Adverse effects of anticholinergic activity on cognitive functions in Alzheimer's disease.

BACKGROUND: Elderly patients with Alzheimer's disease (AD) take more medicines, other than those for anti-dementia agents, than healthy people and are sensitive to anticholinergic medications. There are only a few reports, however, on the relationship between cognitive function and anticholinergic activity in AD patients, which is caused by taking prescribed medication. METHODS: We measured serum anticholinergic activity (SAA) in 76 AD patients referred to a Psychogeriatric Unit and separated them into SAA positive group (n= 26, SAA (+) group) and SAA negative group (n= 50, SAA (-) group). The difference in demographic data and cognitive functions were compared between the two groups. RESULTS AND CONCLUSIONS: The total scores of the Mini-Mental State Examination (MMSE), the score of MMSE domain of registration and recall were significantly lower (P < 0.05) and the Functional Assessment Staging (FAST) score, the number of different kinds of prescribed psychotropic medications (the number of prescribed psychotropic medications) were significantly higher (P < 0.05) in the SAA (+) group than in the SAA (-). These results suggest that a higher number of psychotropic medications prescribed leads to a tendency for SAA to be positive and that anticholinergic activity accelerates Alzheimer's pathology and decreases cognitive function, especially memory in AD patients. We should more prudently prescribe psychotropic medications to AD patients, because the prescribed psychotropic medications are one of the important causes of decline in cognitive function of AD patients by way of anticholinergic activity.

Expression of A-kinase anchor protein 13 and Rho-associated coiled-coil containing protein kinase in restituted and regenerated mucosal epithelial cells following mucosal injury and colorectal cancer cells in mouse models.

We demonstrate the expression patterns of A-kinase anchor protein 13 (AKAP13), a scaffold protein that acts upstream of Rho signaling, and Rho-associated coiled-coil containing protein kinase (ROCK) 1/2 in mouse colorectal cancer and during the healing stage of mouse colitis. BALB/c mice received an intraperitoneal injection of azoxymethane at 10mg/kg, followed by two 7-day cycles of 3% dextran sulfate sodium (DSS) administered through their drinking water to induce colon cancer, or a 7-day administration of 4% DSS to induce colitis. The colorectal tissue was then analyzed for gene expression, histopathology, and immunohistochemistry. In the colorectal cancer, AKAP13 and ROCK1/2 were highly expressed in adenocarcinoma compared to the control tissue and low-grade dysplasia. In colitis, AKAP13 and ROCK1 were highly expressed in the restituted and regenerated mucosa but were only moderately expressed in the injured mucosal epithelium, compared to the normal epithelium that exhibited weak expression levels. ROCK2 was weakly expressed in these cells, consistent with the expression of AKAP13 and ROCK1. Furthermore, we found several clumps of epithelial cells expressing AKAP13 and ROCK1/2 in the lamina propria during the mucosal healing process, and these cells also expressed interleukin-6, which is a multipotential cytokine for both inflammation and healing. These data suggest that AKAP13 was expressed in relation with ROCK1/2, which probably play an overall role in both mucosal healing and tumorigenesis.

Expression of thymidine phosphorylase correlates with microvessel density in prostate cancer.

Angiogenesis in the growth and development of prostate cancer was the focus of this study. Various angiogenic factors and their clinicopathologic correlations with the progression of prostate cancer have been examined. Thymidine phosphorylase is identical to platelet-derived endothelial cell growth factor (TP/PD-ECGF) and has angiogenic activity. We investigated the expression of TP/PD-ECGF in prostate cancer and its association with angiogenesis or clinicopathologic findings in 81 cases with prostate cancer. Western blot analysis using a specific monoclonal antibody 654-1 revealed the existence of a 55 kDa TP/PD-ECGF protein in human prostate cancer tissue. Cancer tissue showed low-positive immunostaining in 32 cases (39.5%) and high positivity in 49 cases (60.5%). This protein expression indicated a statistically significant association with microvessel density (low vs. high TP/PD-ECGF expression group: mean +/- SD, 37.3+/-27.0 vs. 53.1+/-28.0 microvessels in three fields, p<0.05). No correlation was found between the expression of TP/PD-ECGF and nuclear grade, glandular differentiation, clinical stage or overall survival rate. TP/PD-ECGF may play an important role in tumor angiogenesis in prostate cancer tissues. Although the expression of TP/PD-ECGF was not correlated with clinical outcome in patients with prostate cancer, there remains the possibility that TP/PD-ECGF may support or modify the tumor growth through angiogenesis in cooperation with other factors.

Evaluation of skin phototoxicity study using SD rats by transdermal and oral administration.

Guinea pigs are the most frequently used animals in phototoxicity studies. However, general toxicity studies most often use Sprague-Dawley (SD) rats. To reduce the number of animals needed for drug development, we examined whether skin phototoxicity studies could be performed using SD rats. A total of 19 drugs that had previously been shown to have phototoxic potential and 3 known phototoxic compounds were administered transdermally to guinea pigs and SD rats. Eleven of the potentially phototoxic drugs and 2 of the known phototoxic compounds were also administered orally to guinea pigs and SD rats. After administration, the animals were irradiated with UV-A (10 J/cm(2)) and UV-B (0.25 J/cm(2) in guinea pigs and 0.031 J/cm(2) in SD rats) with doses based on standard phototoxicity study guidelines and the results of a minimum erythema dose test, respectively. In the transdermal administration study, all of the known phototoxic compounds and 7 of the drugs induced phototoxic reactions. In the oral administration study, both known phototoxic compounds and 5 drugs induced phototoxic reactions in both species; one compound each was found to be toxic only in SD rats or guinea pigs. The concordance rate of guinea pigs and SD rats was 100% in the transdermal administration study and 85% in the oral administration study. This study demonstrated that phototoxicity studies using SD rats have the same potential to detect phototoxic compounds as studies using guinea pigs.

[Initial failure in open pyeloplasty for ureteropelvic junction obstruction].

We retrospectively reviewed the records of 23 patients (25 kidneys) who underwent open pyeloplasty for ureteropelvic junction obstruction (UPJO) between 1980 and 2001, focusing on failures. The patients included 17 men and 6 women, ranging from 3 months to 69 years old (mean 15.9 years). The followup period was 6 months to 19 years (mean 8.6 years). Anderson-Hynes pyeloplasty, Y-V plasty, Hëllstrom's operation and simple pelvi-ureterostomy were performed in 22, 1, 1 and 1 kidney, respectively. We successfully repaired 21 of 25 renal units (success rate 84.0%). Of the four patients (4 kidneys) with persistent UPJO occurring in this primary pyeloplasty series, repeat pyeloplasty was performed on 2 patients, nephrectomy on 1 patient and balloon dilatation on 1 patient. Infection and prolonged urinary drainage seem to result in fibrosis of periureteral tissues. Inadequate stitches may cause granuloma in the lumen of the anastomosis. The techniques and complications associated with open pyeloplasty are discussed.

[Urinary continence after radical retropubic prostatectomy: a modification in the technique of apical dissection].

Urinary incontinence impairs the quality of life for patients following radical prostatectomy. We retrospectively reviewed the records of 36 patients who underwent radical retropubic prostatectomy between 1987 and 2002, and achieved the time from operation until urinary continence. A modification in the technique of apical dissection was introduced in 1999 and applied in 12 cases of consecutive radical prostatectomy. The principles for this technique were based on sharp division of the dorsal vein complex, continuous suturing cut edges of lateral pelvic fascia, and anterior anastomotic sutures including lateral pelvic fascia as well as urethra and bladder neck. None of the patients undergoing the new technique used pads at 6 months. With introduction of this technique, the rate of continence at 12 months increased from 58.3 to 100.0%. Our results suggest that the surgical technique of apical dissection is an important factor associated with postprostatectomy in continence.

[Neurogenic voiding dysfunction after sacrococcygeal teratoma resection].

A 6-year-old girl was referred to our department due to pyelonephritis. Voiding cystourethrogram (VCUG) revealed grade 4 vesicoureteral reflux (VUR) and urethral deformity (stenosis and lateral deviation). She had a history of sacrococcygeal teratoma resection in the newborn. Urodynamic study revealed a large-capacity hypotonic bladder and poor bladder emptying. Magnetic Resonance Imaging of the spine demonstrated no abnormal findings. Despite conservative therapy, there were no improvement of VUR. Then, urethral dilation and anti-reflux-surgery were performed. Six months after the operation, VCUG showed no VUR. However, she has persistent residual urine due to neurogenic voiding dysfunction, and is being treated with a regimen of frequent timed voiding to reduce urinary residual and urinary tract infection.

Maintenance of hepatic differentiation by hepatocyte attachment peptides derived from laminin chains.

Hepatocytes rapidly lose hepatic functions upon isolation from liver, perhaps due to disrupted cell/matrix interactions. The matrix macromolecule laminin-111 consists of three chains, α1, ß1, and γ1; it is a major component of Matrigel, which can maintain hepatic differentiation. We previously showed that the A13 peptide (RQVFQVAYIIIKA, α1 chain 121-133) derived from mouse laminin α1 exhibits hepatocyte attachment activity and maintains hepatic differentiation. Here, we sought to identify hepatocyte adhesive sequences from the mouse laminin ß1 and γ1 chains using 22 synthetic peptides that show biological activity for fibrosarcoma cells. Nine peptides showed hepatocyte attachment activity. Of these, B160 (VILQQSAADIAR, ß1 chain 1607-1618), and C16 (KAFDITYVRLKF γ1 chain 139-150) exhibited the most potent activity. Hepatocytes cultured on both peptides also maintained expression of albumin, tyrosine aminotransferase, tryptophan-2,3-dioxygenase, and cytochrome P450. The morphology of hepatocytes on both peptides was a rounded shape typical for hepatic differentiation. We also characterized the nature of adhesion to the peptides. Heparin and EDTA inhibited cell attachment to both peptides, suggesting that hepatocyte attachment to the peptides was mediated by multiple receptors. The identification of active sequences regulating hepatic functions may facilitate the design of hepatocyte culture substrata that can regulate specific cellular behaviors in the context of a bioartificial liver.

The influence of synthetic peptides derived from the laminin alpha1 chain on hepatocyte adhesion and gene expression.

Laminin-111, a heterotrimer composed of the laminin alpha1, beta1, and gamma1 chains, has been used as a biomaterial for primary cell culture to maintain cellular functions. Our previous studies have reported that synthetic peptides derived from laminin alpha1 exhibit biological functions such as influencing cell adhesion, migration, angiogenesis, and tumor metastasis. In this study we screened hepatocyte attachment peptides using twenty-five biologically active peptides from laminin alpha1 and examined the maintenance of hepatic function on the peptides using primary rat hepatocytes. Peptide A13 (RQVFQVAYIIIKA), mouse laminin alpha1 chain residues 121-133, exhibited the strongest activity. Furthermore, primary hepatocytes on A13 peptide maintained expression of hepatic differentiation markers such as tyrosine aminotransferase, tryptophan-2,3-dioxygenase, and cytochrome P450. We also determined the active core sequence of A13 using systematically truncated N- and C-terminal peptides. The results indicated that the nine-amino acid sequence RQVFQVAYI was critical for A13's hepatocyte adhesion activity. However, the truncated peptides could not interact with beta1-intgerin and maintain expression of hepatic differentiation markers. The amino acid sequence of A13 peptide was required for regulating hepatocyte behavior. The hepatocyte adhesive peptides can be utilized in tailoring synthetic biomaterials in order to achieve a specific cellular response.

Successful treatment of disseminated extragonadal germ cell cancer with intensive conventional chemotherapy after first-line high-dose chemotherapy.

High-dose chemotherapy (HDCT) with peripheral blood stem cell (PBSC) support has been investigated as a first-line treatment in patients with poor risk germ cell cancer. However, effective management of patients with residual cancer after HDCT has not been well addressed, and the outcome in such patients is poor. Here, we report a case of disseminated germ cell cancer successfully treated with intensive conventional chemotherapy after HDCT. A 31-year-old man presented with a bulky mass at the retroperitoneum, which had invaded the lumbar and sacral vertebra, and multiple lung and liver metastases. The patient's serum beta subunit of human chorionic gonadotrophin (beta-hCG) was elevated to 2600 IU (cut-off value <0.1 IU). At the time of diagnosis of poor risk germ cell cancer of extragonadal origin, he underwent two cycles of BEP (bleomycin, etoposide, and cisplatin) chemotherapy and PBSC harvest followed by three cycles of HDCT with PBSC transplantation. The liver metastases disappeared. The retroperitoneal bulky mass and multiple lung metastases shrank but were still present, and the serum beta-hCG level was not completely normalized. An additional three courses of BEP and five courses of VIP (cisplatin, ifosfamide, etoposide) normalized the beta-hCG level. Pathological evaluation of the residual masses revealed no viable cancer cells at either site. The patient is alive without disease recurrence 5 years after completion of chemotherapy.

A simple technique for facilitating kidney entrapment using a laparoscopic sack during retroperitoneal laparoscopic radical nephrectomy.

The mouth of a LapSac was opened horizontally using a guidewire and, thereafter, the kidney was moved onto the center of the mouth. Forceps lifted the mouth and the specimen entered into the sack automatically under its own weight. Use of this technique facilitated kidney entrapment.

Transitional cell carcinoma in a single ectopic ureter opening into the ejaculatory duct.

The incidence of an ectopic ureter in male patients is low. The ectopic ureter in men often ends at the seminal tract in association with renal dysgenesis. Malignant transformation of this closed, nonfunctional urothelial system has been reported only once. To our knowledge, we report the first case of primary transitional cell carcinoma in a single ectopic ureter with a dysplastic kidney that terminated in the ejaculatory duct.

Multipoint methylation analysis indicates a distinctive epigenetic phenotype among testicular germ cell tumors and testicular malignant lymphomas.

Hypermethylation of tumor-suppressor genes has been implicated in the pathogenesis of human cancers. Although a growing number of genes showing hypermethylation is being reported in human cancer, methylation profiles of tumor-related genes in testicular neoplasms have not been well elucidated. This study was designed to show the methylation profiles of multiple CpG islands in testicular germ cell tumors (TGCTs) in comparison with those in testicular malignant lymphomas. We studied the methylation status of E-cadherin, CDKN2B, CDKN2A, BRCA1, RB1, VHL, RASSF1A, RARB, and GSTP1 by use of TGCT tissues and testicular malignant lymphoma tissues (25 primary TGCT tissues and three primary testicular lymphoma tissues). Methylation was not observed in E-cadherin, CDKN2B, CDKN2A, BRCA1, RB1, VHL, RASSF1A, RARB, and GSTP1 in any of the TGCT tissues. In contrast, all three (100%) of the testicular lymphoma tissues demonstrated hypermethylation of E-cadherin, RASSF1A, and RARB, but not CDKN2B, CDKN2A, BRCA1, RB1, VHL, and GSTP1. These data demonstrate that a distinctive epigenetic phenotype underlies the TGCTs and testicular lymphomas at the CpG sites of E-cadherin, RASSF1A, and RARB; a distinctive epigenetic phenotype was not observed among seminomatous TGCTs and non-seminomatous TGCTs at the CpG sites examined.