Effects of anticholinergic drug withdrawal on memory, regional cerebral blood flow and extrapyramidal side effects in schizophrenic patients

It has been suggested that anticholinergic drugs impair immediate memory and working memory in patients with schizophrenia. Opinions remain divided as to the influence of anticholinergic drug withdrawal on the psychopathology and extrapyramidal side effects (EPS) in these patients. In our previous study, regional cerebral blood flow (rCBF) was reduced in all regions of patients taking anticholinergic drugs. Anticholinergic drugs were withdrawn in 21 schizophrenic inpatients. Immediate and verbal working memory, rCBF, psychopathology, and EPS were investigated before and after anticholinergic withdrawal. There was improvement in immediate memory, verbal working memory, and psychopathology, as well as an increase in rCBF after withdrawal from anticholinergic drugs. EPS showed no significant changes. Factors that may predict the improvement of immediate memory after withdrawal of anticholinergic drugs are more severe baseline psychopathology and use of a higher anticholinergic drug dose at baseline. Improvement of working memory may be predicted by a higher baseline rCBF in the left anterior cerebral artery region. Withdrawal from anticholinergics should be considered in schizophrenic patients, and it is important to taper these drugs over at least four weeks.     

Effect of angiotensin converting enzyme inhibition on myocardial phosphoinositide metabolism visualised with 1-[1-11C]-butyryl-2-palmitoyl-rac-glycerol in myocardial infarction in the rat

We recently reported that myocardial phosphoinositide (PI) metabolism can be visualised by 1-[1-11C]-butyryl-2-palmitoyl-rac-glycerol (11C-DAG) in rats with myocardial infarction (MI). Angiotensin II, the receptors for which are expressed predominantly in infarcted areas with active fibrogenesis rather than in non-infarcted regions, is involved in the upstream signalling systems of PI metabolism and plays an important role in the process of left ventricular (LV) remodelling after MI. We therefore hypothesised that the distribution of 11C-DAG after MI may be affected by the inhibition of angiotensin converting enzyme, which is one of the most important factors in the development of LV remodelling after MI. Rats were injected with 11C-DAG after 3 or 10 weeks of treatment with captopril or no treatment following coronary artery ligation, and quantitative autoradiography was performed. Cells occupying the infarcted region were identified by immunohistochemistry. Compared with untreated rats, treatment with captopril for 3 weeks after MI elicited a reduction in the 11C-DAG uptake in the infarcted region (P<0.05) but not in the non-infarcted region, and was associated with a 22% decrease in the heart weight/body weight ratio. The thallium-201 distribution in the infarcted area was similarly low in the rats with and rats without the 3-week captopril treatment after MI. Abundant macrophages and myofibroblasts occupied the infarcted area in both rats with and rats without the captopril treatment for 3 weeks after MI. The 11C-DAG radioactivity in the infarcted region in the untreated rats was lower 10 weeks after MI than 3 weeks after MI (P<0.01). This finding was in agreement with the results of immunohistochemistry demonstrating that the number and size of macrophages and myofibroblasts were remarkably reduced in rats 10 weeks after MI compared with 3 weeks after MI. Captopril treatment for 10 weeks after MI did not decrease the 11C-DAG radioactivity in the infarcted area further. These data suggest that 11C-DAG is useful for visually detecting regions with activated PI metabolism after MI, and that captopril reduces PI metabolism in the infarcted region in the relatively early phase of MI, which might contribute to the attenuation of ventricular remodelling.     

Biological characteristics in bladder cancer depend on the type of genetic instability.

PURPOSE: Malignant tumors show an inherent genetic instability that can be classified as microsatellite instability (MSI) or chromosomal instability (CIN). To elucidate the differences in biological characteristics of bladder cancer between the two types of genetic instability, the expression of the mismatch repair (MMR) proteins, Aurora-A and p53 proteins, the number of centrosomes, numerical aberrations of chromosomes and 20q13, and DNA ploidy were examined in 100 human urothelial carcinomas of the bladder. EXPERIMENTAL DESIGN: Expressions of the MLH1, MSH2, Aurora-A, and p53 proteins and the numbers of centrosomes were immunohistochemically assessed. Numerical aberrations of chromosomes 7, 9, 17, and 20q13 spots were evaluated by fluorescence in situ hybridization, and DNA ploidy was assessed by laser scanning cytometry. RESULTS: The expression levels of the MMR related-proteins decreased in 9 of 100 tumors. Tumors with low MLH1 or MSH2 expression (designated as MSI cancers) were not linked with centrosome amplification, Aurora-A overexpression, increased p53 immunoreactivity, 20q13 gain, DNA aneuploidy, and disease progression. MSI cancers showed a favorable prognosis. CIN cancers (49 cases), defined as tumors with a large intercellular variation in centromere copy numbers, were associated more frequently with centrosome amplification, Aurora-A overexpression, increased p53 immunoreactivity, and 20q13 gain than the others (51 cases). Tumors with disease progression were included in the CIN cancer group. CONCLUSIONS: The present observations suggest that there are differences in the biological characteristics of the two types of genetic instability.     

Phosphorylation of p38 mitogen-activated protein kinase downstream of bax-caspase-3 pathway leads to cell death induced by high D-glucose in human endothelial cells

Because high D-glucose significantly stimulates endothelial cell death, we examined the molecular mechanisms of high D-glucose-induced endothelial apoptosis. Treatment of human aortic endothelial cells with high D-glucose (25 mmol/l), but not mannitol and L-glucose, resulted in a significant decrease in cell number and a significant increase in apoptotic cells as compared with a physiological concentration (5 mmol/l). Interestingly, high D-glucose treatment significantly increased bax protein, accompanied by translocation of bax protein from cytosol to mitochondria-enriched heavy membrane fraction. In contrast, the expression and distribution of bcl-2 protein were not altered by high D-glucose. In addition, the activity of caspase-3 proteases was increased after exposure to high glucose, whereas caspase inhibitors prevented endothelial cell death induced by high D-glucose. On the other hand, p38 mitogen-activated protein kinase (MAPK) was markedly phosphorylated and showed sustained phosphorylation after stimulation. A specific inhibitor of p38 MAPK, SB 203580, and the overexpression of kinase-inactive p38 MAPK significantly attenuated cell death induced by high D-glucose in human aortic endothelial cells, whereas at 6 h after high D-glucose treatment, SB 203580 and overexpression of kinase-inactive p38 MAPK did not attenuate caspase-3 activation induced by high D-glucose. Importantly, caspase inhibitors significantly attenuated the sustained phosphorylation of p38 MAPK induced by high D-glucose. Thus, we finally focused the MAPK kinase (MEK) kinase 1 (MEKK1) to further examine the cross-talk between p38 MAPK and the bax-caspase proteases pathway. High D-glucose treatment induced MEKK1 cleavage, whereas caspase inhibitors significantly attenuated the cleavage. Importantly, kinase-inactive MEKK1 also blocked the phosphorylation of p38 MAPK induced by high D-glucose. Here, we demonstrated that high D-glucose induced apoptosis in human endothelial cells through activation of the bax-caspase proteases pathway and through phosphorylation of p38 MAPK mediated by MEKK1. Phosphorylation of p38 MAPK downstream of the bax-caspase pathway may play a pivotal role in endothelial apoptosis mediated by high D-glucose.     

Chemopreventive effect of 24R,25-dihydroxyvitamin D(3) in N, N'-dimethylhydrazine-induced rat colon carcinogenesis

In this study we investigated the effects of 24R,25-dihydroxyvitamin D(3) [24R,25(OH)(2)D(3)] on N,N'-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. For experiments 1 and 2, 50 F344 male, 6-week-old rats were divided into five groups in each experiment. Animals were given s.c. injections of DMH once a week for 4 weeks. Those in groups 1-5 were given 24R,25(OH)(2)D(3) in the diet (10, 5, 2.5, 1.25 or 0 p.p.m., respectively) during the post-initiation stage in experiment 1 and during the initiation stage in experiment 2. At termination, the numbers of aberrant crypt foci (ACF) in the rat colonic mucosa were decreased dose-dependently in rats treated with 24R,25(OH)(2)D(3) during the post-initiation stage, but not in the initiation stage. For experiment 3, 15 male, 9-week-old rats were divided into three groups and given 24R,25(OH)(2)D(3) in the diet (10, 5 or 0 p.p.m.). Animals were injected with 5-bromo-2'-deoxyuridine (BrdU) i.p. 1 h before death to examine DNA synthesis in the colon mucosa. BrdU labeling indices were decreased dose-dependently in colonic crypts of rats treated with 24R, 25(OH)(2)D(3). In experiment 4, using the multicarcinogenic protocol we could analyze our data with respect to not only one separate organ, but at the organism level. Sixty-eight male, 6-week-old rats were treated with DMH, N-methylnitrosourea, 2, 2'-dihydroxy-di-n-propylnitrosamine, diethylnitrosamine and N-butyl-N-(4-hydroxybutyl)nitrosamine in weeks 1-4 and were then given 24R,25(OH)(2)D(3) in the diet (5, 1 or 0 p.p.m.) throughout weeks 5-30. Examination of the development of tumors and preneoplastic lesions in various organs revealed that 24R, 25(OH)(2)D(3) inhibited colonic tumor development significantly but exerted no effects on tumor induction in other organs. In conclusion, these results strongly indicate that 24R,25(OH)(2)D(3) inhibits colon carcinogenesis specifically, without any enhancement of carcinogenesis in other organs, when administered in the post-initiation phase.     

Psychiatric disorders following first breast cancer recurrence: prevalence, associated factors and relationship to quality of life

OBJECTIVE: The purpose of this study was to investigate the prevalence of and factors associated with psychiatric disorders and the impact on quality of life (QOL) in patients with first breast cancer recurrence. METHODS: We analyzed the baseline data on 50 consecutively enrolled recurrent breast cancer patients, participating in a feasibility study of multifaceted psychosocial intervention. Psychiatric disorders, including major depressive disorder (MDD), dysthymic disorder, panic disorder, post-traumatic stress disorder (PTSD), generalized anxiety disorder and adjustment disorders (AD), were evaluated according to the Structured Clinical Interview for the DSM-III-R and IV. The patients' demographic data, biomedical factors, social support, mental adjustment to cancer, personality traits and QOL were also evaluated. RESULTS: Eleven (22%) met the DSM-III-R and IV criteria for MDD, PTSD or AD (MDD, 2%; PTSD, 2%; AD, 20%). Univariate analysis indicated that current doxorubicin/cyclophosphamide, presence of a confidant, past history of MDD, helplessness/hopelessness and neuroticism were significantly associated with psychiatric disorders. On multivariate logistic regression analysis, past history of MDD and helplessness/hopelessness were significant associated factors. Psychiatric disorders were significantly associated with lower functional scales ('emotional functioning', 'body image' and 'future perspective') and higher symptom scales ('appetite loss', 'diarrhea', 'fatigue' and 'nausea-vomiting') in QOL. CONCLUSIONS: The result suggests that asking about history of depression and appropriate intervention, including psycho-education, are needed for patients with first breast cancer recurrence in order to detect and manage psychological distress. Although further studies are needed to clarify causal links between psychiatric disorders and QOL, patients' psychiatric disorders were associated with QOL.     

Influence of toll-like receptor 4, CD14, tumor necrosis factor, and interleukine-10 gene polymorphisms on clinical outcome in Japanese critically ill patients

The innate recognition of microbial components and subsequent activation of cytokine network are important in the pathophysiology of sepsis. Recently, functional gene polymorphisms in molecules associated with these responses were demonstrated. On the other hand, it has been claimed that there are ethnic differences in genetic polymorphisms. This study investigated toll-like receptor (TLR) 4, CD14, tumor necrosis factor (TNF)-alpha and -beta, and interleukin (IL)-10 gene polymorphisms in 197 Japanese critically ill patients and 214 healthy control subjects to evaluate the influence of these polymorphisms on clinical outcome. No Japanese participant carrying TLR4Asp299Gly or Thr399Ile was detected. No association of CD14-159C/T polymorphisms with genotype frequency or sepsis mortality was observed. Frequency of TNF-alpha-308 GA genotype was significantly higher in the sepsis group than in the control group and TNF-alpha-308GA and IL-10-592CC genotypes were related to poor outcome of sepsis. Ethnic differences in genetic variations are very important issues and the frequencies in this study differ from those previously reported in Caucasians. In conclusion, this study may indicate that TNF-alpha-308G/A and IL-10-592C/A polymorphisms involved in subsequent activation of cytokine network had a larger effect on clinical outcome in patients with sepsis than TLR4Asp299Gly, Thr399Ile, and CD14-159C/T polymorphisms associated with the initial host-microbial interaction.     

Longitudinally partitioned coronary sinus: an unusual anomaly of the coronary venous system

We report a case of a patient with advanced heart failure who had a longitudinally partitioned coronary sinus. With multidirectional fluoroscopic views and a careful approach to the target lumen, a left ventricular lead for biventricular pacing was placed successfully in the left marginal vein.     

Radical prostatectomy for localized prostate cancer

With widespread use of PSA screening, radical prostatectomy has gained popularity among Japanese urologists over the last decade. Recent understanding of pelvic anatomy and improvement in surgical technique have substantially reduced its morbidity. Early recovery of urinary continence is possible and improvement of sexual function after surgery may be enhanced by use of sildenafil and nerve reconstructive surgery. As prostate cancer is increasingly diagnosed at early stages and therefore with more favorable survival outcomes, the basis on which patients select primary therapy has shifted toward considerations of health-related quality of life. Accordingly, QOL assessment has become an important form of outcomes based research that may weigh heavily on the treatment selection by patients.