Distinct effects of pitavastatin and atorvastatin on lipoprotein subclasses in patients with Type 2 diabetes mellitus.

AIMS: Effects of pitavastatin and atorvastatin on the lipid profile and lipoprotein subclasses were compared in patients with Type 2 diabetes with dyslipidaemia. METHODS: Patients with Type 2 diabetes with hypercholesterolaemia and/or hypertriglyceridaemia were randomized to receive pitavastatin 2 mg (n = 16) or atorvastatin 10 mg (n = 15) for 6 months, and blood lipid and lipoprotein profiles and cholesterol and triglyceride contents of 20 lipoprotein subclasses, determined by high-performance liquid chromatography, were compared. RESULTS: At baseline, cholesterol in VLDL and LDL subclasses were increased equally in two groups of patients with diabetes as compared with normolipidaemic control subjects. As compared with baseline, serum levels of total cholesterol, LDL cholesterol, non-HDL cholesterol, LDL cholesterol:HDL cholesterol ratio and apolipoprotein B were decreased after 1, 3 and 6 months of treatment with atorvastatin and pitavastatin. Serum triglyceride levels were decreased after 1, 3 and 6 months of atorvastatin, but only at 3 months of pitavastatin. Serum HDL cholesterol was increased after 1, 3 and 6 months of pitavastatin, whereas HDL cholesterol was even decreased after 6 months of atorvastatin. Cholesterol levels of most VLDL and LDL subclasses were decreased equally in both groups. However, only pitavastatin increased cholesterol of medium HDL subclass. Serum triglyceride and triglyceride contents in VLDL and LDL subclasses were decreased only by atorvastatin. CONCLUSIONS: The impact on lipoprotein subclass profiles was different between pitavastatin and atorvastatin. It may be beneficial to determine lipoprotein subclass profile and select the appropriate statin for each profile in patients with diabetes with an additional cardiovascular risk such as low HDL cholesterol or hypertriglyceridaemia.

Autologous tumor-specific cytotoxicity of tumor-infiltrating lymphocytes derived from human renal cell carcinoma.

Conditions for generating and expanding cytotoxic tumor-specific, tumor-infiltrating lymphocytes (TIL) were studied to improve the efficacy of adoptive cancer immunotherapy. Thus, we have examined the growth and cytolytic patterns of bulk culture TIL from human renal cell carcinoma (RCC) cultured in low (20 U/ml) or high (1,000 U/ml) dose interleukin (IL)-2, with or without irradiated autologous tumor stimulation. By 55 days in culture, TIL grown in the presence of IL-2 without tumor stimulation lost their lytic activity, whereas those exposed to tumor stimulation maintained high levels of cytotoxicity against autologous and/or nonautologous tumor targets. Only TIL grown with low dose IL-2 and autologous tumor maintained long-term (over 4 months in culture) specific cytotoxicity against the autologous tumor, even upon cryopreservation and regrowth. These TIL were 88-97% and 80% positive for CD3 and CD8, with a persistent subset exhibiting CD4+ CD8+ double positive staining. Their specific cytotoxic activity was major histocompatibility complex Class I-restricted and inhibited by pretreating the TIL with anti-CD3 monoclonal antibody. TIL exposed to the four types of culture conditions, low or high dose IL-2, with or without irradiated autologous tumors, and exhibiting different lytic specificities, all expressed mRNA for interferon-gamma and tumor necrosis factor (TNF)-alpha, but not for IL-1-beta, IL-4, IL-6, and granulocyte-macrophage colony stimulating factor. The degree of TNF-alpha mRNA expression correlated with the degree of autologous tumor-specific cytotoxicity of these TIL. This initial report demonstrates that antigen-specific cytotoxicity against the autologous tumor does, in fact, exist within the RCC tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Triiodothyronine resuscitates the impaired liver function after Pringle's maneuver.

OBJECTIVE: To evaluate the changes in thyroid hormone levels and the effectiveness of exogenous triiodothyronine (T3) in shock caused by prolonged use of Pringle's maneuver (cross-clamping of hepatic triads). DESIGN: Pringle's maneuver was performed on dogs for 1 hour. In the T3 group (n = 7), 1 microgram/kg per hour of T3 was administered intravenously for 3 hours after declamping. In the control group (n = 7), the same volume of saline solution without T3 was administered. MAIN OUTCOME MEASURES: Serum T3, reverse T3, thyroxine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and the ketone body ratio (AKBR), which reflect the hepatic energy charge, were measured. Tissue blood flow, tissue blood velocity, and tissue blood mass of the liver were measured by means of a laser Doppler flowmeter. Oxygen saturation of the hemoglobin in the liver tissue was measured by tissue near-infrared spectroscopy. Dogs were observed until the seventh postoperative day. RESULTS: In the control group, the low T3 syndrome was observed. None of the dogs recovered from the shock and none survived for more than 24 hours. In the T3 group, all dogs recovered from the shock and survived. In the control group, hepatic tissue blood flow and oxygen saturation of hemoglobin in liver tissue were decreased, and the AKBR was deteriorated. In the T3 group, however, these parameters were markedly improved. CONCLUSION: It is suggested that T3 administration is beneficial in managing the critical resuscitation period of liver function after Pringle's maneuver is performed in dogs.

Prevalence of intestinal parasitic infection in five farms in Holambra, São Paulo, Brazil.

A parasitological survey was carried out on 222 inhabitants of five farms in Holambra, located 30 km north of Campinas, São Paulo, Brazil, on October 1992. Approximately 70% of the inhabitants were found to be infected with at least one species of intestinal parasite. The positive rates of 6 helminths and 7 protozoan species detected are as follows: 5.4% Ascaris lumbricoides; 8.6% Trichuris trichiura; 19.8% Necator americanus; 10.4% Strongyloides stercoralis; 1.4% Enterobius vermicularis; 0.9% Hymenolepis nana; 3.2% Entamoeba histolytica; 2.7% E. hartmanni; 9.9% E. coli; 14.0% Endolimax nana; 2.3% Iodamoeba butschlii; 10.4% Giardia lamblia; 37.8% Blastocystis hominis. The positive rates of helminth infection were generaly higher in the younger-group under 16 years-old than those in the elder group aged 16 or more, whereas the infection rates of protozoan species were higher in the elder group. The infection rate of Strongyloides was found to be 10.4% by a newly developed sensitive method (an agarplate culture methods).

Gelatin particle indirect agglutination test for serodiagnosis of schistosomiasis: comparative study with enzyme-linked immunosorbent assay.

A new serological test, the gelatin particle agglutination test (GPAT), was used for the serodiagnosis of schistosomiasis mansoni. This technique showed the sensitivity (90.6%) and specificity (97.8%) close to those of enzyme-linked immunosorbent assay. The GPAT can be easily and rapidly performed without specialized equipment, by using lyophilized antigen-coated gelatin particles. The test also seems to be useful for mass screening of Schistosoma infection in field conditions.

St. Jude Medical prosthetic aortic valve malfunction due to pannus formation.

According to the literature, the incidence of pannus formation with the St. Jude Medical prosthetic aortic valve has been reported at 0.03% and 0.14% (per patient-year), with no case report of St. Jude Medical prosthetic aortic valve malfunction due to pannus formation. Between 1980 and 1999, 1,186 patients underwent aortic valve replacement at our institute. We encountered 2 aortic valve malfunctions due to pannus formation, including the case of a 53-year-old woman who suffered a St. Jude medical aortic valve malfunction 13 years after the initial operation. A second aortic valve replacement was successful and the postoperative course was uneventful. The possibility of pannus formation on St. Jude Medical aortic valves must thus be considered and its mechanism clarified.

[Efficacy and safety of a single oral dose of pilsicainide in supraventricular arrhythmia after coronary artery bypass grafting].

We evaluated the efficacy and safety of administration of a single oral dose of Pilsicainide, a class Ic antiarrhythmic agent, in 34 patients (26 men, 8 women, age from 48 to 81, mean age 66 +/- 8 years) who developed supraventricular arrhythmia after coronary artery bypass grafting (CABG). A total of 42 episodes of postoperative supraventricular arrhythmia, with the majority occurring 2-4 days after CABG, were classified as follows: paroxysmal atrial fibrillation, 34; paroxysmal atrial flutter, 6; and sinus tachycardia, 2. Sinus rhythm was restored in 32 episodes (78%) by treatment with oral pilsicainide given in a single dose of 50 ro 100 mg. Successful conversion was obtained within 90 minutes in 44% and 3 hours in 56% of episodes, with a mean conversion time of 119.2 +/- 107.5 minutes after the administration of pilsicainide. The mean conversion times tended t highlight the difference between the 50 mg and 100 mg doses, but this difference was not statistically significant (p = 0.053). The ventricular rate was significantly reduced from 123.3 +/- 29.5 beats/min to 85.6 +/- 19.9 beats/min (p < 0.0001), however no significant changes in blood pressure or no significant side effects were observed. The results of the present study suggest that a single oral dose of pilsicainide, administered for its favorable pharmacokinetic profile and lack of hemodynamic side effects, is a valuable drug for converting supraventricular arrhythmia to sinus rhythm in most patients after CABG.

[Hemodynamic evaluations of patients with small aortic annulus with St. Jude Medical prosthetic heart valve].

As the elderly population in Japan increases, senile degenerative aortic valvular disease also tends to increase. These patients often have a small aortic annulus. The problem of "valve-patient-mismatch" occurs when a small prosthesis is inserted into a patient with a small aortic annulus. To avoid annular enlargement after aortic valve replacement (AVR), we tried to use a small-sized St. Jude Medical (SJM) valve. From September 1988 through November 1996, 110 AVR were performed in our institution. In these cases, 30 underwent AVR with a small sized SJM valve (male < or = 21 mm, female < or = 19 mm). Dobutamine stress echocardiography was performed in 19 patients who had undergone AVR with a small-sized SJM valve. Surgical results were also compared between patients with small aortic annulus and those with normal-sized aortic annulus. Using Doppler echocardiography, pressure gradients (PG), cardiac index (CI), effective orifice area (EOA), and performance index (PI) were calculated at rest and during stress. The mean body surface area (BSA) of patient who had undergone AVR with SJM19A, 19HP and 21A was 1.40, 1.42 and 1.56 m2, respectively. With dobutamine stress, heart rates, PG and CI increased significantly. Mean and maximum PG of patients with 19HP (8.0 and 15.4 mmHg at rest, 12.9 and 28.0 mmHg under stress, respectively) and 21A (9.5 and 19.1 mmHg at rest, 16.5 and 35.3 mmHg under stress, respectively) were relatively low. EOA index (EOAI) of patient with 19HP showed the highest values mean 0.93 cm2/m2. PIs tended to be higher with HP models than with standard models. The tests were completed without significant side effects such as frequent ventricular arrhythmias. Among the cases with small aortic annulus, there were no operative deaths or hospital deaths. There were also no late deaths, episodes of hemorrhage or thrombosis. Conclusions. In our institution, AVR was performed safely without any aortic annular enlargement with a small aortic anulus in small BSA patients. Postoperative hemodynamic data obtained by echocardiography were satisfactory for all patients at rest and even during maximum dobutamine stress test.

[Application of simultaneous flow cytometric bromodeoxyuridine (BrdU)/DNA analysis. 2. Basic study to apply as a chemosensitivity test].

We developed a new method to rapidly measure the effectiveness of certain anticancer drugs by analyzing their effects on cell kinetics and cell cycle progression of labeled cells using simultaneous flow cytometric BrdU/DNA analysis. Three anticancer drugs, adriamycin (ADR), vincristine (VCR), and cisplatin (CDDP) were tested using the cultured cell line (MBT-2) originated from FANFT-induced mouse bladder tumor. The effects of these drugs were compared with percent colony survivals calculated by colony assay. The anticancer effects (IC90 levels) of ADR and CDDP could be determined by analyzing the effect of the drug on cell kinetics and cell cycle progression using the aforementioned method. However, in the case of VCR no relationship was found between the effect of the drug on cell kinetics and its anticancer effectiveness. Therefore, we must search for a better parameter for VCR, such as the inhibition rate of BrdU uptake.

[Application of simultaneous flow cytometric bromodeoxyuridine (BrdU)/DNA analysis. 1. Basic and technical studies].

The precise in vitro and in vivo BrdU labeling methods and the optimal combination of HCl concentration, treatment time and temperature for DNA denaturation for use in simultaneous flow cytometric BrdU/DNA analysis were investigated. An EPICS C Cell Sorter with computer analyser was used. 1) For precise labeling of exponentially growing MBT-2 cells the cell should be exposed to 10 microM BrdU for 30 min. 2) For optimal labeling of mouse subcutaneous MBT-2 tumor cells 40 micrograms of BrdU per gram should be injected intraperitoneally for 1 hour. 3) The procedure yielding the most quantitative results for DNA denaturation was treatment of the cells with 4N HCl for 20 min at 20 degrees C. Under these conditions, reliable data were always obtained. In the future, this flow cytometric two-color analysis will be applied to clinical fields and further development is expected.

[Flow cytometric bromodeoxyuridine (BrdU)/DNA analysis--study with urogenital tumors].

We performed the simultaneous flow cytometric bromodeoxyuridine (BrdU)/DNA analysis in combination with in vitro BrdU labeling method using seven human urogenital tumors. The DNA content and incorporated BrdU content of each tumor cell was analyzed quantitatively using this flow cytometric method. The cell kinetics of each cell line of heterogeneous tumor could be analyzed by this combined method. In the near future, by establishing a procedure decreasing non-specific staining of cells, the development of this flow cytometric two-color analysis in clinical fields is expected.

[Prostate-specific antigen (PA) and deoxyribonucleic acid (DNA) analysis in prostatic epithelial cells using flow cytometry].

We developed a new method to analyze simultaneously cellular prostate-specific antigen (PA) content and deoxyribonucleic acid (DNA) content of each prostatic epithelial cell by using flow cytometry (FCM). We report the possibilities of this method and we analyzed firstly 8 samples from 6 patients with benign prostatic hypertrophy (BPH). The content of cellular PA and DNA of prostatic epithelial cells can be analyzed simultaneously. The PA is synthesized only in the cells with a 2C DNA content (G0/1 cells) and not in the S- or G2M-phase cells. In the near future, by applying this analytical method to prostatic cancer samples we could obtain more interesting knowledge of the behavior of prostatic cancer.

[Subrenal capsule assay for chemosensitivity test of urological malignancy].

We evaluated the subrenal capsule assay with a chemosensitivity test using 47 fresh surgical explants, including 16 renal cell carcinomas and 10 uroepithelial cancers. Forty-one explants were evaluable and 166 drug tests were performed. Forty-seven tests (28.3%) were found to be sensitive. Ten of 16 renal cell carcinomas involved a sensitive drug, 3 involved more than 2 sensitive drugs. VP-16, ADM, BLM and 5-FU were the most sensitive compared with the others. Concerning the uroepithelial cancers, 8 of 10 involved a sensitive drug, 5 involved more than 2 sensitive drugs. CDDP and VP-16 were more effective than the other drugs. This result showed a good correlation with the clinical therapeutic efficacy using CDDP. In the future, we hope to evaluate the clinical correlation between clinical efficacy and this assay.

[Flow cytometric analysis of DNA ploidy using paraffin-embedded germ cell tumors].

The DNA content of paraffin-embedded materials was determined retrospectively using flow cytometry (FCM) in 36 germ cell tumors, and related to histological type, clinical staging and tumor marker. These histograms were classified from the basis of mode and variance into a diploid and an aneuploid pattern. We could evaluate the DNA histograms in 20 of 36 specimens (56%). Aneuploid patterns were found in 11 of 20 evaluated cases, but there was no correlation between ploidy patterns and histological types. Aneuploid patterns were demonstrated in 2 of 6 stage I cases (33%), and 4 of 5 stage II cases (80%) in seminomas. The difference between stage I and II cases was not statistically significant. There was no correlation between clinical staging and DNA content in non-seminomas. Of the seminomas with elevated human chorionic gonadotropin (HCG) titers, 3 of 4 cases showed aneuploid patterns. These findings indicate that the determination of DNA ploidy in seminomas may prove to be of prognostic value.

[Clinical study of prostate cancer--statistical analysis in the last 10 years].

Fifty one cases of prostate cancer were treated at Yamaguchi University Hospital during 10 years since 1975. Age distribution was between 43 and 90 years old with an average of 70.9 years. Chief complaints were difficulty on micturition (33%), complete urinary retention (19.6%), macroscopic hematuria (15.7%), and frequency (13.7%). Clinical stage was classified as 1 case (2%) with stage A, 7 cases (13.7%) with stage B, 20 cases (39.2%) with stage C and 23 cases (45.1%) with stage D cancer. Histological grade was classified as 9 cases (17.6%) with well differentiated type of adenocarcinoma, 15 cases (29.4%) with moderately differentiated type and 27 cases (52.9%) with poorly differentiated type. The 5-year actual survival rate was 75% for stage A&B, 50% for stage C and 60% for stage D. The 10-year actual survival rate was 20% for stage A&B, 17% for stage C and 20.5% for stage D. There were no statistically significant differences between stage, grade and survival rate. According to specific cause 18 cases (58%) were cancer deaths including 8 cases (15.7%) of refractory disease, and 4 cases (12.9%) of cardiovascular complication. Five of the eight refractory cases could survive over one year by multimodal treatment. Local irradiation to prostate was most effective to control symptoms against locally refractory prostate cancer.

[Cell kinetic study of urogenital tumors utilizing in vitro BrdU-labelling method and anti-BrdU monoclonal antibody].

With the aim to apply a rapid analytic method of cell kinetics using in vitro BrdU labelling and anti-BrdU monoclonal antibody to the clinical fields, we investigated the cell kinetics of 20 urogenital malignant tumors. The DNA synthesizing cells which take up BrdU in its nuclei can be detected so clearly, since the labelling index (LI) is easily identified. The correlations between LI and age and with histological grade and stage of 14 transitional cell cancers of urinary tract were investigated. There was no correlation between LI and age. The LI of high grade groups (G2 & G3) were significantly higher than that of the low grade group (G1) (p less than 0.05). Also between LI of pT1 group and pT3 group, there was a statistical significance (p less than 0.05) and generally LI tended to increase according to stage progression. Therefore, the cytokinetic data obtained from the before mentioned method can be utilized as a useful marker for measuring malignant potentials of each tumor.

[Pharmacokinetics of high-dose cisplatin administration (relationship between pharmacokinetics and administration schedule)].

Three cases of urogenital malignancy were treated with 80-120/m2 of cisplatin by a 0.5-hour (rapid) or 4-hour (slow) infusion. Each patient received three courses of repeated chemotherapy. The kinetics of total platinum was measured up to 48 hours in the blood and urine. The blood peak concentrations were achieved 6.0 micrograms/ml by rapid infusion, 2.0 micrograms/ml by slow infusion. The time dependent urinary excretion rate against total administered dose was 40% in 60 min. by rapid infusion, 20% in 16 hours by slow infusion. The volume of distribution correlated with infusion time. Rapid infusion way of cisplatin could be better to treat the patient with bulky tumor mass or patients with uroepithelial cancer like CIS, because a higher blood and urine concentration can be obtained than by slow infusion.

[Expression of proliferating cell nuclear antigen in superficial bladder cancer--application to paraffin-embedded tissue sections].

It is important to know the proliferating ability and the malignant potential of each tumor. We studied 56 cases of pTa to pT1 superficial bladder tumors using immunohistochemical staining for proliferating cell nuclear antigen (PCNA), and compared the results with the clinical course of each patient. We obtained the following results. 1) We detected the PCNA positive nuclei in all cases, and the PCNA positive rates varied within a range of 1.1-77.5% with a mean of 34.0%. 2) The PCNA positive rate showed no correlation with age, sex, duration of paraffin-embedded, or pathological stage, but showed a significant correlation with the number of tumors, pathological grade of malignancy, or non-recurrence rate. PCNA positive rate of Grade 1 cases (n = 19, 15.6%: mean) was significantly lower than those of Grade 2 cases (n = 27, 39.9%) or Grade 3 cases (n = 10, 53.1%) (P < 0.01). The recurrence rate of the cases with PCNA positive rates of more than 34% (n = 24) was significantly higher than that of the cases with a PCNA positive rate of less than 34% (n = 32) (P < 0.05). In conclusion, the method of counting the rate of PCNA positive nuclei is considered to be very useful because of its applicability to paraffin-embedded tissue sections and the simple and rapid techniques. Our results in bladder cancer tissues suggest that this method may also be useful for investigating the proliferating ability and the malignant potential of tumors in general.

[Clinical evaluation of Cernilton in benign prostatic hypertrophy].

Twenty patients with benign prostatic hypertrophy were treated with Cernilton, 6 tablets a day for an average of 13.2 weeks. Subjective effectiveness was observed in the improvement of sense of residual urine (92%), retardation (86%), night frequency (85%), strain on urination (56%), protraction (53%) and forceless urinary stream (53%). The overall subjective effectiveness was 80% of patients, and the overall objective effectiveness was 54% of patients. Night frequency, residual urine volume and tidal urine volume were improved significantly. The overall effectiveness was 80%. No side effects were observed.

[Clinical study of sonography and percutaneous nephrostomy in pyonephrosis].

Sonography and percutaneous nephrostomy (PNS) were performed on 16 patients with pyonephrosis and the following results were obtained. Sonography revealed a dilated collecting system in all cases within which, however, neither debris nor gas was observed in any case, the pelvocaliceal system appeared hypoechoic in 2 cases and anechoic in 14 cases. From the clinical symptoms and the dilated collecting system demonstrated by sonography, pyonephrosis was diagnosed in 14 cases. The purulent fluid aspirated from the collecting system confirmed the diagnosis in all cases. The clinical condition was stabilized by PNS and antibacterial therapy in all cases. However, in 5 of the patients with pyrexia for more than 6 days before PNS, sepsis developed in 3 cases and pyrexia continued for more than 3 days after the treatment in 4 cases. The affected 11 kidneys showing recovery of renal function following PNS were all salvaged by elective surgery. These findings suggest that prompt diagnosis by needle aspiration is necessary, even in the absence of any sonographically characteristic findings, whenever pyonephrosis is suspected. Our experience suggests that PNS is a useful therapeutic procedure for pyonephrosis.