Efficacy of multidrug therapy combined with mizoribine in children with diffuse IgA nephropathy in comparison with multidrug therapy without mizoribine and with methylprednisolone pulse therapy

AIM: To evaluate the efficacy of prednisolone, warfarin, and dipyridamole therapy combined with mizoribine (PWDM) in the treatment of diffuse immunoglobulin A (IgA) nephropathy in comparison with prednisolone, warfarin, and dipyridamole therapy without mizoribine (PWD) and with methylprednisolone pulse therapy (PWD pulse). METHODS: We collected data on 61 patients diagnosed with diffuse IgA nephropathy, and these patients were retrospectively divided into three groups without randomization. Group A included 21 patients before 1987 who were treated with PWD for 24 months, group B included 20 patients from 1987 to 1989 who were treated with PWD pulse therapy for 24 months, and group C included 20 patients after 1990 who were treated with PWDM for 24 months. Clinical features and pathological findings in each group were analyzed retrospectively. RESULTS: The time from initiation of therapy in group A, group B, and group C was 8.9 +/- 5.2, 8.1 +/- 3.9, and 7.7 +/- 3.8 years, respectively. At the latest follow-up examination, the mean urinary protein excretion (mg/m2/h) was 17 +/- 10 in group A, 22 +/- 20 in group B, and 6 +/- 6 in group C and had decreased significantly in group C as compared with the other groups. The activity index in all three groups was lower at the second biopsy than that at the first biopsy (5.1 +/- 0.8 vs. 6.5 +/- 2.1 in group A, p < 0.05; 5.6 +/- 0.9 vs. 6.6 +/- 1.7 in group B, p < 0.01, and 4.5 +/- 1.0 vs. 6.8 +/- 1.9 in group C, p < 0.01). The chronicity index in groups A and B at second biopsy was higher than at first biopsy (7.3 +/- 1.4 vs. 4.8 +/- 1.0 in group A, p < 0.01, and 8.1 +/- 2.0 vs. 5.3 +/- 0.9 in group B, p < 0.01), but was unchanged in group C. At the latest follow-up examination, 1 patient (4.8%) in group A, 3 patients (15%) in group B, and none (0%) in group C had renal insufficiency. CONCLUSION: These results suggest that PWDM appears to be more effective than PWD or PWD pulse in ameliorating proteinuria and histological severity of patients with IgA nephropathy.     

Stage-dependent effect of pancreatic transplantation on diabetic ocular complications in the Spontaneously Diabetic Torii rat

BACKGROUND: In terms of the temporal relationship between pancreas transplantation (PTx) and reversal of diabetic ocular complications, it has been difficult but important to determine a "point of no return." Thus, it is of great clinical interest to evaluate the efficacy of PTx on diabetic ocular complications. METHODS: A spontaneous type 2 diabetic model of Spontaneously Diabetic Torii (SDT; RT1) rats was used in the present study, and syngeneic PTx was performed. RESULTS: In the control SDT rats that received no treatment, hyperglycemia (>250 mg/dL) was developed from 25.2+/-3.9 weeks of age. Lens opacity was observed in all rats at 15 weeks after the onset of diabetes. Fluorescein angiography and immunohistochemistry detected the nonperfusion area and neovascularization in the retina at 5 weeks of diabetes. Daily insulin treatment could not prevent or reverse the ocular changes in our experiment. Fluorescein filling defect of the retinal vessels was observed at 10 weeks of diabetes. However, in the PTx rats, normoglycemia was achieved at all experimental time points. Diabetic cataract and retinopathy could have been prevented and improved if PTx had been performed at 5 weeks, but not at 10 weeks after the onset of diabetes. With PTx treatment, an inhibition of angiogenesis in the retina at 5 weeks after the onset of diabetes was demonstrated by immunohistochemistry. CONCLUSIONS: Our results indicate that the potential use of the SDT rat for diabetes study and the positive effect of PTx performed before the "point of no return" could prevent and cure diabetic ocular complications.     

Survey of types of repercussions as a result of performance evaluation in hospital nursing

This article is part of a study about performance evaluation in nursing and aims to identify and describe the measures adopted on the basis of the nursing staff performance evaluation that was carried out at municipal district hospitals in the Paraiba Valley Region - S?o Paulo, Brazil. Data were collected by means of a questionnaire, which was applied among the nurses in charge of the Nursing or Continuous Education Services. The obtained data allowed us to verify that, although 66.7% of the hospitals do not have a Continuous Education Service, 80.9% carry out performance evaluation and indicate the adoption of several measures according to the observed results. Educational measures prevailed, such as: orientation (97.0%), training (79.4%), updating/recycling (70.6%) and discussion of the result with the employee (88.2%). It was also verified that, in a significant percentage of the hospitals, the performance evaluation results do not only offer support for promotions (20.6%) and several incentives (58.8%), but also for employees' dismissal (58.8%).     

Human CYP4B1 gene in the japanese population analyzed by denaturing HPLC

Human CYP4B1 is a CYP4 enzyme with activity towards xenobiotics. Five alleles of human CYP4B1 have been identified in French Caucasians, but allelic variants of enzyme have not been determined in the Japanese population. To establish a rapid and sensitive means of detecting variant CYP4B1 alleles, we analyzed those of 192 Japanese individuals using denaturing HPLC (DHPLC). We then determined the optimal conditions required to detect SNPs for each PCR fragment. Analysis by DHPLC revealed the novel alleles, CYP4B1(*)6 (517C>T and 1033G>A) and CYP4B1(*)7 (AT881-882-del, 993G>A, and 1018C>T), as well as 3 known alleles. The frequencies of the CYP4B1(*)1, (*)2, (*)3, (*)4, (*)5, (*)6, and (*)7 alleles in 192 Japanese individuals were 0.490, 0.328, 0.154, 0, 0.016, 0.008, and 0.005, respectively. The allele frequencies among Japanese relative to those in French Caucasians for CYP4B1(*)1 (0.490 vs. 0.724) and CYP4B1(*)2 (0.328 vs. 0.147) significantly differed. Our results suggest that high throughput DHPLC can rapidly detect pharmacologically important variants in CYP genes.     

Radiofrequency ablation combined with transcatheter arterial chemoembolization for hepatocellular carcinoma--CT examination during the follow-up period

Radiofrequency ablation (RFA) combined with transcatheter arterial embolization (TAE) can increase the volume of coagulation necrosis to treat patients with hepatocellular carcinoma. Furthermore, in clinical practice, RFA combined with TAE using iodized oil and gelatin sponge often induced the sub-segmental or segmental necrosis toward the liver periphery of the ablated lesion. In this study, we compared the CT findings and histological characteristics of peripherally spreading necrosis induced by this combination therapy for 12 patients with hepatocellular carcinoma. In all cases, complete necrosis of ablated lesions and peripherally spreading necrotic areas were confirmed by CT examination. The histochemical (lactate-dehydrogenase, maleate-dehydrogenase, and NADPH-diaphorase) stained specimens, biopsies from ablated lesions and peripherally spreading necrotic areas, were absent suggesting a 100% cellular destruction. No incomplete local treatments after the therapy were obtained during the 4-26 months of follow-up periods. We conclude that RFA combined with TAE using iodized oil and gelatin sponge makes it possible to induce the segmental or sub-segmental necrosis including tumors.     

Oncolytic viral therapy for human ovarian cancer using a novel replication-competent herpes simplex virus type I mutant in a mouse model

OBJECTIVE: Attenuated mutant strains of herpes simplex virus (HSV) have been effectively used for treatment of malignant brain tumors. As HSV-1 can infect and lyse a variety of cell types, other malignancies may also benefit from such treatment. We sought to test the feasibility of HSV-1 mutant-mediated gene therapy treatment of ovarian cancer. METHODS: We prepared two attenuated mutant HSV-1 strains. An HSV-1 mutant, hrR3, has replaced the gene encoding ribonucleotide reductase (RR) with the lacZ reporter gene. We also developed a new replication-competent HSV-1 mutant, HR522; this virus, expressing the lacZ reporter gene, induces syncytium formation in infected cells. We compared the efficacy of HR522 with, paclitaxel (Taxol) and hrR3 in the treatment of nude mice harboring human ovarian cancer cells. We also examined the effect of the prodrug ganciclovir (GCV) on the treatment mediated by these HSVs. Survival was evaluated by Kaplan-Meier method and log-rank test. RESULTS: The survival of mice treated with a high-titer hrR3 (5 x 10(7) plaque-forming units [PFU]) was significantly prolonged as compared with the group given paclitaxel (P < 0.0001, log-rank test). Although the survival of mice treated with high-titer HR522 (5 x 10(7) PFU) was not significantly prolonged compared with paclitaxel-treated group (P = 0.212, log-rank test), GCV markedly enhanced the efficacy of HR522 administration (P < 0.005, vs paclitaxel, log-rank test). The lacZ gene product, visualized using 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal) histochemistry, was detected in HR522-treated tumors in areas also exhibiting apoptotic changes. CONCLUSIONS: These findings indicate that the combination of HR522 and GCV possesses significant therapeutic potential for treatment of ovarian cancer. Such viral therapy offers a novel approach to reductions in the dissemination of ovarian cancer.     

No clinical correlation between bilirubin levels and severity of retinopathy of prematurity

PURPOSE: To evaluate the hypothesis that bilirubin has a protective effect against the development of severe retinopathy of prematurity (ROP). METHODS: An assessment of 76 infants born at 24 and 25 weeks' gestation and admitted to the level III neonatal intensive care unit at Saitama Children's Medical Center was made. Indirect ophthalmoscopy fundus examinations were performed on all infants to identify the degree and progression to threshold ROP. We analyzed the daily bilirubin levels and grouped the patients according to the severity of ROP based on the infant's worst ROP examination. The first group was comprised of infants with less than stage 3 ROP and infants with stage 3 ROP. The second group was infants with less than prethreshold ROP or prethreshold ROP, and infants with threshold ROP. Next, we divided the infants into 3 groups: less than prethreshold ROP, prethreshold ROP, and threshold ROP. The daily changes in serum bilirubin concentrations during the first 14 days of life were determined for each infant. Three groups (less than prethreshold ROP, prethreshold ROP, and threshold ROP) were comparable as to their basic data, clinical characteristics, and treatments. RESULTS: ROP was found in 76 infants. There were no statistical differences in the clinical characteristics and treatments, excluding the duration of phototherapy, among the 3 groups. During the first 14 days of age, there were no significant differences in the daily mean bilirubin concentrations according to the groups separated by severity of ROP. CONCLUSION: These results indicate that there is no distinct protective effect of bilirubin on the development of severe ROP.     

The restriction of all minerals in the diet enhancing paraquat toxicity is regarded primarily as the shortage of Mg

This study compares the effect of the restriction of Mg with that of all-minerals in the diet on the toxicity of paraquat. To compare the severity of the toxicity, several biological values were examined; kininogen in plasma, thiobarbituric acid reactive substances in liver, Ca level in kidney, and Mg levels in liver and kidney. Osteogenic disorder Shionogi rats that cannot synthesize vitamin C like humans did not display paraquat symptoms after receiving minute amounts of paraquat dichloride, i.e. 125 ppm in the diet for 8 days, and those biological values remained the same as those of the control. Rats fed with Mg at half of the recommended amounts also did not show any changes in those levels. The dosage of 125 ppm paraquat under the restriction of Mg, however, induced paraquat intoxication and increased those levels greatly. This result arises a question whether the intoxication is due to the imbalance of Ca and Mg or due to the shortage of Mg itself, because imbalance of Ca and Mg sometimes induces more serious effects than the shortage of Mg itself. Therefore, we fed rats an all-mineral restricted diet where the balance of Ca and Mg was maintained. The dosage of paraquat under all-mineral restriction, however, induced much more serious intoxication than that under Mg restriction. In conclusion, the shortage of Mg itself seems to be responsible for the induction of paraquat intoxication.     

Biliary bile acid concentration is a simple and reliable indicator for liver function after hepatobiliary resection for biliary cancer

BACKGROUND: The functional recovery of the remnant liver after an extended hepatectomy is critical for the outcome of the patient. The aim of this prospective study was to examine whether biliary bile acids could be an indicator for postoperative liver function. METHODS: Externally drained bile samples were obtained from 51 patients with biliary or periampullary carcinomas before and after surgery. Patients were categorized into 3 groups: group A, 29 hepatectomized patients without liver failure; group B, 7 hepatectomized patients with liver failure (maximum serum bilirubin level, >10 mg/dL); and group C, 15 patients who underwent biliopancreatic resection without hepatectomy, with a good postoperative course. Bile samples were withdrawn 1 day before surgery and on postoperative days 1, 2, 3, 4, 6, and 7. Total bile acids were measured with a 3 alpha-hydroxysteroid dehydrogenase method. RESULTS: Before surgery, the concentration of bile acids was higher in groups A and C than in group B, and correlated significantly with the indocyamine green disappearance rate (KICG) values (R(2) = 0.557; P <.0001). After surgery, bile acid concentrations decreased in all 3 groups until postoperative day 2, which was followed by a gradual increase. The concentration recovered to the preoperative level in groups A and C but remained low in group B. Biliary bile acid concentrations on day 2 correlated significantly with remnant liver KICG values (R(2) = 0.257; P =.0019). Among several parameters studied, including KICG, remnant liver KICG, biliary bile acids, and biliary bilirubin, biliary bile acid concentration had the most predictive power for occurrence of postoperative liver failure. CONCLUSION: Biliary bile acid concentration could be a simple, real-time, reliable indicator of preoperative and postoperative liver function.     

Activation of beta-catenin in prostate epithelium induces hyperplasias and squamous transdifferentiation

The Wnt/beta-catenin signaling pathway is critical for normal mammalian development, the specification of epidermal cells and neoplastic transformation of intestinal epithelium. However, precise molecular information regarding cell-specific responses to beta-catenin signaling has been limited. This question was addressed using a mouse model in which exon 3 of the beta-catenin gene was deleted in several cell types with loxP-mediated recombination utilizing a Cre transgene under control of the mouse mammary tumor virus-long terminal repeat (MMTV-LTR). The stabilization of beta-catenin in prostate epithelium resulted in hyperplasias and extensive transdifferentiation into epidermal-like structures, which expressed keratins 1 and 6, filaggrin, loricrin and involucrin. The cell-specific loss of NKCC1 protein and reduced nuclear Stat5a is further suggestive of a loss of prostate epithelial characteristics. In addition to the prostate, hyperplasias and squamous metaplasias were detected in epithelia of the epididymis, vas deferens, coagulating gland, preputial gland and salivary gland. However, and in contrast to a recent study, no lesions reminiscent of high-grade prostate intraepithelial neoplasia were detected. Since beta-catenin was activated in several cell types and impinged upon the viability of these mice, it was not possible to evaluate the cumulative effect over more than 3 months. To assess long-term consequences of beta-catenin activation, mutant and control prostate tissues were transplanted into the mammary fat pads of wild-type males. Notably, squamous metaplasias, intra-acinous hyperplasia and possible neoplastic transformation were observed after a total of 18 weeks of beta-catenin stimulation. This suggests that the transdifferentiation into squamous metaplasias is an early response of endoderm-derived cells to beta-catenin, and that the development of intra-acinous hyperplasias or neoplastic foci is a later event.