bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between Antibiotic Resistance and the Expression of Dr Adhesin among Uropathogenic Escherichia coli
Authors: Kachroo B.B.
Published: April 2003

Background: Urinary tract infections (UTIs) are a significant health problem and Escherichia coli has been exported to be the primary pathogen in approximately 80% of cases. E. coli express structures called adhesins, fimbriae or pili that help them bind to specific tissue receptors. One such adhesin is Dr, which binds to the complement decay-accelerating factor (CD55) on the host cell. The purpose of the present study was to review the epidemiology and antimicrobial sensitivity spectrum of Dr adhesin-bearing E. coli isolates in women with UTI. Methods and Results: A total of 337 uropathogenic E. coli isolates were collected, and mannose-resistant hemagglutination was observed in 43%, while 12.4% expressed Dr adhesin. All 337 uropathogenic E. coli isolates were found to be resistant to penicillin, oxacillin, bactericin and cloxacillin. None of the isolates was resistant to quinolones. The resistance to sulfamethoxazole was most common (90%), followed by nalidixic acid (51%) and ampicillin (41%). Interestingly, uropathogenic E. coli expressing Dr adhesin had a high incidence of ampicillin resistance (83%), and only 17% of the Dr-bearing isolates were found to be resistant to an ampicillin/sulbactum combination. Conclusion: These results indicate that UTIs may be successfully treated with ampicillin in combination with a β-lactamase inhibitor, so that selective colonization by Dr adhesin-bearing uropathogenic E. coli is prevented, which is probably promoted by treating these patients with ampicillin alone.
Netilmicin: In vitro Activity, Time-Kill Evaluation and Postantibiotic Effect on Microorganisms Isolated from Ocular Infections
Authors: Bonfiglio Giovanni , Scuderi Anna Claudia , Russo Giovanni
Published: April 2003

The in vitro activity of netilmicin and other antibiotics against ocular gram-positive and gram-negative microorganisms was evaluated. Netilmicin showed excellent activity against all the tested microorganisms, with more than 90% susceptibility. Many gentamicin- and tobramycin-resistant strains were still susceptible to netilmicin, although the minimum inhibitory concentration values of netilmicin were higher than those for the fully susceptible strains. In time-kill studies, netilmicin showed bactericidal activity within 1 h against Pseudomonas aeruginosa and Staphylococcus aureus. Moreover, netilmicin showed a postantibiotic effect of 2.4 h against P. aeruginosa and 1.5 h against S. aureus. These values were longer than those showed by ofloxacin, i.e. 2.1 and 1.4 h, respectively.
Improved Tumor Targeting by Regional Carboplatin Application Combined with Gelfoam®
Authors: Pohlen Uwe , Berger Gerd , Reszka Regina , Binnenhei Marion , Buhr Heinz Johannes
Published: April 2003

Regional chemotherapy of liver metastases is a promising alternative to systemic chemotherapy. Despite a number of theoretical advantages, extended life expectancy has only been confirmed in two studies. Since tumors have a concentration-dependent response to cytostatics, the primary goal is to increase the cytostatic concentration applied in tumor tissue. The aim of this study on liver tumor-bearing chinchilla rabbits was to show that the regional application of carboplatin leads to an increased concentration in tumor tissue. A further increase in carboplatin concentration by additional regional application of gelatine powder (Gelfoam®) was demonstrated in a subsequent test; regional compared to intravenous application increased the carboplatin concentration in the tumor tissue by a factor of 12.1 and coapplication with Gelfoam increased the cytostatic concentration by a factor of 44.3.
Investigation of Oxacillin-Hydrolyzing Beta-Lactamase in Borderline Methicillin-Resistant Clinical Isolates of Staphylococcus aureus
Authors: Gál Zsuzsanna , Kovács Péter , Hernádi Ferenc , Barabás György , Kiss László , Iglói Attila , Szabó István
Published: April 2003

Background: Mechanisms of borderline resistance of Staphylococcus aureus to penicillinase-resistant penicillins (PRPs) may include hyperproduction of classical penicillinase and/or production of β-lactamase hydrolyzing also PRPs. Methods: β-Lactamase activity of whole cells and purified enzymes was estimated spectrophotometrically and in isolated cytoplasmic membranes by bioassay with Bacillus subtilis as test strain. Results: Out of 53 clinical isolates of S. aureus, 18 showed oxacillin MIC values from 0.5 to 2 µg/ml, which were reduced by sulbactam and/or clavulanic acid in the case of four isolates producing large quantities of inducible, type A β-lactamase. Cytoplasmic membranes isolated from these strains showed oxacillin-hydrolyzing activity. One of these strains was grown also in the presence of globomycin, an antibiotic known to interfere with the anchorage of membrane lipoproteins; this treatment eliminated the oxacillin-hydrolyzing activity. Conclusions: The resistance in these strains was due to a membrane-bound lipoprotein with oxacillin-hydrolyzing activity.
Piperacillin with and without Tazobactam against Extended-Spectrum Beta-Lactamase-Producing Pseudomonas aeruginosa in a Rat Thigh Abscess Model
Authors: Karadenizli Aynur , Mutlu Birsen , Okay Erdem , Kolayli Fethiye , Vahaboglu Haluk
Published: April 2003

Background: We compared the antibacterial effect of piperacillin, piperacillin-tazobactam and imipenem in a paired rat thigh abscess model. Methods: Two abscesses were provoked in the thighs of rats, one on the right with an extended-spectrum beta-lactamase (OXA-14)-producing Pseudomonas aeruginosa (Ps-162) and the other on the left thigh with a control strain. Results: The colony counts from the abscesses in log 10 colony-forming units per gram (mean ± SD) in the imipenem group were 2.78 ± 1.71 and 3.19 ± 1.66, in the piperacillin-tazobactam group 4.36 ± 0.23 and 2.44 ± 1.97, and in the piperacillin group 4.44 ± 0.21 and 3.71 ± 0.99 for Ps-162 and the control strain, respectively. The mean colony counts were significantly different (p < 0.05) between Ps-162 and the control strain in the piperacillin and piperacillin-tazobactam groups. Conclusion: These data showed that piperacillin and piperacillin-tazobactam were significantly less effective against extended-spectrum beta-lactamase-producing P. aeruginosa, while imipenem was equally effective against both Ps-162 and the control strain in this abscess model.
Effect of Ravuconazole, a New Triazole Antifungal, in a Rat Intraabdominal Abscess Model
Authors: Mikamo Hiroshige , Yin Xiang Hua , Hayasaki Yoh , Satoh Masaru , Tamaya Teruhiko
Published: April 2003

Background: Ravuconazole (BMS-207147) is a long-lasting triazole antifungal agent active against a broad spectrum of fungal pathogens including non-albicans Candida, Aspergillus, Cryptococcus and key dermatophytic fungi. Methods: The efficacy of ravuconazole was evaluated using an experimental intraabdominal abscess model in rats caused by Candida albicans (E81022). Two hundred milligrams of cyclophosphamide per kilogram was injected intraperitoneally into 40 rats. Four days (96 h) after the injection of cyclophosphamide, a mixture of C. albicans and autoclaved rat cecal contents [C. albicans 1.7 × 108 colony-forming units/rat] was inoculated into the peritoneal cavity. The rats were divided into four groups: ravuconazole treated, fluconazole treated, itraconazole treated and untreated. Each antifungal was given orally at a dose of 10 mg/kg twice a day for 5 days. On the day after the last administration, the rats were dissected and the viable fungi in the abscesses were determined. The number of C. albicans in each abscess was determined by a quantitative culture technique. Results: Ravuconazole inhibited abscess formation and significantly decreased the viable cell counts in abscesses in comparison with the untreated group. It’s efficacy was at least equivalent to fluconazole and itraconazole against this pathogen. The rank order of potency (inhibition) was ravuconazole > itraconazole > fluconazole. Conclusion: Taking into consideration the antifungal spectrum of ravuconazole, which includes non-albicans Candida as well as C. albicans and Aspergillus, it is suggested that ravuconazole would be a good agent for the treatment of fungal peritonitis.
Resistance to Vancomycin, LY333328, Ciprofloxacin and Trovafloxacin of Community-Acquired and Nosocomial Strains of Enterococcus faecalis Isolated in Badajoz (Spain) with and without High-Level Resistance to Streptomycin and Gentamicin
Authors: Sánchez-Silos R.M. , Pérez-Giraldo C. , Blanco M.T. , Morán F.J. , Hurtado C. , Gómez-García A.C.
Published: April 2003

In vitro resistance of community-acquired and nosocomial strains of Enterococcus faecalis isolated in Badajoz (Spain) were determined by a microdilution method. The isolates were identified with conventional MicroScan Pos Combo 4 I dehydrated panels. No resistance to glycopeptides was found, but LY333328 was 2–4 times more active than vancomycin. In the nosocomial strains, high-level resistance to streptomycin (HLRS) was 54.7%, and high-level resistance to gentamicin (HLRG) was 38.1%. Resistance to ciprofloxacin and trovafloxacin was 45.3 and 38.9%, respectively. In the community-acquired isolates, HLRS, HLRG, resistance to ciprofloxacin and resistance to trovafloxacin were 44.2, 17.3, 15.4 and 13.5%, respectively. Trovafloxacin was 2–4 times more active than ciprofloxacin against both groups of strains. An association between high-level resistance to aminoglycosides and resistance to fluoroquinolones was noted. The resistance to aminoglycosides did not influence the activity of vancomycin and LY333328.
In vitro Models of a Three-Drug Regimen (Epirubicin, Cisplatin and Fluorouracil) for the Treatment of Colorectal Cancer
Authors: Caliò Elisabetta , Seminara Patrizia , Aronne Teresa , Sbaffi Enrico , Pagani Guazzugli Bonaiuti Valerio , Gargano Letizia , Franchi Fabrizio
Published: April 2003

The activity of epirubicin, cisplatin and 5-fluorouracil (5-FU), as single agents or in combination (ECF), was investigated in three human colon cancer cell lines by two different assays (cell-counting assay and sulforhodamine B assay) in vitro. 5-FU was tested with both short and continuous exposure. Particular interest was focused on the results obtained in the HCT8-FU cell line, a subline with experimentally induced resistance to 5-FU. The positive modulation of both cisplatin and epirubicin cytotoxicity by 5-FU makes the ECF regimen an attractive protocol for combination therapy in colorectal cancer.
Anti-Cachectic Effect of Clarithromycin for Patients with Unresectable Non-Small Cell Lung Cancer
Authors: Sakamoto Masahiro , Mikasa Keiichi , Majima Toshimasa , Hamada Kaoru , Konishi Mitsuru , Maeda Koichi , Kita Eiji , Narita Nobuhiro
Published: April 2003

We have previously reported that long-term treatment with clarithromycin (CAM) increased the median survival of patients with non-small cell lung cancer, and improved various clinical parameters in these patients. In the present study, CAM was administered to 33 patients with unresectable primary non-small cell lung cancer, who had received chemotherapy, radiotherapy or both (basic cancer therapy). Patients with clinical backgrounds matched to the CAM group, who did not receive CAM treatment, were included into this study as a control group (non-CAM group). CAM treatment was initiated 4 weeks after the basic cancer therapy. The non-CAM group did not receive a placebo. Before and after the 3-month treatment with CAM, body weight, serum levels of interleukin-6 (IL-6, a cytokine which, together with TNF-α, plays a crucial role in the development of cancer cachexia), total protein, albumin, cholinesterase and hemoglobin were measured for the evaluation of the patients’ clinical status. There were no statistically significant differences in serum levels of IL-6 between the CAM group before the treatment and the non-CAM group. After 3 months of CAM treatment, serum levels of IL-6 significantly decreased. In contrast, body weight, cholinesterase, and hemoglobin increased to a significant extent. Among these four parameters, however, the decrease in serum IL-6 levels was only statistically correlated with the increase in body weight, but not with that in other parameters. Furthermore, CAM-treated patients whose serum IL-6 levels were decreased after 3 months of treatment survived longer: there was a statistically significant correlation between the decrease in serum IL-6 and survival time. In contrast, in the non-CAM group, these parameters did not change significantly during the study. These results suggest that CAM may reduce the progression of cancer-associated cachexia.
Selection of Klebsiella pneumoniae Mutants with High-Level Cefotaxime Resistance during Growth in Serum Containing Therapeutic Concentrations of Cefotaxime
Authors: Bedenić Branka
Published: April 2003

Background: In a previous investigation of the genetic characterization of extended-spectrum β-lactamases (ESBLs) in Klebsiella pneumoniae from Zagreb, Croatia, 20 strains were found to produce SHV-2 β-lactamase. Those strains displayed varying degrees of β-lactam resistance and a wide range of β-lactamase activity. We concluded that more resistant isolates were hyperproducers of SHV-2 β-lactamase. Methods: In this investigation, we tried to develop hyperproducing variants from 8 low-level SHV-2 β-lactamase-producing Klebsiella strains by subculturing them in serum containing therapeutic concentrations of cefotaxime (CTX). Results: In most cases, there was a moderate increase in CTX resistance (twofold to threefold), except in one strain which displayed a 16-fold increase in the minimum inhibitory concentration (MIC) of CTX after incubation in the serum. That strain showed a marked increase in enzyme activity as well. The strains with a moderate increase in CTX MIC did not produce more enzyme after exposure to the serum, except for one strain which had a threefold rise in β-lactamase activity after exposure to serum. Conclusions: In this investigation, it was established that the mutants with high-level CTX resistance developed very quickly in the biological fluids containing therapeutic concentrations of CTX. It is reasonable to expect that a similar process occurs in patients infected with an ESBL-producing K. pneumoniae strain during antibiotic treatment. Since most of the high-level CTX-resistant mutants did not have a marked rise in β-lactamase activity after exposure to serum, it is possible that the elevated resistance was due to some other mechanism, such as reduced penicillin-binding protein affinity, changes in outer membrane proteins or efflux by multidrug efflux pumps.
Mutation Analysis in a Patient with Succinic Semialdehyde Dehydrogenase Deficiency: A Compound Heterozygote with 103–121del and 1460T > A of the ALDH5A1 Gene
Authors: Aoshima Tsutomu , Kajita Mitsuharu , Sekido Yoshitaka , Ishiguro Yoshiko , Tsuge Ikuya , Kimura Masahiko , Yamaguchi Seiji , Watanabe K.Kazuyoshi , Shimokata Kaoru , Niwa Toshimitsu
Published: April 2003

We saw a 17-month-old boy with moderate psychomotor retardation, and enzymatically diagnosed succinic semialdehyde dehydrogenase (SSADH) deficiency. After extracting mRNA and genomic DNA from his cultured lymphoblasts, we analyzed the entire coding region of the ALDH5A1 gene using reverse transcription-polymerase chain reaction (RT-PCR) and genomic PCR followed by sequencing. He was demonstrated to be a compound heterozygote with two novel mutations (103–121 del and 1460T>A). The former leads to a frameshift and premature termination, and the latter is a missense mutation, V487E. Both mutations were also detected in the genomic DNA. Taken together with previous mutation reports, genetic heterogeneity was suspected for SSADH deficiency, and may account for the wide range of its phenotype.
Cross-Sectional Study of the Prevalence of Parkinson’s Disease in the Kibbutz Movement in Israel
Authors: Anca M. , Paleacu D. , Shabtai H. , Giladi N.
Published: April 2003

Background: The prevalence of PD in Israel has never been studied. Objective: To study the prevalence of Parkinson’s disease (PD) in a well-defined population of the Kibbutz Movement in Israel. The population which lives in kibbutzim is unique because all these people are under close medical care and the demographic data regarding this population are well defined. Methods: Questionnaires were sent to the medical clinics of 270 kibbutzim in Israel to provide demographic details as well as medical information about all PD patients who have been diagnosed by neurologists. Two subgroups were determined: aged over 40 years and over 60 years. Results: Of the total of 73,767 people studied, PD was diagnosed in 180 patients yielding a cross-sectional prevalence rate of 0.24% for the entire population. Age-adjusted prevalence was 0.94% in the population over 60 years and 0.33% in the population over 40 years. The mean age of disease onset was 66.7 ± 11 years. Topographic location was not found to be a risk factor for the development of PD in Israel. Conclusions: The prevalence of PD in the Israeli kibbutz population is similar to that reported in most other population-based studies. We observed an older age at symptom onset in the Kibbutz Movement than most other epidemiological studies.
Anticardiolipin Antibodies and Mortality in Patients with Ischemic Stroke: A Prospective Follow-Up Study
Authors: Tanne David , D’Olhaberriague Luis , Trivedi Ashish M. , Salowich-Palm Leeza , Schultz Lonni R. , Levine Steven R.
Published: April 2003

The purpose of the present prospective observational study was to assess whether or not the presence of anticardiolipin antibodies (aCL) in unselected first ischemic stroke patients is associated with adverse outcome. Consecutive patients (n = 300; mean age 64 years; 48% males) presenting with a first acute ischemic stroke were evaluated for IgG aCL and were systematically followed up. During a median follow-up of 21 months, 58 patients (19%) died. Mortality rates were higher in patients with aCL >20 IgG phospholipid units (GPL) [33 vs. 18%; relative risk (RR) 1.94, 95% confidence interval (CI) 1.02–3.67; p = 0.042] or >40 GPL (40 vs. 19%; RR 2.46, 95% CI 1.05–5.75; p = 0.037). Elevated aCL did not confer an increased risk during follow-up of a combined end point of stroke, myocardial infarction and vascular death or of nonfatal thrombo-occlusive events. Rates of malignancy detected during follow-up were higher among patients with aCL >20 GPL (19 vs. 5%, p = 0.007) and >40 GPL (27 vs. 6%, p = 0.01). The excess mortality associated with elevated aCL was eliminated after adjustment for age, cardiovascular risk factors and malignancy. These results demonstrate that aCL above 20–40 GPL among consecutive ischemic stroke patients is a marker of increased mortality during follow-up, but older age and higher rates of cardiovascular risk factors and malignancy detected during follow-up account for the higher mortality.
Prevalence and Incidence of Major Depressive Disorder in Alzheimer’s Disease: Findings from Two Databases
Authors: Weiner Myron F. , Doody Rachelle S. , Sairam Ramesh , Foster Barbara , Liao Tso-yu
Published: April 2003

Background: Reports on the frequency of major depression in Alzheimer’s disease are conflicting, some suggesting that it is frequent, others suggesting that it is uncommon. Methods: We examined the prevalence and incidence of symptom clusters meeting criteria for major depressive disorder (MDD) in two large series of cases diagnosed prospectively by NINCDS/ADRDA criteria as probable or possible Alzheimer’s disease. Standard DSM-III-R criteria were employed at one site, the CERAD modification of DSM-III-R criteria at the other. Both sites required the presence of depressed mood on direct patient examination at the time of initial evaluation in order to meet criteria for MDD. Results: At the center using standard DSM-III-R criteria (n = 329), there was a 0.9% prevalence of symptom clusters meeting criteria for MDD. At the center using the CERAD modification (n = 586), MDD prevalence was 4.8%. Incidence rates at both centers were below 2% per year over 3 years. Conclusions: We concluded that DSM-III-R MDD is not common in AD patients.
The Alzheimer’s Disease Assessment Scale: Findings from a Low-Education Population
Authors: Liu Hsiu-Chih , Lee Teng Evelyn , Chuang Ya-Yun , Lin Ker-Neng , Fuh Jong-Ling , Wang Pei-Ning
Published: April 2003

We constructed a Chinese version of the cognitive component of the Alzheimer’s Disease Assessment Scale (ADAS-Cog). In order to accommodate illiteracy, the Chinese version used pictures instead of words for assessing recall and recognition. The Chinese ADAS-Cog was administered to 125 individuals with no dementia, 127 with questionable dementia, and 77 with Alzheimer’s disease (AD). Their age range was 51–92 years and their education range was 0–20 years. The Chinese ADAS-Cog had high internal consistency (Cronbach’s alpha = 0.87) and very high interrater reliability (intraclass correlation coefficient, or ICC, = 0.99) and test-retest reliability (ICC = 0.96). It had high correlations with scores on the Clinical Dementia Rating Scale (Pearson’s r = 0.85), the Cognitive Abilities Screening Instrument (CASI, Pearson’s r = –0.88), and CASI-estimated scores on the Mini-Mental State Examination (Pearson’s r = –0.85). Performance on the Chinese ADAS-Cog was uninfluenced by age or gender, nor by education level except within the low education range of 0–6 years. Its memory items were best for early detection of dementia; its language items were best for monitoring the progression of dementia. This study found that the Chinese ADAS-Cog is a good instrument for use with Chinese AD patients.
Efficacy of Olanzapine in the Treatment of Psychosis in Dementia with Lewy Bodies
Authors: Cummings Jeffrey L. , Street Jamie , Masterman Donna , Clark W. Scott
Published: April 2003

Objective: This study sought to determine whether patients with dementia with Lewy bodies (DLB) and psychosis responded to treatment with olanzapine. Methods: This was a post hoc analysis of a subgroup of patients with DLB included in a larger double-blind, placebo-controlled, randomized parallel group trial of olanzapine for the treatment of psychosis in patients with Alzheimer’s disease. Patients meeting the consensus criteria for DLB and exhibiting parkinsonism and visual hallucinations were selected from the initial study. Psychosis was assessed with the Neuropsychiatric Inventory/Nursing Home (NPI-NH) version and the Brief Psychiatric Rating Scale (BPRS). Extrapyramidal symptoms were evaluated with the Simpson-Angus scale. Results: Twenty-nine patients met the criteria for DLB; 10 were randomized to placebo, 5 received 5 mg of olanzapine, 7 received 10 mg of olanzapine and 7 received 15 mg of olanzapine. Patients with DLB treated with 5 mg of olanzapine showed significant reductions in delusions and hallucinations. Patients treated with 10 mg showed a significant reduction in the NPI-NH delusion subscale score. No significant differences were found between the 15-mg group and the placebo group. Confirmatory findings emerged from an analysis of the BPRS. Caregivers reported decreased disruptions in their occupational routines for the group receiving 5 or 10 mg of olanzapine. There was no significant exacerbation of parkinsonian symptoms in any study group, no decrement in Mini-Mental State Examination scores in any of the treatment groups, and symptoms suggestive of anticholinergic toxicity did not differ among treatment groups. Conclusions: This preliminary analysis suggests that olanzapine (5 or 10 mg) reduces psychosis in patients with DLB without worsening parkinsonism.
Factorial Validation of the Severe Impairment Battery for Patients with Alzheimer’s Disease
Authors: Pélissier Charlotte , Roudier Michel , Boller François
Published: April 2003

The Severe Impairment Battery (SIB) estimates the cognitive aptitudes and other skills of severely impaired dementia patients. The main objective of this pilot study was to clearly identify the number of factors present in the SIB and to analyze the relationships between the different cognitive domains explored by the SIB and loss of autonomy. We administered the SIB, the Mini Mental State Examination (MMSE) and two scales of dependency to 48 patients with Alzheimer’s disease in its late stages. A factorial analysis (Principal Components Analysis) showed a 4-factor solution for the SIB: a cognitive factor, a praxis and visuospatial functions factor, the reactivity to external stimuli factor and the social aptitudes factor. A factorial analysis involving the dependency scales showed a cognitive factor, a dependency and constructional praxis factor, the reactivity to external stimuli factor and the social aptitudes factor. Reactivity to external stimuli and social aptitudes were not significantly correlated to cognitive aspects nor to dependency. The finding of dependency as a factor different from cognitive deterioration suggests that, in setting a treatment strategy for demented patients, attempts should be made to treat dependency in its own right. In addition, since reactivity to external stimuli and social aptitudes are not related to cognitive aspects nor to dependency, these functions should also be encouraged and stimulated.
Apolipoprotein E among Korean Alzheimer’s Disease Patients in Community-Dwelling and Hospitalized Elderly Samples
Authors: Kim Jae-Min , Shin Il-Seon , Yoon Jin-Sang
Published: April 2003

This study evaluated the association of the apolipoprotein E Ε4 allele (Ε4) with Alzheimer’s disease (AD) and investigated the relationships of Ε4 with clinical characteristics of AD in both community-dwelling and hospitalized Korean elderly populations. The apolipoprotein E genotypes were compared between a group of 52 community-dwelling patients with AD (C-AD), a group of 52 hospitalized patients with AD (H-AD) and a group of 52 healthy controls matched to C-AD. Clinical characteristics and scores on several assessment scales were compared between C-AD and H-AD as well as between two subgroups within each AD group: those with Ε4 and those without Ε4. For H-AD, the assessment scales were administered again 6 months later, and the temporal course of AD was compared between the subgroups. The frequency of Ε4 was significantly higher in both AD groups than in controls. Between C-AD and H-AD, no differences were found in Ε4 frequency, while symptoms of dementia were significantly severer in H-AD than in C-AD. Within each AD group, no differences were observed in terms of clinical characteristics and scores on the assessment scales between the subgroups. Furthermore, the subgroups of H-AD showed no difference in the rate of progression. In conclusion, there was a significant association of Ε4 with AD. However, no relationships were found between Ε4 and clinical characteristics in either C-AD or H-AD. Furthermore, the rate of progression did not vary with respect to the presence or absence of Ε4 in H-AD. The severer symptoms observed in the hospitalized sample than in those at large might be explained by factors other than the impact of Ε4.
Effects of Rivastigmine on Cognitive Function in Dementia with Lewy Bodies: A Randomised Placebo-Controlled International Study Using the Cognitive Drug Research Computerised Assessment System
Authors: Wesnes K.A. , McKeith I.G. , Ferrara R. , Emre M. , Del Ser T. , Spano P.F. , Cicin-Sain A. , Anand R. , Spiegel R.
Published: April 2003

This study was designed to assess the effects of rivastigmine (Exelon®) on the cognitive functioning of patients suffering from dementia with Lewy bodies. This was a prospective, multi-centre, randomised, double-blind, placebo-controlled exploratory study conducted at sites in the UK, Spain and Italy. The treatment period was 20 weeks with a 3-week posttreatment follow-up. The primary outcome measures were the Cognitive Drug Research (CDR) computerised assessment system and the Neuropsychiatric Inventory. Testing was conducted prior to dosing and then again at weeks 12, 20 and 23. Analysis of the data from the 92 patients who completed the study identified a significant pattern of benefits of rivastigmine over placebo on the CDR system. These benefits were seen on tests of attention, working memory and episodic secondary memory. Taking attention for example, patients given placebo showed a significant deterioration from predosing scores at 12 and 20 weeks, whereas patients on rivastigmine performed significantly above their predosing levels. These effects were also large in magnitude, the decline under placebo at week 12 being 19%, while the improvement under rivastigmine was 23%. The clinical relevance of this 23% improvement was that it took the patients 33% towards being normal for their age on this assessment of attention. These benefits to cognitive function were accompanied by a significant improvement of the other primary outcome measure, the Neuropsychiatric Inventory. Three weeks after discontinuation of rivastigmine, most parameters of cognitive performance returned to predrug levels.
Effect of Surgical Menopause on Cognitive Functions
Authors: Farrag Abdul-kader F. , Khedr Eman M. , Abdel-Aleem Hany , Rageh Tarek A.
Published: April 2003

To investigate the effect of estrogen deficiency on cognitive function in surgically menopausal women, a prospective study was conducted at the University Hospital in Assiut, Egypt, during the period of July 1997 to August 1999. The study included 35 women subjected to total abdominal hysterectomy and bilateral salpingo-oophorectomy for nonmalignant causes. They were subjected to cognitive assessment by Mini-Mental State Examination (MMSE), Wechsler Memory Scale (WMS) subtests, and measurement of auditory Event-Related Potentials (ERPs) and serial serum estradiol levels determination. Eighteen age- and education-, body-weight- and parity-matched control women were recruited for comparison. A significant decline in MMSE, WMS subtests (digit span, visual memory, logical memory and mental control) and prolongation of P300 of ERP latency was observed in the patient group at 3 and 6 months postoperatively. These changes were not observed in the control group. A significant correlation was found between serum estradiol level and mental control subtest score and P300 latency in patients preoperatively. Patients who had a drop of estrogen level >50% had more cognitive function decline. Rapid decline in estrogen level following surgical menopause was associated with a deleterious effect on cognitive function. Such observations may contribute to more understanding of the age-related cognitive decline in females.
Possible Role of Nitric Oxide and Adrenomedullin in Bipolar Affective Disorder
Authors: Savaş Haluk A. , Herken Hasan , Yürekli Muhittin , Uz Efkan , Tutkun Hamdi , Zoroğlu Süleyman Salih , Özen Murat Eren , Cengiz Beyhan , Akyol Ömer
Published: April 2003

Nitric oxide (NO) has been implicated to play a role in the pathogenesis of depressive disorders. Adrenomedullin (AM) induces vasorelaxation by activating adenylate cyclase and also by stimulating the release of NO. AM immune reactivity is present in the brain, consistent with a role as neurotransmitter. Therefore, it is suggested that these two molecules may play a role together in the brain. We aimed to examine AM and NO in bipolar affective disorder (BPAD). Forty-four patients with BPAD and 21 healthy control subjects were included in this study. DSM-IV diagnosis of bipolar affective disorder (type I, manic episodes) was independently established by two psychiatrists and the Turkish version of the Bech-Rafaelson Mania Scale was administered. Also, a semistructured form was used to ascertain several sociodemographic and clinical variables of the patients. AM and NO were studied in plasma. The mean value of plasma NO levels in the BPAD group of 46.58 ± 13.97 µmol/l was significantly higher than that of controls (31.81 ± 8.14 µmol/l) (z = –4.15, p = 0.000). Mean plasma AM levels were found to be increased in patients with BPAD (35.13 ± 5.26 pmol/l) compared to controls (16.22 ± 3.02 pmol/l) (z = –6.16, p = 0.000). AM levels of BPAD patients were approximately 2-fold higher than controls. AM levels were positively correlated with the duration of hospitalization for the current episode and negatively correlated with the total duration of illness. Both NO and AM may have a pathophysiological role in BPAD (type I, manic episodes) and the clinical symptomatology and prognosis of BPAD.
Plasma Catecholamines and Selective Slow Wave Sleep Deprivation
Authors: Tiemeier Henning , Pelzer Eva , Jönck Lothar , Möller Hans-Jürgen , Rao Marie Luise
Published: April 2003

The present study evaluated the effect of slow wave sleep (SWS) deprivation on plasma levels of catecholamines in healthy male volunteers. Eleven volunteers spent 4 nights in the sleep laboratory (2 nights of habituation and 2 further nights); during the latter, 1 night served as control, and in the other, SWS deprivation was performed. Blood was drawn at 30-min intervals. SWS was reduced by 86%; no sleep stage 4 was observed during the SWS-deprived nights. SWS reduction was found not to correlate with catecholamine levels. However, epinephrine levels were found to be sensitive to sleep fragmentation. The time interval between arousals in the SWS-deprived night as well as the difference in sleep efficiency were related to increases in epinephrine levels (p < 0.01 and p < 0.025, respectively). These results support the view that continuity rather than the duration of SWS is important for the recuperative value of sleep.
Receptor-Like Protein Tyrosine Phosphatase γ (RPTPγ), But Not PTPζ/RPTPβ, Inhibits Nerve-Growth-Factor-Induced Neurite Outgrowth in PC12D Cells
Authors: Shintani Takafumi , Maeda Nobuaki , Noda Masaharu
Published: April 2003

Receptor-like protein tyrosine phosphatase γ (RPTPγ) and PTPζ/RPTPβ are RPTPs which structurally resemble each other and form a distinct RPTP family. Both molecules are highly expressed in the central nervous system (CNS), though RPTPγ is distributed also in several peripheral tissues. To date, the functional differences between RPTPγ and PTPζ in neuronal cells have not been made clear because their substrate and ligand molecules have not been fully elucidated. To address this issue, we established PC12D cell transfectants stably expressing rat RPTPγ or PTPζ and analyzed the effects on cellular response to nerve growth factor (NGF). Compared with the parent PC12D cells which extend neurites vigorously in response to NGF, the transfectants expressing RPTPγ showed almost no neurite outgrowth. In contrast, neurite extension in PTPζ-expressing clones on NGF treatment was the same as in parent cells. We investigated differences in tyrosine phosphorylation levels in the cellular proteins in these cells after the NGF treatment before morphological charges appeared. Despite the lack of a response, major proteins and MAP kinase in RPTPγ-expressing PC12D cells displayed normal tyrosine phosphorylation changes on NGF treatment. However, tyrosine phosphorylation levels in the protein components purified with p13suc1 agarose (p13suc1 complex) from RPTPγ-expressing cells were different from those of the control cells. (1) Tyrosine-phosphorylation levels of 140- and 117-kD proteins were significantly reduced. (2) Rapid tyrosine phosphorylation of 58-kD protein induced by NGF was absent. (3) Activities of tyrosine kinases and protein kinase C in the p13suc1 complex were markedly reduced. We found that the p13suc1 complex also contained cytoskeletal proteins such as MAP2 and neurofilaments, but their phosphorylation levels were not different. These results indicate that RPTPγ and PTPζ have different substrate specificities, and RPTPγ inhibits NGF-induced neurite outgrowth of PC12D cells through modulation of the p13suc1 complex.
Delayed Postnatal Development of NMDA Receptor Function in Medium-Sized Neurons of the Rat Striatum
Authors: Hurst Raymond S. , Cepeda Carlos , Shumate Lincoln W. , Levine Michael S.
Published: April 2003

During early postnatal development, the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor plays a dominant role in excitatory amino acid-mediated synaptic transmission in essentially every brain region that has been examined. In contrast, we have found that in the rat striatum, NMDA receptor-mediated current develops later in the medium-sized neurons (MSNs) than currents mediated by activation of non-NMDA receptors. MSNs were identified using infrared video microscopy, and voltage-clamped in a slice preparation using the whole-cell patch-clamp technique. Intrastriatal stimulation was used to evoke excitatory synaptic currents from slices in animals ranging in age from postnatal day (PND) 5 to 60. Though most cells from animals younger than PND 10 failed to respond to synaptic stimulation, postsynaptic responses were occasionally evoked in cells as young as PND 5. Synaptic currents from cells between PNDs 5 and 7 had a significant contribution due to activation of non- NMDA receptors, as evidenced by sensitivity to the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and rapidly rising and falling response components. The relative contribution of NMDA receptors increased approximately twofold from the first to the third postnatal week; no further change was observed through PND 60. At the same ages that the NMDA receptors contributed maximally to the synaptic current, the decay time constant of the NMDA receptor-mediated current decreased significantly. The increasing weight of NMDA receptor-mediated current may reflect a change in the number of functional receptors at the synapse since there was no apparent change in the voltage dependence of the current. To more completely examine receptor function early in postnatal development, NMDA and kainate were applied either iontophoretically or in the bath. Iontophoretic application of NMDA onto cells obtained from rats between PNDs 3 and 5 only occasionally evoked current, provided that the membrane was held at depolarized potentials to remove the Mg2+ block. In contrast, application of kainate consistently evoked a response from cells of the same age group. Bath application of the same agonists provided similar results. Taken together, the present experiments demonstrate that striatal non-NMDA receptor-mediated currents are more mature than NMDA receptor-mediated currents early in development.
Blockade of Endothelin Receptors Reduces Diet-Induced Hypercholesterolemia and Atherosclerosis in Apolipoprotein E-Deficient Mice
Authors: Iwasa Satoshi , Fan Jianglin , Miyauchi Takashi , Watanabe Teruo
Published: April 2003

Objective: Endothelin (ET)-1 has proatherogenic properties, since ET receptor antagonists reduce atherosclerotic lesions in animals. However, we recently demonstrated that ET-1 and ETB receptors are increased in atherosclerotic lesions. To further examine the effects of ETB receptor antagonism on atherogenesis, we investigated the chronic effects of the nonselective ETA/ETB receptor antagonist SB209670 on the development of atherosclerosis in apolipoprotein E (ApoE)-deficient mice. Methods: Ninety-four male mice (10 weeks of age) were randomly divided into four groups: mice fed a Western-type diet or a chow diet with SB209670 treatment (10 mg/kg/day) or placebo for 12 weeks. Results: In mice fed the Western-type diet, but not in mice fed the chow diet, treatment with SB209670 significantly attenuated the increase in plasma total cholesterol, predominantly in the very-low-density lipoprotein and intermediate-density lipoprotein fractions, without altering the plasma triglyceride level. Furthermore, treatment with SB209670 significantly reduced the extent of aortic atherosclerosis, by 53% in mice fed the Western-type diet and by 38% in mice fed the chow diet. Histological analysis revealed that SB209670 prevented the formation of atheromatous plaque lesions by inhibiting the fibroproliferative process. Conclusion: We found that chronic administration of SB209670 reduced diet-induced hypercholesterolemia and atherosclerosis in ApoE-deficient mice. Thus, nonselective ET receptor antagonists may have a therapeutic potential in the treatment of human atherosclerotic disease.
Downregulation of Clusterin Expression in Testicular Germ Cell Tumours
Authors: Behrens P. , Jeske W. , Wernert N. , Wellmann A.
Published: April 2003

Objectives: Clusterin is implicated in many biological processes including cell adhesion, apoptosis and transformation. Clusterin expression was demonstrated during sperm maturation and is overexpressed in different malignancies including breast and prostate carcinomas and anaplastic large-cell lymphomas. Methods: The aim of this study was to determine the expression of clusterin in a series of different germ cell tumours by immunohistochemistry. Twenty-two seminomas, 27 embryonal carcinomas, 22 mature and immature teratomas, 8 yolk sac tumours and 1 chorion carcinoma as well as 30 normal testes were analysed using a monoclonal antibody. Results: In normal testes strong signals were seen in the maturing germ cells and in Leydig cells. In most tumours examined no clusterin expression was detected (84%). Only a focal weak expression was seen in some teratomas (32%), embryonal carcinomas (15%) and yolk sac tumours (25%). Conclusions: Our results suggest that clusterin is associated with normal germ cell development and that the loss of clusterin expression might play a role in the malignant transformation of germ cells.
Inhibitory Effect of Short-Term Bile Duct Ligation on Hepatic Cytochrome P450 of Bile Acid-Depleted Rats
Authors: Agüero Rut M. , Favre Cristian , Rodriguez-Garay Emilio A.
Published: April 2003

In this study we analyzed the effect resulting from a short-term (1 h) bile duct obstruction in bile acid-depleted or taurocholate-replenished rats on liver cytochrome P450 enzyme system activity. Rats were depleted of endogenous bile acids and then subjected to a biliary obstruction for 1 h. Some of these depleted-obstructed rats were replenished previously to the obstruction with exogenous taurocholic acid (TC) and the others were treated with the solvent alone. To study the isolated effect of the bile acid, other rats were also previously depleted and then replenished with TC but they were obstructed briefly (20 min). CYP3A2-linked activity was evaluated in vivo with the aminopyrine breath test and in vitro by the measurement of nifedipine oxidase microsomal activity. The results suggested that bile flow suppression per se might inhibit this CYP-linked activity and that bile acid retention is not involved at least as a sole determinant.
Bromodeoxyuridine Induces p53-Dependent and -Independent Cell Cycle Arrests in Human Gastric Carcinoma Cell Lines
Authors: Peng Dun-Fa , Sugihara Hiroyuki , Hattori Takanori
Published: April 2003

Objectives: This study was designed to clarify the effects of bromodeoxyuridine (BrdU) on cell cycle progression and induction of apoptosis, and to demonstrate the role of P53 in these processes. Methods: We continuously exposed four human gastric carcinoma cell lines with different P53 status (P53 wild-type AGS and MKN-45, P53-mutated MKN-28 and P53-deleted KATO-III) to BrdU in asynchronous and synchronous culture conditions, and analyzed DNA histograms of apoptotic and nonapoptotic cells determined by static DNA cytofluorometry. Results: Continuous exposure to 20 µM BrdU after synchronization with hydroxyurea resulted in S phase delay and G1 arrest in MKN-45 and an increase of apoptosis in the first S/G2 phase in AGS and MKN-45. In the second S phase, a delay of 3–6 h was observed in all the four cell lines. In asynchronous cultures, continuous exposures to 20 and 200 µM BrdU for 72 h or more caused growth suppression with G1 and G2 arrests, respectively, in all the cell lines. Conclusions: These data suggested that the BrdU-induced growth suppression of the cell lines examined was mainly caused by cell cycle arrest rather than cell death, and that the cell cycle arrests in the first S and G1 phases (elicited by BrdU in the single DNA strand) and those in the second S, G2 and G1 phases (elicited by BrdU in the double DNA strands) were mediated by p53-dependent and -independent pathways, respectively.
Autophagy and Nuclear Changes in FM3A Breast Tumor Cells after Epirubicin, Medroxyprogesterone and Tamoxifen Treatment in vitro
Authors: Bilir Ayhan , Altinoz Meric A. , Erkan Melike , Ozmen Vahit , Aydiner Adnan
Published: April 2003

Objective: Autophagy is a form of physiological programmed cell death which is observable after hormonal withdrawal. In this study, the FM3A murine breast tumor cell line was treated with epirubicin alone and with medroxyprogesterone acetate (MPA) or tamoxifen, to determine if structural and kinetic signs of autophagy may also occur in an enhanced manner during epirubicin sensitization via hormonal agents. Methods: One-week soft agar colony growth, 96-hour values of plating and pulse thymidine labeling and electron microscopical examinations were performed following treatment with MPA and tamoxifen alone or with epirubicin. Results: Tamoxifen induced signs of autophagy, which was enhanced when it was combined with MPA. Epirubicin also induced autophagy of secretory granules, which coalesced to form an intracytoplasmic lumen. Combining MPA with epirubicin enhanced the formation of apoptotic blebs and chromatin fragmentation. When epirubicin was combined with tamoxifen, peculiar nuclear structures were formed. Conclusions: Hormonal agents may modulate anthracycline activity towards specific patterns in eliciting cell death, via autophagy and/or as yet unknown nucleolus-specific interactions.
PTEN Expression in Breast and Endometrial Cancer: Correlations with Steroid Hormone Receptor Status
Authors: Kappes Holger , Goemann Christoph , Bamberger Ana-Maria , Löning Thomas , Milde-Langosch Karin
Published: April 2003

Objective: The PTEN (MMAC1/TEP1) tumor suppressor gene is frequently mutated and homozygously deleted in human neoplasms, but there is only sparse information about PTEN protein expression in hormone-dependent female tumors. Therefore, we investigated PTEN expression in 68 breast and 43 endometrial carcinomas. Methods: For PTEN protein detection, we used Western blot analysis followed by densitometry and compared these data with clinicopathologic parameters, the estrogen receptor (ER) and progesterone receptor (PR) status, HER2/neu and the proliferation marker Ki67. Results: We were able to show significantly decreased PTEN protein expression in endometrial carcinomas compared with normal endometrial tissue samples, especially in the endometrioid histological subtype. In contrast, PTEN downregulation was found more rarely in breast cancer. Lower PTEN expression in breast cancer correlated significantly with high ER immunoreactivity (p = 0.008) and was weakly associated with PR expression (p = 0.055) and low histological grading (p = 0.081). No correlation with any of these parameters was observed in endometrial tumors. In both tumor types, no association of PTEN expression with any other analyzed parameter was found. Conclusions: These results suggest that PTEN expression plays different roles in the pathogenesis of endometrial carcinomas and breast cancer. In mammary carcinomas, loss of PTEN expression is mainly found in more differentiated tumors and is probably not a major event in carcinogenesis.