Biomedical subjects

Naoki Yoshimura

Publications and source records attributed to Naoki Yoshimura.

102 records · Page 6Linked to original sources

PubMed2002

Effect of KW-7158, a putative afferent nerve inhibitor, on bladder and vesico-vascular reflexes in rats.

The effects of KW-7158, a putative afferent nerve inhibitor, on reflex bladder activity and vesico-vascular reflexes were evaluated in urethane anesthetized SD rats with normal and xylene-irritated bladders. The bladder was filled with saline until the appearance of large amplitude spontaneous bladder contractions (LA-BC). Vesico-vascular reflexes were measured as increases in systolic arterial blood pressure during LA-BC or when the bladder was distended by a range of pressures. In normal rats, KW-7158 (10 and 100 microg/kg, i.v.) did not alter the amplitude or volume threshold for inducing LA-BC but increased the intercontraction interval. After xylene-irritation, which decreased volume threshold and intercontraction interval and induced small amplitude bladder contractions, KW-7158 increased volume threshold (65%) and intercontraction interval (150%) and decreased the number of small amplitude bladder contractions. Vesico-vascular reflexes induced during LA-BC or by bladder distension were suppressed (19.4-100%) by KW-7158. The effect of KW-7158 to depress vesico-vascular reflexes as well as xylene-induced bladder hyperactivity without altering the amplitude of contractions is consistent with the view that the drug affects reflex bladder activity at least in part by depressing afferent pathways.

Animals↗

PubMed2002

Effects of modified ultrafiltration on coagulation factors in pediatric cardiac surgery.

PURPOSE: Modified ultrafiltration (MUF) after cardiopulmonary bypass (CPB) in children has been reported to reduce the need for postoperative blood transfusion and minimize postoperative blood loss. This study was undertaken to quantify the effects of MUF on coagulation factors in pediatric patients. METHODS: Seven children scheduled to undergo open-heart surgery for congenital heart defects were studied. CPB circuits were primed with crystalloid solutions and no blood transfusions were performed. Hematocrit, platelet count, total plasma proteins, albumin, fibrinogen, prothrombin, factor VII, factor IX, and factor X were measured preoperatively, at the termination of cardiopulmonary bypass, and at the end of modified ultrafiltration. RESULTS: MUF was associated with significant (P < 0.05) increases in hematocrit (17.6% +/- 1.6% to 21.6% +/- 2.4%), platelet count 11.1 +/- 2.5 to 12.8 +/- 2.4 x 10(4)/mm3), total plasma proteins (2.7 +/- 0.3 to 3.4 +/- 0.4 g/dl), and albumin (1.6 +/- 0.2 to 2.1 +/- 0.2 g/dl). Fibrinogen, prothrombin, and factor VII also increased significantly (P < 0.05) during MUF, but factor IX and factor X did not change. CONCLUSION: We conclude that MUF attenuates the dilutional coagulopathy that occurs during CPB in children. There were slight improvements in the coagulation factors when MUF was employed.

Blood Coagulation Factors↗

PubMed2002

Current and future pharmacological treatment for overactive bladder.

PURPOSE: Urinary incontinence and overactive bladder are important and common conditions that have received little general medical attention. We reviewed the magnitude and impact of these conditions, and discuss pharmacotherapy as well as new drugs under investigation. MATERIALS AND METHODS: The main emphasis of this review is pharmacological therapy for the bladder. We discuss currently available agents, drugs under development and pharmacological targets that would be suitable targets for treating overactive bladder. Drugs such as duloxetine that target not bladder smooth muscle, but rather central nervous system control of the micturition reflex are undergoing clinical trials. We also discuss intravesical therapy and alternative drug delivery methods, such as intravesical capsaicin and botulinum toxin, with special emphasis on approaches to modulate bladder afferent nerve function for preventing overactive bladder. RESULTS: There are many advantages to advanced drug delivery systems, including long-term therapeutic efficacy, decreased side effects and improved patient compliance. Future speculation such as gene therapy holds great promise for overactive bladder because it is possible to access all genitourinary organs via endoscopy and other minimally invasive techniques that are ideally suited for gene therapy. CONCLUSIONS: Traditional anticholinergic therapies are limited in their effectiveness. There is great hope for future research regarding voiding dysfunction and urinary incontinence through a focus on afferent nerve intervention for preventing overactive bladder.

Adult↗

PubMed2002

Immunoneutralization of nerve growth factor in lumbosacral spinal cord reduces bladder hyperreflexia in spinal cord injured rats.

PURPOSE: We investigated the effects of intrathecal application of nerve growth factor (NGF) antibodies (Ab) on bladder hyperreflexia in chronic spinalized rats. MATERIALS AND METHODS: In adult female rats an intrathecal catheter was implanted at the level of the L6 to S1 spinal cord, followed by complete transection of the Th8 to 9 spinal cord. At 10 days after spinalization the intrathecal catheter was connected to an osmotic pump for continuous delivery of vehicle or NGF Ab (10 microg daily) for 2 weeks. Awake cystometry was then performed. NGF levels in the L5 to S1 dorsal root ganglia, L6 spinal cord and bladder were also measured using enzyme-linked immunosorbent assay. RESULTS: The number of uninhibited bladder contractions per voiding cycle, maximal pressure of uninhibited bladder contraction and maximal voiding pressure were significantly decreased in NGF Ab treated versus vehicle treated spinalized rats. Intercontraction interval, baseline intravesical pressure, pressure threshold for voiding and voiding efficiency were not significantly changed by NGF Ab treatment. NGF levels in the bladder, L6 spinal cord and L5 to S1 dorsal root ganglia of vehicle treated spinalized rats was 1.6 to 4.8 times higher than in spinal cord intact rats. After intrathecal NGF Ab treatment NGF levels were significantly lower in the L6 to S1 dorsal root ganglia (30% to 35%) and L6 spinal cord (53%) but not in the bladder or L5 dorsal root ganglia compared with levels in vehicle treated spinalized rats. CONCLUSIONS: Increased levels of NGF in the bladder, spinal cord and dorsal root ganglia were associated with bladder hyperreflexia after spinal cord injury. Immuno-neutralization of NGF in the spinal cord suppressed NGF levels in the L6 to S1 dorsal root ganglia, which contain bladder afferent neurons, and also suppressed bladder hyperreflexia. Thus, suppression of NGF levels in afferent pathways could be useful for treating bladder hyperreflexia associated with spinal cord injury.

Afferent Pathways↗

PubMed2002

Diabetic cystopathy correlates with a long-term decrease in nerve growth factor levels in the bladder and lumbosacral dorsal root Ganglia.

PURPOSE It has been proposed that a deficiency in the axonal transport of nerve growth factor (NGF) may have an important role in inducing diabetic neuropathy, which contributes to diabetic cystopathy. Therefore, in streptozotocin (Sigma Chemical Co., St. Louis, Missouri) induced diabetic rats we investigated the relationship of bladder function with NGF levels in the bladder and lumbosacral dorsal root ganglia, which contain afferent neurons innervating the bladder. MATERIALS AND METHODS At 6 and 12 weeks after the induction of diabetes with streptozotocin (65 mg./kg. intraperitoneally) the effects of diabetes on Adelta afferent fiber dependent, conscious voiding were evaluated by metabolic cage measurements and awake cystometry. The effects of diabetes on C-fiber mediated bladder nociceptive responses were also investigated by cystometry with intravesical instillation of 0.25% acetic acid in the rats under urethane anesthesia. NGF levels in the bladder and L6 to S1 dorsal root ganglia were measured by enzyme-linked immunosorbent assay 3, 6, 9 and 12 weeks after streptozotocin injection. RESULTS In diabetic rats NGF levels in the bladder and L6 to S1 dorsal root ganglia were significantly decreased 12 weeks after streptozotocin injection (p <0.01). In cystometry and metabolic cage studies bladder capacity and post-void residual volume were significantly increased 12 weeks after streptozotocin injection (p <0.01). Bladder nociceptive responses revealed by a reduction in inter-contraction intervals after acetic acid infusion were significantly decreased in a time dependent manner 12 weeks after streptozotocin injection.CONCLUSIONS Rats with streptozotocin induced diabetes mellitus showed a significant time dependent decrease in NGF levels in the bladder and L6 to S1 dorsal root ganglia that was associated with voiding dysfunction attributable to defects in Adelta and C-fiber bladder afferents. Therefore, reduced production of NGF in the bladder and/or impaired transport of NGF to L6 to S1 dorsal root ganglia, which contain bladder afferent neurons, may be an important mechanism inducing diabetic cystopathy.

Animals↗

PubMed2002

Targeting afferent hyperexcitability for therapy of the painful bladder syndrome.

The involvement of C-fiber afferent pathways in urinary frequency and pain associated with painful bladder syndrome raises the possibility of multiple targets for the treatment of this disease. Using an in vivo measurement of bladder activity as well as whole-cell patch clamp recording techniques to examine the properties of bladder afferent neurons in animal models of chronic cystitis, we have documented that tetrodotoxin-resistant sodium channels encoded by the Na(v) 1.8 (PN3/SNS) gene and nitric oxide acting via a cyclic guanosine monophosphate (cGMP)-dependent mechanism are important in modulating bladder pain responses. Thus, suppression of C-fiber afferent nerve activity by blocking specific sodium channels, elevating nitric oxide levels, or activating cGMP-dependent pathways might represent novel strategies for the treatment of symptoms in patients with painful bladder syndrome. Another treatment strategy is suppression of release or activity of proinflammatory agents that can cause normally unexcitable C-fiber afferents to become hyperactive or hyperexcitable. This approach to management of bladder pain was tested in patients with painful bladder syndrome by examining the effectiveness of the antiallergic agent suplatast tosilate (IPD-1151T), which suppresses urinary frequency in a rat model of cystitis. IPD-1151T is an immunoregulator that suppresses cytokine production in T-helper 2 cells and inhibits immunoglobulin E antibody formation and antigen-induced histamine release from mast cells. Preliminary data from an open-label clinical trial showed that 16 of 23 (70%) patients responded to treatment with IPD-1151T (300 mg/day orally for 12 months). The finding that expression of platelet-derived endothelial cell growth factor, which can activate mast cells, was lower in the bladder of responders than nonresponders indicates that bladder levels of platelet-derived endothelial cell growth factor may be a useful marker for this disease.

Afferent Pathways↗

PubMed2002

Anomalous origin of the left coronary artery from the pulmonary artery A case using the autologous pulmonary arterial wall graft.

A 10-year-old girl with anomalous origin of the left coronary artery from the pulmonary artery underwent a two coronary system reconstruction with a new technique. Her left coronary artery was stenotic next to its origin and had a severe adhesion with the aorta. We made a bypass grafting between the aorta and the left coronary artery with a roll shaped transected main pulmonary arterial wall graft. The postoperative angiogram showed a good patency of a reconstructed left coronary artery. This technique is considered useful surgical option for bypass grafting to the left coronary artery when the left coronary artery has an obstructive lesion or a difficulty to dissect and mobilize.

Blood Vessel Prosthesis Implantation↗

PubMed2002

Simultaneous repair of pectus excavatum and congenital heart disease over the past 30 years.

OBJECTIVE: Pectus excavatum may be present in patient requiring operations for cardiac defects. The study was undertaken in order to assess our simultaneous repairs of pectus excavatum and congenital heart disease over past 30 years. METHODS: Between 1970 and 2000, 12 patients underwent simultaneous repair of pectus excavatum and congenital heart disease. Six of 12 patients had ventricular septal defects as cardiac malformations (subgroup A). Operative technique, after the intracardiac procedure using cardiopulmonary bypass, consists of total subperichondrial resection of deformed costal cartilages, transection of deformed portion of the sternum in 2-3 points, and fixation of the sternum in elevated position using two Kirschner wires and a bridge external traction. Postoperative catheterization was performed in five of 12 patients (subgroup B). We evaluated the operative data, the improvement of pectus deformity and right ventricular performance retrospectively. The operative data in subgroup A were compared with those in recent random patients with ventricular septal defects only or with pectus excavatum only (control groups). RESULTS: There was no operative death and non-serious complications were seen in nine patients (atelectasis in six, superficial wound infection in two, chylothorax in one). Pectus deformities improved with the drop of vertebral index postoperatively. The mean total operative time and postoperative drainage in subgroup A were 128.4% and 123.7%, respectively of those in the ventricular septal defect control group. The mean perioperative bleeding in subgroup A was more than the sum of those in control groups. Right ventricular end-diastolic (RVEDVI), end-systolic (RVESVI), stroke (RVSVI) volume indices and ejection fraction (RVEF) in subgroup B tended to increase after surgery. In particular, there were significant increases of RVEDVI (35%, P<0.05) and RVSVI (77%, P<0.01). CONCLUSION: Simultaneous cardiac and pectus repairs were performed successfully without serious complications. Moreover, simultaneous repair resulted in an improvement of right ventricular performance with significant increases of RVEDVI and RVSVI.

Abnormalities, Multiple↗

PubMed2002

Suppression of Helicobacter pylori-induced interleukin-8 production in gastric cancer cell lines by an anti-ulcer drug, geranylgeranylacetone.

BACKGROUND: Geranylgeranylacetone (GGA) is an antigastritis and anti-ulcer agent, with as yet an unknown mechanism of action. In this study, we investigated the effect of GGA on Helicobacter pylori-induced interleukin (IL)-8 production and IL-8 mRNA expression in KATOIII cells, an established gastric cell line. METHODS: Interleukin-8 production in H. pylori-infected KATOIII cells was measured by using enzyme-linked immunoassay. The cytotoxicity of H. pylori on KATOIII cells was measured by a 51Cr release assay. The effect of GGA on H. pylori-induced IL-8 mRNA expression was measured by using northern blotting. RESULTS: Interleukin-8 production increased with time and H. pylori dose; the most significant increase was seen within 6-24 h of coculture with H. pylori. A dose of 0.1 mmol GGA suppressed IL-8 production (P = 0.0077) and inhibited H. pylori-induced IL-8 mRNA expression (P = 0.0019). Furthermore, H. pylori-induced gastric mucosal cell injury associated with IL-8 and neutrophil activation was enhanced by NH3, and this enhancement was suppressed by GGA (P = 0.0043). CONCLUSIONS: Helicobacter pylori-infected gastric mucosal cells produce IL-8, which can promote neutrophil activation, thus contributing to mucosal tissue injury associated with H. pylori infection. Agents like GGA, which can suppress IL-8 production may have a protective role in the treatment of mucosal tissue damage seen in H. pylori infection.

Analysis of Variance↗

PubMed2002

Over expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in patients with interstitial cystitis and bladder carcinoma.

PURPOSE: We examined whether the expression of angiogenic factors, such as platelet-derived endothelial cell growth factor/thymidine phosphorylase (PDEGF/TP) and transforming growth factor-beta, in bladder tissue correlates with the severity of symptoms, such as urinary urgency and bladder pain, in patients with bladder carcinoma and interstitial cystitis. MATERIALS AND METHODS: Bladder biopsy was performed in 32 patients with bladder carcinoma, including 19 with interstitial cystitis and 3 controls. Immunohistological staining for PDEGF/TP, transforming growth factor-beta and CD44 was performed in bladder specimens. PDEGF/TP in bladder tissues was also measured by enzyme-linked immunosorbent assay to examine the correlation of the expression of this factor with painful symptoms in patients with bladder carcinoma or interstitial cystitis. RESULTS: Immunohistochemical staining showed that PDEGF/TP stained in the submucosal layer beneath the basement membrane in bladder tissues of patients with interstitial cystitis and peritumoral areas of those with bladder carcinoma. In addition, PDEGF/TP, transforming growth factor-beta and CD44 stained in the same submucosal region and staining was observed at deeper submucosal levels in interstitial cystitis cases with severe rather than mild bladder pain. Quantitative analyses revealed that mean PDEGF/TP expression plus or minus standard deviation in tumor tissues of 10 patients with bladder carcinoma and pain was significantly higher than in tumor tissues of 22 with asymptomatic bladder carcinoma (129.3 +/- 70.7 versus 37.6 +/- 29.2 units per mg. protein). The mean expression of PDEGF/TP in peritumoral mucosa of patients with bladder carcinoma and pain was also significantly higher than in those with asymptomatic bladder carcinoma (75.5 +/- 42.1 versus 12.6 +/- 5.4 units per mg. protein). For interstitial cystitis mean expression in 6 patients with severe bladder pain was significantly higher than in 13 with moderate pain (79.2 +/- 59.2 versus 16.6 +/- 17.5 units per mg. protein). Mean expression in bladder tissues of controls was less than 2.3 units per mg. protein. CONCLUSIONS: These results suggest that angiogenic factors, such as PDEGF/TP and transforming growth factor-beta, may be involved in the inflammatory process to induce painful symptoms in patients with interstitial cystitis or bladder carcinoma. Proteoglycans such as CD44 may contribute to the presentation of these soluble angiogenic factors at the inflammation site.

Aged↗

PubMedDate not supplied

Intravesical antisense therapy for cystitis using TAT-peptide nucleic acid conjugates.

The present study investigated the potential of intravesical instillation for localized reduction of NGF (nerve growth factor) expression in the urinary bladder. Overexpression of NGF has been linked to the pathogenesis of interstitial cystitis (IC). A minimum free energy algorithm was used to predict suitable regions in mRNA of rat betaNGF, which can be targeted for an antisense approach. The candidate antisense oligos were evaluated for their ability to reduce NGF expression in vitro by cotransfecting HEK293 cells with NGF cDNA. A single oligonucleotide ODN sequence was chosen for testing in an acute cystitis model in rat induced by cyclophosphamide. Overexpression of NGF is known to mediate inflammation of bladder in this model. For improved stability, antisense ODN was replaced with antisense peptide nucleic acid (PNA) and its penetration into bladder was facilitated by tethering TAT peptide sequence. Rat bladders were instilled with either antisense or its scrambled control prior to cystitis induction. Cystometrograms performed on rats under urethane anaesthesia exhibited bladder contraction frequency that was significantly decreased in the antisense treated rats than rats treated with the control. NGF immunoreactivity was also decreased in the urothelium of the antisense treated bladders. Our findings demonstrate the feasibility of using TAT-PNA conjugates for intravesical antisense therapy.

Administration, Intravesical↗

PubMedDate not supplied

Recent advances in intravesical drug/gene delivery.

Targeting of drugs administered systemically relies on the higher affinity of ligands for specific receptors to obtain selectivity in drug response. However, achieving the same goal inside the bladder is much easier with an intelligent pharmaceutical approach that restricts drug effects by exploiting the pelvic anatomical architecture of the human body. This regional therapy involves placement of drugs directly into the bladder through a urethral catheter. It is obvious that drug administration by this route holds advantage in chemotherapy of superficial bladder cancer, and it has now become the most widely used treatment modality for this ailment. In recent years, the intravesical route has also been exploited either as an adjunct to an oral regimen or as a second-line treatment for neurogenic bladder. (Lamm, D. L.; Griffith, J. G. Semin. Urol. 1992, 10, 39-44. Igawa, Y.; Satoh, T.; Mizusawa, H.; Seki, S.; Kato, H.; Ishizuka, O.; Nishizawa, O. BJU Int. 2003, 91, 637-641.) Instillation of DNA via this route using different vectors has been able to restrict the transgene expression in organs other than bladder. The present review article will discuss the shortcomings of the current options available for intravesical drug delivery (IDD) and lay a perspective for future developments in this field.

Administration, Intravesical↗