Estimating the Net Utility Gains Among Donors and Recipients of Adult Living Donor Kidney Transplant.

OBJECTIVES: Living donor kidney transplant relieves the disease burden of patients with end-stage renal disease but may shorten donor life expectancy; however, their quality of life (QOL) is preserved. Nevertheless, the magnitude of the net gain of this procedure is unknown. We evaluated the QOL of both donors and recipients concurrently and calculated the net utility gain. METHODS: We recruited 210 subjects who visited the kidney transplantation clinic of a university hospital. Subjects were asked to complete the 5-level EQ-5D-based questionnaire, and patient characteristics were extracted from their medical records. We performed multivariate tobit models analysis to evaluate the QOL change caused by transplant surgery and subsequently ran computational simulations to determine the net utility gains of donors and recipients. We also performed sensitivity analyses. RESULTS: After excluding 16 answers with missing data, we analyzed 203 answers in total. After the transplant surgery, recipients gained 0.07 in utility value while donors lost 0.04. In the net utility analysis, we found that the quality-adjusted life years gained ranged from 7.2 to 7.8 in the most favorable case observed in the combination of middle-aged recipients and elderly donors. Assuming no utility discount, the most favorable combination was that with older donors and younger recipients. CONCLUSIONS: These findings indicated that the QOL improvement in recipients was larger than the loss among donors. When calculating the net utilities, a combination of middle-aged recipients and elderly donors yielded the largest net utility, but this was likely derived from assumption in the discount of QOL.

Recurrent Aphthous Stomatitis Caused by Cytomegalovirus, Herpes Simplex Virus, and Candida Species in a Kidney Transplant Recipient: A Case Report.

Recipients of organ transplants are immunosuppressed and at high risk of oral infection. Oral diseases are often neglected compared with infections of other organs that typically confer higher morbidity. However, severe local symptoms hinder oral intake, decrease quality of life, and are sometimes lethal. Here we describe a case of a 57-year-old woman who developed recurrent aphthous stomatitis after kidney transplantation; the cause of the infection was complex and included cytomegalovirus, herpes simplex virus, and Candida species. Since misdiagnosis of oral diseases impairs patient quality of life and increases morbidity, clinicians should be aware of possible etiologies of oral infections in renal transplant recipients.

El cabello, fuente de información del estado de salud / The hair, source of health information

El cabello y especialmente el localizado en la cabeza provee importante información sobre posibles exposiciones ambientales y/o laborales a diferentes elementos. El pelo puede ser considerado como un producto excretor, y su estudio reflejaría el metabolismo de minerales en el cuerpo. Nuestro propósito en el presente estudio es conocer si datos existentes dan información poblacional sobre la presencia de elementos tóxicos o no a través del análisis del cabello humano. RESULTADOS: Fue analizada la información proveniente de 241 muestras de cabello, de los cuales 163 (67,6%) corresponden al sexo femenino y 78 (32,4%) al masculino. Fueron analizados 22 elementos esenciales y 17 elementos de tóxicos. Entre los elementos esenciales presentaron resultados elevados Calcio (Ca), Magnesio (Mg), Manganeso (Mn), Molibdeno (Mo), Vanadio (V), Estroncio (Sr) y Circonio (Zr); entre los elementos tóxicos tuvieron valores elevados Aluminio (Al), Arsénico (As), Bario (Ba), Bismuto (Bi), Cadmio (Cd), Níquel (Ni), Plomo (Pb), Mercurio (Mg), Plata (Ag), Estaño (Sn). CONCLUSIÓN. Nuestro estudio muestra a nivel poblacional, no individual, puntos de alerta por la carencia o exceso de algunos elementos analizados debiéndose continuar con estudios locales interdisciplinarios en los cuales exista información sobre enfermedades, hábitos alimentarios, hábitos tóxicos, actividad laboral y exposición ambiental a los diferentes elementos. (AU)

Hair, especially localized in the head, provides important information on possible environmental and/or labor exposures to different elements. Hair can be considered as an excretory product, and its study would reflect the metabolism of minerals in the body. Our purpose in this study was to determine whether existing population data provide information on the presence of toxic and non-toxic elements by analizing human hair. RESULTS: We analyzed information from 241 hair samples, of which 163 (67.6%) are from females and 78 (32.4%) are from males. There were analyzed 22 essential elements and 17 toxic elements. Among the essential elements that had elevated results there were: Calcium (CA), magnesium (Mg), manganese (Mn), molybdenum (Mo), vanadium (V), strontium (Sr) and zirconium (Zr); among the toxic elements, those with higher values were: Aluminum (Al), arsenic (As), barium (BA), bismuth (Bi), Cadmium (Cd), Nickel (Ni), lead (Pb), Mercury (Mg), silver (Ag), tin (Sn). CONCLUSION. Our study shows at population level, not individual, warning points due to the lack or excess of some elements analyzed. It is reccommended to continue the research with local interdisciplinary studies which include information on diseases, eating habits, toxic habits, work activity and environmental exposure to different elements. (AU)

Downregulation of Ral GTPase-activating protein promotes tumor invasion and metastasis of bladder cancer.

The small GTPase Ral is known to be highly activated in several human cancers, such as bladder, colon and pancreas cancers. It is reported that activated Ral is involved in cell proliferation, migration and metastasis of bladder cancer. This protein is activated by Ral guanine nucleotide exchange factors (RalGEFs) and inactivated by Ral GTPase-activating proteins (RalGAPs), the latter of which consist of heterodimers containing a catalytic α1 or α2 subunit and a common ß subunit. In Ras-driven cancers, such as pancreas and colon cancers, constitutively active Ras mutant activates Ral through interaction with RalGEFs, which contain the Ras association domain. However, little is known with regard to the mechanism that governs aberrant activation of Ral in bladder cancer, in which Ras mutations are relatively infrequent. Here, we show that Ral was highly activated in invasive bladder cancer cells due to reduced expression of RalGAPα2, the dominant catalytic subunit in bladder, rather than increased expression of RalGEFs. Exogenous expression of wild-type RalGAPα2 in KU7 bladder cancer cells with invasive phenotype, but not mutant RalGAPα2-N1742K lacking RalGAP activity, resulted in attenuated cell migration in vitro and lung metastasis in vivo. Furthermore, genetic ablation of Ralgapa2 promoted tumor invasion in a chemically-induced murine bladder cancer model. Importantly, immunohistochemical analysis of human bladder cancer specimens revealed that lower expression of RalGAPα2 was associated with advanced clinical stage and poor survival of patients. Collectively, these results are highly indicative that attenuated expression of RalGAPα2 leads to disease progression of bladder cancer through enhancement of Ral activity.

JunB promotes cell invasion and angiogenesis in VHL-defective renal cell carcinoma.

Inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene causes both hereditary and sporadic clear-cell renal-cell carcinoma (ccRCC). Although the best-characterized function of the VHL protein (pVHL) is regulation of hypoxia-inducible factor-α (HIFα), pVHL also controls the development of pheochromocytoma through HIF-independent pathways by regulating JunB. However, it is largely unknown how these pathways contribute to the development and progression of ccRCC. In the present study, we confirmed that JunB was upregulated in VHL-defective ccRCC specimens by immunostaining. Short-hairpin RNA (shRNA)-mediated knockdown of JunB in 786-O and A498 VHL null ccRCC cells suppressed their invasiveness. In addition, JunB knockdown significantly repressed tumor growth and microvessel density in xenograft tumor assays. Conversely, forced expression of wild-type, but not dimerization-defective, JunB in a VHL-restored 786-O subclone promoted invasion in vitro and tumor growth and vessel formation in vivo. Quantitative PCR array analysis revealed that JunB regulated multiple genes relating to tumor invasion and angiogenesis such as matrix metalloproteinase-2 (MMP-2), MMP-9 and chemokine (C-C motif) ligand-2 (CCL2) in 786-O cells. JunB knockdown in these cells reduced the proteolytic activity of both MMPs in gelatin zymography and the amount of CCL2 in the culture supernatant. Moreover, shRNA-mediated knockdown of MMP-2 or inhibition of CCL2 activity with a neutralizing antibody repressed xenograft tumor growth and angiogenesis. Collectively, these results suggest that JunB promotes tumor invasiveness and enhances angiogenesis in VHL-defective ccRCCs.

Efficacy of interferon Beta combined with cyclosporine induction and intensified therapy for retreatment of chronic hepatitis C.

OBJECTIVE: Hepatitis C virus (HCV) infection is a major burden after liver transplantation. There is no effective treatment for these patients, therefore management is challenging. Cyclophilins are essential host factors for HCV replication. We have reported herein the efficacy of divided administration of interferon (IFN) beta plus cyclosporine for chronic hepatitis C patients who failed pegylated (Peg)-IFN or IFN combined ribavirin treatment. PATIENTS AND METHODS: We prospectively enrolled 59 patients (median age, 63 years) with genotype 1b who failed to respond to the combinations of IFN plus ribavirin or Peg-IFN plus ribavirin. Our treatment involved induction, intensified, and maintenance therapies. The induction therapy prescribed intravenous 1 MU IFN beta every 4 hours for the first 3 days, 1.5 MU IFN beta every 6 hours for the next 4 days, and then 2 MU IFN beta every 8 hours for 3 weeks. The intensified therapy was the induction therapy shortened to 2 weeks. The maintenance therapy involved Peg-IFN alpha 2b and ribavirin. Cyclosporine was given 4 times daily during the induction and intensified therapies. Ribavirin was given twice daily during the maintenance phase. RESULTS: The end treatment and sustained virological response rates in the present study were 73% (43/59) and 59% (35/59), respectively. The relapse rate was 19% (8/43). Sixteen percent of patients (3/19) were nonresponders. All adverse effects were reversible. The treatment protocol was well tolerated. CONCLUSION: Our protocol should be effective for patients who have failed previous combination therapies.

Voided stain on paper method for analysis of mouse urination.

AIMS: To evaluate the usefulness of a quantification method using filter paper for analyzing minute voided urine of the mouse. METHODS: Voided stain on paper (VSOP) method; the correlation between area of stained spot on a filter paper and amount of applied liquid was calculated. Voiding behavior of the mice was analyzed by placing the animal above the same filter paper and recording voided time and area over 2 hr. The usefulness of the VSOP method was tested in analysis of the voiding behavior of five female 7-week-old ddY mice treated with cyclophosphamide (CPM, 150 mg/kg, intraperitoneally) and five control ones, in comparison with the histology of CPM-induced cystitis. Further, the voided volume of male and female ddY mouse ranging from 2 to 13 weeks was assessed. RESULTS: There was a linear correlation between liquid volume and stained area on the filter paper (y = 16.472x - 22.411, R(2) = 0.9981). Between control mice and those with histologically proven CPM cystitis, there was a significant difference in voided volume (362.7 +/- 51.9 and 127.8 +/- 100.0 microl, < 0.001) and voiding interval (10.30 +/- 3.10 and 4.47 +/- 1.70 min, < 0.001). Voided volume of ddY mice was quantifiable from as early as 2-week old, increased along with their growth and correlated well with their body weight [(voided volume: microl) = 10.8 x (body weight: g) + 32, R(2) = 0.762]. CONCLUSIONS: The VSOP method is a useful tool for evaluating voiding behavior of the mouse, including those with small bladder capacity.

Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3beta with p53.

To improve conventional chemotherapeutic efficacy, a combination use of traditional medicines is effective but detailed mechanisms have been rarely elucidated. In the this study, we attempted to clarify how triptolide (PG490), an oxygenated diterpene derived from a Chinese herb, enhances the cisplatin (CDDP)-induced cytotoxicity in urothelial cancer cells. Our results showed that a combined CDDP/triptolide therapy induced apoptosis in urothelial cancer cell lines with wild-type p53, but not in those with mutant-type p53 or normal human urothelium. As the mechanism, triptolide suppressed CDDP-induced p53 transcriptional activity, leading to p21 attenuation, which promoted apoptosis via the activation of c-Jun N-terminal kinase (JNK) and Bax. We further demonstrated that the functional regulation of p53 by triptolide was mediated by an intranuclear association of p53 with glycogen synthase kinase-3beta (GSK3beta), which was inactivated by protein kinase C (PKC). This modulation of the PKC-GSK3beta axis by triptolide was observed in a cancer-specific manner. A mouse xenograft model also showed that a combined CDDP/triptolide therapy completely suppressed tumor growth without any side effects. We expect that cancer-specific enhancement of CDDP-induced cytotoxicity with triptolide may effectively overcome the resistance to a CDDP-based conventional chemotherapy as a treatment for urothelial cancer.

Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation.

The purpose of this study was to investigate the accumulation of genetic alterations during metachronous and/or synchronous development of multifocal low-grade superficial urothelial tumours in the same patient, by using array-based comparative genomic hybridisation (array-CGH) and FGFR mutation analysis. We analysed 24 tumours (pTa-1 G1-2) from five patients. We had previously identified a clonal relationship among the tumours of each patient by microsatellite analysis. This time, unsupervised hierarchical cluster analysis revealed that the tumours from each patient were clustered together independently of the tumours from the other patients. All of the tumours from a single patient showed a set of 2-7 identical regional or whole-arm chromosomal changes. In addition, several individual alterations were also found. Cladistic diagrams revealed that the accumulation of genetic alterations could not be explained by a linear model, and the existence of a hypothetical precursor cell was assumed in four patients. In some cases, FGFR mutation seemed to occur later during multifocal tumour development. Taken together, these findings suggest that low-grade superficial urothelial tumours accumulate minor genetic alterations during multifocal development, although these tumours are genetically stable.

Health-related quality-of-life after external beam radiation therapy for localized prostate cancer: intensity-modulated radiation therapy versus conformal radiation therapy.

We compared health-related quality-of-life (HRQL) after intensity-modulated radiotherapy (IMRT) with statuses obtained after old and new protocols of three-dimensional conformal radiation therapy (3DCRT) for localized prostate cancer. We measured the general and disease specific HRQL using the MOS 36-Item Health Survey (SF-36), and the University of California, Los Angeles Prostate Cancer Index (UCLA PCI), respectively. IMRT resulted in similar profiles of general and disease-specific HRQL to two other methods within the first year after treatment. Moreover, IMRT gave rise to comparable urinary, intestinal and sexual side effects despite the high dose of radiation applied.

Genotyping of congenital adrenal hyperplasia due to 21-hydroxylase deficiency presenting as male infertility: case report and literature review.

We describe here two infertile male patients who were referred to our hospital with azoospermia at the ages of 33 and 30 years, respectively. Hormonal examinations led to a diagnosis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency in both patients. Genotyping revealed that the patients had a homozygous I172N and a heterozygous compound I172N/IVS2-13A/C>G mutation, respectively. Glucocorticoid replacement therapy succeeded in improving the seminal status of one patient, but not the other. For the latter patient and his wife, a pregnancy was achieved by testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) following genetic counseling. It is important to investigate genotyping and to classify patients on the basis of genotypic information in order to arrive at better treatment strategies for male infertility; especially in counseling of TESE-ICSI.

Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild-type urogenital cancer cell lines.

3-3'-Methylene-bis [4-hydroxycoumarin] (dicoumarol), an inhibitor of NADPH:quinone oxidoreductase 1, has been reported to possess potential antineoplastic effects and the ability to abrogate p53 protein. In the present study, we investigated the cytotoxic effects of dicoumarol in combination with cisplatin (CDDP), using four bladder (RT112, 253J, J82 and UMUC3) and two prostate (LNCap and PC3) cancer cell lines. Single treatment with 100 microM dicoumarol suppressed cell proliferation but did not induce apoptosis at 24 h in all cell lines examined. On the other hand, pretreatment with dicoumarol enhanced cytotoxicity of CDDP in three cell lines with wild type of p53 (RT112, 253J and LNCap), but not in three other cell lines with mutant p53 or in RT112 stable transfectants with a dominant-negative mutant of p53. In RT112 and LNCap, CDDP induced p53 and p21 expression, while pretreatment of dicoumarol suppressed induction of p53/p21 and resulted in sequential activation of c-Jun N-terminal kinase (JNK) in a time-dependent manner. Furthermore, inhibition of JNK, using SP600125, completely suppressed activity of caspases and poly-(ADP-ribose) polymerase cleavage, leading to suppression of enhancement of CDDP-mediated apoptosis by dicoumarol. These results suggested that dicoumarol could enhance cytotoxicity of CDDP in urogenital cancer cells with wild-type p53 through the p53/p21/JNK pathways.

Perioperative antimicrobial prophylaxis in urology: a multi-center prospective study.

Since there are few published reports regarding the impact of urologic surgery on perioperative infections, an epidemiologic analysis was performed on data from 1,156 open or laparoscopic operations in urology collected by the 21 hospitals participating in this study between September 2002 and August 2003. Prophylactic antibiotics were administered intravenously according to our protocol designed on the basis of the invasiveness and contamination levels. The surgical site infection (SSI) rates following clean, clean-contaminated and contaminated surgery were 1.2%. 5.8% and 23.4%, respectively, while the remote infection (RI) rates were 3.5%. 7.1% and 35.9%, respectively. Methicillin-resistant Staphylococcus aureus (MRSA) was most frequently isolated from SSIs as well as RIs, whereas Enterococcus faecalis and Pseudomonas aeruginosa were more frequently discovered in RIs than in SSIs. Several risk factors for SSI and/or RI, such as older age, high ASA score, obesity, diabetes, preoperative chemotherapy, long operation time and much blood loss, were identified by univariate analysis.

Enhancement of arsenic trioxide-induced apoptosis in renal cell carcinoma cells by L-buthionine sulfoximine.

Arsenic trioxide (As2O3) induces clinical remission in acute promyelocytic leukemic patients and apoptosis in various tumor cells in vitro. To develop As2O3-based combination chemotherapy for renal cell carcinoma (RCC), we investigated the cytotoxic effects of As2O3 in combination with chemotherapeutic agents or L-buthionine sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor. Cytotoxicity and synergy were assessed by the MTT assay and isobolographic analysis, respectively. Apoptosis was monitored by Hoechst 33342 staining, flow cytometrical analysis, and DNA fragmentation assay. Treatment of ACHN cells with As2O3 in combination with adriamycin, vinblastine, or 5-fluorouracil induced an antagonistic effect. However, combination treatment with As2O3 and BSO resulted in a synergistic cytotoxic effect. Synergy was also obtained in Caki-1, Caki-2, NC65 cells and freshly derived RCC cells from 6 patients. Simultaneous treatment of ACHN cells with As2O3 and BSO caused significantly more cytotoxicity than the As2O3 first BSO second or the reverse treatment. We further explored the mechanisms underlying this synergistic effect and found that the synergistic cytotoxicity of As2O3 and BSO was realized by inducing apoptosis. This combination markedly decreased intracellular GSH content and GSH-S-transferase (GST) activity. However, neither the intracellular GSH nor GST was decreased by As2O3 with adriamycin, vinblastine, or 5-fluorouracil. Furthermore, the GSH-increasing agents N-acetylcysteine and lipoic acid significantly inhibited the combined cytotoxicity of As2O3 and BSO. These findings indicate that BSO sensitizes RCC cells to As2O3-induced apoptosis through the down-regulation of the intracellular GSH redox system, suggesting the potential application of a combination of As2O3 and BSO for the treatment of RCC.

Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine.

Clinical application of anticancer agents has been often hampered by toxicity against normal cells, so the achievement of their cancer-specific action is still one of the major challenges to be addressed. Previously, we reported that arsenic trioxide (As2O3) could be a promising new drug against not only leukemia but also solid tumors. The cytotoxicity of As2O3 occurred through the generation of reactive oxygen species (ROS), thus inhibiting radical scavenging systems would enhance the therapeutic efficacy of As2O3 provided that normal cells were relatively resistant to such a measure. Here, we report that the combination therapy of As2O3 with L-buthionine-sulfoximine (BSO), which inhibits a critical step in glutathione synthesis, effectively enhanced in vitro growth inhibition effect of As2O3 on all 11 investigated cell lines arising from prostate, breast, lung, colon, cervix, bladder, and kidney cancers, compared with As2O3 treatment alone. Furthermore, this combination enhanced cytotoxicity to cell lines from prostate cancer with less toxicity to those from normal prostate. In vitro cytotoxic assay using ROS-related compounds demonstrated that hydrogen peroxide (H2O2) is a major cytotoxic mediator among ROS molecules. Biochemical analysis showed that combined use of As2O3 and BSO blocked H2O2-scavenging systems including glutathione, catalase, and glutathione peroxidase, and that the degree of this blockade was well correlated with intracellular ROS levels and sensitivity to this treatment. Finally, the effectiveness of the combination therapy of As2O3 with BSO was demonstrated with an orthotopic model of prostate cancer metastasis. We propose that the combination therapy of As2O3 with BSO is a valid means of blockade of H2O2-scavenging system, and that the combination of a ROS-generating agent with an inhibitor of major scavenging systems is effective in terms of both efficacy and selectivity. Furthermore, because the effective doses of both compounds are within clinically achievable range, this report will lead to immediate benefit for the development of a new cancer therapy.

Longitudinal follow-up study of adenoviral vector-mediated gene transfer of dopamine D2 receptors in the striatum in young, middle-aged, and aged rats: a positron emission tomography study.

Overexpression of dopamine D(2) receptors by adenoviral vector-mediated gene transfer in the rat striatum was evaluated by positron emission tomography in vivo and by ex vivo autoradiography in 5-, 13-, and 24-month-old Fischer 344 rats. Each rat had hemilateral gene transfer of D(2) receptors mediated by adenoviral vectors (AdCMV.DopD(2)R) in the striatum with contralateral striatal injection of control vectors (AdCMV.LacZ). At day 2 or 3 after vector injection positron emission tomography or ex vivo autoradiography was performed. The binding potential of a radiolabeled D(2) receptors ligand, [11C]raclopride, was significantly higher in the D(2) receptors gene-transferred striatum than the control side in each age group at a similar degree. The binding potential in the AdCMV.DopD(2)R-injected striatum of 24-month-old rats was similar to that in the AdCMV.LacZ-injected striatum of 5-month-old rats (0.99+/-0.14 versus 0.91+/-0.08). A significant age-associated decrease of the binding potential of [11C]raclopride was found in the control vector-injected side, and a significant increase of the binding potential in the adenoviral vector-injected side in all three age groups, suggesting no aging effect on the overexpression of D(2) receptors. A group of rats underwent follow-up assessment by positron emission tomography. The overexpression of D(2) receptors decreased with time in all three groups; however, the decrease rate of the D(2) receptors expression was significantly smaller in the 24-month-old group than in the 5-month-old group. We confirmed that the adenoviral vector-mediated gene transfer of D(2) receptors compensated the decreased density of striatal D(2) receptors in the 24-month-old rats up to the level in the control striatum of 5-month-old rats, and the decrease rate of the overexpression was significantly smaller in aged rats.