Consumption of diagnostic procedures and other cardiology care in chest pain patients after presentation at the emergency department.

OBJECTIVE: The HEART score serves risk stratification of chest pain patients at the emergency department (ED). Quicker and more solid decisions may be taken in these patients with application of this score. An analysis of medical consumption of 122 acute chest pain patients admitted before the introduction of this score may be indicative of possible savings. METHODS: Numbers of cardiology investigations and clinical admission days were counted. Charged cost of medicine was divided into three categories: ED, in-hospital, and outpatient clinic. RESULTS: The total cost of care was 469,631, with an average of 3849 per patient. Seventy-five percent of this cost was due to hospitalisation under the initial working diagnosis of acute coronary syndrome (ACS). This diagnosis was confirmed in only 29/122 (24 %) of the patients. The low-risk group (41 patients with HEART scores 0-3) included one patient with a previously scheduled CABG. In the remaining 40 patients, hospitalisation occurred in 12/40 (30 %) patients and 30/40 (75 %) patients visited the outpatient clinic. The total cost of medical care after presentation of these 40 patients was 37,641; there were no cases where a new diagnosis of coronary artery disease was made. When medical care in this subgroup is declared redundant, major savings on national medical care budgets could be made. CONCLUSION: If the HEART score were to be routinely applied, diagnostic pathways could be shortened and costs reduced, in particular in low-risk patients.

In vivo manipulation of L1210 cell cycle phase distribution with alpha-difluoromethylornithine, 4-amidinoindan-1-one 2'-amidinohydrazone and N1-acetylspermine.

We investigated whether the in vivo growth inhibitory effect of the combination of 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664A) and alpha-difluoromethylornithine (DFMO) is reversible by treatment with N1-acetylspermine (N1-acSp). DBA-2 mice were inoculated with 10(5) L1210 cell i.p. on day 0. From day 1 they received 2.50 mg CGP 48664A/kg i.p. once daily and 500 mg DFMO/kg i.p. twice daily. On day 5 they received 3 x 2500 nmol N1-acSp i.p. with 15-min intervals. L1210 cell numbers, S-phase percentage and polyamine contents, and liver and spleen polyamine contents were monitored in the following 48 h. Four days treatment with CGP 48664A/DFMO reduced L1210 cell numbers, S-phase, and spermidine. N1-acSp treatment increased L1210 spermidine from < or = 8 h and percentage S-phase from 12 h. Maxima for spermidine and S-phase were reached at < or = 8 and 18 h, respectively. These were below levels of untreated controls. Decreases were noted from 12 and 18 h, respectively. N1-acSp was detectable in L1210 from 0-18 h. Liver spermidine was decreased by CGP 48664A/DFMO. After N1-acSp treatment, liver N1-acSp and N1-acSd increased from < or = 8 h, reached maxima at < or = 8 and 10 h, respectively, and were undetectable from 15 h. We conclude that the in vivo growth inhibitory effect of CGP 48664A/DFMO is reversible by N1-acSp treatment. The liver is probably involved in N1-acSp terminal catabolism. The effect of the polyamine depletion-repletion scheme on S-phase cell numbers may be much more profound than present estimates from 5-bromo-2'-deoxyuridine incorporation.

In vitro manipulation of L1210 cell cycle kinetics with 4-amidinoindan-1-one 2'-amidinohydrazone, alpha-difluoromethylornithine and N1-acetylspermine.

We investigated whether in vitro L1210 growth inhibition by alpha-difluoromethylornithine (DFMO; 740 microM) and 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664A; 1.7 microM) is reversible with N1-acetylspermine (N1-acSp). Influences of N1-acSp dose (1-100 microM), time (0-12 h at 100 microM), aminoguanidine (AG, 1 mM) and cell numbers (at 1 microM N1-acSp) on percentage S-phase, polyamine contents and viability were determined. DFMO/CGP 48664A decreased percentage S-phase from 58 to 26%, decreased spermidine (Sd) and spermine (Sp) contents 3-fold, but did not affect viability. With increasing N1-acSp dose, S-phase percentage and Sd contents increased concomitantly, reaching plateau values that were comparable with those of untreated controls. S-phase and Sd content increased from 4-6 h after N1-acSp administration, reaching plateau values from 11 and 6 h, respectively. N1-acSp content was dose dependent and increased linearly to reach plateau values from 8 h. AG did not affect any of these parameters. Addition of 1 microM N1-acSp to decreasing numbers of DFMO/CGP 48664A-treated cells caused increasing S-phase percentage, Sd and N1-acSp contents. We conclude that cell cycle kinetics of cultured L1210 cells can be manipulated by the induction of growth inhibition with DFMO/CGP 48664A and its subsequent abolishment with N1-acSp. N1-acSp accumulation rate and its subsequent conversion to Sd is relatively slow compared with intracellular Sd needs. The data support the notion that Sd is the most important polyamine for growth.

Catabolism of polyamines in the rat. Polyamines and their non-alpha-amino acid metabolites.

The metabolic fate of stable isotopically labeled polyamines was investigated after their first and second intraperitoneal injection in rats. Using gas chromatographic and mass fragmentographic analyses of acid-hydrolyzed 24-h urines, some aspects of the polyamine metabolism could be elucidated. After the injections with hexadeutero-1,3-diaminopropane, only labeled 1,3-diaminopropane was recovered from the urine samples. The rat injected with tetradeuteroputrescine excreted labeled putrescine, gamma-amino-n-butyric acid, 2-hydroxyputrescine and spermidine, while the urine samples of the rat after the injections with tetradeuterocadaverine contained labeled cadaverine and delta-aminovaleric acid. The injections of hexadeuterospermidine led to the appearance of labeled spermidine, isoputreanine, putreanine, N-(2-carboxyethyl)-4-amino-n-butyric acid, putrescine, gamma-amino-n-butyric acid, 1,3-diaminopropane, beta-alanine and spermine. After the injections with bis(2-carboxyethyl)-1,4-diaminobutane, spermidine, isoputreanine, putreanine, N-(2-carboxyethyl)-4-amino-n-butyric acid, putrescine, 1,3-diaminopropane, beta-alanine, 2-hydroxyputrescine and possibly gamma-amino-n-butyric acid were recovered. Clear differences between the metabolism after the first and second injection were noted for putrescine, spermidine and spermine, which is suggestive for enzyme induction and/or the existence of salvage pathways.

4-Amidinoindan-1-one 2'-amidinohydrazone (CGP 48664A) exerts in vitro growth inhibitory effects that are not only related to S-adenosylmethionine decarboxylase (SAMdc) inhibition.

The competitive S-adenosylmethionine decarboxylase (SAMdc; EC 4.1.1.50) inhibitor 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664A) inhibits growth more effectively than the irreversible SAMdc inhibitor 5'-[[(Z)-4-amino-2-butenyl]methylamino]-5'-deoxyadenosine (AbeAdo), while having similar effects on polyamine contents. We hypothesized that growth inhibition by CGP 48664A is not merely accomplished by SAMdc inhibition. Concentration-related growth inhibitory effects of AbeAdo, CGP 48664A and methylglyoxal bis(guanylhydrazone) (MGBG) were investigated in L1210 cells that were additionally exposed to 10 microM AbeAdo. This concentration causes maximal growth inhibition, profound SAMdc inhibition and plateau polyamine contents. Almost complete inhibition of functional SAMdc activity by 10 microM AbeAdo was confirmed by demonstration of poor conversion of tetradeuterated spermidine to tetradeuterated spermine by gas chromatography-mass spectrometry. Increasing AbeAdo did not affect L1210 cell numbers, viability, nor polyamine contents. MGBG proved highly toxic. CGP 48664A did not affect L1210 polyamine contents, but cell numbers and viability decreased dose-dependently to 50% and 70% of control, respectively. We conclude that CGP 48664A inhibits L1210 growth not only through SAMdc inhibition, but also by an as yet poorly understood second effect with higher IC50. The alleged second effect of CGP 48664A appears important for its potent antitumor effect.

Stroop interference and disorders of selective attention.

Fourteen patients with right-hemisphere CVA and 8 patients with a left-hemisphere CVA were examined for selective attention deficits using a variant of the Stroop color-word task: the picture-word interference task. Experiments 1 and 2 first compared the performance of the two patient groups and a control group in three tasks of increasing difficulty: picture-word detection, word reading, and picture naming. The results showed that (a) the two patient groups were significantly slower than the control group, but did not differ from each other, and (b) the difference in mean RT between the two patient groups and the control group did not increase with task difficulty. In Experiment 3, the subjects were required to name pictures while ignoring accompanying distractors: nonletter symbols, unrelated words or semantically related words. In this task, the right hemisphere patients showed a much larger semantic interference effect than both the left hemisphere patients and the control group. It is argued that this finding most probably reflects problems in visual selective attention with the right hemisphere patients.

Urinary polyamines and their metabolites during new combination chemotherapeutic treatments of high grade non-Hodgkin lymphoma.

Nineteen patients with non-Hodgkin lymphoma of unfavourable histology (15 high grade and 4 intermediate grade) were treated with two new combination chemotherapeutic schemes. Except for one all were partial (8) or complete (10) responders to treatment. Polyamines were measured in every spontaneously voided urine sample. Pretherapeutically all (11) stage III and IV patients had borderline or increased urinary putrescine (Pu) and sum of isoputreanine, spermidine and spermine (sigma Isoputr,Sd,Sp), except for the non-responder. Except for one, all (8) stage I and II patients had normal urinary Pu and sigma Isoputr,Sd,Sp. Posttherapeutically patients with pretherapeutically increased sigma Isoputr,Sd,Sp returned to normal (5), borderline (2), or slightly increased (3) levels. The post-therapeutic achievement of normal or borderline sigma Isoputr,Sd,Sp was not necessarily connected with accomplishment of complete remission. From the start of therapy until clinical restaging, partially or completely responding stage III and IV patients excreted 5-234 mmol sigma Isoputr,Sd,Sp per mol of creatinine above the mean normal value plus 2 SD. For stage I and II patients and the clinical non-responder this parameter amounted to 0-5 mmol/mol of creatinine. Peaks in urinary Pu and sigma Isoputr,Sd,Sp follow-up curves were related in time to the administration of chemotherapeutics. For responding stage III and IV patients the rate of the decrease of sigma Isoputr,Sd,Sp levels paralleled the clinically observed rate of tumour load reduction. This study suggests that notably for non-Hodgkin lymphoma patients with high tumour loads the constant monitoring of polyamines can provide information on pretherapeutic spontaneous tumour cell loss, the efficacy of chemotherapeutic combinations, the kinetics-, and (within certain limitations) the extent of therapeutically induced tumour cell death.

Microbial influences on urinary polyamine excretion.

We determined diamines, polyamines, their monoacetylated conjugates and some of their catabolites in urines of healthy persons during decontamination of the gastrointestinal tract and patients with urinary tract infections. The compounds were also measured after in vitro incubation of urines from healthy persons and patients. During decontamination the urinary excretion of total putrescine decreased by a small amount. This fall was for the greater part accountable to monoacetylated putrescine. Free putrescine levels were increased in urines of patients with urinary tract infections, decreased after therapy, and increased after incubation of the pretherapeutical samples. Total cadaverine decreased during decontamination and increased during recontamination. The changes were partly accountable to monoacetylated cadaverine. Free cadaverine levels of patients with urinary tract infections were normal and did not change after therapy. These data show that, under normal conditions, a small part of monoacetylated putrescine and a considerable part of monoacetylated cadaverine originate from the gastrointestinal tract, and that urinary tract infections lead to an increase of free putrescine. The microbial synthesis of putrescine in the gastrointestinal- and urinary tracts, should therefore be taken into account for the interpretation of urinary putrescine levels as a parameter for body cell turnover.

Investigation of applicability of a mid-infrared spectroscopic method using an attenuated total reflection accessory and a new near-infrared transmission method for determination of faecal fat.

In many laboratories, the titrimetric method of Van de Kamer is used for the analysis of faecal fat content of patients suspected of steatorrhoea. We investigated the applicability of a mid-infrared (MIR) spectroscopic method, using an attenuated total reflection (ATR) accessory, and a new near-infrared (NIR) spectroscopic method. For the NIR method, sealed plastic bags containing the stool samples were used as transmission cells. Standardization was obtained using a previously described MIR method, with a NaCl flow-cell, as reference method. Partial least-squares regression was used for the calibration of each method. Full cross-validation of the calibration set was used for the internal validation of each method. Fifteen per cent of the stool samples could not be estimated with the ATR method within reasonable accuracy limits compared with the reference. The standard error of prediction of the NIR method was 1.1 g/dL. We conclude that the new NIR method is a promising technique for routine use. However, further experiments need to be done with triplicate measurements of each sample and the use of an external validation set.

Performance of 225 Dutch school children on Rey's Auditory Verbal Learning Test (AVLT): parallel test-retest reliabilities with an interval of 3 months and normative data.

Performance on Dutch adaptations of Rey's AVLT was examined in a sample of 225 6- to 12-year-old Dutch school children, selected to be representative of the general population. With an interval of 3 months, they were tested twice, using two out of three test forms which proved to be parallel. No test-retest practice effects were apparent. Age had a considerable impact on test performance. Measured imperfectly, socioeconomic background and intellectual level had some additional influence, as did the examiner who administered the tests. Boys made more errors than girls. Normative data corresponded well with those collected in a smaller Australian sample, suggesting usefulness outside The Netherlands. With a parallel test-retest reliability of.70, which was reduced to.59 when the influence of age was taken into account, the most reliable AVLT measure was the total number of words correctly recalled over the five learning trials. On the basis of reliability data, implications for the clinical use of the AVLT are discussed.

[Cognitive functions and school achievement of children who were treated for acute lymphatic leukemia at a young age]. / Cognitieve functies en schoolprestaties van kinderen, die op jonge leeftijd werden behandeld voor acute lymfatische leukemie.

Neuropsychologic tests were performed in 40 children with acute lymphoblastic leukemia. They all had been treated at a young age with systemic chemotherapy, cranial irradiation and intrathecal methotrexate. The test results showed a high risk for learning disabilities. Visual motor integration problems were present early after cessation of treatment, but most cognitive defects became apparent about 2 years after stopping therapy. At that time 23% (9/40) of the children required special school types and 30% (12/40) needed additional help within their residential school. Problems with arithmetic were most prominent. Future study of patients who did not receive prophylactic irradiation of the brain will help to clarify the potential causative role of cranial irradiation in these cognitive defects.

Feasibility of neuropsychological assessment in leukaemia patients shortly after diagnosis: directions for future prospective research.

AIMS: To study neuropsychological functioning of newly diagnosed children with acute lymphoblastic leukaemia (ALL) within two weeks after diagnosis in order to determine the feasibility of a sibling controlled prospective study design. METHODS: Fifty consecutive patients (median age at testing 6.6 years, range 4-12) were included in a prospective, longitudinal, nationwide study. Treatment would include intrathecal and systemic chemotherapy according to the DCLSG ALL-9 protocol. Children were evaluated with an extensive neuropsychological battery including measures of intelligence, memory, attention, language, visual-constructive function, and fine-motor abilities within two weeks after start of the chemotherapy. The control group consisted of 29 healthy siblings (median age at testing 8.2 years, range 4-12), who were tested <4 weeks after the patients' assessment. RESULTS: Mean scores on Wechsler Intelligence Scales did not differ significantly between patients and siblings; mean IQ scores for both the patients and the controls were high average. To examine specific neuropsychological functions, norm scores based on the exact age were acquired by fitting procedures, but no significant differences were found. CONCLUSIONS: Neuropsychological assessment of patients during early hospitalisation is feasible. The results indicate no adverse effect of illness and psychological factors on IQ and neuropsychological functioning of patients with recently diagnosed ALL. The prospective design of this study of cognitive late effects of chemotherapy will allow discrimination between adverse sequelae of disease and treatment.

Cerebrovascular complications of L-asparaginase therapy in children with leukemia: aphasia and other neuropsychological deficits.

Children with acute lymphoblastic leukemia (ALL), treated with L-asparaginase are at risk for cerebral thrombosis or hemorrhage because of coagulation protein deficiencies. The results and the importance of serial neuropsychological examinations after such complications in three children with ALL are presented. All patients showed marked aphasia and other cognitive deficits. Recovery was complete in two of three children.

Transient mutism and speech disorders after posterior fossa surgery in children with brain tumours.

Four patients aged 5 to 9 years with large tumours located in the posterior fossa (PNET, ependymoma or astrocytoma) are presented. Patients received standard neuropsychological assessments, including speech evaluation, prior to surgery. Following tumour resection, these 4 children developed transient mutism or different types of speech and cognitive disorders, associated with behavioural disturbances. We describe course and results of repeated postoperative neurological and neuropsychological evaluations. Full recovery of speech was seen in 3 out of 4 patients; the only child with persistent symptoms was the one who already had neuropsychological deficits before surgery. However, despite fast recovery of the speech disorders more persistent behavioural problems were found in 3 out of 4 patients. Possible pathogenesis anatomical location of this "cerebellar speech syndrome" are discussed, as well as the relevance of repeated neuropsychological assessments.

Growth inhibition of two solid tumors in mice, caused by polyamine depletion, is not attended by alterations in cell-cycle phase distribution.

We studied the effect of polyamine depletion on growth and cell cycle characteristics of subcutaneously grown Lewis lung carcinoma (LLC) and fibrosarcoma (FIO 26) in mice. Polyamine depletion was achieved by inhibition of ornithine decarboxylase using 2-(difluoromethyl)ornithine, limitation of exogenous polyamines by administration of a polyamine-poor diet and decontamination of the gastrointestinal tract, and inhibition of endogenous polyamine reutilization by N,N'-bis-(2,3-butadienyl)putrescine (MDL 72527). Determination of S-phase cells was performed in tumor-cell suspensions by flow cytometry and in tumor tissue sections by microscopy, following in vivo labelling with 5-bromo-2'-deoxyuridine (BUdR). DNA synthesis rate was estimated from the incorporation of in vivo-injected [3H]-thymidine (3H-TdR). Both solid tumors almost completely stopped growing after access to polyamines was blocked. Growth inhibition was, however, not attended by changes in cell-cycle-phase distribution. Paradoxically, we measured increased in vivo 3H-TdR incorporation rates and unaltered BUdR-linked staining intensity in treated tumors. Injection of putrescine into treated LLC-bearing mice resulted in an increase in intracellular putrescine and spermidine concentrations, a slight increase in the number of S-phase cells and a marked drop in DNA synthesis rate within the following 9 hr.

Determination of N-(3-acetamidopropyl)pyrrolidin-2-one, a metabolite of spermidine, in urine by isotope dilution mass fragmentography.

A capillary gas chromatographic method with mass spectrometric detection for the determination of N-(3-acetamidopropyl)pyrrolidin-2-one, the monoacetyl conjugate of isoputreanine-gamma-lactam, in urine has been developed. Using a quantification based on stable isotope dilution mass fragmentography, age-dependent normal values for the urinary excretion of N-(3-acetamidopropyl)pyrrolidin-2-one by 44 apparently healthy control subjects were determined. Quality control data and normal values for 27 adults are given. The method was applied to the monitoring of the chemotherapeutic treatment of two patients with high-grade non-Hodgkin lymphoma.

Experimental chemotherapy in children with cancer--a parent's view.

Parental attitude and the parents' perceptions of a child's responsibilities were measured by mailing a questionnaire to 156 parents of cured children of the Pediatric Oncology Center, University of Groningen. Simplistically, the questionnaire concerned parental judgment on (1) the role of the child in decisions about experimental therapy, (2) what information should be related to the child and by whom, (3) parental attitudes toward experimental therapy, and (4) the parents' opinions about ethical aspects of proposing experimental therapy. A high response rate (87.8%) was achieved. A majority of the respondents would allow a child take responsibility in deciding about experimental therapy. In their opinion the median age (16 years) at which a child should be allowed to give consent was higher than the median age (12 years) at which a child should merely be involved in the decision. Parents were more likely to overrule the child's decision if the child decided against experimental therapy than if the child chose the therapy (p less than 0.001). Parents found it more difficult to talk about death than about experimental therapy, and parents would be more willing to involve the physician in discussing experimental therapy than in discussing imminent death with a child (p less than 0.001). Many respondents (68%) felt that the child should be given both altruistic reasons and reasons of self-interest for participating in experimental therapy. About half of all of the respondents believed that a pediatric oncologist should always advise experimental therapy for the benefit of similarly afflicted patients.

Magnetic resonance imaging of the brain and neuropsychological evaluation in children treated for acute lymphoblastic leukemia at a young age.

PURPOSE: To evaluate the adverse late effects of ALL treatment on cognitive functions and brain morphology; to integrate the results of a neuropsychological and neuroradiological study. PATIENTS AND METHODS: Cranial magnetic resonance imaging (MRI) and neuropsychological assessments (NA) were performed in 35 children treated for acute lymphoblastic leukemia (ALL) with cranial irradiation (CI) and intrathecal and intravenous methotrexate. Patients were under the age of 7 years (MD: 3.5 years) at diagnosis; median follow-up at MRI and NA was 8 years since diagnosis. RESULTS: MRI's were classified as definitely abnormal in 51% and as probably abnormal in another 17% of the patients. White matter damage was most frequently seen. MRI abnormalities were not related to CI dose or age at diagnosis. Patients showed significantly lower scores, compared to the norm group on measures of intelligence, verbal auditory memory, visual motor integration, and fine motor functioning. Lower scores significantly correlated with higher CI dose (25-32 Gy compared to 18-20 Gy) and younger age at diagnosis (< 4.0 years compared to > or = 4.0 years). Forty percent of the patients had to be referred to schools for learning disabled. CONCLUSIONS: ALL treatment, including CI and MTX, at a young age is associated with persistent cognitive impairment and MRI abnormalities. However, no correlation was found between MRI results and neuropsychological or academic performance.

Simultaneous determination of polyamines, N-acetylated polyamines and the polyamine analogues BE-3-3-3 and BE-4-4-4-4 by capillary gas chromatography with nitrogen-phosphorus detection.

We describe a method for the profiling of polyamines, N-acetylated polyamines and the polyamine analogues N1,N11-bis(ethyl)norspermine (BE-3-3-3) and 1,19-bis(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4) in L1210 murine leukaemia cells by capillary gas chromatography with nitrogen-phosphorus detection. The method makes use of four intemal standards. Prepurification comprises deproteinization, isolation with Sep-Pak silica at pH 9.0, conversion to heptafluorobutyryl derivatives and postderivatization organic fluid extraction. Within- and between-series precisions (given as CV.s) for analysis of 1-2x10(6) cells were: putrescine 5.5 and 29.4%; spermidine 1.6 and 7.1%; and spermine 3.2 and 7.6%, respectively. Recoveries relative to the respective internal standards, were in the 70.6-104.7% range. Accuracy and precision of measurements of BE-4-4-4-4 can probably be improved by the introduction of a separate pentamine internal standard. We conclude that the method can be used for studying the effect of BE-3-3-3 and BE-4-4-4-4, and possibly their metabolites, on polyamine homeostasis (biosynthesis, retroconversion, transport, terminal catabolism) and polyamine function.