NeuroAiD® (MLC601) and amyloid precursor protein processing.

BACKGROUND: Amyloid precursor protein (APP) undergoes cleavage under physiological conditions, predominantly by α- and γ-secretases, to form the nonpathogenic sAPPα and p3 fragments. By contrast, amyloid-beta (Aß) is produced via proteolytic cleavage by ß- and γ-secretases. In Alzheimer's disease (AD), APP is preferentially processed via the amyloidogenic pathway, producing large amounts of Aß that form the major constituent of senile plaques and tau-containing neurofibrillary tangles. Similarly, stroke patients have a higher level of Aß around the area of infarct, suggesting that Aß may mediate at least some of the secondary neurotoxicity observed in stroke patients. METHODS: To investigate the effects of MLC601 (NeuroAiD(®)) on regulation of APP processing, the human neuroblastoma cell line SH-SY5Y was used for all experiments. Stocks of MLC601 were prepared at a final concentration of 50 mg/ml. Cells were treated with different concentrations of MLC601 before assessing changes in the levels of released lactate dehydrogenase (LDH), full-length APP and secreted sAPPα. RESULTS: Concentrations of MLC601 between 1 and 1,000 µg/ml significantly lowered the levels of LDH released into the media when compared to control cells. In contrast, MLC601 concentrations at 5,000 and 10,000 µg/ml resulted in a significant increase in the LDH release. Treatment with 100, 500 and 1,000 µg/ml of MLC601 significantly increases the levels of sAPPα secreted by SH-SY5Y into the media. Treatment with 1,000 µg/ml of MLC601 significantly decreased the levels of full-length APP. CONCLUSION: MLC601 is a possible modulator of APP processing and has implications as a putative therapeutic strategy for the treatment of poststroke dementia and AD.

Anticipatory and consummatory components of the experience of pleasure in schizophrenia: cross-cultural validation and extension.

This study examined anticipatory and consummatory pleasure in schizophrenia patients with and without negative symptoms. Negative symptom patients experienced less anticipatory pleasure than non-negative symptom patients; only one facet of consummatory pleasure was unaffected in negative schizophrenia. Greater pleasure deficits were correlated with more severe positive and negative symptoms.

An audit of nephroureterectomy for upper tract urothelial carcinoma.

BACKGROUND: The boundary of nephroureterctomy has been revisited and lymph node dissection has been recommended recently. We investigated the role of synchronous ipsilateral adrenalectomy in treating patients with upper tract urothelial carcinoma. METHODS: 110 patients with clinically localized upper tract urothelial carcinoma treated by nephroureterectomy and bladder cuff resection were retrospectively evaluated. 70 patients underwent nephroureterectomy without concomitant ipsilateral adrenalectomy, whereas nephroureterectomy and ipsilateral adrenalectomy was performed in other 40 patients. Cancer specific, metastasis and local recurrence free survival during a follow-up of median 46 months were analyzed. RESULTS: No patient had adrenal metastasis among the 40 adrenalectomized patients. A total of 4 patients developed local recurrences; including 1 of the 70 adrenalectomy-sparing and 3 of the 40 adrenalectomized patients (p = 0.102, chi-square test). Five patients with adrenalectomy and four without adrenalectomy had distant metastases (p = 0.212, chi-square test). The five-year local recurrence free survival (p = 0.09, log-rank test), metastasis-free survival (p = 0.292, log-rank test), and cancer-specific survival (p = 0.117, log-rank test) did not have significant difference between both groups. CONCLUSIONS: This is the only study in recent 2 decades to evaluate the necessity of synchronous adrenalectomy in treating localized upper tract urothelial carcinoma. Adrenal-sparing nephroureterectomy seems justified for clinically localized upper tract urothelial carcinoma.

Urachal adenocarcinoma following kidney transplantation: the first case report.

A 53-year-old man who underwent successful kidney transplantation for stage 5 chronic kidney disease presented to our clinic with intermittent painless gross hematuria. Urachal adenocarcinoma, stage III A by Sheldon system, was diagnosed after serial histopathologic and radiological studies. The patient was treated with extended partial cystectomy, en bloc resection of urachus and umbilicus, pelvic lymphadenectomy, and ileocystoplasty. There were no complications seen in this patient. Neither urachal adenocarcinoma recurrence, metastasis, nor de novo uroileal cancer developed during 48-month follow-up. His reconstructed bladder functioned efficiently, without compromising the transplanted kidney function. Our case demonstrated that conservative surgery and augmentation ileocystoplasty could be offered to kidney transplant recipients with localized urachal carcinoma.

Characterization of histamine H3 receptors in Alzheimer's Disease brain and amyloid over-expressing TASTPM mice.

BACKGROUND AND PURPOSE: Histamine H3 receptor antagonists are currently being evaluated for their potential use in a number of central nervous system disorders including Alzheimer's Disease (AD). To date, little is known about the state of H3 receptors in AD. EXPERIMENTAL APPROACH: In the present study we used the radiolabelled H3 receptor antagonist [3H]GSK189254 to investigate H3 receptor binding in the amyloid over-expressing double mutant APPswe x PSI.MI46V (TASTPM) transgenic mouse model of AD and in post-mortem human AD brain samples. KEY RESULTS: No significant differences in specific H3 receptor binding were observed between wild type and TASTPM mice in the cortex, hippocampus or hypothalamus. Specific [3H]GSK189254 binding was detected in sections of human medial frontal cortex from AD brains of varying disease severity (Braak stages I-VI). With more quantitative analysis in a larger cohort, we observed that H3 receptor densities were not significantly different between AD and age-matched control brains in both frontal and temporal cortical regions. However, within the AD group, [3H]GSK189254 binding density in frontal cortex was higher in individuals with more severe dementia prior to death. CONCLUSIONS AND IMPLICATIONS: The maintenance of H3 receptor integrity observed in the various stages of AD in this study is important, given the potential use of H3 antagonists as a novel therapeutic approach for the symptomatic treatment of AD.

Clinical and radiographic investigation of the adjunctive effects of a low-power He-Ne laser in the treatment of moderate to advanced periodontal disease: a pilot study.

OBJECTIVE: To evaluate the adjunctive effect of a low-power He-Ne laser in the non-surgical periodontal treatment of patients with moderate to advanced chronic periodontitis. BACKGROUND DATA: Laser applications in dental treatment are now more common in the literature. However, limited data are available on the potential effects of the low-power laser as an adjunct to non-surgical periodontal therapy for managing patients with moderate to advanced periodontal disease. MATERIALS AND METHODS: Sixteen patients with probing pocket depth (PPD) > or =5 mm and comparable bone defects on both sides of the mouth were recruited. Supragingival plaque (PL), bleeding on probing (BOP), PPD, and probing attachment level (PAL) were recorded at baseline and at 3, 6, 9, and 12 mo, while gingival crevicular fluid (GCF) samples and standardized intra-oral radiographs for digital subtraction radiography were taken at baseline and at 1, 3, 6, 9, and 12 mo. After non-surgical mechanical periodontal treatment, the test sites were selected randomly and irradiated with a low-power He-Ne laser (output power 0.2 mW) for 10 min for a total of eight times in the first 3-mo period, while the control sites received no additional treatment. RESULTS: PL percentage (83-16%) and BOP percentage (95-34%) decreased significantly after 12 mo. Statistically significant changes in reductions of PPD and GCF volume, gain in PAL, and increase in recession were seen in both test and control sites when compared to baseline (p < 0.05). No statistically significant differences in any clinical parameters or radiographic findings were found between the test and control sites. Changes in GCF volume were significant only at 3 mo in the test sites. CONCLUSION: Within the limits of this pilot study, the use of the low-power He-Ne laser as an adjunct to non-surgical periodontal therapy in patients with moderate to advanced chronic periodontitis did not seem to provide additional clinical benefit.

Optimal C2 concentration of cyclosporin corrected with good efficacy and safety in Asian kidney transplant recipients.

INTRODUCTION: Calcineurin inhibitors (CNI) are known for their renal toxicity. Lower CNI exposure is a reasonable option to mitigate potential CNI-induced renal toxicity. Herein we have presented our long-term results after lower cyclosporine (CsA) exposure in the first year. MATERIALS AND METHODS: Between 1997 and 2004, 63 renal transplant recipients received CsA-based immunosuppression. CsA dosing was adjusted according to the 2-hour whole blood concentration (C2) level. We retrospectively reviewed acute rejection and graft survivals rates, as well as whole blood C2 levels. RESULTS: Review of serial mean C2 concentrations at 1, 2, 3, 6, and 12 months after transplantation were 1341, 1241, 1191, 1059, and 927 ng/mL, respectively. These levels were slightly lower than those suggested by the Consensus for C2 levels by Levy et al in 2002, namely, 1600 to 2000 ng/mL (mean, 1700); 1400 to 1600 ng/mL (mean, 1500); 1200 to 1400 ng/mL (mean, 1300); 1000 to 1200 ng/mL (mean, 1100), and 800 to 1000 ng/mL (mean, 900), respectively. Acute rejection rate at 3 months and 1 year are 17.5% and 23.8%. Graft survival at 1 year was 97% and at 5 years, 89%. Two patient were lost to fulminant hepatitis and acute myocardial infarction during the first year, which were not associated with underimmunosuppression. CONCLUSION: Appropriate CsA C2 levels may be lower among Taiwanese. Our C2 dosing strategy resulted in good outcomes with acceptable side effects in our single-center experience. Appropriate CsA C2 levels for Asians deserve more attention in trials of larger scale; most reference levels are presently concluded from studies of Caucasians.

Sirolimus does not absolutely abolish the occurrence/recurrence of urothelial carcinoma in renal transplant recipients.

OBJECTIVE: Sirolimus (SRL), an immunosuppressant shown to possess anti-proliferative properties, was hypothesized to mitigate the occurrence of posttransplantation malignancy. We examined its effect on posttransplantation urothelial carcinoma (UC). METHODS: This retrospective case analysis included renal allograft recipients with UC treated with SRL in a single institute. RESULTS: Among 90 renal recipients treated with SRL, 6 had previous/new-onset UC in the native kidney/ureter or bladder: at a mean period of 28 months (range, 7-49) of administering SRL for these recipients, UC occurred/recurred in 4 of the 6 patients. Individual cases are presented in detail. CONCLUSION: SRL does not absolutely abolish the occurrence/recurrence of UC among renal transplant recipients. Its potency as an anti-cancerous immunosuppressant for transplant recipients with UC deserves to be further defined in larger studies, probably by controlling SRL blood levels at lower or much higher ranges than used herein.

Loss of [3H]4-DAMP binding to muscarinic receptors in the orbitofrontal cortex of Alzheimer's disease patients with psychosis.

RATIONALE: Neuropsychiatric behaviours in Alzheimer's disease (AD) patients have been associated with neocortical alterations of presynaptic cholinergic and muscarinic M2 receptor markers. In contrast, it is unclear whether non-M2 muscarinic receptors have a role to play in AD behavioural symptoms. OBJECTIVES: To correlate the alterations of neocortical postsynaptic muscarinic receptors with clinical features of AD. MATERIALS AND METHODS: [(3)H]4-DAMP were used in binding assays with lysates of Chinese hamster ovary (CHO) cells stably transfected with M1-M5 receptors. [(3)H]4-DAMP was further used to measure muscarinic receptors in the postmortem orbitofrontal cortex of aged controls and AD patients longitudinally assessed for cognitive decline and behavioural symptoms. RESULTS: [(3)H]4-DAMP binds to human postmortem brain homogenates and M1-, M3-, M4- and M5-transfected CHO lysates with subnanomolar affinity. Compared to the controls, the [(3)H]4-DAMP binding density is reduced only in AD patients with significant psychotic symptoms. The association between reduced [(3)H]4-DAMP binding and psychosis is independent of the effects of dementia severity or neurofibrillary tangle burden. CONCLUSIONS: This study suggests that the loss of non-M2 muscarinic receptors in the orbitofrontal cortex may be a neurochemical substrate of psychosis in AD and provides a rationale for further development of muscarinic receptor ligands in AD pharmacotherapy.

Latent structure of the Test of Everyday Attention in a non-clinical Chinese sample.

The validity and clinical viability of Posner and Petersen's (1999) 3-factor model of attention was tested through a confirmatory factor analysis of attentional performance (Test of Everyday Attention [Robertson, I. H., Ward, T., Ridgeway, V., & Nimmo-Smith, I. (1996). The structure of normal human attention: The Test of Everyday Attention. Journal of the International Neuropsychological Society, 2, 525-534]) in a sample of 133 Chinese participants. This study served both as a cross-cultural replication of the clinical implementation of this leading theoretical model of attention, and as a more stringent test of the validity of the hypothesized attentional processes underlying human cognitive control. The results support the validity of a 3-factor model of attention consistent with that proposed by Posner and Petersen (selective attention, sustained attention, and attentional switching/control), and demonstrate that clinical assessment of neuroanatomically-distinct attentional processes using simulated real life activities is possible.

Latent structure of the Test of Everyday Attention: convergent evidence from patients with traumatic brain injury.

AIM: The present study aimed to examine the nature of attention distinctions among sub-tests of the Test of Everyday Attention (TEA) underlying the performance of patients with traumatic brain injury (TBI). METHOD: Confirmatory factor analysis was performed among a group of 92 patients with TBI experiencing chronic post-concussive symptoms. Comparisons were made of the fit of the previously identified models based on exploratory factor analysis, comprising three-to-four factors. MAIN OUTCOME: The results indicated that the 3-factor model with a visual selection component, a sustained attention component and a switching component provided an appropriate account of attentional performance than the other two 4-factor models. CONCLUSION: These findings are consistent with those of healthy sample. This study, therefore, provides convergent evidence on the latent structure of the TEA. It is consistent and stable across healthy and clinical populations.

Diet, vegetarian food and prostate carcinoma among men in Taiwan.

In a case-control study in a veterans hospital in Taiwan, we compared 237 histology-confirmed prostate carcinoma cases with 481 controls, frequency matched by age, for their consumption of vegetarian food, namely soybean products, rice, wheat protein and other vegetables. The multivariable logistic regression analysis showed a significant association with such food (odds ratio (OR)=0.67, 95% confidence interval (CI)=0.47, 0.94). This beneficial effect presented for men with body mass index (BMI) < or =25 kg m(-2) (OR=0.50, 95% CI=0.32, 0.76) but not for men with greater BMI. The OR of prostate carcinoma for men with BMI < or =25 kg m(-2) was 1.74 (95% CI=1.21, 2.51), compared with men with higher BMI (>25 kg m(-2)). Other significant risk factors associated with the disease included higher income (OR=2.40, 95% CI=1.07, 5.42), physical activity (OR=1.75, 95% CI=1.08, 2.83), being married (OR=2.49, 95% CI=1.40, 4.43) and coffee consumption (OR=1.88, 95% CI=1.07, 3.30). Stratified analysis also showed that the consumption of fish/shellfish had an adverse association for men with higher BMI. This study suggests that the intake of the low fat local vegetarian food has a protective effect against prostate carcinoma for thin men in this study population.

Overweight, obesity, weight-related concerns and behaviours in Hong Kong Chinese children and adolescents.

AIM: To study the prevalence of overweight and obesity, and weight-related concerns and behaviours among overweight, obese and non-overweight children and adolescents. METHODS: We carried out a cross-sectional survey of all Chinese students in primary schools in the Central and Western District of Hong Kong in March 2002. Thirty-one of 32 schools participated, and 5402 boys and 5371 girls aged 8 to 15 y who completed a standardized questionnaire were included. We used the International Obesity Task Force definition (IOTF reference) to define overweight and obesity. RESULTS: The prevalence (95% CI) of overweight was 16.4% (15.7-17.1%) (19.9% in boys, 12.9% in girls), and that of obesity was 7.7% (7.2-8.2%) (10.3% in boys and 5.1% in girls). The combined prevalence of overweight and obesity was similar to that based on the local reference. Overweight children had more concerns about their weight than obese children. They were more likely than obese children to feel fat, wish to be lighter, diet and exercise to lose weight. Although obese children were heavier, they did not make more effort to lose weight than overweight children. CONCLUSIONS: The differences in weight-related concerns and behaviours among overweight, obese and non-overweight children suggested good validity of the IOTF reference and the self-reported data. The differences between overweight and obese children suggested that the two groups had different psychological states and that they needed different weight management programmes and other intervention strategies.

Microencapsulation of acetaminophen into poly(L-lactide) by three different emulsion solvent-evaporation methods.

Poly(L-lactide) (PLLA) microcapsules containing acetaminophen (APAP) were prepared by three emulsion solvent-evaporation methods including an O/W-emulsion method, an O/W-emulsion co-solvent method and a W/O/W-multiple-emulsion method. The average size and morphology of the microcapsules varied substantially among these three preparation methods. Various alcohol and alkane co-solvents were found to exert significant impact on the O/W-emulsion co-solvent method and a more lipophilic co-solvent such as heptane appeared to enhance drug encapsulation with an efficiency nearly double of the O/W-emulsion method. When a small amount of water was added as the internal aqueous phase in the W/O/W-multiple-emulsion method, the encapsulation efficiency was found nearly triple of that for the O/W-emulsion method. While having a higher encapsulation efficiency, the microcapsules prepared by the W/O/W-multiple-emulsion method had as good controlled release behaviour as those prepared by the O/W-emulsion method. The release kinetics of microcapsules prepared by the O/W-emulsion method and the O/W-emulsion co-solvent (alcohol) method fitted the Higuchi model well in corroboration with the uniform distribution of APAP in PLLA matrix, i.e. the monolithic type microcapsules. However, the release kinetics of microcapsules prepared by the O/W-emulsion co-solvent (alkane) method and the W/O/W-multiple-emulsion method fitted the first-order model better, indicating the reservoir type microcapsules.

Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer's disease.

RATIONALE: Previous studies have demonstrated reductions of serotonin 5-HT 2A receptors in the neocortex of Alzheimer's disease (AD) patients. However, it is unclear whether such losses play a role in the cognitive decline of AD. OBJECTIVES: To correlate neocortical 5-HT 2A receptor alterations with cognitive decline in AD. METHODS: Postmortem frontal and temporal cortical 5-HT 2A receptors were measured by [3H]ketanserin binding in aged controls as well as in a cohort of AD patients who had been longitudinally assessed for cognitive decline and behavioral symptoms. RESULTS: 5-HT 2A receptor densities in both regions were reduced in severely demented AD patients compared to age-matched controls. In the temporal cortex, this reduction also correlated with the rate of decline of Mini-Mental State Examination (MMSE) scores. The association between 5-HT 2A receptor loss and cognitive decline was independent of the effects of choline acetyltransferase (ChAT) activity and presence of behavioral symptoms. CONCLUSIONS: Our data suggest that loss of neocortical 5-HT 2A receptors may predict for faster cognitive decline in AD, and point to serotomimetics as potentially useful adjuvants to cholinergic replacement therapies.

Use of Hem-o-lok clips effectively lengthens renal vein during laparoscopic live donor nephrectomy.

We retrospectively reviewed our last 12 laparoscopic donor nephrectomies (LDNs) in which both the renal artery and the renal vein were controlled using 2 Hem-o-lok clips (Weck Closure Systems, Research Triangle Park, NC, United States) on the proximal sides and the vessels were divided without securing the graft-side vessels (group 1). We compared the results with our 12 immediately preceding LDN donors in whom the arteries were controlled with 3 endoclips and the veins were controlled with staplers (group 2). The length of the vein was significantly longer (approximately 4 mm difference) in group 1, mainly due to trimmed staples from the graft vessels. Both cohorts of donors had uneventful surgery with no complications, and all the recipients recovered smoothly without any delayed graft function. Average operation time and warm ischemia time were similar among both groups (189 vs 207 minutes; 168 vs 149 seconds, respectively; both P > .1). We conclude that the use of Hem-o-lok effectively lengthens graft renal veins and is less costly during LDN.

Solitary port-site metastasis after laparoscopic bilateral nephroureterctomy for transitional cell carcinoma in a renal transplant recipient.

A renal transplant recipient with upper tract transitional cell carcinoma developed a solitary port-tract recurrence 8 months after a hand-assisted laparoscopic bilateral nephroureterectomy and was successfully managed by a local wide excision and adjuvant radiotherapy. Follow-up for 3 years after the salvage therapy showed no evidence of local recurrence or distant metastasis. This patient is the first one in the literature to have a solitary port-site metastasis of transitional cell carcinoma in renal transplant recipients.

Pharmacokinetic variability of sirolimus in Taiwanese renal transplant recipients.

To evaluate the pharmacokinetic variability of sirolimus (Rapamycin, SRL) in our renal transplant (RTx) recipients, dose-normalized trough concentration (C(0)) of SRL, and their intrasubject coefficients of variation (%CV) were analyzed. Thirty-eight patients were enrolled in regimens containing SRL. Concomitant immunosuppression included steroids (n = 38), cyclosporine (n = 33), tacrolimus (n = 3), and mycophenolate mofetil (n = 7). The mean dose-normalized C(0) was 2.13 +/- 0.91 ng/mL/mg. The intrasubject %CV of the dose-normalized C(0) ranged from 14% to 88% and averaged 42% in our series. The mean dose-normalized C(0) of SRL in our RTx recipients was much lower than that reported in Phase III trials. The intrasubject variation of dose-normalized C(0), even after administrating SRL for 6 months, could still be quite prominent. Thus, we suggest that, to maintain adequate therapeutic concentrations, periodic (monthly or bimonthly) SRL C(0) measurement is necessary in Taiwanese (Oriental) patients receiving SRL.

Use of simulect can reduce the incidence of acute rejection and demonstrates with superior 3-year patient and graft survival rates in renal transplantation.

BACKGROUND: Acute rejection is a major cause of graft loss in renal transplantation. Because the highest risk for acute rejection is in the first month posttransplantation, improved prophylaxis could be most beneficial in this period. Simulect administration provides 30 to 45 days of immunoprophylaxis against acute rejection during the critical period after transplantation. OBJECTIVES: We sought to assess the incidence of acute rejection episodes and the safety and tolerability of Simulect plus Neoral immunosuppression. Patient and graft survival rates up to 3 years posttransplantation were evaluated. METHOD: Forty-one transplant recipients received Simulect by intravenous infusion of an initial 20-mg dose on the day of renal transplantation and a second 20-mg dose on day 4 posttransplant. All renal recipients received immunosuppression with Neoral and steroid. RESULTS: There were eight cases (19.5%) of acute rejection within 1 year. The rejection episodes were easily reversed with steroid pulse therapy in seven patients except for graft loss. The 1-, 2-, and 3-year graft survival rates were 95%, 93%, and 88%, respectively. Overall, the 3-year patient survival rate was 100%. CONCLUSIONS: Simulect in combination with Neoral and steroid-reduced the incidence of acute rejection without an increase in adverse events. The low incidence and severity of acute rejection may have led to the superior 3-year patient and graft survival rates in renal transplantation.

Transitional cell carcinoma in renal transplant recipients.

We describe our experience in managing transitional cell carcinoma (TCC) in renal transplant (RTx) recipients. Nineteen RTx recipients (7 men; 12 women) presented with hematuria or hydronephrosis of native kidneys and were suspected with TCC were reviewed retrospectively; 17 of them proved to have TCC. The mean interval of the occurrence of TCC was 58.7 months (range, 3-144 months) after RTx. The patients with suspected upper tract lesions received bilateral nephroureterectomies (BNU) and bladder cuff resection. Transurethral resection of the bladder tumor (TUR-BT) was performed in patients with concomitant or solitary superficial bladder lesions. Of the 15 patients with upper tract TCC, 8 had bilateral lesions pathologically, but only 2 of them were suspected preoperatively on image study. With a mean follow-up of 28 months (range, 1-57 months) both the overall graft and patient survival rates were 76%; 4 patients with advanced diseases at presentation died. Bladder recurrence was noted in 6 patients (35%). Transplant patients with hematuria warrant detailed study of the whole urinary system and periodic ultrasonography of the native kidneys is recommended in all RTx recipients. Simultaneous BNU for the native kidneys is mandatory if there is any evidence of TCC in either renal/ureteral unit.