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Effect of TCN2 776C>G on vitamin B 12 cellular availability in end-stage renal disease patients. Background Transcobalamin II is a serum protein that transports vitamin B 12 from the intestine to the tissues. This complex, holo-transcobalamin II, may reflect vitamin B 12 availability in the body. Conflicting data exist with regard to the effect of a polymorphism in the gene coding for transcobalamin II, TCN2 776C>G, on transcobalamin II levels in the general population, which in turn may affect holo-transcobalamin II, vitamin B 12 , as well as total homocysteine (tHcy) plasma levels. The effect of TCN2 776C>G on vitamin B 12 cellular availability in dialysis patients is unknown. Methods We examined the effect of TCN2 776C>G on holo-transcobalamin II, vitamin B 12 , and tHcy plasma concentrations in 120 dialysis patients. Results Holo-transcobalamin II levels were normal or supranormal in all patients and showed a linear association with albumin ( r = 0.205, P = 0.025) and with vitamin B 12 ( r = 0.778, P = 0.001), but not with age, creatinine, body mass index, tHcy, ln-tHcy, vitamin B 6 , plasma folate, and red blood cell folate concentration. TCN2 776C>G showed no effect on holo-transcobalamin II, vitamin B 12 , and tHcy concentration [one-way analysis of variance (ANOVA), post-hoc Scheffe test]. Multiple linear regression analyses showed that albumin and B 12 are independently associated with holo-transcobalamin II, whereas TCN2 776C>G and MTHFR 677C>T had no effect. Independent predictors of ln-tHcy included creatinine, red blood cell folate, and the MTHFR 677TT genotype. There was also an effect of the TCN2 776CC genotype on ln-tHcy levels in this multivariate analysis, however, that deserves cautious interpretation because there was no effect of TCN2 genotypes by ANOVA and Scheffe test [median ln-tHcy concentrations according to TCN2 genotypes (μmol/L): CC, 3.22; CG, 3.30; GG, 3.23]. Conclusion TCN2 776C>G does not influence holo-transcobalamin II or vitamin B 12 levels, and has no major effect on tHcy concentrations of end-stage renal disease patients.

The aim of this study was to assess survival and prognostic factors of 98 consecutive patients with unresectable glioblastoma multiforme (GBM) after stereotactic biopsy. Patients were diagnosed between 1993 and 1998, and the treatment modality subsequent to stereotactic biopsy was determined by the year of diagnosis. Before 1995, patients did not receive further specific therapy after stereotactic biopsy (n=36). In 1996, patients were administered radiotherapy starting within 6 weeks after stereotactic biopsy (n=24). From 1997 to 1998, patients received combined radio-/chemotherapy (RCT; CCNU orally) starting within 2 weeks after stereotactic biopsy (n=38). Patients' age ranged from 21 to 84 (median 64) years and their median Karnofsky performance score 2 weeks after stereotactic biopsy was 80 (range 60-100). Survival and prognostic factors were analyzed with respect to administered treatment modalities (without specific therapy versus radiotherapy versus combined RCT), with respect to age (oror=50 years), gender, Karnofsky performance score (or=or80), tumor location (frontal, parieto-temporal, central, occipital) and tumor size (oror=5 cm; tumor multiplicity was considered as diameter5 cm) by the Kaplan-Meier method, by log-rank test and multivariate Cox regression analysis. Post-biopsy treatment modality was the strongest predictor for survival. Median (range) survival was 9 (3-47) weeks in those without specific therapy, 13 (5-54) weeks in patients receiving radiotherapy and 31 (11-101) weeks in patients receiving combined RCT (por=0.001). Ageor=50 years (por=0.05) in addition to tumor size in multivariate Cox analysis were found to be of significant influence onto survival, too. Combined RCT could be performed on a complete outpatient basis. Toxicity consisted of mild asymptomatic thrombocytopenia. We conclude that the administration of combined RCT within a minimum interval after stereotactic biopsy yielded a significant increase in survival. Patients' acceptance was excellent. These results encourage us to treat even patients with unresectable GBM with combined RCT.

A total of 55 patients with histologically proven glioblastoma multiforme (total gross resection: n=24, subtotal resection: n=20, stereotactic biopsy: n=11) were treated with the combination of dacarbazine (D) (200 mg m(-2)) and fotemustine (F) (100 mg m(-2)) and concomitant radiotherapy (2 Gy day(-1), 5 days per week using limited fields up to 60 Gy) to assess efficacy and toxicity of this regimen. Survival (median survival, 12-, 18- and 24-month survival rates) and time to progression (median time to progression (TTP), 6-month progression-free survival) were analysed by Kaplan-Meier's method. A total of 268 (range 1-8, median: 5) cycles were administered. Median survival is 14.5+ (range: 0.5-40+) months, and the 12-, 18- and 24-month survival rates are 58, 29 and 23%, respectively. Median TTP from the start of D/F therapy is 9.5+ (range: 0.5-33+) months. The 6-month progression-free survival is 54%. Partial remissions were observed in 3.6%. Main toxicity was thrombocytopenia. Five patients were excluded from further D/F application, four patients because of prolonged thrombocytopenia NCI-CTC grades 3 and 4 and one patient because of whole body erythrodermia. One patient died because of septic fever during thrombocytopenia and leukopenia NCI-CTC grade 4 after the first cycle. No other toxicities of NCI-CTC grade 3 or 4 occurred. The treatment is feasible in a complete outpatient setting and the results of the D/F regimen justify further investigations with these compounds.

Purpose: The aim of this study was to investigate the severity and time-course of alterations in gastroduodenal and intestinal permeability in relation to nausea/emesis following administration of the highly emetogenic polydrug regimen IFADIC (ifosfamide, Adriamycin, dacarbazine) using a differential lactulose/mannitol absorption (SLM) test. We also assessed the ease of administration and patients' tolerance of the SLM test. Methods: The SLM test was performed in seven patients with soft tissue sarcomas on days 1, 3 and 14 of cycle I and cycle III of chemotherapy; seven healthy volunteers served as controls. The degree of correlation between the clinical grade of nausea/emesis according to WHO criteria and gastroduodenal permeability, expressed in terms of urinary sucrose excretion, and intestinal permeability, expressed in terms of the permeability index (urinary lactulose to mannitol permeability ratio), was also assessed. Results: The permeability index values were significantly different (P≤0.01) on days 1, 3 and 14 during both cycles of chemotherapy. The median permeability index on day 3 was higher (P≤0.01) in patients with nausea/emesis than in those without symptoms. Additionally, the permeability index when nausea was present (day 3) was higher (P≤0.01) than when nausea/emesis was absent (days 1 and 14). In 59% of patients the increased permeability index on day 3 was accompanied by nausea/emesis of WHO grade 3. Gastroduodenal permeability did not alter consistently following chemotherapy. Conclusions: Our study confirms an acute, transient increase in intestinal permeability following the polydrug regimen IFADIC, accompanied by nausea/emesis of WHO grade 3 in the majority of patients. Normal intestinal permeability was achieved on day 14 in all patients, thus allowing intensified 2-weekly treatment administration. The SLM test may be recommended as a feasible test for the objective assessment of alterations in intestinal permeability following chemotherapy administration.

Context.—The new hematology analyzer Sysmex XE-2100 (TOA Medical Electronics, Kobe, Japan) has a novel, combined, white blood cell differential technology and a special reagent system to enumerate nucleated red blood cells.Design.—Performance evaluation of both technologies of the Sysmex XE-2100 according to the H20-A protocol of the National Committee for Clinical and Laboratory Standards and comparison of the results with those for the hematology analyzer Sysmex NE-8000 (TOA Medical Electronics).Specimens.—Five hundred forty-four blood samples randomly chosen from various inpatient and outpatient departments of the Vienna University hospital.Results.—Five-part white blood cell differential counts on the XE-2100 revealed excellent correlation with the manual reference method for neutrophils, lymphocytes, and eosinophils (r = .925, .922, and .877, respectively) and good correlation for monocytes and basophils (r = .756 and .763, respectively). The efficiency rates of flagging for the presence of ≥1% abnormal white blood cells were 83% (XE-2100) and 66% (NE-8000). The correlation of automated and microscopic nucleated red blood cell counts was excellent (r = .97).Conclusions.—From the present evaluation and our former experience with other types of Sysmex analyzers, we conclude that the new white blood cell differential technology of the XE-2100 represents a further development toward more efficient flagging of abnormal white blood cells.

BACKGROUND The major diagnostic role of peripheral lymphocyte subset typing is to distinguish between malignant and reactive conditions. METHODS The present study evaluates the screening efficacy of flow cytometric lymphocyte subset typing for the presence of a lymphoid malignancy. Four hundred samples were analyzed with a combination of anti-T-, B-, and natural killer (NK)-cell monoclonal antibodies. RESULTS Two hundred and twenty (55%) samples showed a normal distribution of lymphocyte subsets, 73 (18%) samples exhibited unspecific alterations of lymphocyte subsets, 19 (5%) samples exhibited a reactive phenotype typical of Epstein-Barr virus/cytomegalovirus (EBV/CMV) infection, and 88 (22%) samples expressed a phenotype suggestive of lymphoma. The most predictive independent factor of a lymphoma-specific phenotype was the absolute lymphocyte count (P = 0.0001, odds ratio 73.225). Seventy-eight percent of samples containing ≥4 × 109/l lymphocytes and 2% of samples with lymphocyte counts

Angiotensin converting enzyme inhibitors (ACE-I) are a mainstay for the treatment of heart failure, and of diabetic microalbuminuria. Recently ACE-I have been found to decrease plasma levels of circulating vascular cell adhesion molecule-1 (cVCAM-1) in patients with congestive heart failure. As increased cVCAM-1 levels are pathognomonic for diabetics with microangiopathy, we investigated the effects of ACE-I on plasma levels of cVCAM-1, intercellular adhesion molecule (cICAM-1), and cE-selectin in microalbuminuric diabetics. In addition, the effects of ACE-I on plasma levels of plasminogen activator inhibitor (PAI-1) and of tissue plasminogen activator (TPA) were studied. Fosinopril (10 mg/day) was administered over 12 weeks to 11 microalbuminuric patients with non-insulin-dependent diabetes mellitus (NIDDM). As expected, baseline plasma concentrations of cE-selectin, cICAM-1, and cVCAM-1 were markedly higher in patients than in healthy control subjects (n = 82; P.001). PAI-1 levels in NIDDM were similar to those in control subjects, whereas TPA levels were about 25% lower in patients than in control subjects (P = .013). Serum levels of cVCAM-1 decreased by -19% (CI: -25% to -13%) after treatment with fosinopril (P = .003) and were no longer different from those of the control group. In contrast, plasma levels of cE-selectin, cICAM-1, PAI-1, and TPA were unaffected. As expected microalbuminuria decreased by -44% (CI: -65 to -22; P = .004). In conclusion, fosinopril lowered cVCAM-1 levels along with microalbuminuria in NIDDM. This may represent a novel mechanism of action of ACE-I in diabetes-associated endothelial dysfunction. Whether decreased VCAM-1 expression is responsible for the observed reduction in microalbuminuria, deserves further investigation.

In this paper we present novel concepts for user interfaces based on agents actively exploring their environment, including the user's behavior. These autonomous agents are active entities in a hypermedia artwork on the development and artistic challenge of three-dimensional sculpturing on video screens and with laser installations. Such an approach challenges current paradigms of user interfaces in a fundamental way. Each individual, users and agents alike, is forced to construct their own concepts and strategies to operate successfully, based on their experiences. The strategies of the agent cannot be conveyed explicitly. Instead, they emerge from concepts of the domain, concepts of the users, the agent's own drives, and the interactions between users and the agent; all together they form the main source for the generation of new concepts and strategies. The history of behavior-based robotics provides us with similar evidence that active exploration in particular as opposed to mere deliberation constitu...

Determination of hemoglobin A1c (HbA1c) is one of the most important monitoring procedures for long-term control of diabetes mellitus. Several analytical methods have been developed for the measurement of glycohemoglobin (GHb). Those most frequently used are ion-exchange chromatography for HbA1c and affinity chromatography for total GHb. In this study, a new turbidimetric immunoassay for HbA1c (Boehringer Mannheim, Germany) was evaluated that was performed on a Hitachi 911 clinical chemistry analyzer (Boehringer Mannheim). Good linearity in the range of 5% to 15% HbA1c, within-run and between-run coefficients of variation ranging from 2.4% to 5.9% were obtained. Results of 179 diabetic and nondiabetic patients showed good correlation to those of a routine HPLC method (r = 0.96). In addition, HbA2, HbS, and HbF in samples from nondiabetic patients were not detected by the immunoturbimetric assay and the "labile" HbA1c fraction (Schiff base) did not interfere with the new test.

We analyzed binding sites for quinuclidinyl benzilate (QNB) and hemicholinium-3 (HC-3) by quantitative slice autoradiography and the activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in spinal cord of 5-7 patients with amyotrophic lateral sclerosis (ALS). In the ventral horn, QNB binding sites were markedly reduced (38% of controls; P less than 0.001), whereas HC-3 binding sites were only moderately affected (76%, P less than 0.01). Losses in cholinergic marker enzymes were inconsistent. The loss of muscarinic binding sites in the ventral horn was the most reliable cholinergic disease marker in ALS.

The survival of 357 consecutive patients with newly diagnosed glioblastoma multiforme (GBM) in three treatment groups reflecting different time-periods of diagnosis (A: 1982-1984; B: 1994/1995; C: 1996-1998) was analysed to assess the impact and the potential improvement of changing treatment strategies in our tertiary-care center.Group A (n = 100) included all consecutive patients diagnosed from 1982 to 1984 and served as the historical control. Group B (n = 93) included all consecutive patients diagnosed in 1994/1995 and group C (n = 164) those diagnosed from 1996 to 1998. Survival in the three treatment groups (A vs. B vs. C) was analysed according to treatment given after neurosurgical intervention (i.e. no specific therapy versus radiotherapy versus combined radio-/chemotherapy), and according to first-line chemotherapy, age (40, 40-60,60), sex, and tumor location (hemispheric versus bilateral or multifocal tumors, and tumors involving eloquent brain areas). Survival was analysed using Kaplan-Meier's non-parametric method. A p-value0.05 was considered statistically significant.Patients in groups A and B received radio- and/or chemotherapy to a varying extent (radiotherapy: group A: 22%, group B: 62%; chemotherapy: group A: 6%, group B: 33%). Chemotherapy was administered after termination of radiotherapy in both groups. In group C, 96% of patients received combined radio-/chemotherapy which was administered concomitantly and started within three weeks after surgery. Median survival was 5.2 months in group A, 5.1 months in group B and 14.5 months in C (p0.0001). Nine patients in group A (9%), 9 in group B (10%) and 40 in group C (25%) survived more than 18 months (p0.05).Survival improvement in group C might be attributable to the early start of combined radio-/chemotherapy. Therapy was administered on a complete outpatient basis, enabled by a dedicated interdisciplinary neuro-oncologic team caring for group C. Toxicity was mild and patients' acceptance excellent.

The aim of this study was to assess the efficacy and toxicity of a combination of dacarbazine (D) and fotemustine (F) administered to a homogenous group of patients with recurrent or progressive glioblastoma multiforme (GBM). Thirty-one patients with computed tomography or magnetic resonance imaging scan evidence of recurrent or progressive GBM after first-line chemotherapy with nitrosoureas as well as radiation therapy were given a combination of D (200 mg/m2) and F (100 mg/m2). At 30 min after termination of D administration, F was given over 60 min. Treatment was performed in an outpatient setting every 21 days. A total of 140 cycles (range 1-12 cycles; median 4 cycles) was administered. One partial response (3%) lasting for 11 weeks was observed. Sixteen (52%) patients reached stable disease lasting between 7 and 94 weeks. Median survival from start of the D/F combination was 45 (range 10-150) weeks. Median time to progression was 17 (3-101) weeks for all patients. Major toxicity was myelosuppression resulting in exclusion from study in seven (23%) patients [due to thrombocytopenia common toxicity criteria (CTC) grade 2 persisting longer than 3 weeks in three patients, due to thrombocytopenia CTC grade >/=3 in three and due to leukopenia CTC grade 3 in one patient]. No other toxicity than alopecia occurred. We conclude that the D/F combination is a well-tolerated second-line regimen and can be administered in a complete outpatient setting. D/F shows efficacy even in nitrosourea-pretreated patients and justifies further investigation.

The effect of thiamine (vitamin B(1)) or riboflavin (vitamin B(2)) availability on fasting total homocysteine (tHcy) plasma levels in end-stage renal disease patients is unknown. A cross-sectional study was performed in a population of non-vitamin supplemented patients maintained on continuous ambulatory peritoneal dialysis. Red blood cell availability of thiamine (alpha-ETK) and of riboflavin (alpha-EGR), along with other predictors of tHcy plasma levels, was considered in the analysis. There was a linear association of alpha-EGR with tHcy plasma concentrations (P = 0.009), which was not observed for alpha-ETK. Among red blood cell vitamins, alpha-EGR was the only predictor of tHcy levels (P = 0.035), whereas alpha-ETK, red blood cell pyridoxal-5-phosphate supply (alpha-EGOT) and red blood cell folate levels had no effect. The risk for having a high tHcy plasma levels within the fourth quartile (plasma tHcy38.3 micromol/L) was increased by an alpha-EGRmedian (odds ratio, 4.706; 95% confidence interval, 1.124 to 19.704; P = 0.026). By way of contrast, alpha-ETK had no effect in these analyses. Independent predictors of tHcy plasma levels were serum albumin, alpha-EGR, red blood cell folate, and certain MTHFR genotypes. A logistic regression analysis showed that the MTHFR genotype is a predictor for having a tHcy plasma concentration within the fourth quartile. In summary, riboflavin availability, as measured by alpha-EGR, is a determinant of fasting tHcy plasma levels in peritoneal dialysis patients. This finding may have implications for tHcy lowering therapy in individuals with end-stage renal disease.

We have developed an algorithm for the stochastic simulation of ligand–receptor interactions based on 104–105fictitious binding sites. Reversible receptor binding was simulated by alternate random selection of sites, the first selection resulting in “occupation” if the selected site was “free,” the second selection resulting in “dissociation” if the selected site was “occupied.” We show that the mathematical formalism of mass action kinetics is predicted on purely statistical grounds. The model was extended by the introduction of two further selections, simulating a conformational change in the ligand–receptor complex (“receptor isomerization model”). All random selections were gauged separately by “probability barriers,” taking the place of macroscopic kinetic rate constants. Simulation of gradual increases and gradual decreases of the fraction of occupied fictitious binding sites in the receptor isomerization model, using various combinations of “rate constants,” resulted in biexponential time dependencies, in agreement with predictions from the integrated rate equations. Stochastic simulation of molecular processes is a powerful and versatile technique, providing the researcher with a means of studying mechanisms of increasing complexity.

In this study, the authors evaluated a closed tube total hematology analysis system, Sysmex HS-430 (HS), which consists of two automated hematology analyzers, Sysmex NE-8000, the reticulocyte analyzer, Sysmex R-3000, and a slide preparation unit integrated in an automated sample transport system (TOA Medical Electronics, Kobe, Japan). The suitability of the system was compared with a conventional hematology system (CS) consisting of two single standing Coulter STKS analyzers (Hialeah, FL), one automated reticulocyte counter Sysmex R-1000, and the manual blood smear preparation. Evaluation was performed following the concept suggested by the Austrian-German societies for Clinical Chemistry and Laboratory Medicine that includes the evaluation of personnel supply. Eight consecutive series with a total of 4,896 samples were analyzed on both systems. Evaluation revealed that the analysis time per series was 238 minutes on the HS-430 and 359 minutes on the CS. The mean analyzer down times because of technical reasons were 36 minutes on the HS and 32 minutes on the CS. The down time because of "nontechnical" reasons was 31 minutes on the HS-430, but 173 minutes on the CS, which was mainly because of discontinuous sample loading of analyzers of the CS. The average direct technical time effort for complete blood cell count (CBC) analyses, reticulocyte counts, and blood smear preparations per series was 23 minutes on the HS and 245 minutes on the CS. In summary, these data show that an automated system like the HS-430 saves 222 minutes of manual activities arising in a large routine hematology laboratory with a mean throughout of 612 samples per day. Furthermore, the system improves intralaboratory turnaround times, avoids human errors by automated sample identification, and guarantees more safety for laboratory staff by minimizing the contact with potential biohazards.

Cyclosporine is a widely used and potent immunosuppressant drug with a narrow therapeutic index. Therefore, cyclosporine concentrations should be monitored closely. Various automated immunologic methods for cyclosporine whole blood determinations are available. Two new methods, fluorescence polarization immunoassay (FPIA) for the AxSYM by Abbott Laboratories, Chicago, IL, and the cloned enzyme donor immunoassay (CEDIA) by Boehringer Mannheim, Mannheim, Germany, have been introduced. In addition, Dade Behring improved its enzyme multiplied immunoassay (EMIT) assay. The present study evaluated all 3 new methods in comparison with high-performance liquid chromatography (HPLC) and the FPIA for the TDx analyzer. We measured whole blood cyclosporine concentrations of 179 samples obtained from 127 patients after kidney, bone marrow, heart-lung, and liver transplantation. All 4 automated immunologic methods can be used for routine measurement of cyclosporine whole blood concentrations. Disadvantages, such as higher cross-reactivity (Abbott TDx, CEDIA) or a limited linearity range (EMIT), are accompanied by advantages, such as a high precision (Abbott TDx) or an easy sample handling procedure (CEDIA). Information presented in this article should help to find the most adequate cyclosporine method for each medical laboratory.