Experimental immune-mediated blepharoconjunctivitis in rats induced by immunization with ragweed pollen.

BACKGROUND: A study was performed to compare the effects of immunization with ragweed pollen (RW) in two different adjuvants on the characteristics of a previously described model of experimental immune-mediated blepharoconjunctivitis (EC) in rats. METHODS: Lewis or Brown Norway (BN) rats were immunized with 100 microg of RW in emulsion with aluminum hydroxide [Al(OH)3] or complete Freund's adjuvant (CFA). Three weeks later, the animals were challenged with eye drops containing RW in PBS. Twenty-four hours after topical challenge, eyes, blood, and lymph nodes were obtained for histology, measurement of antigen-specific antibodies, and proliferation or cytokine assays, respectively. In addition to active immunization, recipients of RW-primed lymph node cells were challenged and evaluated as above. RESULTS: RW in both adjuvants induced infiltration with predominantly mononuclear cells in Lewis rats and eosinophils in BN rats. As well as active immunization, eosinophils were detected only in BN rats by adoptive transfer of cells. Lymphocyte proliferative responses to RW were high in immunized Lewis rats when CFA was used as an adjuvant. In contrast, proliferative responses in BN rats were higher when Al(OH)3 was used. RW-specific IgE was detected only in BN rats. There were no significant differences in RW-specific IgG1/IgG2a ratio among the four groups. Lewis rats had higher level of RW-specific interferon-gamma in the culture supernatant. CONCLUSIONS: The characteristics of EC are different in Lewis and BN rats, dependent on the genetic background of the rat strains. The response to RW was similar to other previously used antigens, such as ovalbumin.

Prostate-specific amplification of expanded polyglutamine expression: a novel approach for cancer gene therapy.

For cancer gene therapy, it is of primary importance to develop a system to sufficiently and selectively express therapeutic genes in cancer cells. In this study, we showed that an approximately 5.3-kb promoter region of the prostate-specific antigen (PSA) gene can replicate the endogenous expression pattern, although its expression is very weak. We then developed a novel two-step transcriptional activation system in which the PSA promoter drives an artificial transcriptional activator, GAL4-VP16 fusion protein, and it in turn activates transgene expressions under the control of GAL4-responsive elements. By using this system, transgene expressions can be greatly augmented while maintaining prostate-specific expression. Finally, we applied this system to drive an expanded polyglutamine, a potent proapoptotic molecule, to induce apoptosis selectively in PSA-positive prostate cancer cells. This novel system would provide an ideal approach for cancer gene therapy applicable not only to prostate cancer but to other cancers as well.

Quantitative trait loci associated with promoting effects of sodium L-ascorbate on two-stage bladder carcinogenesis in rats.

In the two-stage rat bladder carcinogenesis model using N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as an initiator and sodium L-ascorbate (SA) as a promoter, we found a notable strain difference between F344/DuCrj (F344) and WS/Shi (WS) rats in susceptibility to the promoting effect of SA. Twenty each of F344, WS and reciprocal F1 hybrid rats were given 0.05% BBN in their drinking water for 4 weeks and then a basal diet with (BBN-SA group) or without (BBN group) a 5% SA supplement for 32 weeks. In F344 and also in reciprocal F1 hybrids, the number of tumors per rat was significantly higher in the BBN-SA group than in the BBN group (P < 0.0001). In contrast, WS rats were not significantly affected by either treatment (P = 0.8). These findings indicate that F344 rats are highly susceptible to the promoter effect of SA, but WS rats are not. Linkage analysis of 108 WSx (WS x F344) F1 backcrosses revealed that this difference was related to a quantitative trait locus mapped on rat Chr. 17 (maximum LOD score, 3.86) named Bladder Tumor Susceptible-1 and possibly another locus on Chr. 5 (maximum LOD score, 2.39). This study has provided the first evidence that host genes influence the risk of bladder cancer development.

A glycine-rich RNA-binding protein mediating cold-inducible suppression of mammalian cell growth.

In response to low ambient temperature, mammalian cells as well as microorganisms change various physiological functions, but the molecular mechanisms underlying these adaptations are just beginning to be understood. We report here the isolation of a mouse cold-inducible RNA-binding protein (cirp) cDNA and investigation of its role in cold-stress response of mammalian cells. The cirp cDNA encoded an 18-kD protein consisting of an amino-terminal RNAbinding domain and a carboxyl-terminal glycine-rich domain and exhibited structural similarity to a class of stress-induced RNA-binding proteins found in plants. Immunofluorescence microscopy showed that CIRP was localized in the nucleoplasm of BALB/3T3 mouse fibroblasts. When the culture temperature was lowered from 37 to 32 degrees C, expression of CIRP was induced and growth of BALB/3T3 cells was impaired as compared with that at 37 degrees C. By suppressing the induction of CIRP with antisense oligodeoxynucleotides, this impairment was alleviated, while overexpression of CIRP resulted in impaired growth at 37 degrees C with prolongation of G1 phase of the cell cycle. These results indicate that CIRP plays an essential role in cold-induced growth suppression of mouse fibroblasts. Identification of CIRP may provide a clue to the regulatory mechanisms of cold responses in mammalian cells.

Pros-Eight transurethral radiofrequency thermotherapy for benign prostatic hyperplasia: preliminary clinical results.

BACKGROUND: We have developed a new transurethral thermotherapy device using 8MHz radiofrequency (RF) for the treatment of patients with symptomatic benign prostatic hyperplasia (BPH). We report the safety and effectiveness of the initial clinical experience with this device. METHODS: Sixty patients with symptomatic BPH were subjected to a single 1-hour treatment under local anesthesia. The treatment device uses extracorporeal RF capacitive heating in combination with radiative heating and conductive cooling of the urethra. RESULTS: In the 49 patients evaluable at 3 months, the mean International Prostate Symptom Score decreased from 17.8 to 13.1 (P < 0.0001) and the Quality of Life score decreased from 4.4 to 3.4 (P < 0.0005). Maximum flow rate increased from 8.1 to 9.7 mL/s (P < 0.05) at 3 months. Overall effectiveness by Homma's response criteria was as follows; excellent 4.1%, good 10.2%, fair 38.8% and poor 46.9%. Side effects were minimal. Gross hematuria was seen in 3 patients and erosion of the external urethral meatus was seen in 2 patients, but none had urinary retention. CONCLUSIONS: In this initial clinical trial, transurethral RF thermotherapy was safe and resulted in modest symptomatic improvement. Further investigations for optimizing the treatment protocol seem warranted.

Transurethral microwave thermotherapy for benign prostatic hyperplasia: relation between clinical response and prostate histology.

The effectiveness of transurethral microwave thermotherapy (TUMT) for BPH has been confirmed. To identify the characteristics of the ideal candidate, retrospective analysis and morphometric study of prostatic tissue were performed. Forty-two patients with symptomatic BPH were included in the study; these comprised 10 patients treated for more than 3 months with anti-androgen pre-TUMT (group A) and 32 fresh cases (group B). Subjective and objective responses were evaluated at 2 months post TUMT. In 12 fresh cases who underwent pre-TUMT biopsy of the prostate, the stromal-to-epithelial ratio was determined via quantitative image analysis on a computer-assisted morphometry system. No significant differences in baseline patient characteristics were found between the two groups: age, prostate volume, peak flow rate (PFR), or International Prostate Symptom Score (I-PSS). However, significant differences in treatment outcome were found between the two groups (group A vs. group B, respectively): total energy delivered to the prostate: 96 kJ vs. 125 kJ: I-PSS decrease from baseline: 5.9 vs. 11.6; PFR increase from baseline: 1.1 vs. 4.7 ml/sec. There was a positive correlation between the I-PSS change from baseline and the stromal-to-epithelial ratio of the prostatic tissue (r = 0.4857). The results suggest that microwave interacts poorly with the prostate due to the artificially created "lack" of glandular tissue. The morphometric study also supports the contention that the histological composition of the prostatic tissue plays an important role in terms of microwave thermal interactions and treatment outcome.

Newly developed transurethral radiofrequency thermotherapy device for benign prostatic hyperplasia: a pilot study in canine prostate.

The safety and efficacy of transurethral microwave thermo-therapy (TUMT) for the treatment of symptomatic benign prostatic hyperplasia (BPH) have been demonstrated in the urological literature. Since a radiofrequency electromagnetic wave has deeper and more even transmission of heat to tissues than a microwave, we have developed a new prototype device for transurethral thermotherapy using a radiofrequency electromagnetic wave. The device consists of a microcomputer-controlled heat generator operating at 8 Mhz, a temperature monitoring system, a urethral cooling system and a urethral applicator and a rectal thermosensor probe. A balloon electrode encased in a specialized Foley catheter is connected parallel to twin plate electrodes on both sides of the pelvic region. An 8-MHz electromagnetic wave is directed to the prostate by means of capacitive coupling. The water coolant continuously perfused through the catheter allows high temperatures within the prostate while preserving the urethral mucosa. Heating experiment using agar phantom showed the hot spots to be distributed at 0.5-3 cm from the catheter surface. Heating experiment using canine prostates demonstrated that an intraprostatic temperature of > 48 degrees C could be achieved while the urethral and rectal temperatures had not exceeded 36 and 40 degrees C respectively. Histological examination immediately after the experiment showed the urethral mucosa to be preserved while coagulation necrosis of the periurethral prostate accompanied with congestion and hemorrhage of small blood vessels were observed at 5-8 mm from the urethra. The bladder and the rectum showed no gross alterations. Histopathological examination 10 days after the experiment revealed the intact urethral mucosa and mild mononuclear infiltration around the destroyed periurethral glands.(ABSTRACT TRUNCATED AT 250 WORDS)

Increasing the thermal dose in transurethral microwave thermotherapy produces no improvement in therapeutic efficacy.

BACKGROUND: Transurethral microwave thermotherapy (TUMT) is a minimally invasive treatment for benign prostatic hyperplasia (BPH). It has been reported that increased thermal dose and higher intraprostatic temperatures resulted in improved clinical response. Recently we treated BPH patients with the prostatron device using a new version of software (Prostasoft 2.5), which was intended to increase thermal delivery by allowing maximum power up to 70W. The safety and clinical results were compared between the patients treated with Prostasoft 2.5 and those treated with the currently available software (Prostasoft 2; maximum power up to 50W). METHODS: A total of 105 patients were treated successively with two treatment protocols. Sixty-three patients were treated with Prostasoft 2 between September 1992 and July 1993, while 42 were treated with Prostasoft 2.5 between August 1993 and April 1994. Therefore, this investigation was a retrospective nonrandomized study. There was no significant difference in the baseline patient characteristics between the two groups. RESULTS: Total thermal dose delivered to the prostate was significantly higher in the Prostasoft 2.5 group than that in the Prostasoft 2 group (137 kJ versus 116 kJ, P < 0.05). No serious complications were encountered in either group. Six months after TUMT, in both the Prostasoft 2.5 and Prostasoft 2 groups there was an improvement in patient condition as measured by the mean I-PSS, QOL, and peak flow rate values, as well as the overall therapeutic efficacy. The two groups differed in the amount of posttreatment improvement from between 8% and 22%, but this difference was not statistically significant. CONCLUSIONS: Our study suggests that higher thermal dose attained by Prostasoft 2.5 does not necessarily result in more pronounced clinical improvement, although clinical response to TUMT has often been reported to be dependent upon thermal dose.

Transurethral microwave thermotherapy for benign prostatic hyperplasia: clinical results after a 1-year follow-up.

Since September 1992, 63 patients with symptomatic benign prostatic hyperplasia (BPH) have been treated with transurethral microwave thermotherapy (TUMT) using the Prostatron device. The International Prostate Symptom Score (I-PSS) and quality of life (QOL) score were used to evaluate subjective symptoms. The mean I-PSS (total, irritative and obstructive scores) and QOL scores had decreased by 40, 38, 45 and 40%, respectively, at 12 months (p < 0.0001). While the mean peak flow rate had increased by 72% (p < 0.001). The clinical efficacy at 12 months was 42%, using a modification of the response criteria proposed at the 2nd International Consultation on Benign Prostatic Hyperplasia. There were no significant differences in the baseline and treatment parameters between those who responded favorably to TUMT and those who did not. The total thermal dose delivered to the prostate did not predict clinical response. However, there was a positive correlation between I-PSS or QOL at baseline and % reduction at 3, 6 and 12 months, and a negative correlation between peak flow rate at baseline and % increase at 3 and 6 months. There were no major complications associated with TUMT during the follow-up period. In summary, our 1-year clinical results are compatible with previous reports, suggesting that TUMT is a safe, effective and lasting non-surgical treatment for BPH. However, evaluation of efficacy should be based on uniform criteria to facilitate comparisons of different clinical trials. The most suitable patient profiles for TUMT could not be identified by retrospective analysis.

Transurethral microwave thermotherapy for benign prostatic hyperplasia: patient characteristics in good and poor responders.

Transurethral microwave thermotherapy (TUMT) has been shown to produce a clinical benefit in patients with symptomatic benign prostatic hyperplasia. In order to identify the features of the ideal candidate, a retrospective analysis was conducted in 32 patients who were followed for 2 mo or more. Good responders (GR) were defined as having their Siroky peak flow rate (PFR) standard deviation (SD) increase by < 0.5 or a decrease in the International Prostatic Symptom Score (I-PSS) of > 10 (22 patients). Poor responders (PR) were defined as having their PFR SD increase by < or = 0.5 and their I-PSS decrease by < or = 10 (10 patients). The prostate volume, pre-TUMT I-PSS and intravesical opening pressure were significantly greater in the GR group, while there were no significant differences between the 2 groups for the other baseline patient characteristics: age, prostate length, PFR, PFR SD, post-voiding residual volume and quality of life. Concerning the operational parameters, significantly more total energy was delivered to the prostate in the GR group (mean 131 kJ) than in the PR group (mean 101 kJ). Moreover, the 7 patients with anti-androgen therapy pre-TUMT received less total energy and 5 of the 7 were poor responders. These results suggest that patients with apparent obstructive symptoms and with moderate enlargement of prostate could benefit more from this less invasive therapy. Clinical response seems to be dose-dependent and patients with a history of recent anti-androgen treatment may have a less favorable response.(ABSTRACT TRUNCATED AT 250 WORDS)

[Transurethral microwave thermotherapy for benign prostatic hyperplasia: clinical evaluation with International Prostate Symptom Score (I-PSS)].

Forty patients with symptomatic benign prostatic hyperplasia were treated with a single session of transurethral microwave thermotherapy (TUMT) using a Prostatron. The clinical effectiveness was evaluated by analyzing the subjective and objective responses following the treatment. The International Prostate Symptom Score (I-PSS) and quality of life (QOL) scale were used to evaluate the subjective symptoms. At three months after treatment, significant improvements in I-PSS (p < 0.0001). QOL (P < 0.0001), and peak flow rate (Qmax) (p < 0.05) were observed. Improvement of both I-PSS and Qmax was found in 90% (18/20) of the patients at 2 months. Although 15 patients noted transient urinary retention and 15 patients had mild to moderate macroscopic hematuria immediately after TUMT, no severe adverse effects occurred during the follow-up period. A significant correlation was found between I-PSS improvement and the total thermal dose delivered. However, the thermal dose could not be predicted in each case. The preliminary findings suggest that TUMT by Prostatron is safe and effective as a nonsurgical treatment for benign prostatic hyperplasia. The clinical response seems to be thermal dose dependent. I-PSS is clinically sensitive and is useful in practice.

Anti-promoting effect of nordihydroguaiaretic acid on N-butyl-N-(4-hydroxybutyl)nitrosamine and sodium saccharin-induced rat urinary bladder carcinogenesis.

The effects of oral administration of nordihydroguaiaretic acid (NDGA), an antioxidant and inhibitor of arachidonic acid metabolism, on rat bladder carcinogenesis were examined. Six-week-old male Fischer 344 rats were given drinking water containing 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine for 4 weeks. Following this 4-week period, diet containing 5% sodium saccharin (SS) with or without 0.1% NDGA supplement was given to the rats for 36 weeks. The incidences of papillary or nodular (PN) hyperplasia and of papilloma in the group treated with SS plus NDGA were significantly lower than those in the group treated with SS alone. The number of PN hyperplasic foci per 10 cm of basement membrane in rats treated with SS plus NDGA was also lower than that in the group treated with SS alone. These results suggest that NDGA has an anti-tumor-promoting effect on rat bladder carcinogenesis.

Evaluation of the usefulness of a novel injectable cephalosporin, E1040, and ceftazidime for management of complicated urinary tract infections caused by Pseudomonas aeruginosa and Proteus mirabilis by using the rat urolithiasis model.

A novel injectable cephalosporin, E1040, significantly eradicated Pseudomonas aeruginosa from the urine, in contrast to ceftazidime, in rats with complicated P. aeruginosa urinary tract infections associated with urinary stones, suggesting that E1040 is a prospective therapeutic agent in the management of refractory Pseudomonas urinary tract infections.

[Inhibitory effects of Hachimijiogan on micturition reflex via the locus coeruleus].

Pharmacological studies were undertaken to elucidate the role of Hachimijiogan in the micturition reflex via the locus coeruleus, using alpha-chloralose-anesthetized cats. Rhythmic contractions of the urinary bladder induced by continuous infusion of saline into the bladder were dose-dependently inhibited by intravenous injection of Hachimijiogan (10, 30 and 90 mg/kg), as well as flavoxate hydrochloride (1 and 3 mg/kg). In contrast, contraction of the urinary bladder elicited by electrical stimulation of the locus coeruleus was significantly suppressed by intravenous injection of flavoxate, but not affected by that of Hachimijiogan. These results suggest that Hachimijiogan acts on the afferent pathway from the urinary bladder to the locus coeruleus, thereby inhibiting the micturition reflex, while it has no effects on the efferent pathway from the locus coeruleus to the urinary bladder.

[Clinical experience of local hyperthermia for benign prostatic hyperplasia].

A total of 20 patients with benign prostatic hyperplasia underwent transrectal local hyperthermia. For heating of the prostate gland, the PROSTATHERMER (Biodan-Medical System, Israel) was used. Patients were treated twice weekly, for 1 hour, with 6 sessions on an outpatient basis. Four of the 20 patients who had acute toxicity such as urethral irritability due to urethral thermoprobe could not tolerate the treatment. In the majority of the patients who were completely treated, a significant decrease in frequency of nocturia, decrease in post-void residual urine capacity and increase in urine flow rate were observed. No significant change in prostate volume was noted. With a mean follow-up of 6 months, only 1 patient required subsequent prostatic resection. These findings indicate that local hyperthermia applied by this method is effective in the treatment of benign prostatic hyperplasia and that improvement of the thermometry system is needed.

Multidisciplinary treatment of invasive bladder cancer.

To improve cure rates of locally invasive bladder cancer patients, we have performed radiation therapy prior to radical cystectomy in 88 patients since 1980. Until 1984, a total dose of 40 Gy for 4 weeks had been irradiated to the pelvic cavity of 46 patients, while 24 Gy with or without hyperthermia for 2 weeks has been applied to 42 patients since 1985. The treatment efficacy was assessed histopathologically according to the evaluation system proposed by Shimosato et al. in 1971. Approximately 50% of the patients responded well to this preoperative therapy. Among these patients, those with pT3 lesion showed significantly favorable prognoses as compared with the same stage patients who did not respond to the radiation therapy. However, the survival rates of the other pT stage patients did not correlate with the responsiveness to radiation. These results suggest that pT3 stage patients are the best candidates for preoperative radiation therapy, while radical cystectomy alone is adequate for those with superficially invasive lesions. Systemic chemotherapy should be properly built into the treatment strategy for those with locally far-advanced bladder cancer.

Effects of retinoids and inhibitors of arachidonic acid metabolism on tumor-promoter-induced soft agar colony formation of mouse epidermal cells and rat urinary bladder cells.

Effects of retinoids and inhibitors of arachidonic acid metabolism on tumor-promoter-induced soft agar colony formation of mouse epidermal cells and rat bladder cells were evaluated. Topical application of retinoic acid, an anti-tumor-promoter, to female SENCAR mouse skin inhibited 12-O-tetradecanoylphorbol-13-acetate-induced soft agar colony formation of mouse epidermal cells, an event proposed to be essential for tumor promotion. Effects of dietary retinyl acetate, nordihydroguaiaretic acid (NDGA) and quinacrine hydrochloride on colony formation of rat bladder cells were then examined. Male Fischer 344 rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine for 3 weeks, followed immediately by the administration for 9 weeks of 5% sodium saccharin supplemented with or without 0.05% retinyl acetate, 0.1% NDGA or 0.01% quinacrine hydrochloride. Saccharin-induced colony growth was significantly inhibited by the administration of retinyl acetate or NDGA, suggesting that these two agents have anti-tumor-promoting effects on rat bladder carcinogenesis. Thus, the colony-forming assay might be useful for early detection of anti-tumor-promoters of skin and bladder.

[Beneficial effect of zinc supplementation on pruritus in hemodialysis patients with special reference to changes in serum histamine levels].

Persistent pruritus is one of the most common symptoms in hemodialysis patients. The cause of pruritus is not known, and conventional treatment for pruritus is rarely helpful. Some authors thought that release of histamine from increased mast cells in uremic patients was the cause of pruritus. On the other hand, there have been a number of reports suggesting that uremic patients are zinc deficient. In vitro as well as in vivo studies have demonstrated that zinc has an inhibitory effect on various functions of some cells, such as histamine release from mast cells. In this study, we examined the serum zinc and histamine levels in 19 hemodialysis patients with persistent pruritus and the effect of zinc supplementation on the pruritus. In patients with pruritus, the serum zinc level decreased and serum histamine level increased, showing a negative correlation between them. Oral zinc sulfate, 445 mg daily for two months, relieved pruritus subjectively in 53% of the patients. After treatment, serum histamine levels decreased significantly, as well as serum zinc levels increased significantly. These findings suggest that zinc deficiency participates in increased histamine levels in dialysis patients, and subsequently in the development of uremic pruritus.

[A study on the cause of urolithiasis of the upper urinary tract--clinical study of risk factors in the formation of stones in the upper urinary tract].

Various risk factors and inhibitors of the stone formation of the upper urinary tract have been pointed out in urine. We examined the amount of daily excretion of several important risk factors (calcium, phosphorus, urate and oxalate) and inhibitors (magnesium and citrate) in the urine of 21 healthy males, 13 male single stone formeks and recurrent and/or multiple stone formers before and after taking the regular diet which contains 500 mg of calcium and 1,000 mg of phosphorus a day. The daily excretion of calcium, phosphorus and magnesium indicated no significant differences among the 3 groups. The excretion of oxalate in urine for 24 hours was significantly decreased in the stone formers after taking the regular diet. The urinary excretion of the urate per body surface area in the stone formers was significantly higher than that in the healthy control. The amount of the excretion of the citrate in urine in the recurrent and/or multiple stone formers was significantly lower than that in the other 2 groups. Many patients of the recurrent and/or multiple urinary stones had more than two abnormal values of above-mentioned risk factors and inhibitors. These results suggest that the causes of the formation of the upper urinary stone were not single but multiple and that the dietary advice to these patients was important against the recurrence of the urolithiasis.

[Inhibitory effects of aromatic retinoic acid analog, administered alone or in combination with mitomycin C, on the in vitro growth of rat bladder carcinoma cells].

The effects of an aromatic retinoic acid analog (Ro 10-9359), its metabolite (Ro 10-1670) and mitomycin C (MMC) on the in vitro growth of rat bladder carcinoma cells, BC50-TC were examined. The growth of the cells treated with 10(-4) M of either of the retinoids for 1 hour was not inhibited. The growth of the cells was inhibited by 37% and 93%, respectively, by the 3-day treatment with Ro 10-9359 and Ro 10-1670, at the concentration of 5 X 10(-5) M. The retinoids given in combination with MMC produced additive effects. Slight synergism was suggested at high concentrations of the retinoid. The fact that the retinoids exhibited anti-tumor activity in vitro might preclude indirect effects from being the only factor in the inhibition of the tumor growth in vivo, but the fact that antagonism with MMC did not occur in vitro whereas it did in vivo suggests that the indirect effects of the retinoid might be more important in mediating the anti-tumor effects. Regardless of the mechanism of action, care should be taken when prescribing retinoids with MMC or other cytotoxic agents.