Ionized acrylamide-based copolymer / terpolymer hydrogels for recovery of positive and negative heavy metal ions.

In this study, we explored the effective capture of both cations and anions onto a single adsorbent. Acrylamide (AAm) served as the polymer backbone, onto which co-monomers sodium p-styrenesulfonate (SS) and N,N-dimethylaminopropyl acrylamide (DMAPAA) were grafted, creating ionized polymer hydrogel adsorbents. These adsorbents were engineered for the synergistic separation and recovery of heavy metal cations and anions from concentrated solutions, focusing specifically on industrially significant ions such as Ni2+-, Cu2+, Zn2+ and (Cr2O7)2-. The adsorption and desorption behaviors of the AAm terpolymer hydrogels were investigated across various pH solutions, considering the competition and concentrations of these specific metal ions. Moreover, the study delved into the effects of the internal pH environment within the hydrogel adsorbents, determining its impact on the type of metal adsorbed and the adsorption capacity. Our findings indicated that the adsorption of cations was enhanced with a higher proportion of SS relative to DMAPAA in the hydrogel. In contrast, significant anion capture occurred when the concentration of DMAPAA exceeded that of SS. However, equal ratios of SS and DMAPAA led to a noticeable reduction in the adsorption of both types of substrates, attributed to the counteractive nature of these co-monomers. To enhance the adsorption efficiency, it may be necessary to consider methods for micro-scale separation of the two types of monomers. Additionally, the adsorption capacity was observed to be directly proportional to the swelling capacity of the hydrogels. For complete desorption and separation of the cations and anions from the adsorbent, the application of concentrated NaOH solutions followed by HNO3 was found to be essential. Given the varying concentrations of cation and anion pollutants, often present in heavy metal factory effluents, it is crucial to fine-tune the ratios of DMAPAA and SS during the synthesis process. This adjustment ensures optimized efficiency in the decontamination and recovery of these significant heavy metal ions.

Inhibition of aldo-keto reductase 1C3 overcomes gemcitabine/cisplatin resistance in bladder cancer.

Systemic chemotherapy with gemcitabine and cisplatin (GC) has been used for the treatment of bladder cancer in which androgen receptor (AR) signaling is suggested to play a critical role. However, its efficacy is often limited, and the prognosis of patients who develop resistance is extremely poor. Aldo-keto reductase 1C3 (AKR1C3), which is responsible for the production of a potent androgen, 5α-dihydrotestosterone (DHT), by the reduction of 5α-androstane-3α,17ß-dione (5α-Adione), has been attracting attention as a therapeutic target for prostate cancer that shows androgen-dependent growth. By contrast, the role of AKR1C3 in bladder cancer remains unclear. In this study, we examined the effect of an AKR1C3 inhibitor on androgen-dependent proliferation and GC sensitivity in bladder cancer cells. 5α-Adione treatment induced the expression of AR and its downstream factor ETS-domain transcription factor (ELK1) in both T24 cells and newly established GC-resistant T24GC cells, while it did not alter AKR1C3 expression. AKR1C3 inhibitor 2j significantly suppressed 5α-Adione-induced AR and ELK1 upregulation, as did an AR antagonist apalutamide. Moreover, the combination of GC and 2j in T24GC significantly induced apoptotic cell death, suggesting that 2j could enhance GC sensitivity. Immunohistochemical staining in surgical specimens further revealed that strong expression of AKR1C3 was associated with significantly higher risks of tumor progression and cancer-specific mortality in patients with muscle-invasive bladder cancer. These results suggest that AKR1C3 inhibitors as adjunctive agents enhance the efficacy of GC therapy for bladder cancer.

Artepillin C overcomes apalutamide resistance through blocking androgen signaling in prostate cancer cells.

Prostate cancer has a relatively good prognosis, but most cases develop resistance to hormone therapy, leading to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) antagonists and a cytochrome P450 17A1 inhibitor have been used to treat CRPC, but cancer cells readily develop resistance to these drugs. In this study, to improve the therapy of CRPC, we searched for natural compounds which block androgen signaling. Among cinnamic acid derivatives contained in Brazilian green propolis, artepillin C (ArtC) suppressed expressions of androgen-induced prostate-specific antigen and transmembrane protease serine 2 in a dose-dependent manner. Reporter assays revealed that ArtC displayed AR antagonist activity, albeit weaker than an AR antagonist flutamide. In general, aberrant activation of the androgen signaling is involved in the resistance of prostate cancer cells to hormone therapy. Recently, apalutamide, a novel AR antagonist, has been in clinical use, but its drug-resistant cases have been already reported. To search for compounds which overcome the resistance to apalutamide, we established apalutamide-resistant prostate cancer 22Rv1 cells (22Rv1/APA). The 22Rv1/APA cells showed higher AR expression and androgen sensitivity than parental 22Rv1 cells. ArtC inhibited androgen-induced proliferation of 22Rv1/APA cells by suppressing the enhanced androgen signaling through blocking the nuclear translocation of AR. In addition, ArtC potently sensitized the resistant cells to apalutamide by inducing apoptotic cell death due to mitochondrial dysfunction. These results suggest that the intake of Brazilian green propolis containing ArtC improves prostate cancer therapy.

Disease flare patterns and predictors of systemic lupus erythematosus in a monocentric cohort of 423 Japanese patients during a long-term follow-up: The JUDE study.

OBJECTIVE: To clarify the clinical features of systemic lupus erythematosus (SLE) patients, factors associated with flares, and changes over time. METHODS: Patients having SLE with a visiting history were entered into the Juntendo University Database of Erythematosus. We included 423 cases in the long-term follow-up analysis, and 383 cases were followed for 10 years after the initiation of any therapeutic intervention (comparative analysis: 1973-1982, 82 cases; 1983-1992, 141, and 1993-2002, 160). We assessed changes in the patients' background characteristics, disease symptoms, flare rates, etc. RESULTS: Among the 423 cases, the mean follow-up period was 25.9 years, and mean number of flares was 0.51. Of those, 31.9% had ≥1 flares. Thrombocytopenia at onset contributed to the flares. For disease symptoms at onset, a recent trend in increasing thrombocytopenia was observed. The combination rate of immunosuppressive agents for diseases other than lupus nephritis was slightly increased, and there was no improvement until the first flare or in the flare rate. CONCLUSIONS: Thrombocytopenia at onset is predictive factor for flares. Since SLE is a diverse disease with varying symptoms at recurrence, the treatment guidelines should be improved for thrombocytopenia from a long-term perspective.

Urethral caruncle in a 9-year-old girl: a case report and review of the literature.

INTRODUCTION: Urethral caruncles are the most frequent benign tumors of the female urethra. Most of them are found in post-menopausal women, and they are rare in childhood. Only a few pediatric cases have been published in the literature. In this report, we present an unusual case of a pediatric patient with a urethral caruncle, along with a review of the literature. CASE PRESENTATION: A 9-year-old Mongolian girl was referred to our hospital with a 2-week history of frequent adherence of a small amount of blood to her underwear. We found a sessile smooth margin, a clear boundary and an elastic, soft red tumor over the entire circumference of the urethral meatus. At the beginning, because of the child's age, urethral prolapse was suspected. There was no response after 3 weeks of conservative treatment with steroid ointment. With the patient under general anesthesia, a partial tumor resection was performed for the purpose of histological examination. The tumor excision was limited to about 1/2 laps of the urethral meatus to prevent the development of urethral stricture. On the basis of clinical and histopathological examinations, a diagnosis of a urethral caruncle was made. Post-operatively, steroid ointment application to residual masses was continued, and these disappeared about 6 months later. Our patient was free of recurrence and had had no complications after 3 years of follow-up. CONCLUSIONS: Urethral caruncles are rare in children, and the possibility of malignancy is slight during this period. Biopsy of the mass is not required for diagnosis. It should be indicated only if the mass has other characteristics that raise suspicion of malignancy. In previously reported cases, all of the tumor was removed. However, the trigger of the caruncle in childhood is chronic inflammation. Conservative therapy with steroid ointment should be the core treatment. However, it may be necessary to proceed to treatment because caruncles take a long time to heal. The case that we describe in this report will serve as an example for similar cases in the future.

Age-dependent prognostic effect by Mitosis-Karyorrhexis Index in neuroblastoma: a report from the Children's Oncology Group.

Prognostic effects of Mitosis-Karyorrhexis Index (MKI) used in the International Neuroblastoma Pathology Classification (INPC) are age-dependent. A total of 4,282 neuroblastomas reviewed at the Children's Oncology Group Neuroblastoma Pathology Reference Laboratory (8/1/2001-3/31/2012) included 2,365 low-MKI (L-MKI), 1,068 intermediate-MKI (I-MKI), and 849 high-MKI (H-MKI) tumors. Cox proportional hazards models were fit to determine age cut-offs at which the relative risk of event/death was maximized in each MKI class. Backward-selected Cox models were fit to determine the prognostic strength of the age cut-offs for survival in the presence of other prognostic factors. The age cut-offs used in the INPC for L-MKI tumors (<60 months, n  =  2,710, 84.0% ± 1.0% event-free survival [EFS], 93.8 ± 0.7% overall survival [OS] vs ≥60 months, n  =  195, 49.8% ± 4.6% EFS, 71.7% ± 4.1% OS; P < 0.0001) and I-MKI tumors (<18 months, n  =  568, 83.8% ± 2% EFS, 93.7% ± 1.3% OS vs ≥18 months, n  =  500, 51.4% ± 2.9% EFS, 66.7% ± 2.7% OS; P < 0.0001) were within the effective range for distinguishing prognostic groups. As for H-MKI tumors (no cut-off age in the INPC, 51.0% ± 2.2% EFS, 64.4% ± 2.1% OS), a new cut-off of 3-4 months was suggested (<4 months, n  =  38, 82.3% ± 8.4% EFS, 81.8% ± 8.5% OS vs ≥4 months, n  =  811, 49.6% ± 2.2% EFS, 63.7% ± 2.1% OS, P  =  0.0034 and 0.0437, respectively). Multivariate analyses revealed that cut-offs of 60 and 18 months for L-MKI and I-MKI tumors, respectively, were independently prognostic. However, the cut-off of 4 months for H-MKI tumors did not reach statistical significance in the presence of other factors. The age cut-offs for MKI classes (60 months for L-MKI, 18 months for I-MKI, no cut-off for H-MKI) in the current INPC are reasonable and effective for distinguishing prognostic groups with increased risk of event/death for older patients.

Biophoton emission induced by heat shock.

Ultraweak biophoton emission originates from the generation of reactive oxygen species (ROS) that are produced in mitochondria as by-products of cellular respiration. In healthy cells, the concentration of ROS is minimized by a system of biological antioxidants. However, heat shock changes the equilibrium between oxidative stress and antioxidant activity, that is, a rapid rise in temperature induces biophoton emission from ROS. Although the rate and intensity of biophoton emission was observed to increase in response to elevated temperatures, pretreatment at lower high temperatures inhibited photon emission at higher temperatures. Biophoton measurements are useful for observing and evaluating heat shock.

Increased serum concentration of BAFF/APRIL and IgA2 subclass in patients with mixed connective tissue disease complicated by interstitial lung disease.

B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are known to be crucial for B cell maturation and survival, and increased expression of these factors in various autoimmune diseases has been reported. Human B cells produce two IgA subclasses: IgA1 and IgA2, the latter being abundant in the distal intestine, saliva, colostrum and bronchial fluid. We investigated these parameters in patients with mixed connective tissue disease (MCTD) complicated by interstitial lung disease (ILD+), and compared them with those in MCTD patients without ILD (ILD-). Sixty-three MCTD patients were divided into two groups: 21 ILD+ patients and 42 ILD- patients. In each patient group we analyzed soluble BAFF/APRIL using ELISA, and IgA1 and IgA2 using double immunodiffusion. Furthermore, we analyzed BAFF-APRIL receptors, BCMA, BAFF-R and TACI, using flow cytometry. The ILD+ patients had significantly higher levels of BAFF/APRIL than the ILD- patients. There were significant correlations between BAFF/APRIL, BAFF/KL-6 and APRIL/KL-6. Although there was no significant inter-group difference in the serum IgA1 level, ILD+ patients had a significantly elevated IgA2 level in comparison with ILD- patients. Moreover, although there were no significant inter-group differences in the expression of BCMA, BAFF-R and TACI on B cells, the expression of BAFF-R was significantly decreased in the ILD+ patients. In recent years, relationships between BAFF/APRIL and IgA subclass have been reported. Our results suggest that an elevated level of BAFF/APRIL drives the maturation of B cells, subsequently leading to IgA2 class switching, and possibly to the development of ILD in patients with MCTD.

Phenotype conversion from rheumatoid arthritis to systemic lupus erythematosus by introduction of Yaa mutation into FcγRIIB-deficient C57BL/6 mice.

We previously established an IgG Fc receptor IIB (FcγRIIB)-deficient C57BL/6 (B6)-congenic mouse strain (KO1), which spontaneously develops rheumatoid arthritis (RA), but not systemic lupus erythematosus (SLE). Here, we show that when Y chromosome-linked autoimmune acceleration (Yaa) mutation was introduced in KO1 strain (KO1.Yaa), the majority of KO1.Yaa mice did not develop RA, but instead did develop SLE. This phenotype conversion did not depend on autoantibody specificity, since KO1.Yaa mice, compared with KO1, showed a marked increase in serum levels of both lupus-related and RA-related autoantibodies. The increase in frequencies of CD69(+) activated B cells and T cells, and the spontaneous splenic GC formation with T follicular helper cell generation were manifest early in life of KO1.Yaa, but not KO1 and B6.Yaa, mice. Activated CD4(+) T cells from KO1.Yaa mice showed upregulated production of IL-21 and IL-10, compared with the finding in KO1 mice, indicating the possibility that this aberrant cytokine milieu relates to the disease phenotype conversion. Thus, our model is useful to clarify the shared and the disease-specific mechanisms underlying the clinically distinct systemic autoimmune diseases RA and SLE.

[The first case of adenine phosphoribosyltransferase deficiency with APRT*Q0 (M1I) mutation in Japan].

Adenine phosphoribosyltransferase (APRT) deficiency is an enzyme deficiency associated with purine metabolism, a hereditary disease that causes recurrent 2, 8-DHA stone formation due to a complete or partial APRT defect and slowly damages the renal function. Since APRT deficiency can be treated to prevent its progression to renal insufficiency, it is important to detect APRT gene mutations and make a definite diagnosis early. A 3.5-year-old girl presented with painful urination and dysuria, and was admitted to our hospital. The analysis of stones collected after spontaneous passage revealed 2, 8-dihydroxyadenine (DHA) urolithiasis. To make a definite diagnosis, we searched for the APRT gene mutations reported in Japanese. However, no APRT Q0 mutation was identified. Only a heterogeneous mutation, APRT J, was noted. Subsequently, we screened the gene mutation regions reported from Europe and the United States and identified a heterogeneous mutation at the start codon of APRT Q0 from methionine to valine. This is the first report of this mutation in Japan. She was diagnosed with APRT deficiency caused by a compound heterogeneous mutation: APRT Q0/(M1V) APRT J (M136T). We believe that the same gene mutation has been inherited among other Japanese. For the future genetic diagnosis of APRT deficiency, this is a valuable case.

Beneficial effects of (-)-epigallocatechin gallate on ischemia-reperfusion testicular injury in rats.

BACKGROUND/PURPOSE: The purpose of the study was to determine the effect of (-)-epigallocatechin gallate (EGCG) on testicular ischemia-reperfusion injury in rats. METHODS: Forty male Wistar rats were assigned to 5 groups. A sham operation was performed on the animals in group 1. In group 2, after 4 hours of unilateral testicular ischemia, 4 hours of testicular reperfusion was performed with EGCG administered 1 hour before reperfusion. In group 3, the same surgical procedure as in group 2 was performed, but without EGCG. Serum superoxide dismutase activity, creatine kinase, and lactate dehydrogenase were then measured in blood samples from groups 1 to 3. In group 4, after 4 hours of unilateral testicular ischemia, testicular reperfusion was performed. In group 5, the same procedure as in group 4 was performed, but with EGCG administered 1 hour before reperfusion. For groups 4 and 5, bilateral orchiectomy was performed for histologic examination 4 weeks after reperfusion was started. RESULTS: Serum superoxide dismutase activity was significantly higher in group 2 than in group 3. The ratios of bilateral testicular weight, mean seminiferous tubule diameter, and germinal epithelial cell thickness were significantly higher in group 5 than in group 4. CONCLUSIONS: Therapy with EGCG before reperfusion might exert protective effects via antioxidant activities in a rat experimental model of testicular ischemia-reperfusion injury.

[The first case of adenine phosphoribosyltransferase deficiency with APRT Q0 (M1V) mutation in Japan].

Adenine phosphoribosyltransferase (APRT) deficiency is an enzyme deficiency associated with purine metabolism, a hereditary disease that causes recurrent 2, 8-DHA stone formation due to a complete or partial APRT defect and slowly damages the renal function. Since APRT deficiency can be treated to prevent its progression to renal insufficiency, it is important to detect APRT gene mutations and make a definite diagnosis early. A 3.5-year-old girl presented with painful urination and dysuria, and was admitted to our hospital. The analysis of stones collected after spontaneous passage revealed 2, 8-dihydroxyadenine (DHA) urolithiasis. To make a definite diagnosis, we searched for the APRT gene mutations reported in Japanese. However, no APRT Q0 mutation was identified. Only a heterogeneous mutation, APRT J, was noted. Subsequently, we screened the gene mutation regions reported from Europe and the United States and identified a heterogeneous mutation at the start codon of APRT Q0 from methionine to valine. This is the first report of this mutation in Japan. She was diagnosed with APRT deficiency caused by a compound heterogeneous mutation : APRT Q0/(M1V) APRT J (M136T). We believe that the same gene mutation has been inherited among other Japanese. For the future genetic diagnosis of APRT deficiency, this is a valuable case.

Glicentin inhibits internalization of enteric bacteria by cultured INT-407 enterocytes.

Glicentin, the main component of enteroglucagon, has trophic effects on intestinal mucosa. It may also have an inhibitory effect on extraintestinal invasion of enteric bacteria. We have established an in vitro bioassay system for determining the effects of recombinant human glicentin on bacterial internalization by confluent enterocytes. An INT-407 cell line was serum-deprived for 2 days and was then treated on transwell filters for 24 h with a medium containing one of the following: glicentin 100 ng-1 microg/ml, glucagons-like peptide-2 (GLP-2) 1 microg/ml, 10% fetal bovine serum (FCS), or without any growth factors. Pure cultures of Salmonella enteritidis, Escherichia coli, and Enterococcus faecalis were introduced to the upper chambers of the filter units. Following 2 h of incubation the numbers of bacteria in the lower chambers were measured. Pretreatment of enterocytes with glicentin inhibited bacterial internalization compared to untreated or GLP-2 enterocytes. Glicentin was associated with inhibition of enterocyte internalization of enteric bacteria by a mechanism that might be related to the integrity of the enterocyte adhesive junctions and tight junctions and to the production of sIgA. Glicentin seems to have a function as a barrier-sustaining agent that inhibits extraintestinal invasion of enteric bacteria.

Neuroblastoma detected by mass screening: the Tumor Board's role in its treatment.

Japan has a nationwide mass-screening program for neuroblastoma in 6-month-old infants. Neuroblastoma can regress spontaneously, and some institutions observe selected cases. We evaluated the management of screened neuroblastoma at our hospital since 1997 when an observation program was introduced. Criteria for the observation program were stage-I, stage-II, or stage-IVs tumors, urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels <40 microg/mg creatinine, tumor <5 cm in diameter, no invasion to the intraspinal canal or great vessels, and parental consent to participate. Patients who did not meet observation criteria underwent surgery or mild chemotherapy according to the location of the tumor. If patients met observation criteria after chemotherapy, surgical intervention was no longer performed. Thirty-six patients attended our hospital for screened neuroblastoma from 1997 to 2002. Thirty-three patients who were managed at our hospital participated in this study. Ten subjects met observation criteria. Tumors regressed in 7 patients (mean follow-up period 36.3 months) with corresponding decreases in VMA and HVA levels (group A). Three underwent surgery (group B) because of increasing VMA and HVA levels, increase in tumor size, or guardian's request. Twenty-three subjects did not meet observation criteria. Four patients underwent primary surgery (group C), and 19 patients had chemotherapy initially. Fourteen patients met observation criteria after chemotherapy and two are still having chemotherapy (group D). Three patients required surgery due to insufficient regression of their tumors (group E). Fourteen subjects in group D had marked decreases in VMA and HVA levels and tumor size (mean follow-up period 29.1 months), and tumors were not detected using imaging techniques in 8 patients. Histological examination of all resected specimens during the study period showed favorable histology and no N-myc amplification. There was no evidence of unfavorable prognosis in any of the 33 subjects, although 1 patient who underwent primary surgery had a vanishing kidney 1 year later and 1 patient had multiple bony metastases after complete resection of tumor, which was treated by chemotherapy. Until the real significance of mass screening for neuroblastoma as a public health measure is confirmed, observation with careful follow-up should be adopted more extensively because it has a favorable outcome in many cases, and is associated with minimal therapeutic complications.

Congenital diaphragmatic hernia: efficacy of ultrasound examination in its management.

To date, uniform standards for congenital diaphragmatic hernia (CDH) management have not existed. The purpose of this study was to evaluate the evolving clinical outcome of the patients with CDH and to present our recent management protocol using echocardiography. Sixty patients treated for CDH at our hospital from 1978 through 2001 were reviewed. Periods of treatments were divided arbitrarily into three periods;1978-1991 (period I, n=26), 1992-1994 (period II, n=6), 1995-2001 (period III, n=28). Immediate repair was performed during period I. We performed preoperative stabilization and delayed repair since the start of period II, and nitric oxide (NO) was introduced in period III. In period III, our management strategy was the use of fentanyl for sedation and analgesia; vasoactive agents such as dopamine, dobutamine, and prostaglandin E1 in selected cases; the use of high-frequency oscillating ventilation (HFOV), inhaled NO; and venovenous extracorporeal membrane oxygenation (ECMO) if indicated. The details of stabilization management and the timing of surgery were determined using echocardiography to evaluate pulmonary hypertension (PH) by measuring dimension and shunt patterns through the ductus arteriosus (DA), right pulmonary artery (rPA) and left pulmonary artery (lPA). Overall, 42 of 60 patients survived (70%). The number of patients surviving in each period was 14 of 26 (54%) in period I, 4 of 6 (67%) in period II, and 24 of 28 (86%) in period III. Seventeen of 28 patients in period III required inhaled NO (group A). Of these 17 patients, 5 required ECMO; of these 5, 3 were long-term survivors. The remaining 11 patients from period III who were managed without NO (group B) survived. In left-sided CDH cases, the dimension of DA at admission in group A (5.07+/-1.79 mm) was significantly larger than in group B (2.99+/-1.68 mm) (P<0.01). The dimension of rPA in group A (3.37+/-0.80 mm) was significantly smaller as compared with group B (4.28+/-0.72 mm) (P<0.01). Although the dimension of lPA was not significantly different between group A (3.03+/-0.74 mm) and group B (3.46+/-0.48 mm), lPA blood flow was noticeably stronger in group B. DA shunt patterns were bi-directional (53%), right-to-left (40%) and left-to-right (7%) in group A, whereas no patients in group B showed a right-to-left shunt pattern. After confirmation of closure of DA or dominant left-to-right shunt, and marked increase of pulmonary arterial blood flow, patients in both group A and B underwent surgery successfully. In four non-survivors, findings of improving PH were not observed. We conclude that echocardiographic examination is useful to manage persistent pulmonary hypertension with recent treatment modalities including NO and HFOV and to determine the proper timing of surgery, which contributes to an improved outcome of CDH.