Inhibition of intestinal cholesterol absorption might explain cholesterol-lowering effect of telmisartan.

WHAT IS KNOWN AND OBJECTIVE: Telmisartan, an angiotensin II type 1 receptor blocker (ARB), acts as a partial agonist for peroxisome proliferator-activated receptor-γ, and thus improves abnormalities of glucose metabolism and hypertriglyceridaemia in addition to its documented blood pressure-lowering effects. Recently, it has been demonstrated that telmisartan also lowers the levels of total cholesterol and low-density lipoprotein (LDL) cholesterol levels. This study was designed to investigate the mechanism of cholesterol reduction. METHODS: We measured serum levels of cholestanol, a cholesterol absorption marker, and lathosterol, a cholesterol synthesis marker, in 20 patients with both hypercholesterolaemia and hypertension. Ten patients were treated with telmisartan and the remaining 10 with fluvastatin. RESULTS: After 3 months of treatment, total and LDL cholesterol levels decreased in the telmisartan group (P<0.01 for both total and LDL cholesterol levels) and the fluvastatin group (P<0.001 for both total and LDL cholesterol levels). The change in cholestanol level after 3 months of treatment was positively correlated with the levels of total (R=0.72, P<0.05) and LDL cholesterol (R=0.81, P<0.01) in the telmisartan group. The change in lathosterol level was positively correlated with the levels of total (R=0.88, P=0.001) and LDL cholesterol (R=0.89, P=0.001) in the fluvastatin group. WHAT IS NEW AND CONCLUSIONS: Our results suggest that the cholesterol-lowering effect of telmisartan might be caused by inhibition of cholesterol absorption, whereas that of statins is by inhibition of cholesterol synthesis. If confirmed, co-treatment with the two agents may be useful for synergistically lowering cholesterol in hypertensive patients.

Computed tomography appearance of Hem-o-lok clips in patients who have undergone laparoscopic nephrectomy or nephroureterectomy.

BACKGROUND AND OBJECTIVES: Hem-o-lok clips are safe and reliable for controlling the renal vasculature. We retrospectively evaluated the CT appearance of Hem-o-lok clips in patients who had undergone laparoscopic radical nephrectomy (LRN) or nephroureterectomy (LRU) as well as their appearance on ex vivo CT scans. METHODS: Between January 2006 and December 2006, 19 patients underwent LRN or LRU, and their CT images were reviewed within 5 postoperative months. The Hem-o-lok clips were radiopaque in all of the patients' CT images, and their radiodensity value was 222 Hounsfield Units (HU). To confirm that Hem-o-lok clips are radiopaque on CT images, an ex vivo CT scan was performed. RESULTS: We confirmed that these clips are radiopaque on CT images and that they have a radiodensity of 223 HU. CONCLUSION: We conclude that the Hem-o-lok clips are radiopaque on CT images. It is important for urologists and radiologists to be aware of the CT appearance of Hem-o-lok clips when following up patients who have undergone LRN or LRU.

Sulfatides are associated with neointimal thickening after vascular injury.

BACKGROUND: Sulfatides are known to be a native ligand of P-selectin. Platelet-leukocyte interaction via the cross-talk between P-selectin and Mac-1 (CD11b/CD18) plays an important role in the mechanism of neointimal thickening after vascular injury such as that seen in post-stent restenosis. However, the roles of sulfatides on restenosis have not been elucidated. METHODS: Serum sulfatide levels, P-selectin expression on the surface of platelets, and activated Mac-1 on the surface of neutrophils were serially measured using both coronary sinus and peripheral blood samples in 21 patients who underwent coronary stent implantation. RESULTS: The trans-cardiac gradient (coronary sinus minus peripheral blood) of the sulfatide levels significantly increased at 15 min (-1.47+/-2.87 to 0.59+/-1.44 nmol/ml, p<0.001), compared to baseline levels. The maximum response of the trans-cardiac gradient of P-selectin expression on the surface of platelets at 15 min after stent implantation (R=0.55, p<0.01), and that of activated Mac-1 on the surface of neutrophils at 48 h (R=0.59, p<0.01), were both positively correlated with that of serum sulfatide levels at 15 min. The angiographic late lumen loss was correlated with the trans-cardiac gradient of sulfatide levels at 15 min (R=0.48, p<0.05), platelet P-selectin expression at 15 min (R=0.42, p<0.05) and activated neutrophil Mac-1 expression at 48 h (R=0.46, p<0.05), but not with values at other sampling points. CONCLUSIONS: Sulfatides may play a physiological role on inflammation in vascular injury and the development of neointimal thickening.

Effects of retinoic acid and interferon-gamma on expression of the retinoic acid receptor in mouse renal cell carcinoma.

The clinical outcome of interferon-gamma treatment of metastatic renal cell carcinoma remains unsatisfactory. To overcome this, a reagent that has a different action on cancer cells is desired. One such candidate may be 13-cRA (cis retinoic acid), a vitamin A derivative known to markedly regulate the differentiation and proliferation of normal and neoplastic cells. Moreover, 13-cRA demonstrates a remarkable synergistic effect with IFN-gamma in certain types of cancer. We investigated the efficacy of concomitant administration of 13-cRA and IFN-gamma. The in vivo anti-tumor effects were evaluated in a lung metastasis model using a mouse renal cell carcinoma cell line (RenCa). The in vitro anti-tumor effects were also assessed by MTT assay. The presence of retinoic acid receptors (RAR)-alpha, -beta and -gamma was examined by PCR analysis. The influence of IFN-gamma on these retinoic acid receptors was evaluated by Northern blotting. IFN-gamma showed anti-tumor effects both in vivo and in vitro. This effect was enhanced synergistically with concomitant 13-cRA treatment. RenCa cells expressed RAR-alpha, and -gamma, but not -beta according to PCR analysis. IFN-gamma treatment increased the expression level of RAR-alpha and RAR-gamma according to Northern blot analysis. Combination therapy using IFN-gamma and 13-cRA showed synergistic anti-tumor effects, which exceeded those of each therapy alone. Moreover, IFN-gamma treatment increased RAR-alpha and RAR-gamma expression. Thus, the augmented anti-tumor effects of IFN-gamma and 13-cRA may be attributable to enhanced expression of RAR-alpha and RAR-gamma by IFN-gamma treatment.

[Malignant lymphoma of the prostate: a case report].

A case of a primary malignant lymphoma of the prostate is presented. An 82-year-old man visited our hospital complaining of anal pain. Digital rectal examination revealed an enlarged prostate gland, which caused a rectal stricture. A computed tomographic scan and magnetic resonance imaging (MRI) showed a large mass arising from the prostate and protruding to the rectum. According to the Working Formulation, he was diagnosed with non-Hodgkin's lymphoma of B-cell origin, diffuse, mixed, small and large cell. The results of bone marrow puncture and imaging studies led to the diagnosis of primary malignant lymphoma of the prostate. Because of poor performance status deriving from severe anal pain, radiation therapy was performed to control the pain. After improvement of his performance status, he received combination chemotherapy consisting of cyclophosphamide, adriamycin, vincristine and predonisone (CHOP regimen). His prostate markedly diminished in size, but pneumonia developed. His respiratory condition rapidly deteriorated, and he died of respiratory failure about two and a half months after the onset of his illness. Malignant lymphoma involving the prostate, whether primary or secondary, is very rare. In our understanding, this case is thought to be the 28th clinical case of a malignant lymphoma of the prostate in Japan.

Comparison of hemodynamic effects of enhanced external counterpulsation and intra-aortic balloon pumping in patients with acute myocardial infarction.

This study compared the hemodynamic effects of enhanced external counterpulsation and intra-aortic counterpulsation in patients with acute myocardial infarction. Results demonstrated similarity between these 2 methods, except enhanced external counterpulsation had a transient effect of increasing right atrial pressure, pulmonary capillary wedge pressure, and cardiac index.

Protection by a cyclic AMP-specific phosphodiesterase inhibitor, rolipram, and dibutyryl cyclic AMP against Propionibacterium acnes and lipopolysaccharide-induced mouse hepatitis.

OBJECTIVE AND DESIGN: To study the effect of cellular cAMP-increasing agents on Propionibacterium acnes (P. acnes) and lipopolysaccharide (LPS)-induced mouse hepatitis. MATERIAL: Male BALB/c mice were used. Macrophages/Kupffer cells isolated from P. acnes-primed murine liver were used for the in vitro study. TREATMENT: Type IV phosphodiesterase (PDE)-specific inhibitor, rolipram, was administered (10, 30 mg/kg, p. o.). Dibutyryl cyclic AMP (dbcAMP) was injected (10, 100 mg/kg, i.p.) into the mice. METHOD: Plasma TNFalpha estimated by the use of an L-929 cell cytotoxic assay and plasma transaminase activities were measured for the in vivo study. The LPS-induced production of TNFalpha in vitro from the cultured macrophage/Kupffer cells was determined by ELISA. RESULTS: Rolipram suppressed the elevation of plasma transaminases induced by injection of LPS, and dbcAMP had a tendency to suppress them. Both agents attenuated the LPS-induced release of TNFalpha in vivo, and suppressed the TNFalpha production from the cultured macrophage/Kupffer cells. CONCLUSIONS: These results suggest that rolipram and dbcAMP have potential to inhibit TNFalpha production from activated macrophage/Kupffer cells, and it may be partially involved in the protecting effect in the P. acnes/LPS hepatitis model.

Synergistic anti-tumor effect of 13-cRA and IFN-alpha/beta in mouse renal cell carcinoma.

The synergistic anti-tumor effect of 13-cis retinoic acid (13-cRA) and interferon-alpha/beta (IFN-alpha/beta) was investigated using a highly metastatic mouse renal cell carcinoma cell subline (RenCa/F). Although 13-cRA inhibited tumor growth in vivo as well as in vitro, IFN-alpha/beta did not. Combined administration of 13-cRA and IFN-alpha/beta significantly enhanced the anti-tumor effect of 13-cRA. The retinoic acid receptor (RAR)-alpha and RAR-gamma were expressed in RenCa/F cells. Treatment with IFN-alpha/beta did not influence the expression level of these receptors at the mRNA level, which suggests that the synergism of 13-cRA and IFN-alpha/beta is not mediated through the RAR.

Clinical study of renal cell carcinoma with brain metastasis.

BACKGROUND: The clinical outcome of patients with renal cell carcinoma with brain metastasis was analyzed. METHODS: Nine patients (median age, 60 years) with primary renal cell carcinoma and distant metastasis, including brain metastasis, were treated. The median time to the development of brain metastasis was 15 months after the initial visit. Patients with poor performance status or progressive disease were treated with interferon or conservative therapy alone. Patients with good performance status and other well-controlled metastatic foci were treated either with radiotherapy, or by tumorectomy of brain metastasis, or both. The median follow-up was 26 months after the initial visit. RESULTS: The 1-year, cause-specific survival rate was 17%. Of the 5 patients treated with alpha-interferon alone, all died of disease after the treatments, without improvement of performance status, 1 to 4 months after the diagnosis of brain metastasis. Two of 4 patients who underwent radiotherapy were treated with a combination of gamma-knife and tumorectomy of brain metastasis. They remained alive 10 and 22 months after diagnosis of brain metastasis. The 2 patients who underwent the combination treatment of gamma-knife and tumorectomy showed improvement of their performance status after these treatments for brain metastasis. CONCLUSION: Brain metastasis is an unfavorable prognostic factor in renal cell carcinoma. Although a larger number of patients would be necessary to demonstrate the definitive effects of gamma-knife treatment, our results suggest that the combination of gamma-knife and tumorectomy of brain metastases may be recommended for selected patients with good performance status and other well-controlled metastatic foci.

Clinical evaluation of random biopsy of urinary bladder in patients with superficial bladder cancer.

BACKGROUND: Superficial bladder cancer has a tendency to recur in the urinary bladder. One reason for recurrence is the presence of concomitant carcinoma in situ (CIS) or dysplasia. However, the usefulness of random biopsy of the urinary bladder has been unclear. METHODS: Between September 1990 and March 1996, 83 patients with superficial bladder cancer underwent mucosal biopsy of 6 different sites in the urinary bladder with macroscopically normal findings (random biopsy). The relationship between a positive biopsy (CIS or dysplasia) and the tumor characteristics was examined. The disease-free survival of the patients according to the biopsy results was determined. RESULTS: The positive biopsy rate was 24.1% (CIS, 14.5%; dysplasia, 9.6%). The incidence of positive biopsy in patients with high-grade (G3), pT1 tumors, 3 or more and non-papillary wide-based tumors was significantly higher than that in patients with 1 or 2 tumors, low-grade (G1, G2), pTa tumors and papillary tumors (P < 0.05). In patients with a single papillary tumor, positive biopsy was found in 9.5%. The disease-free survival in patients with a positive biopsy did not differ from that in patients with a negative biopsy, because intravesical bacillus Calmette-Guérin was instilled in patients with a positive biopsy. CONCLUSION: Our results indicate that random biopsy is useful for detecting concomitant CIS or dysplasia and in the choice of drugs for intravesical instillation.

Detection of hepatitis C virus helicase activity using the scintillation proximity assay system.

The C-terminal two-thirds of the nonstructural protein 3 (NS3) of hepatitis C virus (HCV) possesses RNA helicase activity. This enzyme is considered to be involved in the viral replication and is expected to be one of the target molecules of anti-HCV drugs. The conventional method for the measurement of RNA helicase activity includes the step of gel electrophoresis which makes the screening of multiple samples inconvenient. In this study, to establish a high-throughput screening system for HCV helicase inhibitors, we applied the scintillation proximity assay (SPA) system to the detection of this enzymatic activity. We could detect the helicase activity using the NS3 protein purified by an immunoaffinity column. The activity was dependent on the concentration of the enzyme and the reaction time. The RNA helicase activity measured by the SPA system was in a good correlation with that obtained by the conventional method. Furthermore, the SPA system showed better reproducibility and less deviation of the data than the conventional method, which makes the former suitable for quantitative analysis. Since any separation step is not required and microtiter plates can be used in this method, it has the advantage of dealing with multiple samples.

[Standardization of serum lipid examination: an attempt in Oita].

There is an obvious difference in currently available clinical laboratory data between hospitals. With the advent of information systems, the clinical laboratory information in the future must be standardized so that it can be used in medical treatment and health control throughout the life patients time. Establishing publicly acknowledged standards is essential for standardization to be translated into practice. The standards for clinical laboratory examination in Japan are approved by consensus in the Japanese Committee for Clinical Laboratory Standards (JCCLS). However, standards have yet to be established for most laboratory examinations. This poses is a major obstacle in promoting the standardization. Standardization should be implemented carefully with consideration of the worldwide trend. That is probably the reason why the consultation and approval at JCCLS have been delayed, but it is hoped that standards will be established as soon as possible. The committee for quality control survey in Oita Medical Association organized a Lipid Unit of the Sectional Committee for Standardization in 1994 and has since implemented standardization according to the lipid standardization program of the U.S. Centers for Disease Control and Prevention (CDC) with some modifications. Measures for improvement have been adopted for a trial period in parallel with four surveys, and in September, 1995 all 9 hospitals passed the standardization test performed on the basis of the CDC provisions for certification. The Oita Medical Association plans to expand the lipid standardization to all parts of the prefecture using the trial of standardization by the Lipid Unit as a model.

[Clinical evaluation of tandem PSA for the diagnosis and follow-up of prostate cancer].

The Tandem PSA test was performed simultaneously with assay of Markit-M PA and gamma-seminoprotein to determine its usefulness for the diagnosis of prostate cancer in a total of 81 patients with prostate diseases. The diagnosis was untreated prostate cancer in 16 patients including 2 with T1c tumor, benign prostatic hyperplasia in 56 patients, and other diseases in 9 patients. Tandem PSA, Markit-M PA, and gamma-seminoprotein showed a sensitivity of 81.3, 62.5, and 68.8%, respectively, while the specificity was 67.7, 81.5, and 72.3%, respectively. Tandem PSA had the highest sensitivity, although the specificity and accuracy were the lowest. These results were considered to be due to the fact that the PSA level becomes significantly higher with an increase in the weight of benign prostatic hyperplasia. This indicates that the PSA density should be considered to improve the specificity of Tandem PSA. Use of the Tandem PSA/gamma-seminoprotein ratio was also examined as a possible method which might improve the specificity. Patients with benign prostatic hyperplasia and prostate cancer had a ratio of 1.53 +/- 0.966 and 3.21 +/- 1.811 (mean plus standard deviation), respectively, and these 2 groups showed a significant difference (p = 0.0008). This indicates that calculation of the Tandem PSA/gamma-seminoprotein ratio may be useful to improve the specificity of Tandem PSA for the diagnosis of prostate cancer.

[Radical prostatectomy for localized prostate cancer].

We studied 81 patients who underwent radical prostatectomy for prostate cancer. Ten, 57 and 14 patients were clinically diagnosed with stage T1, T2 and T3, respectively. Pelvic lymph node dissection was performed prior to prostatectomy in all cases. The neurovascular bundle was preserved in 21 patients. Compared with pathological stage, the accuracy rate of clinical staging in T1, T2 and T3 was 40, 46 and 64% respectively. Approximately half of the patients clinically diagnosed with stage T2 were pT3. The positive rate of lymph node in pT2 and pT3 was 3.3 and 37% respectively, showing a marked difference between these two pathological stages. The 3-year non-recurrence rates were 89% in patients with pT2 and 79% in pT3. In the well differentiated carcinoma group, no patients had recurrence for up to 3 years. All of the patients with infiltration (INF) gamma showed recurrence within 3 years. Fifty-five patients had no problem on urination post-operatively, while the other 23 patients had a mild or moderate incontinence and the remaining 3 patients had a small urine stream. Regarding erectile potency, 4 out of 18 evaluable patients were potent.

[Clinical analysis of 169 patients with prostate cancer].

At Matsumoto National Hospital, 169 patients with prostate cancer were diagnosed between April 1986 and May 1994. The prostate cancer incidence was the highest in the latter half of the seventies, with an average age of 74.3 years. The clinical stage was defined as A1, A2, B, C, and D2 in 24 (14.2%), 38 (22.5%), 39 (23.1%), 23 (13.6%) and 45 (26.6%) patients, respectively. The clinical stage was not correlated with the patient's age. Incidental carcinoma was discovered in 5.8% of the patients who underwent prostatectomy for benign prostatic hypertrophy (BPH). At initial diagnosis, the tumor was well, moderately, and poorly differentiated adenocarcinoma in 71 (42.0%), 64 (37.9%), and 34 (20.1%) patients, respectively. The median follow-up period was 38.7 months. The over all five-year crude survival rate was 54.8%, while the cause-specific five-year survival rate was 80.0%. The five-year crude survival rate was 58.4, 82.0, 55.2, 42.5 and 37.4%, for patients with cancer at stage A1, A2, B, C, and D. The survival rate was higher for patients with cancer at clinical stage A and shorter for those with cancer at clinical stage D than in other stages. Prognosis was also worse in patients with moderately or poorly differentiated adenocarcinoma than in those with well-differentiated adenocarcinoma. The clinical stage and the pathological grade are important as prognostic factors, although the high incidence of death from other diseases shows that the patients' age should be considered to choose the modality of therapy. These findings indicate that intensive treatment of the patients in clinical stage A2, B and C prostate cancer in combination with screening for the men between 50 and 75 years old for early cancer detection is required.

[Bowel anastomosis using valtrac in urologic surgery].

Valtrac, a biofragmentable anastomosis ring, was used in 10 patients who underwent total cystectomy and urinary tract reconstruction. The primary disease was bladder tumor, neurogenic bladder, and sigmoid colon cancer invading the bladder in 8, 1, and 1 of the patients, respectively. There were 8 ileo-ileostomies and 2 ileo-colostomies. No patient developed anastomotic leakage or insufficiency. Symptoms of mild bowel obstruction were observed in 3 patients, but they improved with conservative management. The outcome was good in all the patients without further ileus during a follow-up period of 1 to 12 months (median: 7.3 months). The most important advantage of this device is that precise bowel anastomosis is standardized and can be achieved safely and quickly. Our findings indicate that the Valtrac system offers a reliable and reproducible alternative to conventional anastomotic techniques in urologic surgery.

Structure of the 5'-flanking regulatory region of the mouse gene encoding the clearance receptor for atrial natriuretic peptide.

A full-length cDNA, encoding the mouse atrial natriuretic peptide clearance receptor (ANP-CR), was isolated from a mouse lung cDNA library. The deduced amino acid sequence of the mouse ANP-CR, showing a typical tripartite organization which lacks a guanylyl cyclase domain, was extremely well conserved compared with the ANP-CR homologs. To understand the molecular mechanisms underlying the regulation of mouse ANP-CR gene expression and to define the essential DNA sequences for the transcriptional activity, a genomic clone containing over 9 kb of the 5'-flanking region of the mouse ANP-CR gene has been isolated from a mouse genomic library. Sequence analysis revealed that the 2.3-kb region upstream from an ATG codon of the mouse ANP-CR gene contained a number of putative regulatory elements; TATA box, CAAT box, cAMP response element, AP-1 and two shear stress responsive elements. Additionally, an unusual feature was the presence of the tandem-repeated AP-2-like elements, which were closely overlapped with SP-1 element. Promoter analysis using deletion plasmids in mouse Balb/3T3 cells, highly producing ANP-CR mRNA, demonstrated that deletion of the sequence from -144 to +46 relative to the transcription start point caused a dramatic decrease of the transcriptional activity and that the TATA box at -269 was not essential for the basal transcriptional activity. Primer extension analysis indicated that transcription of the mouse ANP-CR gene starts from at least two major sites, suggesting that the sequence from -144 to +46, which was shown to involve a novel sequence composed of tandem-repeated TATA-box-like elements, contained promoter sequences. Furthermore, cis-acting negative elements were shown to be situated in three regions (from -1178 to -708, from -707 to -625 and from -248 to -145) of the mouse ANP-CR gene promoter.

[A clinical and pathological study of radical prostatectomy for prostate cancer].

BACKGROUND: Thirty-one patients with prostate cancer underwent radical prostatectomy and simultaneous pelvic lymphadenectomy at Matsumoto National Hospital between 1988 and 1994. Prognostic factors are discussed from their clincopathological findings. METHODS: The patients ranged from 54 to 80-year-old, with an average age of 69.9 years. The median follow-up period was 44 months. The diagnosis was confirmed by needle biopsy or transurethral resection of the prostate. All the patients received short-term endocrine therapy preoperatively, and only noncuratively resected patients underwent adjuvant therapy postoperatively. At initial diagnosis, the tumor grades were well, moderately, and poorly differentiated adenocarcinoma in 9, 12, and 10 patients, respectively. The clinical stage was defined as A2, B, C, D1, and D2 in 12, 4, 6, 3, and 6 patients, respectively. RESULTS: A difference of tumor grade was found between the initial diagnosis and the final diagnosis based on the resected prostate in 8 patients (26%), with 7 of them (88%) showing an increase in grade in the final diagnosis. Also revealed was that 11 of the 25 patients (44%) in stage A2, B, C, or D1 had been understaged preoperatively. The five-year actuarial survival rates were 100%, 92%, and 51% for patients with well, moderately, and poorly differentiated adenocarcinoma, respectively, with a significant difference noted between well and poorly differentiated adenocarcinoma (p = 0.03). Recurrence only developed in patients with pathological stage D tumors. However, the presence or absence of lymph node metastasis did not affect the crude 5-year survival rate. Several stage D patients were successfully treated by radical prostatectomy and adjuvant therapy, achieving long survival. CONCLUSION: These results indicate that patients in clinical stage C have tumors which exhibit differing biological behavior. These patients should be analyzed and classified more precisely so that the most appropriate therapy can be chosen.

[Primary malignant lymphoma of the adrenal gland: a case report].

A 65-year-old woman visited our hospital complaining of general fatigue and nausea. CT scan revealed a homogeneous mass in the left adrenal gland, which was seven centimeters in diameter. Mild swelling of the right adrenal gland was also suspected. We failed to find the primary tumor, although a metastatic non-functioning adrenal tumor was suspected. Adrenalectomy was performed under the diagnosis of a non-functioning adrenal tumor. Pathological examination showed a non-Hodgkin's lymphoma. Since a bleeding tendency gradually developed following the operation, a bone marrow biopsy was done, revealing an invasion by tumor cells. Patients with a malignant lymphoma involving the bone marrow should not be operated on because fatal complications may develop postoperatively. A malignant lymphoma should be considered as a possible diagnosis of adrenal tumors, although it is very rare.

A continent urinary valve by a subfascial ileal segment in dogs.

We created a new continent urinary valve in 6 dogs by placing an ileal segment between the anterior rectus sheath and rectus muscle in an antiperistaltic fashion. This ileal segment maintained urinary continence sufficiently and was readily catheterizable. Since it is easy to construct, the subfascial ileal valve will be applicable to construction of continent urinary reservoirs.