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PubMed2002

[The effect of phosphodiesterase type 3 inhibitor on chorio-retinal blood flow in rabbits eyes].

PURPOSE: To investigate the ocular effect of intravenous administration of a phosphodiesterase type 3 inhibitor (NSP-805) and to compare the effect of NSP-805 with that of a calcium antagonist (nicardipine hydrochloride) on chorio-retinal blood flow in anesthetized albino rabbits. METHODS: Twenty-four female albino rabbits (weighting 2.0-4.0 kg) were anesthetized with intravenous injection. NSP-805(40 micrograms/kg and 100 micrograms/kg) and nicardipine of 40 micrograms/kg were intravenously administrated to the anesthetized rabbits. Intravenously administration of 20% dimethyl sulfoxide (DMSO) was used as a vehicle. Chorio-retinal blood flow was measured with a laser Doppler flowmeter at baseline and every 20 minutes after intravenous administration for 120 minutes. Heart rates and systemic blood pressure were monitored. Baseline measurements were compared with every 10 minutes after intravenous administration. Differences between the drug groups and vehicle group were analyzed. RESULTS: After administration of a low dose of NSP--805 (40 micrograms/kg) and nicardipine (40 micrograms/kg), the chorio-retinal blood flow was significantly increased (p < 0.05). A high dose NSP-805(100 micrograms/kg) reduced systemic blood pressure significantly, but the increase of chorio-retinal blood flow was less than that at the low dose of NSP-805(40 micrograms/kg) and nicardipine (40 micrograms/kg). Chorio-retinal blood flow in the NSP 805(40 micrograms/kg) and nicardipine (40 micrograms/kg) groups was significantly increased over that in the control group (20% DMSO) (p < 0.05). CONCLUSION: The results suggest that the NSP-805 has the potential of increasing chorio-retinal blood flow in rabbit eyes.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Vitamins K2, K3 and K5 exert in vivo antitumor effects on hepatocellular carcinoma by regulating the expression of G1 phase-related cell cycle molecules.

A number of studies have shown that various vitamins K, specifically vitamin K2, possessed antitumor activity on various types of rodent- and human-derived neoplastic cell lines. However, there are only a small number of reports demonstrating in vivo antitumor effects of vitamins K. Furthermore, the mechanism of antitumor effects of vitamins K still remains to be examined. In the present study, we examined the antitumor effects of vitamins K2, K3 and K5 on PLC/PRF/5 human hepatocellular carcinoma (HCC) cells in vivo. Furthermore, to examine the mechanism of antitumor actions of these vitamins K, mRNA expression levels of various G1 phase-related cell cycle molecules were evaluated by using a real-time reverse transcription-polymerase chain reaction (RT-PCR) method. HCC-bearing animals were produced by implanting PLC/PRF/5 cells subcutaneously into athymic nude mice, and drinking water containing vitamin K2, K3 or K5 was given to the animals. Treatments with vitamins K2, K3 and K5 were shown to markedly inhibit the growth of HCC tumors. To examine the mechanism of in vivo antitumor effects of vitamins K, total RNA was extracted from HCC tumors, and the expression of G1 phase-related cell cycle molecules was quantitatively examined. Real-time RT-PCR demonstrated that the expression of the cell cycle-driving molecule, cyclin-dependent kinase 4 (Cdk4), in HCC was significantly reduced by the treatments with vitamin K2, K3 and K5. Conversely, the expression of the cell cycle-suppressing molecules, Cdk inhibitor p16INK4a and retinoblastoma, in HCC was significantly enhanced by the treatments with vitamins K2, K3 and K5. These results indicate that vitamins K2, K3 and K5 exert antitumor effects on HCC by regulating the expression of G1 phase-related cell cycle molecules. These results also indicate that vitamins K2, K3 and K5 may be useful agents for the treatment of patients with HCC.

Alanine Transaminase↗
PubMed2005

Differential regulation of perforin expression in human CD4+ and CD8+ cytotoxic T lymphocytes.

OBJECTIVE: Because perforin is an essential cytolytic mediator of cytotoxic T lymphocytes (CTLs), it is important to understand the regulatory mechanisms of perforin expression in CTLs. In the present study, we investigated the relationship between cytotoxic activity, perforin expression, and cell-activated status of CD4(+) and CD8(+) CTLs. METHODS: Herpes simplex virus-specific CD4(+) CTL clones and Epstein-Barr virus-specific CD8(+) CTL clones were established, and their cytotoxic activities were examined in both the activated and resting phases. Perforin mRNA expression was examined by reverse transcriptase polymerase chain reaction quantitatively. Transcriptional regulation of perforin was examined by electrophoretic mobility shift assay. RESULTS: The degrees of cytotoxic activity of CD8(+) CTLs did not differ significantly between the two phases; however, CD4(+) CTLs in the activated phase appeared to be significantly more cytotoxic than those in the resting phase. Similarly, expression levels of perforin mRNA in activated and resting CD8(+) CTLs did not differ significantly, but activated CD4(+) CTLs appeared to express perforin more abundantly than resting CD4(+) CTLs. In addition, it appeared that binding of STAT5 to the perforin gene promoter was increased in activated CD4(+) CTLs compared to resting CD4(+) CTLs; however, there was no significant detectable difference of STAT5 binding activity to the perforin gene promoter between activated and resting CD8(+) CTLs. CONCLUSIONS: The present study has revealed a difference in the control of perforin expression between CD4(+) and CD8(+) CTLs; that is, perforin is expressed constitutively in memory CD8(+) CTLs, but is dependent on cell activation in memory CD4(+) CTLs.

Antigens, CD↗
PubMed2004

Effects of grapefruit juice on pharmacokinetics of atorvastatin and pravastatin in Japanese.

AIMS: To investigate the effects of repeated grapefruit juice (GFJ) intake on the pharmacokinetics of atorvastatin and pravastatin in Japanese subjects. METHODS: Two randomized, two-way crossover studies were performed. GFJ or water was given to two groups of 10 subjects each three times daily for 2 days. On the third day, single 10 mg doses of atorvastatin or pravastatin were orally administered with GFJ or water, and an additional 250 ml of GFJ or water was taken before lunch and dinner. Plasma concentrations of atorvastatin and its metabolites were determined over 48 h postdosing and of pravastatin and its metabolites over 24 h postdosing. RESULTS: Compared with in the water group, the AUC(0,48 h) of atorvastatin acid significantly increased by 1.40 fold (95% CI 1.02, 1.92; P < 0.05) when atorvastatin was taken with GFJ. AUC(0,48 h) and C(max) of atorvastatin lactone significantly increased by 1.56 (95% CI 1.33, 1.83; P < 0.001) and 1.29 fold (95% CI 1.09, 1.51; P < 0.01), respectively, when atorvastatin was taken with GFJ. No significant changes were detected in any pravastatin pharmacokinetic parameter examined when pravastatin was taken with GFJ. However, AUC(0,24 h) of pravastatin lactone increased 1.31 fold (95% CI 1.01, 1.71; P < 0.05) with GFJ intake. CONCLUSIONS: GFJ was confirmed to significantly affect the pharmacokinetics of atorvastatin but had little or no effect on those of pravastatin in Japanese subjects.

Adult↗
PubMed2006

Comparison of the endothelialization of small intestinal submucosa, dacron, and expanded polytetrafluoroethylene suspended in the thoracoabdominal aorta in sheep.

PURPOSE: This study was undertaken to evaluate and compare endothelialization of small intestinal submucosa (SIS), Dacron, and expanded polytetrafluoroethylene (ePTFE) in high-pressure flow without aortic wall contact and to evaluate the suitability of SIS as a vascular graft material. MATERIALS AND METHODS: In 12 adult sheep, three types of membrane leaflets of similar thickness (approximately 200 mum) were suspended within large square stents without contact with the thoracoabdominal aortic wall: SIS (n = 12), Dacron (n = 12), and ePTFE (n = 12). Each animal received one leaflet of each material. Aortograms were obtained before and after percutaneous implantation and when the animal was killed at 8 weeks (n = 6) or 18 weeks (n = 6). Cell coverage and remodeling of SIS, Dacron, and ePTFE membranes were assessed by gross and histologic microscopic examinations. RESULTS: Thirty-five successfully implanted leaflets were evaluated. SIS showed progressive remodeling. Thirty-three leaflets exhibited thickening as a result of neointimal formation and endothelialization, most likely from circulating endothelial cells. Dacron exhibited the greatest and most progressing degree of neointimal formation and endothelialization, followed by SIS and then ePTFE. With SIS and ePTFE, neointimal formation decreased with time, but endothelialization was stable. Uneven neointimal formation and endothelialization on the outer surfaces and distal leaflet positions were seen. CONCLUSIONS: SIS showed progressive remodeling with moderate and regressive neointimal formation and moderate stable endothelialization. Further study of its durability and incorporation into the aortic wall needs to be performed to evaluate its suitability as a cover for aortic endografts.

Animals↗
PubMed2003

Induction of indefinite survival of fully allogeneic cardiac grafts and generation of regulatory cells by intratracheal delivery of alloantigens under blockade of the CD40 pathway.

BACKGROUND: The authors previously showed that intratracheal delivery (ITD) of donor splenocytes induced prolonged survival of fully allogeneic cardiac grafts in mice. In this study, this treatment protocol was combined with blockade of the CD40 pathway in an attempt to induce operational tolerance. METHODS: CBA mice were given donor splenocytes (1x107) or Kb peptide (100 microg) by ITD with or without antibody specific for mouse CD40 ligand (MR1, 200 microg) 7 days before transplantation of a C57BL/10 heart. Also, splenocyte (5 x 107) from primary recipient CBA mice given ITD of donor splenocytes or Kb peptide plus MR1 were adoptively transferred into naive CBA secondary recipients 7 days after the pretreatment and C57BL/10 hearts were transplanted into those recipients the same day. RESULTS: ITD of donor splenocytes and Kb peptide induced prolonged survival of cardiac grafts (median survival time [MST], 74 and 56 days, respectively), whereas naive control mice and mice pretreated with syngeneic splenocytes had acute graft rejection (MST in both groups, 7 days). When MR1 was included, all grafts survived indefinitely (>200 days), but mice pretreated with MR1 alone had graft rejection (MST, 54 days). Mice bearing cardiac grafts had acceptance of skin grafts from C57BL/10 but not BALB/c mice, demonstrating that operational tolerance was induced. Secondary recipients given adoptive transfer of splenocytes from primary recipients of the combined treatment had acceptance of C57BL/10 grafts, suggesting that regulatory cells were generated within 7 days of pretreatment. CONCLUSIONS: ITD of donor splenocytes or Kb peptide under blockade of the CD40 pathway induced operational tolerance and generated regulatory cells.

Adoptive Transfer↗
PubMed2003

Combination of assay of human telomerase reverse transcriptase mRNA and cytology using bile obtained by endoscopic transpapillary catheterization into the gallbladder for diagnosis of gallbladder carcinoma.

OBJECTIVES: It is difficult to make accurate diagnoses of polypoid lesions in the gallbladder. To increase the diagnostic accuracy, we have developed an endoscopic technique to obtain gallbladder bile, termed endoscopic transpapillary catheterization into the gallbladder (ETCG). We evaluated the usefulness of a molecular biological approach to the diagnosis of gallbladder carcinoma, in which gallbladder bile obtained by the ETCG technique is used. METHODS: Twenty patients undergoing an operation because of suspicion of gallbladder carcinoma were enrolled. Twelve patients were confirmed to have gallbladder carcinoma, and four were found to have chronic cholecystitis. Two patients with polypoid lesion were diagnosed as having an inflammatory polyp and a hyperplastic polyp, respectively. The remaining two patients with polypoid lesions were diagnosed as having a cholesterol polyp. Gallbladder bile collected by the ETCG technique was evaluated cytologically and also analyzed for telomerase activity and mRNA for human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase. In 14 patients, hTERT mRNA in resected specimens (fixed in 10% formalin and embedded in paraffin) was also examined. RESULTS: Cytology of gallbladder bile was positive in eight of 11 examined patients (72.7%) with gallbladder carcinoma. hTERT mRNA was detectable in gallbladder bile as well as in resected neoplastic tissues in four of 12 patients (33.3%) with carcinoma. Conversely, telomerase activity was negative in all eight examined patients with carcinoma. Overall, either cytology or hTERT mRNA of gallbladder bile was positive in 10 of 12 patients (83.3%) with gallbladder carcinoma. Cytology, hTERT mRNA, and telomerase activity were negative in eight patients with benign disease. CONCLUSIONS: The combination of cytology and hTERT mRNA analysis of gallbladder bile might be helpful for the preoperative diagnosis of gallbladder carcinoma.

Adult↗
PubMed1989

Immunocytochemical localization of amelogenins in the deciduous tooth germs of the human fetus.

The immunocytochemical localization of amelogenins in the developing deciduous tooth germs of 6-month-old human fetuses was investigated by the protein A-gold method using an antiserum against porcine 25K amelogenin. The inner enamel epithelial cells and underlying matrix showed no amelogenin-like immunoreactivity. Distinct immunoreactivity was initially shown by fine fibrils found beneath the intact basal lamina of preameloblasts at the early differentiation stage. At the late differentiation stage, amelogenin-like immunoreactivity was shown by a fine granular material within the extracellular matrix as well as by the Golgi apparatus, secretory granules, lysosomal structures, coated vesicles, and coated pits of preameloblasts with a disrupted basal lamina. At the formative stage, the localization of immunoreactivity in secretory ameloblasts was similar to that in preameloblasts during the late differentiation stage. However, immunopositive coated vesicles and coated pits were only found at the early stage of matrix formation. The calcified enamel matrix and stippled material showed intense immunoreactivity. Immunocytochemical labeling of the enamel matrix appeared as a gradient, decreasing from the enamel surface to the dentinoenamel junction. No maturation stage of ameloblasts existed in the tooth germs examined. In predentin and dentin, amelogenin-like immunoreactivity was occasionally detected on odontoblasts and their processes, but odontoblasts and cells of the stratum intermedium contained no immunoreactive elements. These findings confirmed that the secretory ameloblast in the human deciduous tooth germ is responsible for the synthesis and secretion of enamel proteins.

Amelogenin↗
PubMed2006

Aortic root necrosis after surgical treatment using gelatin-resorcinol-formaldehyde (GRF) glue in patients with acute type A aortic dissection.

BACKGROUND: Although gelatin-resorcinol-formaldehyde (GRF) glue is used for surgical repair of acute type A aortic dissections, late complications possibly ascribed to toxic effects of GRF glue have been reported. We analyzed the benefits and risks of using GRF glue. PATIENTS AND METHODS: Between January 1990 and August 2003, 269 consecutive patients underwent emergency operations for acute type A aortic dissection. GRF glue was not used in 47 patients (non-GRF group) who were operated on until May 1995 and was used in the 222 (GRF group) who underwent operation subsequently. RESULTS: The rate of in-hospital mortality was significantly higher in the non-GRF group (31.9%) than in the GRF group (12.6%) (p<0.0001). In the GRF group, false aneurysms were found in 31 patients (31/194 survivors, 16.0%) 1-65 (mean, 30+/-18) months after initial operation. Reoperation was done in 24 of these patients. At reoperation, the site to which GRF glue was applied had degenerated, and the anastomosis between the aortic root and prosthesis had opened widely, creating a false aneurysm and resulting in aortic regurgitation with prolapse of the coronary cusps. The mortality rate of reoperation was 4.2% (1/24). CONCLUSION: The use of GRF glue improved the short-term outcome of surgery for acute type A aortic dissection, but was associated with a high incidence of false aneurysms forming at the site of proximal anastomosis, where GRF glue had been applied. Patients in whom GRF glue has been used should be carefully followed up after surgery.

Acute Disease↗
PubMed2006

Influence of chemotherapeutic agents and cytokines on the expression of 5-fluorouracil-associated enzymes in human colon cancer cell lines.

BACKGROUND: Several studies have demonstrated that intratumoral expression of catabolizing and anabolizing enzymes for 5-fluorouracil (5-FU) is important in the response of cancers to 5-FU-based chemotherapy. We investigated the influence of other chemotherapeutic agents or cytokines, which are often administered for enhancing the efficacy of 5-FU, on the tumoral expression of 5-FU-associated enzymes, i.e., dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS), orotate phosphoribosyl transferase (OPRT), and thymidine phosphorylase (TP). METHODS: Human colon cancer cell lines (HT-29, Caco-2, and DLD-1) were incubated with 5-FU and with 5-FU combined with cisplatin, camptothecin, paclitaxel, mitomycin C, interferon, or TNF-related apoptosis-inducing ligand. mRNA expression of 5-FU-associated enzymes was assessed by real-time PCR. Activity of each enzyme and intracellular 5-FU accumulation after incubation with such agents were also evaluated. RESULTS: Each agent had a synergistic effect on the cytotoxicity of 5-FU. All chemotherapeutic agents other than cytokines induced marked alteration of the mRNA expression profile of 5-FU-associated enzymes; depression of DPD, elevation of TS, and slight suppression of OPRT and TP. In accordance with mRNA expression, enzyme activity of DPD was significantly depressed by such agents. Furthermore, although 5-FU itself increased DPD mRNA expression, a mechanism considered to be related to the acquisition of 5-FU resistance, the addition of cisplatin or camptothecin significantly inhibited the 5-FU-induced elevation of DPD. CONCLUSIONS: 5-FU-associated enzymes in colon cancer cells were greatly influenced by various chemotherapeutic agents; in particular, DPD expression was depressed. These results appear important in planning chemotherapy and also in understanding the development of adverse effects of 5-FU.

Antimetabolites, Antineoplastic↗
PubMed1999

Diagnosis and treatment of priapism: experience with 5 cases.

OBJECTIVES: Priapism is a rare disease, but needs early intervention and appropriate management. We present 5 cases, 2 of nonischemic high-flow priapism and 3 of ischemic low-flow priapism. METHODS: Focusing on the differential diagnosis of priapism between the nonischemic high-flow type and the ischemic low-flow type, we reviewed the medical records of 5 patients. RESULTS: Of the examinations carried out, cavernosography, blood gas analysis of cavernosal blood, color Doppler ultrasound, and internal pudendal arteriography were useful in differentiating the type of priapism. Complete detumescence of the penis in 2 cases of high-flow priapism and 3 cases of low-flow priapism was achieved by selective embolization with gelform and by glandular-cavernosal shunting, respectively. No recurrence was observed in any patient, and postoperative erectile function was preserved in 4 patients and is unknown in 1. CONCLUSIONS: These results indicate that angiographic studies provide the most reliable information for the differentiation of the type of priapism. However, color flow Doppler ultrasound and cavernosal blood gas determination can obviate the need for angiographic studies and are noninvasive. Although conservative treatment or even expectant management may be feasible with high-flow priapism, aggressive treatment should be carried out for low-flow priapism immediately after initial treatment fails to achieve detumescence of the penis. Selective embolization of the internal pudendal artery may be the treatment of choice for patients with high-flow priapism.

Adult↗
PubMed2003

Sufficient prophylactic efficacy with minor adverse effects by intravesical instillation of low-dose bacillus Calmette-Guérin for superficial bladder cancer recurrence.

BACKGROUND: Intravesical instillation of bacillus Calmette-Guérin (BCG) is the most efficient strategy for prophylaxis of superficial bladder cancer recurrence. Adverse effects of BCG are major obstacles, but the reduction of BCG dose could minimize these effects. The efficacy and adverse effects of half-dose (40 mg) BCG, Tokyo 172 strain, were prospectively evaluated. METHODS: A total of 93 patients with superficial bladder cancer (pTa or pT1) were sequentially assigned to receive either 40 or 80 mg of BCG after transurethral resection. BCG was administered weekly for 6 weeks postoperatively. Eighty patients observed longer than 12 months after BCG therapy (41, 40 mg group; 39, 80 mg group) were analyzed. RESULTS: BCG therapy course was completed in 71 patients. Tumor recurrence was recognized in 11 of 40 patients in the 40 mg group and in 5 of 31 patients in the 80 mg group. There was no significant difference in tumor recurrence rate between the two groups (P = 0.547). BCG therapy was withdrawn in 1 patient in the 40 mg group and in 8 patients in the 80 mg-group because of BCG-related adverse effects. The morbidity of BCG-related toxicity was significantly higher in the 80 mg group. CONCLUSION: Half-dose of BCG Tokyo 172 strain had a similar efficacy and its toxicity was significantly lower compared to the standard dose. Thus, half-dose of this strain might be suitable, at least for initial BCG therapy, for the prophylaxis of bladder cancer recurrence. Further study would be necessary to clarify the efficacy of low-dose instillation in high-risk patients.

Adjuvants, Immunologic↗
PubMed2001

Prognostic factors and survival after hepatic resection for hepatocellular carcinoma without cirrhosis.

BACKGROUND: Detailed follow-up of patients with chronic hepatitis has resulted in increased diagnosis of hepatocellular carcinoma (HCC) in patients without cirrhosis. Despite numerous studies on hepatic resection, the prognostic factors for intrahepatic recurrence and survival are not well known for patients with HCC without cirrhosis. METHODS: Among 349 patients with HCC treated in the past 13 years, cirrhosis was absent in 126 patients (36 per cent). Curative hepatic resection was carried out in 100 (79 per cent) of these patients. Risk factors for intrahepatic recurrence and prognostic factors for survival were evaluated by univariate and multivariate analyses. RESULTS: Postoperative morbidity and mortality rates were 22 and 3 per cent respectively. The 5- and 10-year disease-free and overall survival rates were 31 and 50 per cent, and 22 and 47 per cent respectively. Blood loss, surgical resection margin, intrahepatic metastasis, portal vein invasion and extent of hepatic resection were independently associated with overall survival. However, the only risk factors for intrahepatic recurrence were portal vein invasion and hepatitis C virus (HCV) infection. The former was related to early recurrence while the latter was related to later recurrence. The 5-year disease-free survival rate was 58 per cent in patients with hepatitis B virus infection while it was 6 per cent in patients with HCV infection (P < 0.001). CONCLUSION: In the treatment of HCC without cirrhosis, major hepatectomy is advocated to prevent early recurrence. Liver transplantation may be required for patients with HCV infection.

Adult↗
PubMed2002

Cancer-associated retinopathy associated with invasive thymoma.

PURPOSE: To report a case of cancer-associated retinopathy associated with invasive thymoma. DESIGN: Interventional case report. METHOD: A 41-year-old Japanese woman was observed between February 1998 and May 2001. Ophthalmologic examinations and systemic examinations were performed. The patient received treatment including corticosteroid pulse therapy, plasmapheresis, and thymectomy. RESULTS: The patient developed progressive visual dysfunction including bilateral visual acuity loss, concentric contraction of visual fields, and color vision loss. In both eyes, retinal vessel attenuation and retinal pigment epithelium degeneration were observed with fundus ophthalmoscopy and fluorescein angiography. Response in electroretinogram was reduced, suggesting both rod and cone dysfunction. Autoantibody against 23-kD cancer-associated retinopathy (CAR) antigen (antirecoverin antibody) was detected in the patient's serum. A mediastinal tumor that was histopathologically diagnosed as invasive thymoma was detected and was surgically resected. During more than 3 years of follow-up, no other malignancy was detected despite extensive systemic evaluation. The patient also suffered from subclinical myasthenia gravis. Although temporary improvement of visual function was observed after treatment with steroid pulse therapy and plasmapheresis' light perception of each eye was lost in the end. CONCLUSIONS: The patient was diagnosed as having CAR. Invasive thymoma was considered to be the causative tumor because there had been no evidence that suggested other systemic malignancy during more than 3 years of follow-up.

Adult↗
PubMed1996

Mite-specific induction of interleukin-2 receptor on T lymphocytes from children with mite-sensitive asthma: modified immune response with immunotherapy.

BACKGROUND: The efficacy of immunotherapy is still controversial. To elucidate the mechanisms of immunotherapy, we studied mite-specific induction of IL-2 receptor (IL-2R) expression on T lymphocytes from children with mite-sensitive asthma. METHODS: Peripheral blood mononuclear cells were obtained from 28 children with mite-sensitive asthma: 13 had never received house dust immunotherapy (nonimmunotherapy group), 15 had been receiving house dust immunotherapy at the time of the study (immunotherapy group). After a 6-day culture with or without Dermatophagoides farinae (Df) antigen, the expression of IL-2Rp55 (CD25) and p75 on CD4+ or CD8+ T lymphocytes was measured by flow cytometry. RESULTS: The nonimmunotherapy group showed significant Df-specific CD25 induction on CD4+ T lymphocytes (delta CD4+ CD25+) but little induction on CD8+ T lymphocytes (delta CD8+ CD25+). delta CD4+ CD25+ was correlated with the severity of the disease. In the immunotherapy group delta CD8+ CD25+ was significantly higher than in the nonimmunotherapy group or in normal subjects and correlated with Df-specific IgG4 and cumulative doses of house dust extract, whereas delta CD4+ CD25+ was similar in the nonimmunotherapy and the immunotherapy groups. IL-2Rp75 was not induced either on CD4+ or CD8+ T lymphocytes. CONCLUSIONS: Our data suggest that house dust immunotherapy may have induced Df-specific CD8+ T lymphocytes in patients with mite-sensitive asthma and that the efficacy of immunotherapy may be attributed to the generation of Df-specific CD8+ T lymphocytes.

Adolescent↗
PubMed2003

Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis.

BACKGROUND: Conventional measures of the severity of alveolar proteinosis (AP) include alveolar-arterial oxygen gradient ([A - a]DO(2)), vital capacity (VC), and carbon monoxide transfer factor (TLCO), but alternative serological measures have been sought. Granulocyte-macrophage colony stimulating factor (GM-CSF) neutralising autoantibody is found in patients with idiopathic acquired AP. We have investigated the interrelationships between the levels of this antibody and those of surfactant protein (SP)-A and -B, lactate dehydrogenase (LDH), and conventional measures of disease severity, and the capacity of these parameters to predict the response to rhGM-CSF treatment. METHODS: Blood levels of anti-GM-CSF antibodies, SP-A, SP-B, LDH, and [A - a]DO(2), VC, and TLCO were measured before rhGM-CSF treatment and every 2 weeks thereafter in 14 patients with AP. RESULTS: At baseline, high levels of anti-GM-CSF antibodies and increased SP-A and SP-B levels were seen in all patients, and LDH was raised in 83%. SP-A was highly correlated with [A - a]DO(2), VC, and TLCO (p</=0.02), but other markers were not. Only a normal LDH level was predictive of a response to rhGM-CSF treatment (p=0.03). During treatment a correlation between conventional and serological variables within patients was seen only between SP-A and [A - a]DO(2) (p=0.054), LDH levels and [A - a]DO(2) (p=0.010), and LDH levels and VC (p=0.019). CONCLUSIONS: Of the serological parameters studied, only SP-A and LDH levels were correlated with conventional measures of disease severity, with LDH most accurately reflecting [A - a]DO(2) and vital capacity. Only a normal LDH level predicted a higher likelihood of response to treatment with GM-CSF.

Adolescent↗
PubMed2005

Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy: restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor.

BACKGROUND: Diabetic cardiomyopathy (DCM) is characterized by microvascular pathology and interstitial fibrosis, which leads to progressive heart failure; however, the pathogenesis of DCM remains uncertain. METHODS AND RESULTS: Using the streptozotocin-induced diabetic rat model, we evaluated the natural course of DCM over a period of 1 year by serial echocardiography, Western blot analysis for vascular endothelial growth factor (VEGF), endothelial progenitor cell assays, myocardial blood flow measurements, and histopathologic analysis that included terminal dUTP nick end-labeling (TUNEL), capillary and cardiomyocyte density, and fibrosis area. Downregulation of myocardial VEGF expression preceded all other features of DCM and was followed by increased apoptosis of endothelial cells, decreased numbers of circulating endothelial progenitor cells, decreased capillary density, and impaired myocardial perfusion. Apoptosis and necrosis of cardiomyocytes ensued, along with fibrosis and progressive diastolic and then systolic dysfunction. To provide further evidence of the central role of VEGF in the pathophysiology of DCM, we replenished myocardial VEGF expression using naked DNA gene therapy via direct intramyocardial injection of plasmid DNA encoding VEGF (phVEGF165). VEGF-replenished rats showed increased capillary density, decreased endothelial cell and cardiomyocyte apoptosis, and in situ differentiation of bone marrow-derived endothelial progenitor cells into endothelial cells. These anatomic findings were accompanied by significant improvements in cardiac function. CONCLUSIONS: These findings suggest that downregulation of VEGF may compromise microvascular homeostasis in the myocardium and thereby play a central role in the pathogenesis of DCM.

Animals↗
PubMed1997

Lymph node spread from carcinoma of the gallbladder.

BACKGROUND: Lymph node spread is the most common pattern of progression in gallbladder carcinoma (GBC) and is a prognostic factor. The purpose of this study was to determine the prevalence of lymph node metastases in patients with resected advanced GBC, and to evaluate the curative effects of radical surgery for patients with lymph node metastasis. METHODS: One hundred and eleven consecutive patients who had undergone radical surgery for GBC were included in this study. The pattern of lymph node metastases was examined histopathologically, using the TNM staging of the American Joint Committee on Cancer. RESULTS: There was no neurovascular invasion or lymph node involvement in 15 patients with pT1 tumors. Sixty of 96 patients with pT2-4 tumors had lymph node metastases. The pericholedochal lymph node was the most common metastatic lymph node, followed by the cystic lymph node. The frequency of metastases in retroportal, posterosuperior pancreaticoduodenal, and interaorticocaval lymph nodes was >15% in all cases. pT3-4 tumors had significantly more lymph node involvement (79%) and significantly higher N2:N1 ratios (2.5) than pT2 tumors (46% and 0.6, respectively). There was no difference in 5-year survival between N0 and N1 groups in pT2-4 tumors (66% in N0 and 53% in N1). Patients with N2 disease had a significantly worse prognosis, but 4 patients survived >5 years. CONCLUSIONS: The cystic and pericholedochal lymph nodes are the initial site of spread from GBC. The frequency of lymph node involvement is strongly influenced by the depth of invasion of the primary tumor. GBC limited to such lymph node metastases can be cured by surgery in >50% of such cases.

Adenocarcinoma↗