Successful therapeutic use of a single-dose of rituximab on relapse in adults with minimal change nephrotic syndrome.

Minimal change nephrotic syndrome (MCNS) usually is considered to have a good renal prognosis, but the frequency of relapses is a therapeutic challenge to physicians. The treatment of patients with multiple relapses remains a matter of controversy, because few controlled studies are available. We report the case of a 25-year-old man who experienced relapses of MCNS. Single-dose rituximab therapy (total dose 500 mg) was given during the fourth relapse. Complete remission occurred 10 days later, when no CD19/20-positive B cells were detected in the blood. This the first report of efficacy of single-dose rituximab therapy to treat multi-relapsing MCNS in an adult patient.

Antioxidant compound from the rhizomes of Kaempferia rotunda L.

This research aimed to investigate the antioxidant effect from rhizomes of K. rotunda for finding the active compounds by DPPH free radical scavenging activity assay. The chloroform-soluble extract of the rhizomes of K. rotunda showed significant scavenging effect on the on 1,1-diphenyl-2-picryl hydrazyl (DPPH) free radicals (IC50 = 180 microg mL(-1)). Two compounds of the chloroform-soluble extract were isolated and identified. Compound 1, 2'-hydroxy-4,4',6'-trimethoxy-chalcone was found as the active constituent (IC50 = 142 microg mL(-1)). Compound 2, (+)-crotepoxide, was inactive (IC50 = 1516 microg mL(-1)). The structures of compounds 1 and 2 were identified based on the basis of spectral evidence, Mass Spectrophotometry (MS) and 2D-NMR (2 dimension of Nuclear Magnetic Resonance) data including Heteromolecular Multiple Quantum Coherence (HMQC) and Heteromolecular Multiple Bond Correlation (HMBC) and comparison to published values.

Inhibitors of aldose reductase and advanced glycation end-products formation from the leaves of Stelechocarpus cauliflorus R.E. Fr.

Two dihydroflavonol glycosides, engeletin and astilbin, were isolated from an EtOAc extract of the leaves of Stelechocarpus cauliflorus R.E. Fr. (Annonaceae). The inhibitory activity of engeletin against a recombinant human aldose reductase (IC50 value=1.16 microM) was twice that of quercetin as a positive control (2.48 microM), and 23 times greater than that of astilbin (26.7 microM). Engeletin inhibited the enzyme uncompetitively. Astilbin was about as potent as the positive control, quercetin, in its inhibition of advanced glycation end-products formation. These flavonoids displayed therapeutic potential in the prevention and treatment of diabetic complications.

Esophageal cancer after distal gastrectomy.

The effect of gastrectomy on the subsequent development of esophageal cancer was investigated. Duodenogastroesophageal reflux is thought to be common in patients after distal gastrectomy, but whether this contributes to the development of esophageal cancer in such patients is controversial. We retrospectively evaluated 153 patients who underwent subtotal esophagectomy for thoracic esophageal cancer between January 2002 and July 2005. They were divided into two groups, according to whether or not they had previously undergone a gastrectomy: group 1, comprising 14 patients who had undergone gastrectomy and group 2, comprising 139 patients who had not. Clinical profiles of the patients were obtained from the medical records and the whole resected esophagus was histopathologically examined. The interval between gastrectomy and esophagectomy in group 1 was significantly shorter in the patients who had undergone gastrectomy for gastric cancer (10.5 +/- 4.2 years) than in those who had undergone gastrectomy for a peptic ulcer (28.9 +/- 3.0 years). The interval was also somehow shorter in the patients for whom anastomosis had been performed by Billroth I (21.3 +/- 5.6 years) compared with Billroth II (29.7 +/- 3.2 years), although the difference did not reach its statistical significance (P = 0.11). Moreover, the proportion of lower third tumors in patients after gastrectomy was significantly higher compared with that of the patients with intact stomach. These findings suggest that a history of gastrectomy is associated with more lower-third squamous cell esophageal carcinoma.

DNA vaccine against hamster oral papillomavirus-associated oral cancer.

Previously we developed a carcinogenesis model involving the combination of 9,10-dimethyl-1,2-benzanthracene (DMBA) application with physical wounding of hamster lingual mucosa. The presence of a novel hamster oral papillomavirus (HOPV) was demonstrated and its genome sequenced. In the present study, this HOPV hamster model was used to test whether vaccination with the L1 gene could prevent the development of oral carcinoma. DNA plasmids encoding the L1 gene or the vector alone were injected intramuscularly into 20 vaccinated and 20 control hamsters, respectively. The lingual tips of the hamsters were painted with DMBA for 8 weeks. A portion of the lingual tips was excised, and the tips were then painted daily with DMBA until the animals were killed 13 days later. All control hamsters developed lingual carcinoma, whereas 12 of the L1-vaccinated hamsters showed no lesions. These results suggest that immunization with L1 DNA vaccines may prevent the development of papillomavirus-associated oral cancer.

Aldose reductase inhibitors from the leaves of Myrciaria dubia (H. B. & K.) McVaugh.

Ellagic acid (1) and its two derivatives, 4-O-methylellagic acid (2) and 4-(alpha-rhamnopyranosyl)ellagic acid (3) were isolated as inhibitors of aldose reductase (AR) from Myrciaria dubia (H. B. & K.) McVaugh. Compound 2 was the first isolated from the nature. Compound 3 showed the strongest inhibition against human recombinant AR (HRAR) and rat lens AR (RLAR). Inhibitory activity of compound 3 against HRAR (IC50 value = 4.1 x 10(-8) M) was 60 times more than that of quercetin (2.5 x 10(-6) M). The type of inhibition against HRAR was uncompetitive.

CSF hypocretin measures in patients with obstructive sleep apnea.

The majority of patients with narcolepsy-cataplexy were reported to have very low cerebrospinal fluid (CSF) hypocretin-1 (orexin-A) levels. The hypocretin-1 levels of secondary excessive daytime sleepiness (EDS) disorders are not known. In this study, we found that CSF hypocretin levels in the patients with obstructive sleep apnea syndrome were within the control range. The low hypocretin levels seem to reflect only the presence of cataplexy and DR2 positive in narcoleptics but not EDS itself.

Aldose reductase inhibitors from the nature.

Aldose reductase (AR) is an NADPH dependent enzyme that catalyses the reduction of the aldehyde to the corresponding alcohols. Diabetic complications including neuropathy, nephropathy, cataracts and retinopathy are considerately caused by accumulation of sorbitol, which is produced from glucose by AR in polyol pathway. The aim of AR inhibitor therapy is to normalize the elevated flux of blood and sorbitol through the polyol pathway in the target tissue. A large number of inhibitors have been prepared synthetically, and some of them are used therapeutically. However, none of them is satisfactory. From the plants, many AR inhibitors have been found, which are discussed in this review. By the structure based functioning of AR and its inhibitors, some will be developed promising in the treatment of diabetic complications. The main structural features of the inhibitors will be a polar head group and a hydrophobic ring system. The plants that contain the AR inhibitors may prevent from diabetic complications.

Aldose reductase inhibitors from the fruits of Caesalpinia ferrea Mart.

Aldose reductase inhibitors were isolated from an extract of the dry fruits of Caesalpinia ferrea Mart. (Leguminosae). Compound 2 was identified as ellagic acid by comparison with a reference sample. The structure of compound 1 was elucidated as 2-(2,3,6-trihydroxy-4-carboxyphenyl) ellagic acid on the basis of spectral evidence, especially 2D-NMR data (HMQC, HMBC and NOESY). These two compounds inhibited aldose reductase in a non-competitive manner.

Cytotoxic polyacetylenes from the twigs of Ochanostachys amentacea.

Bioassay-guided investigation of the twigs of Ochanostachys amentacea using LNCaP (hormone-dependent human prostate cancer) cells as a monitor led to the isolation of three alkynes, the known (S)-17-hydroxy-9,11,13,15-octadecatetraynoic acid (minquartynoic acid, 1) and two novel analogues, (S)-17,18-dihydroxy-9,11,13,15-octadecatetraynoic acid (2) and (S)-17-hydroxy-15E-octadecen-9,11,13-triynoic acid (3). Compounds 1-3 were tested against a panel of human tumor cell lines and found to be significantly cytotoxic.

Cytocidal effect and DNA damage of nedaplatin in vitro by simulating pharmacokinetic parameters.

PURPOSE: The pharmacodynamic effects of cis-diammine(glycolato)platinum (nedaplatin, 254-S) in vitro have been reported, but the dosage and exposure time in vitro have not always been based on clinical observations of the drug's actions in vivo. Regardless of the actual exposure conditions used, the effect of cell-cycle nonspecific anticancer agents such as nedaplatin is believed to depend on the area under the drug concentration-time curve (AUC). In this study, we evaluated the pharmacodynamics of nedaplatin in vitro, especially in relation to its AUC dependency, in terms of cell survival and DNA crosslinking. METHODS: BG-1 human ovarian cancer cells were treated with various concentrations of nedaplatin to simulate the pharmacokinetics of administration in a clinical setting. The BG-1 cells were exposed to nedaplatin dissolved in medium containing serum using constant concentration conditions, either high (maximum 7.69 mg/l) or low (average 1.33 mg/l). These concentrations were based on doses used in clinical studies. We then adjusted the exposure conditions in vitro to simulate the elimination of the drug from serum in vivo as follows: T1/2 alpha 1.20 h and T1/2 beta 2.70 h. The AUC values were set at 4, 8, 16, 25 and 40 mg.h/l for all exposure conditions. A colony-formation assay for the surviving fraction and an alkaline-elution assay for DNA crosslink measurement were done for the pharmacodynamic evaluation with comparison on the basis of the AUC value. RESULTS: Exposure to a low concentration for a long time was the most effective of the exposure conditions at the same AUC value. The greater the AUC value, the higher the crosslink index under all exposure conditions. This index tended to increase particularly after exposure to the low concentration. The natural logarithm of the surviving fraction (Y') was a linear function of the crosslink index regardless of the drug-exposure condition: ln(Y') = -87.2x + ln(5.79), R2 = 0.89. The threshold cytocidal effect was associated with a crosslink index of 0.02. CONCLUSION: There was a strong correlation between the cytocidal effect of nedaplatin and DNA crosslink formation. The cytocidal effect and DNA crosslinking in vitro depended on the exposure conditions used to define the AUC. Therefore, a new pharmacokinetic-pharmacodynamic model for nedaplatin must be constructed to investigate the most effective administration procedure in vivo.

Experimental study of vascularized nerve graft: evaluation of nerve regeneration using choline acetyltransferase activity.

A comparative study of nerve regeneration was performed on vascularized nerve graft (VNG) and free nerve graft (FNG) in Fischer strain rats. A segment of the sciatic nerve with vascular pedicle of the femoral artery and vein was harvested from syngeneic donor rat for the VNG group and the sciatic nerve in the same length without vascular pedicle was harvested for the FNG group. They were transplanted to a nerve defect in the sciatic nerve of syngeneic recipient rats. At 2, 4, 6, 8, 12, 16, and 24 weeks after operation, the sciatic nerves were biopsied and processed for evaluation of choline acetyltransferase (CAT) activity, histological studies, and measurement of wet weight of the muscle innervated by the sciatic nerve. Electrophysiological evaluation of the grafted nerve was also performed before sacrifice. The average CAT activity in the distal to the distal suture site was 383 cpm in VNG and 361 cpm in FNG at 2 weeks; 6,189 cpm in VNG and 2,264 cpm in FNG at 4 weeks; and 11,299 cpm in VNG and 9,424 cpm in FNG at 6 weeks postoperatively. The value of the VNG group was statistically higher than that of the FNG group at 4 weeks postoperatively. Electrophysiological and histological findings also suggested that nerve regeneration in the VNG group was superior to that in the FNG group during the same period. However, there was no significant difference between the two groups after 6 weeks postoperatively in any of the evaluations. The CAT measurement was useful in the experiments, because it was highly sensitive and reproducible.

Cytocidal effect and DNA damage of nedaplatin: a mathematical model and analysis of experimental data.

PURPOSE: Cell cycle non-specific anticancer agents such as cis-diamminedichloroplatinum(II) are believed to depend linearly on the value of the area under the drug concentration time curve, which is supported by a mathematical model. However, the quantitative non-linear phenomena of both the cytocidal effect and DNA crosslink formation by cisdiammine(glycolato)platinum (nedaplatin) have been shown in vitro. Therefore, we developed a new mathematical model to explain these phenomena. METHODS: We assumed that nedaplatin enters intracellular fluid from medium through simple diffusion to form DNA crosslinks that kill cells. We developed a mathematical model to represent this assumption using differential equations that we then solved using an original computer program. The calculated results were compared with the experimental data. RESULTS: The drug's simple diffusion rate constant, the DNA crosslink formation rate constant, and the crosslink-dependent cell death rate constant in the model were 1.8 x 10(-14) (l h-1), 1.6 x 10(8) (l mol-1/2 h-1), 5.45 x 10(1) (mol-1), respectively. The model fits the experimental results statistically. The model also demonstrated theoretical proof that continuous exposure at a low dose was superior to the short exposure at a high dose seen in published experimental data. CONCLUSIONS: We developed a mathematical model to describe the non-linear pharmacodynamic effect of nedaplatin in vitro. This model may provide a novel drug infusion procedure for cancer patients.

Serum KL-6 levels in patients with pulmonary complications after allogeneic bone marrow transplantation.

KL-6, a mucinous high-molecular weight glycoprotein expressed on type 2 pneumocytes, has been shown to be elevated in the serum and bronchoalveolar lavage fluid of patients with interstitial pneumonitis (IP). We measured the serum levels of KL-6 in patients after they had undergone allogeneic bone marrow transplantation (BMT) to determine whether KL-6 could be a clinically useful indicator for the development of IP. The serum concentrations of KL-6 were determined by a sandwich-type enzyme-linked immunosorbent assay using an anti-KL-6 monoclonal antibody. A total of 1028 samples were tested from 76 patients (78 transplantations) who received BMTs. The KL-6 values were markedly elevated in patients with pulmonary complications, but not in those with acute and chronic graft-versus-host disease, hemorrhagic cystitis, herpes encephalitis, sepsis, and veno-occlusive disease. The serum levels of KL-6 from patients with pulmonary complications were significantly higher than from those without pulmonary complications (P < .001) and those with other complications (P < .001). Of the 12 patients with pulmonary complications, 6 had idiopathic IP (IIP). The levels were not high at the onset of IIP. Four of 6 IIP patients showed marked elevations of KL-6 levels in parallel with the severity of IP and died of respiratory failure without response to treatment. Assessment of serum KL-6 levels might not be useful for the early diagnosis of IP, but may be a useful indicator for monitoring the severity of IP after BMT.

Effects of sesquiterpenoids from "Oriental incenses" on acetic acid-induced writhing and D2 and 5-HT2A receptors in rat brain.

Six sesquiterpenoids, namely jinkoh-eremol, agarospirol, alpha- and beta-santalols, dehydrocostus lactone and costunolide, isolated from oriental incenses inhibited acetic acid-induced writhing in mice. The incidence of writhing produced by jinkoh-eremol, alpha-santalol and costunolide were revealed by administration of naloxone (mu-, kappa- and delta-antagonists). Inhibitory activities of alpha-santalol on opioid receptors were shown only by the delta antagonist, but not by the mu- and kappa-antagonists. The delta2-antagonist, but not the delta-antagonist, inhibited the activity of alpha santalol. The mechanism of inhibitory activity on the opioid receptor by alpha-santalol was different from that of morphine. Alpha-santalol was shown to be the most potent of the six as an antagonist of dopamine D2 and serotonine 5-HT2A receptor binding. The effect of alpha-santalol, was the same as that of chlorpromazine as an antipsychotic agent, although alpha-santalol was less potent than chlorpromazine.

Successful graft-versus-leukemia effect of second bone marrow transplantation on relapsed leukemia cutis that was refractory to intensive chemotherapy and donor lymphocyte transfusions in a patient with acute monocytic leukemia.

We report a patient with acute monocytic leukemia (AMoL; M5) who received a second bone marrow transplantation (BMT) with graft-versus-leukemia (GVL) effect on relapsed leukemia cutis, which had been refractory to intensive chemotherapy and donor lymphocyte transfusions (DLTs). A 21-year-old woman was diagnosed with AMoL and achieved complete remission after intensive chemotherapy. The patient received a nonmanipulated allogeneic BMT from her HLA-identical father. Skin tumors developed in her upper extremities, chest, and thigh 11 months after BMT. Leukemia cutis was confirmed by skin biopsy. There was no evidence of relapse in bone marrow. The patient received several courses of chemotherapy and DLTs for the skin relapse, but the skin tumors persisted. The patient then received a second BMT from the same donor. On day 80, grade II acute graft-versus-host disease developed, and the remaining skin tumors were eradicated on day 98, most probably because of GVL effect.

Red ginseng ameliorated place navigation deficits in young rats with hippocampal lesions and aged rats.

Effects of hippocampal lesions and aging on spatial learning and memory and ameliorating effects of red ginseng on learning deficits were investigated in the following two experiments: performance of young rats with selective hippocampal lesions with red ginseng by mouth (p.o.; Experiment 1) and aged rats with red ginseng (p.o.; Experiment 2) in the spatial tasks was compared with that of sham-operated or intact young rats. Each rat in these two behavioral experiments was tested with the three types of spatial-learning tasks (distance movement task, DMT; random-reward place search task, RRPST; and place-learning task, PLT) in a circular open field using intracranial self-stimulation as reward. The results in the DMT and RRPST tasks indicated that motivational and motor activity of young rats with hippocampal lesions with and without ginseng were not significantly different from that of sham-operated young rats in Experiment 1. However, young rats with hippocampal lesions displayed significant deficits in the PLT task. Treatment with red ginseng significantly ameliorated place-navigation deficits in young rats with hippocampal lesions on the PLT task. Similarly, red ginseng improved performance of aged rats on the PLT task in Experiment 2. The results, along with previous studies showing significant effects of red ginseng on the central nervous system, suggest that red ginseng ameliorates learning and memory deficits through effects on the central nervous system, partly through effects on the hippocampal formation.

Clinical application of malignancy potential grading as a prognostic factor of human esophageal cancers.

BACKGROUND: Various biologic markers have been reported to be prognostic factors in human esophageal cancers. In the current study, we established a new tumor-grading system representing the malignancy potential of cancer cells and compared it with the clinical-stage system. METHODS: Tumor samples from 77 patients with squamous cell carcinoma of the esophagus were immunohistochemically evaluated for the expression of 10 molecules: the cell cycle-related molecules of cyclin D1, Rb, p16INK4, p27KIP1, and PCNA; the cell-cell adhesion molecules of E-cadherin, alpha-catenin, and beta-catenin; and the heat shock proteins of HSP27 and HSP70. RESULTS: P27KIP1, beta-catenin, and HSP70 were selected for their high hazard ratio in multivariate analysis, and the number of their disordered molecules was used to define the malignancy grade (MG). Five-year survival rates were 83%, 54%, 17%, and 0% for MG1, MG2, MG3, and MG4. The gradation of survival curves was better for MGs than for clinical stages. MGs and clinical stages showed significant correlation; however, 55% of those in higher clinical stages (stage 3 or 4) had lower MG (MG1 or 2) and showed better prognosis than others in their group (stage 3 or 4 and MG3 or 4). The proportions of shorter survival span to cancer death patients (less than 1 year) were 0%, 33%, 75%, and 100% in MG1, 2, 3, and 4, but the clinical stage was not associated with the survival span. CONCLUSIONS: The grading of malignancy potential is clinically useful, especially for selecting patients who may show good prognosis in the advanced clinical stage and for predicting short survival span. These predictions are not possible with the clinical-stage system, which is based on the anatomic spread of cancer cells.

Loss of p27(KIP1) expression predicts poor prognosis in patients with esophageal squamous cell carcinoma.

Immunohistochemical studies of cell cycle-regulating proteins were conducted on tissue samples from 106 patients with esophageal squamous cell carcinoma. Reduction of p27(KIP1) was observed in 41 (39%) cases and was significantly associated with a poor prognosis by univariate and multivariate analyses (p = 0.015). In contrast, p16(INK4) expression was reduced in 55 (52%) of the cases and was not correlated with prognosis. p27(KIP1) was not correlated with the PCNA index, while p16(INK4) expression was inversely correlated with the PCNA index (p = 0.01). The expression of these two proteins was not correlated with the clinicopathological parameters of the patients. Nodal status was shown by univariate analysis (p = 0.01) to be a prognostic factor, and poorly differentiated tumors were significantly associated with a poor prognosis by multivariate analysis (p = 0.027). Thus, reduction of p27(KIP1) plays an important role in the progression of esophageal squamous cell carcinomas and is considered to be an independent prognostic indicator of this disease.