CPT-11) and cisplatin (CDDP). The patient was a 67-year-old man who was diagnosed as having double cancer (stage IIIb pulmonary adenocarcinoma and stage 0 [or 1] well-differentiated adenocarcinoma of the ascending colon). Two courses of chemotherapy (CPT-11, 60 mg/m², days 1 and 8; CDDP, 30 mg/m², days 1 and 8) were performed. The combination therapy of CPT-11 and CDDP was very effective. In Japan, there have been few published reports describing the use of CPT-11 for the treatment of gastrointestinal cancer. We think that the use of CPT-11 in gastrointestinal cancer is promising. Received: August 18, 1999 / Accepted: March 24, 2000     

Probiotics inhibit nuclear factor-kappaB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition

BACKGROUND AND AIMS: The extent and severity of mucosal injury in inflammatory bowel diseases are determined by the disequilibrium between 2 opposing processes: reparative and cytoprotective mechanisms vs. inflammation-induced injury. Probiotics may provide clinical benefit by ameliorating colitis; however, their mechanisms of action remain largely unknown. Our objective was to investigate microbial-epithelial interactions that could explain the beneficial therapeutic effects of probiotics. METHODS: The effect of VSL#3-conditioned media on the nuclear factor-kappaB pathway in young adult mouse colonic epithelial cells was assessed by using monocyte chemoattractant protein-1 enzyme-linked immunosorbent assays; IkappaBalpha, IkappaBbeta, and p105 immunoblot analysis; and nuclear factor-kappaB luciferase reporter gene and proteasome assays. Effects on heat shock proteins were determined by electrophoretic mobility shift assay and immunoblot for heat shock proteins 25 and 72 in young adult mouse colonic cells. Cytoprotection against oxidant injury was determined by chromium 51 release and filamentous and globular actin assays. RESULTS: VSL#3 produces soluble factors that inhibit the chymotrypsin-like activity of the proteasome in gut epithelial cells. Proteasome inhibition is an early event that begins almost immediately after exposure of the epithelial cells to the probiotic-conditioned media. In addition, these bacteria inhibit the proinflammatory nuclear factor-kappaB pathway through a mechanism different from the type III secretory mechanisms described for other nonpathogenic enteric flora. They also induce the expression of cytoprotective heat shock proteins in intestinal epithelial cells. CONCLUSIONS: The resulting inhibition of nuclear factor-kappaB and increased expression of heat shock proteins may account for the anti-inflammatory and cytoprotective effects reported for probiotics and may be a novel mechanism of microbial-epithelial interaction. These effects seem to be mediated through the common unifying mechanism of proteasome inhibition.     

Separation Methods of T Cells,Natural Killer,and Dendritic Cells from Peripheral Blood of Cancer Patients using Interleukin-2 and Functional Analysis of Natural Killer Cells after Separation

We aimed to induce three different immune cell subsets from a single blood sample from cancer patients to target different biological characters of cancer cells. In the presence of 6000 IU/ml IL-2, natural killer (NK) cells adhere to plastic. By using this ability, we could separate dendritic cells, T cells, and NK cells from peripheral blood mononuclear cells. The cultured NK cells demonstrated higher nonspecific cytotoxicity against tumor cell lines than did the T cells. Furthermore, adherent NK cells demonstrated higher cytotoxicity than nonadherent NK cells, although there was no difference between adherent and nonadherent NK cells in natural cytotoxicity receptors (NKp30, NKp44, NKp46) and NKG2D expression. With these results, we confirmed that we could induce dendritic cell, T cell, and higher cytotoxic NK cells from a single blood draw, and this methodology facilitates to the use of these cells for clinical grade conditions.     

Morphological divergence in the curvature of human femoral diaphyses: Tracing the central mass distributions of cross-sections

The diaphysis of the human femoral bone has a physiological anterior curvature; additionally, there is a curvature to the medial side or lateral side. In addition to compression stress from gravity during standing, walking, and running, these bones are continuously exposed to complex stresses from the traction forces of the various strong muscles attached to them. The femoral diaphysis is subjected to these mechanical stresses, and the direction and size of its curvature are defined according to Wolff's law and the mechanostat theory of Frost. The purpose of this study was to quantitatively evaluate the curvature of the femoral diaphysis in Japanese skeletons by determining the curve connecting the central mass distributions (CMD) of cross-sectional images. A total of 90 right femora (46 males and 44 females) were randomly selected from modern Japanese skeletal specimens. Full-length images of these bones were acquired using a clinical computed tomography scanner. The range between the lower end of the lesser trochanter and the adductor tubercle of each femur was divided at regular intervals to obtain ten planes, and nine levels were analyzed. The CMD curve was determined by connecting the CMDs of each of the nine cross-sections. First, the CMD of a cross-section in each of the nine slices was calculated, and the nine trajectories were superimposed from above. Then, by converting the shape of the entire CMD curve to superimpose the coordinates of the endpoint on the starting point, a closed arc representing the curvature of the femur was determined. For both males and females, the patterns varied from mostly medial to largely lateral curvature. The size of the curvature also varied for individuals. By analyzing only the coordinates of the vertex of the CMD curve of each femoral bone, the outlines of the diaphyseal curvatures could be recognized. The femora were thereby divided into two groups: medial bending and lateral bending. Considering males and females together, the number in the lateral-curvature group (n = 51) was larger than that in the medial-curvature group (n = 39). Moreover, the average age of the lateral-curvature group was significantly higher than that of the medial-curvature group (p < 0.05). In males, with an increase in the cortical bone proportion of the cross-sectional area, the anterior vertex of diaphyseal bending tended to be more prominent. This cortical proportion was significantly higher in the medial-curvature groups than in the lateral-curvature group (p < 0.01). The phenomena observed in this study may be related to pathophysiologies such as atypical fractures of the femur and osteoarthritis of the knee joints.     

Pharmacokinetics of 4′-cyano-2′-deoxyguanosine,a novel nucleoside analog inhibitor of the resistant hepatitis B virus,in a rat model of chronic kidney disease

IntroductionThe novel nucleoside analog, 4′-cyano-2′-deoxyguanosine (CdG), possesses inhibitory activity against both the wild-type and resistant hepatitis B virus. Since the dosage of the currently available nucleoside analog preparations needs to be adjusted, depending on renal function, we investigated the effect of renal dysfunction on the pharmacokinetics of CdG in a rat model of chronic kidney disease (CKD).MethodsCKD model rats were either intravenously or orally administered CdG at a dose of 1 mg/kg. The concentration of CdG in plasma, organs (liver and kidney) and urine samples were determined by means of a UPLC system interfaced with a TOF-MS system.ResultsFollowing intravenous administration, the plasma retention of CdG was prolonged in CKD model rats compared to healthy rats. In addition, the clearance of CdG was well correlated with plasma creatinine levels in CKD model rats. Similar to the results for intravenous administration, the plasma concentration profiles of CdG after oral administration were also found to be much higher in CKD model rats than in healthy rats. However, the results for the organ distribution and urinary excretion of CdG, the profiles of which were similar to that of healthy rats, indicated that CdG did not accumulate to a significant extent in the body.ConclusionThe extent of renal dysfunction has a direct influence on the pharmacokinetics (plasma retention) of CdG without a significant accumulation, indicating that the dosage of CdG will be dependent on the extent of renal function. .     

Contribution of increased minimal coronary resistance and attenuated vascular adaptive remodeling to myocardial ischemia in patients with systemic hypertension and ventricular hypertrophy

This study assessed the impact of coronary vascular adaptive remodeling and coronary vascular reactivity on myocardial ischemia in patients with hypertension and left ventricular hypertrophy. Myocardial ischemia is associated with impaired endothelium-independent vasodilation of resistance coronary arteries and increased minimal coronary resistance. These changes may occur in association with lumen reduction caused by attenuated adaptive remodeling in response to plaque accumulation.     

Predictive factors for postoperative tachyarrhythmia after thoracoscopic esophagectomy and the usefulness of landiolol hydrochloride for its treatment

Background

Tachyarrhythmia after esophagectomy is a severe complication that should not be underestimated because of its negative impact. The aims of this study were to clarify the cause and impact of postoperative tachyarrhythmia after thoracoscopic esophagectomy. Additionally, we analyzed the usefulness of landiolol administration for postoperative tachyarrhythmia.

Methods

We evaluated the predictive factors for tachyarrhythmia onset after surgery and its clinical impact in 127 patients who underwent thoracoscopic esophagectomy with extended lymphadenectomy. Moreover, we analyzed the efficacy of landiolol for postoperative tachyarrhythmia.

Results

Tachyarrhythmia developed in 38 of the 127 patients. Multivariate analysis showed that advanced age, heart disease, and hyperlipidemia were associated with postoperative tachyarrhythmia. Hyponatremia, hypoalbuminemia, and leukocytosis on postoperative day 3 were significantly associated with tachyarrhythmia onset. The incidence of all complications and respiratory complications, including pneumonia, was significantly higher in patients with than in those without tachyarrhythmia. The mortality rate in the tachyarrhythmia group tended to be higher than that in the nontachyarrhythmia group. Landiolol as a treatment for tachyarrhythmia immediately decreased heart rate and safely reduced subsequent respiratory complications.

Conclusion

In elderly patients with cardiac disease or hyperlipidemia, surgeons should be alert for the occurrence of tachyarrhythmia after esophagectomy. Postoperative tachyarrhythmia is a marker of morbidities with particular emphasis on respiratory complications. However, it can be adequately managed by landiolol, resulting in fewer respiratory complications. Landiolol might be a safe and convenient agent for managing postoperative tachyarrhythmia after thoracoscopic esophagectomy, resulting in lower mortality and morbidity rates.