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Female sex hormones affect susceptibility to systemic lupus erythematosus (SLE). To determine the effect of female sex hormones at onset of SLE on the survival of these patients, a retrospective survey was performed. The charts of 168 females SLE patients were evaluated to study the disease course, in particular the presence and kind of SLE criteria. Patients were classified as either belonging to the 'high female sex hormone at onset (HH)' or 'low female sex hormone at onset (LH)' group according to age at diagnosis. The statistics of the Dutch population, matched for age, were used to control for differences in life expectancy in these groups. A Cox regression model revealed that the relative mortality risk of HH patients vs HH controls was 4.2 times higher than the relative mortality risk of LH patients compared to LH controls. No differences in the frequency of SLE criteria between HH and LH patients were found that could explain the observed difference in mortality risk. [ABSTRACT FROM PUBLISHER]

Background: Although radioiodine therapy in differentiated thyroid carcinoma without radioiodine accumulation has not been considered harmful, increased thyrotrophin levels during thyroxine withdrawal without the benefit of radiotoxicity as well as the selection of de-differentiated cells may have disadvantageous effects on tumour course., Objective: We therefore analysed retrospectively the effects of radioiodine therapy on the course of serum thyroglobulin levels as a tumour marker in patients with progressive residual or metastatic differentiated thyroid carcinoma, with or without radioiodine accumulation on post-therapeutic whole body scintigraphy., Patients and Methods: Patients who had undergone radioiodine therapies with sufficient pre- and post-therapy thyroglobulin measurements to allow for regression analysis and not preceded or followed by other treatment modalities within a 1-year interval were selected. All patients had undergone total thyroidectomy and ablative therapy. Thirty-nine patients and radioiodine therapies were included (10 males, 29 females, mean age 57 years), and divided into a negative- (n = 17) and a positive post-therapeutic whole body scintigraphy group (n = 22). Pre- and post-therapeutic thyroglobulin course were analysed using non-linear regression, comparing the difference in the thyroglobulin growth coefficient b1 post- and pre-therapy (delta b1: b1(post-therapy)-b1(pre-therapy)). In addition, absolute post- and pre-therapeutic thyroglobulin levels, radiological follow-up and clinical outcome were also analysed., Results: The two groups were comparable with respect to age, sex, tumour stage, histology and prior therapies. Differences between post- and pre-therapeutic b1 values differed significantly in the positive post-therapeutic whole body scintigraphy group (delta b1: -0.65 microg/l-1 years-1, P < 0.001) but not in the negative post-therapeutic whole body scintigraphy group (delta b1: -0.14). Absolute serum thyroglobulin levels and radiological follow-up revealed a favourable response of radioiodine therapy in the positive whole body scintigraphy group but not in the negative group. Delta b1 was related significantly with clinical outcome as revealed by receiver operator curves (ROC): all patients with a positive delta b1 (n = 8) had an unfavourable outcome (progression or death), whereas from the 31 patients with negative delta b1, 61% had an unfavourable outcome., Conclusion: We did not find disadvantageous effects of a single radioiodine therapy on serum thyroglobulin increments in patients with negative post-therapeutic whole body scintigraphy. However, as we did not observe a beneficial effect either, we would not advise the continuation of radioiodine therapy in patients with negative post-therapeutic whole-body scintigraphy, unless a positive response is observed in individual cases.

Objective: Knowledge about the impact of joint impairment on functional ability is needed in planning care and setting treatment goals in children with juvenile idiopathic arthritis (JIA). We investigated the relationship between joint impairments and upper and lower limb function., Methods: Twenty-one children with systemic JIA with an average age of 9.2 years and a mean disease duration of 4.8 years participated in this study. Joint impairments were assessed by the following variables: joint counts on swollen (JCS) and tender (JCT) joints and the loss of joint motion as determined by the Joint Alignment and Motion scale (JAM). Functional performance and functional ability were determined by the Juvenile Arthritis Functional Assessment Scale (JAFAS) and Childhood Health Assessment Questionnaire (CHAQ), respectively. The relationship between impairments and functional disabilities was studied at the level of (1) the complete instruments, (2) upper and lower limb function separately, and (3) the individual joints and items., Results: Regarding complete instruments, the Spearman rank correlation between functional disabilities and loss of joint motion was moderate to good (JAM/CHAQ rs = 0.66, JAM/JAFAS rs = 0.77). A fair correlation was found between functional disabilities and the joint count on swollen joints (JCS/CHAQ rs = 0.45, JCS/JAFAS rs = 0.52), but no significant relationship was found with the number of tender joints (JCT/CHAQ rs = 0.02, p > 0.05, and JCT/JAFAS rs = 0.14, p > 0.05). At the extremity level (upper and lower limb function), the relationship between functional disabilities and the loss of joint motion appeared to be stronger in the leg than in the arm. At the level of the individual joints and questionnaire items, loss of joint motion in hip or shoulder joint appeared to be the most important factor in predicting limitation in leg or arm function., Conclusion: Our study shows that with respect to joint impairments, loss of joint motion is the strongest indicator of functional disability in children with systemic JIA. Loss of joint motion has a greater effect on lower limb function.

Several techniques to determine apoptotic frequencies in tumors have been described. In this study, we report that biochemical detection of enzymatic caspase-3 activity is a simple and quantitative technique to measure apoptosis in colorectal tumor cells. The relevance of the level of apoptosis in colorectal cancer for the clinical course remains unclear. Therefore, we studied the correlation between caspase-3 activity and prognosis of the disease in relation to different factors known to be involved in apoptosis induction. High caspase-3 activity significantly correlated with a higher risk of recurrence and was preferentially found in tumors of the right side of the colon. No correlation was detected between high caspase-3 activity and altered protein expression of p53, beta-catenin, or proteins of mismatched repair genes. This indicates that high caspase-3 activity has no evident correlation with the genetic Wnt-signaling or the mismatch repair mutational pathways. The caspase-3 activity significantly correlated with CD57(+) tumor infiltrating cells. Therefore, high caspase-3 activity in right-sided tumors might be induced by a specific lymphocytic reaction.

Previous experiments in a syngeneic rat liver tumor model using the colon adenocarcinoma CC531 demonstrated that injection of interleukin-2 (IL-2) induced significant antitumor responses. Furthermore, it was found that this treatment strategy was accompanied by an increase in the number of natural killer (NK) cells in and around the tumor. In the present study, the role of endogenous NK cells in IL-2-mediated antitumor responses was further elucidated by depleting tumor-bearing rats of NK cells, using the anti-CD161A mouse IgG1 antibody 3.2.3. Rats were depleted either after or prior to tumor induction and subsequently treated with IL-2. The results demonstrated that depletion of NK cells in tumor-bearing rats did not influence IL-2-induced antitumor effects. In addition, injection of IL-2 in NK-cell-depleted rats induced repopulation of NK cells in the peripheral blood from 3 days on and further after the last injection with IL-2. Therefore, the possibility cannot be excluded that de novo recruited NK cells play a role in attaining IL-2 mediated antitumor effects, but NK cells, which were present before or during the start of IL-2 therapy, were not relevant.

Objective: To compare the measurements of body temperature with the tympanic infrared thermometer and the digital rectal thermometer., Design: Prospective, comparative., Setting: Beatrix Hospital, Gorinchem, the Netherlands., Patients and Methods: A total of 2057 almost simultaneous measurements of rectal and tympanic temperature were performed in 164 patients in 9 different wards., Results: The mean difference between the two methods was 0.45 degree C with a standard deviation of 0.57 degree C. The tympanic temperature was lower than the rectal temperature. The differences ranged from -1.5 to 3.6 degrees C. The correlation coefficient was 0.69. If a rectal temperature > 37.8 degrees C was applied as the criterion of fever, the diagnosis was not made in 175/291 measuring moments (60%) with the tympanic thermometer. If a tympanic temperature > 37.8 degrees C was applied as the criterion of fever, the rectal thermometer failed to show fever in 16/132 measuring moments (12%)., Conclusion: The low sensitivity of the tympanic measurement to establish fever renders the tympanic infrared thermometer unsuitable for use as a fever thermometer.

The aim of this study was to investigate whether there is an effect of perioperative blood transfusion on the outcome of radical hysterectomy with lymphadenectomy for cervical cancer. One hundred and thirty-one patients with cervical cancer were treated by Wertheim radical hysterectomy in the period from 1984-1991. Eighty-six patients received blood transfusions during surgery or within two weeks, whereas 45 patients did not receive any blood transfusion. Transfused and non-transfused patients did not differ with respect to mean age, race, weight, FIGO-stage, cell-type, grade, size, depth of invasion and nodal involvement. Transfused patients had more blood loss, longer surgical time and lower haemoglobin levels. Using log rank analysis, the calculated five-year survival was 81% for the transfused group and 84% for the non-transfused group, a non-significant difference. The five-year disease-free survival rate was 87% for the transfused group and 88% for the non-transfused group. This study suggests that perioperative blood transfusion does not adversely influence survival after the Wertheim operation for cervical cancer.

Mentally healthy subjects show increased plasma concentrations of the neuropeptides, arginine vasopressin (AVP) and oxytocin (OT), under conditions of stress, but data are lacking about plasma concentrations of AVP and OT in patients with major depression. We thus assessed plasma concentrations of AVP and OT in patients with major depression (n = 52) and healthy controls (n = 37). Mean plasma AVP concentrations were higher in the group of depressed patients than in controls. A subgroup of 16 patients showed very high levels of plasma AVP, but no other feature differentiating this subgroup from the other patients was found. In-patients showed higher plasma AVP levels than out-patients, and melancholic patients had higher plasma AVP levels than did nonmelancholic patients. Plasma AVP levels were slightly related to psychomotor retardation and significantly inversely to neuroticism. Patients' plasma OT concentrations had a wider range than in controls. AVP and AVP-mediated functions may be a factor in the clinical picture of depression, possibly by influencing the activity of the hypothalamic-pituitary-adrenal axis.

Objective: The present study was designed to evaluate the effects of early angiotensin converting enzyme (ACE) inhibition on left ventricular enlargement in patients with anterior wall infarction following reperfusion therapy., Methods: Seventy-one consecutive patients with an anterior wall myocardial infarction were randomly allocated to enalapril (n = 36) or placebo (n = 35). All patients received either thrombolytic therapy (n = 46) or underwent primary coronary angioplasty (n = 25). Medication was started within 48 h admission to hospital and continued for 48 weeks. The process of left ventricular remodelling was assessed with two-dimensional echocardiography at 3 weeks and 1 year after the acute onset, and was related to the severity of the residual stenosis of the infarct-related artery., Results: Baseline left ventricular ejection fraction was 39.2% +/- 8.7%. During the study period left ventricular end-diastolic volume index increased from 48.2 +/- 9.9 ml.m-2 to 54.6 +/- 12.2 ml.m-2 at 3 weeks, and to 59.4 +/- 17.0 ml.m-2 after 1 year I control patients (P < 0.001). In the enalapril-treated patients, left ventricular end-diastolic volume index increased from 50.0 +/- 16.1 to 57.7 +/- 19.3 ml.m-2 at 3 weeks, and to 61.9 +/- 22.7 ml.m-2 after 1 year (P < 0.001). Both at 3 weeks and after 1 year, no overall differences in left ventricular volumes were observed between the enalapril and the placebo group (both ns). However, patients with a residual stenosis severity of > or = 70% in the infarct-related artery (n = 43) showed significant attenuation of remodelling by enalapril (n = 22) when compared to placebo (n = 21). In patients on enalapril, left ventricular end-diastolic volume index increased from 47.0 +/- 13.0 to 53.7 +/- 17.7 ml.m-2 compared to 48.0 +/- 9.6 to 60.3 +/- 16.3 ml.m-2 in control patients (P < 0.03). Also diastolic filling parameters were significantly improved in patients with > or = 70% residual stenosis., Conclusion: In patients with an anterior wall infarction and a severe residual infarct-related coronary artery stenosis following reperfusion, treatment with enalapril prevents the process of left ventricular remodelling. As left ventricular dilatation is an early process we suggest that treatment with ACE inhibition should be started as soon as possible in this group of patients.

Objectives: To establish the effect of the atypical neuroleptic clozapine on chorea, voluntary motor performance, and functional disability in patients with Huntington's disease., Methods: Thirty three patients with Huntington's disease participated in a double blind randomised trial. A maximum of 150 mg/day clozapine or placebo equivalent was given for a period of 31 days. Assessments were performed in the week before and at the last day of the trial. Chorea was scored using the abnormal involuntary movement scale (AIMS), the chorea score of the unified Huntington's disease rating scale (UHDRS), and judgement of video recordings. Voluntary motor performance was assessed using the UHDRS motor scale. Patients and their partners completed a questionnaire regarding functional disability. Twelve patients already used other neuroleptic medication, which was kept unchanged during the trial period. Results of neuroleptic naive and neuroleptic treated patients were analysed separately., Results: Clozapine tended to reduce chorea in neuroleptic naive patients only (AIMS); improvement seemed more pronounced in patients receiving higher doses of clozapine. Other measures of chorea (UHDRS chorea score, video ratings) showed no improvement. Clozapine had no beneficial effect on chorea in patients already receiving neuroleptic medication. Voluntary motor performance did not improve with clozapine. Neuroleptic naive patients reported aggravation of functional disability, possibly reflecting the frequent occurrence of side effects. Adverse reactions forced trial termination in six patients and dose reduction in another eight, and consisted mainly of drowsiness, fatigue, anticholinergic symptoms, and walking difficulties., Conclusions: Clozapine has little beneficial effect in patients with Huntington's disease, although individual patients may tolerate doses high enough to reduce chorea. Because adverse reactions are often encountered, clozapine should be used with restraint in this patient group.

Genetic factors associated with rheumatoid arthritis (RA) might involve variant tumour necrosis factor (TNF)-alpha genes. Therefore, polymorphisms at positions -308, -238, -376, -163 and +70 relative to the transcription initiation site were studied with respect to the susceptibility to, or severity of, RA. TNF-alpha genotypes of 283 RA patients and 116 healthy individuals were determined. Clinical data were obtained from patient files and questionnaires. The distribution of TNF-alpha alleles was similar in RA patients and healthy controls. With respect to disease severity, the TNF-alpha -238GA genotype was found to be associated with the absence of erosions [odds ratio (OR) 4.1, confidence interval 1.0-17]. In addition, this genotype was associated with a lower number of hand joints affected by erosions within the first 3 yr of disease onset compared to -238GG. The association between the -238 polymorphism and radiographic progression was independent of the presence of HLA-DR4. In line with this observation, the OR for the presence of erosions in patients with both risk factors (DR4 and -238GG) compared to patients who lack these factors was 11.1 (1.8-6.8). No associations between the TNF-alpha -308, +70 and -376 alleles and susceptibility to, or severity of, RA could be demonstrated. Our data indicate that the TNF-alpha -238GA genotype is associated with decreased radiologically detectable progression of RA.

After myocardial infarction, left ventricular volume and ejection fraction can be assessed by echocardiography, magnetic resonance imaging and radionuclide angiography to guide therapy and determine prognosis. Whether a measured parameter gives the same results irrespective of the method used and the observer who performs the analysis is only partly known. Intra-observer and inter-observer variability were determined for echo and magnetic resonance imaging. Left ventricular ejection fraction measured by these techniques was related to radionuclide angiograms performed in the same period. Intra-observer variability for both echo and MRI was low and in most instances below 5%. Inter-observer variability for the echo and MRI measurements were substantially higher than intra-observer variability. Comparison of the three imaging modalities revealed systematic differences. Therefore, in clinical studies, left ventricular volume and function parameters have to be measured with the same technique and by the same observer in qualified core laboratories.

Objective: Dysregulation of tumour necrosis factor alpha (TNF alpha) production is thought to be important in rheumatoid arthritis. Since pentoxifylline and thalidomide inhibit endotoxin induced TNF production in vitro, these drugs were tested in an open study in rheumatoid arthritis patients to assess toxicity, the effect on TNF production, and the antiarthritic effects., Methods: 12 patients with active rheumatoid arthritis were treated with 1200 mg pentoxifylline and 100 mg thalidomide a day during 12 weeks. In addition, TNF production was assessed by ex vivo whole blood cultures stimulated with endotoxin., Results: Adverse events such as xerostomia, drowsiness, and constipation occurred in almost all patients, which led to discontinuation in three. The drugs halved the TNF production capacity during treatment (ANOVA, P < 0.03) whereas production capacity of interleukin (IL) 6, IL-10, and IL-12 was not affected. Of the nine patients who completed the study, five fulfilled the ACR-20% response criteria after 12 weeks of treatment., Conclusions: Although pentoxifylline/thalidomide reduced the production capacity of TNF, the benefit/side effects ratio was poor due to multiple adverse effects, while clinical observation suggests limited efficacy.

Objective: Our goal was to validate cardiac measurements derived from multishot echo planar MRI (EPI) as compared with the well validated conventional GRE technique., Method: Ten healthy subjects underwent breath-hold EPI and non-breath-hold GRE imaging in the short axis orientation of the left ventricle (LV) on a standard 1.5 T MR system. Ten section levels were obtained to encompass the entire LV. Measurements were obtained of end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), LV mass, time to end-systole (TES), and peak filling rate (PFR). Analysis of variance was performed to determine agreement between GRE- and EPI-derived measurements., Results: The acquisition time for EPI was much shorter than that for GRE (2.5 vs. 15 min). Both imaging techniques yielded good quality images allowing LV volumetrics. Agreement between GRE and EPI was best for measurements of EDV, SV, and LV mass; somewhat less agreement was found for ESV, EF, TES, and PFR. The intraobserver variability for measuring TES and PFR was higher for GRE than EPI (one sided F test; critical values at p = 0.05 were > 3.18)., Conclusion: Multishot EPI of the heart provides accurate measurements of LV function and mass in a time-efficient manner.

Visually guided saccades, memory-contingent saccades, and antisaccades were studied with an infra-red reflection technique in 12 patients with idiopathic blepharospasm and in controls. Latencies of the three kinds of saccades were prolonged. Peak velocities and gains did not differ. Our results indicate an initiation defect in the saccadic system, which may be localized in the caudate nucleus.

Between 1980 and 1989, 8 wedge and 17 flap main bronchoplasties were done in 24 patients (4 carcinoid tumors, 4 benign lesions, 17 carcinomas). Bronchial anastomotic stenoses, pulmonary function, and survival were evaluated. Preoperative ventilation/perfusion scans with preoperative and postoperative spirometry were done in all patients except two who underwent a wedge bronchoplasty. Postoperative bronchoscopy was done in all patients. Follow-up was complete for the patients with carcinoma (N = 17). In the wedge group bronchial anastomotic stenoses occurred in three (38%) of eight patients. All three patients had serious postoperative complications (persistent atelectasis in one, prolonged ventilatory support in two); one patient died and the other two had impaired postoperative pulmonary function. Complete function recovery occurred in only three (38%) of eight patients who underwent wedge bronchoplasty. In the flap group, bronchostenosis occurred in 3 (18%) of 17 patients. The associated complications (mucus retention, minor atelectasis, partial lobar torsion) were mild. Complete pulmonary function recovery occurred in 13 (76%) of 17 patients who had flap bronchoplasty. Actuarial survival, for the patients with carcinoma, was 88%, 47%, and 41% after 1, 3, and 5 years, respectively. The local recurrence rate was 25% (4/16). In our series, flap main bronchoplasties were effective for the resection of bronchial tumors with local involvement of the adjacent main bronchus. Wedge main bronchoplasties, however, were associated with substantial postoperative complications.

We determined the variables associated with the progression and duration of illness of patients with Parkinson's disease (PD) and investigated the cause of death. In 474 patients with parkinsonism, who visited the Academic Hospital between January 1, 1960 and August 31, 1993, we did a survival analysis with the following covariates: age at onset, initial symptom (tremor or rigidity/hypokinesia), age at reaching Hoehn and Yahr stage III, dementia-free period, and levodopa treatment. A total of 345 patients with parkinsonism fulfilled the criteria of idiopathic PD; 258 of them were still alive on the closing date of this study. There were significantly more men than women (1.43:1). Medical advice was sought in an earlier stage by men and by patients with tremor as presenting symptom. For patients with rigidity/hypokinesia as first symptom, the duration of illness until reaching Hoehn and Yahr stage III was shorter than for patients starting with tremor alone. If the initial symptom is tremor, patients develop dementia less frequently and later after onset than when tremor is not involved. Reaching Hoehn and Yahr stage III and developing dementia both, limit the patient's survival time. The mortality risk for a patient was found to be increased from the moment levodopa treatment was started as compared to those patients who had not yet started with the treatment. The effect of levodopa on survival could not be disentangled from effects of other factors related to the start of levodopa treatment.

Remodeling of the left ventricle after myocardial infarction can be documented by calculation of left ventricular volume and mass, using endocardial and epicardial tracings of multilevel multiphase short-axis cine magnetic resonance (MR) imaging series. We assessed left ventricular volume and mass from 8 slices and during 12 phases of the cardiac cycle in seven patients with an anterior wall myocardial infarction; one patient was studied twice, leaving eight MR examinations to be evaluated. Purpose of this study was to assess the intra-observer and inter-observer variability of epicardial volume, endocardial volume, and left ventricular mass from contours manually traced by two independent observers. For the eight MR examinations, epicardial volume was found to be 292 +/- 51 ml (mean +/- SD) at end-diastole, which decreased to 237 +/- 55 ml at end-systole. Endocardial volume was 141 +/- 31 ml at end-diastole, which decreased to 79 +/- 27 ml at end-systole. Left ventricular ejection fraction was 45 +/- 8%. Mean left ventricular mass, when averaged over all patient studies and all phases, was 159 +/- 30 g. Intra-observer and inter-observer variability were found to be 3.5% and 5.2% for endocardial volume, 2.0% and 2.5% for epicardial volume, and 3.6% and 3.6% for left ventricular mass, respectively. The contour analysis showed a statistically significant phase effect in the endocardial contour in the midventricular slices, which was resolved after establishing a more precise definition for the tracing of the endocardial border. In conclusion, left ventricular volume and mass in patients with an anterior wall myocardial infarction can be assessed with high reproducibility and reliability from manual contour tracings. A precise protocol for the definition of endocardial and epicardial contours is required to obtain reproducible and reliable results.

To investigate the effects of the altered composition of the helper T cell compartment in ageing on the humoral response to influenza vaccine, we investigated correlations between helper T cell subsets and anti-influenza antibody responses in 23 JUNIEUR healthy young and 41 SENIEUR healthy elderly subjects. Naive helper T cell numbers (CD4+ CD45RA+) were negatively correlated with antibody production to two of the four strains investigated in JUNIEURS only. By contrast, memory helper T cell numbers (CD4+CD45ROhi) were positively correlated with in vivo IgG antibody titres to three of the four vaccine strains. Age-related differences in the composition of the helper T cell compartment, however, did not explain the lower IgG antibody response that was observed to two of the four vaccine strains examined.

Oxidation of low-density lipoprotein (LDL) may play a causal role in atherosclerosis. In this study we analyzed whether the severity of progression of coronary atherosclerosis is related to the susceptibility of LDL to oxidative modification. On the basis of repeated coronary angiography, 28 coronary bypass patients were divided into two groups: group A, 12 patients with, and group B, 16 patients without progression of coronary atherosclerosis. The lag time, reflecting the resistance of LDL to oxidative modification, was significantly smaller in group A as compared with group B (81 +/- 10 and 93 +/- 15 min, respectively). Besides differences in cholesterol and apolipoprotein B concentrations, the difference in susceptibility of LDL to oxidation significantly contributes to the differences between the progression and the non-progression group (P = 0.02). In the combined groups of patients, the lag phase of LDL for oxidation was positively correlated with LDL cholesterol ester to protein ratio (r = 0.53, P = 0.01). It is concluded that LDL samples obtained from coronary bypass patients differ with respect to their oxidizability depending on progression of atherosclerosis following coronary bypass surgery.

Several studies have suggested that the glutathione/glutathione S-transferase (GSH/GST) system is involved in resistance of tumors toward ifosfamide and other cytostatic agents. Besides, ifosfamide metabolites (in vitro) as well as ifosfamide treatment (in vivo) have been shown to decrease cellular GSH availability. In the present study, the in vivo effects of three different ifosfamide treatment schedules on the GSH/GST system were studied in patients with advanced cancers (n = 24): continuous i.v. infusions of 1300 mg/m2 daily for 10 days and 5000 mg/m2/day for 24 h, as well as a 4-h infusion of 3000 mg/m2 daily for 3 days. The GSH/GST system was characterized by administering bromisoval, a probe drug to assess GSH conjugation activity in vivo, as well as by daily monitoring of GSH concentrations in blood cells and plasma. Bromisoval pharmacokinetics was assessed before and at the end of the ifosfamide treatment. Blood cell GSH levels decreased significantly (P < 0.05) during the 3- and 10-day ifosfamide treatment schedules; the 24-h treatment had no effect. The ifosfamide treatment schedules had only minimal effects on bromisoval pharmacokinetics. Assuming that the kinetics of the probe drug provide an accurate reflection of enzyme activity, this suggests that GST activity remains unchanged. Because GSH conjugation of bromisoval enantiomers requires both GST activity and GSH availability, these results also indicate that, despite the 35% decrease in GSH in blood cells of two patient groups, the GSH availability of the cancer patients was not rate-limiting for GSH conjugation of bromisoval enantiomers. If GSH levels in blood cells reflect those in tumors/other tissues, the present results indicate that ifosfamide may be used clinically to decrease GSH levels. However, whether a 35% decrease is sufficient to increase tumor sensitivity toward (other) cytostatics remains uncertain.

Increased effort of retrieval from memory is considered to be a feature of cognition in subcortical neurological diseases, such as multiple sclerosis (MS). Free word association provides a means to investigate alterations in automatic and effortful retrieval. Using this procedure we investigated whether in MS free word association would shift from commonality towards idiosyncrasy, as a result of effortful, controlled retrieval. The MS group consisted of a cohort of outpatients, who suffered from chronic but quiescent MS. The patients responded with perfectly normal association patterns. Apparently, impairment of retrieval, or more specifically increased effort of retrieval, from memory does not hold true generally in MS. In patients with obvious physical handicaps (mean Kurtzke DSS = 4 +/- 2) we could not demonstrate abnormal associative processes.

Objective: To determine effectiveness of technetium-99m labelled polyclonal human immunoglobulin G (99mTc-IgG) scintigraphy to monitor variation in arthritis activity in patients with rheumatoid arthritis (RA)., Methods: The results of semiquantitative 99mTc-IgG scintigraphy were compared with those of examination before and 26 weeks after initiation of parenteral gold treatment in 19 patients with RA., Results: Clinical and laboratory variables of arthritis activity as well as the scores of 99mTc-IgG scintigraphy were significantly lower after gold treatment compared to the scores before treatment. However, the difference between the mean scores of 99mTc-IgG scintigraphy before and after treatment was statistically significant for more joints than such difference in scores for joint pain and joint swelling., Conclusion: 99mTc-IgG scintigraphy is able to reflect variations in arthritis activity in patients with RA.

The aim of this cross-sectional study was to compare the role of aging in measures reflecting diurnal activity and immobility in 60 parkinsonian patients with predominant features of hypokinesia and rigidity and 100 healthy subjects aged 50 to 98 years. In the patients, we also studied the relation between disease duration and subjective and objective measures of disease severity. Motor activity was recorded during 5 successive days at home with a wrist-worn activity monitor. For each subject, two mean measures reflecting the diurnal activity level and the relative proportion of activity and immobility were calculated. Diurnal measures of activity revealed in both groups a prominent absolute reduction of activity and an increase of the time spent without movement ("immobility") with advancing age. Parkinsonian patients showed significantly lower values for both motor-activity measures than did the healthy subjects. The rate of the age-related decline of both diurnal activity measures in both groups, however, is comparable. Disease duration showed no relation with subjective and objective measures reflecting disease severity. This study shows that if care is taken to control for disease severity, the rate of the age-related decline of measures reflecting diurnal activity and immobility is similar in both groups. The lack of relation between disease duration and subjective and objective measures of disease severity suggests that the rate of progression of Parkinson's disease can be reliably studied only by means of longitudinal studies.

The relative influence of diabetes mellitus-related and physiological factors on vibration perception thresholds was assessed in 353 patients in a hospital-based setting (173 insulin-dependent and 180 non-insulin dependent patients, aged 51.1 +/- 15.9 years) and 80 healthy controls (aged 43.3 +/- 15.2 years) employing a Biothesiometer. Vibration perception thresholds were bilaterally measured at the thumbs, medial malleoli and halluces. Sixty (17.0%) older patients had off-scale thresholds (> 50 V). As no systematic side differences were found, values of contralateral sites were averaged. Considering the effects of age, height, gender and skin temperature in controls, age accounted for 46.7 and 52.2% threshold variance at the ankles and halluces, respectively, while height explained 5.1 and 5.1%, respectively. At the thumbs, only age was of relevance. Age relationships with vibration thresholds in health did not differ from published reports at any site. In the patient group, influences of age, height, gender, skin temperature, years from diagnosis, HbAlc, serum creatinine, drop in systolic blood pressure on standing, and ankle/arm blood pressure indices were assessed for each type of diabetes. For both types, age and height again had relevant effects at the lower extremities as did age and gender at the thumbs. Skin temperature was only marginally significant at the halluces of NIDDM patients. Of the disease-related factors, HbAlc had the strongest effect: for both IDDM and NIDDM higher levels were associated with lower vibration sensitivity. Increasing disease duration led to significantly higher thresholds in IDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The incidence and prevalence of celiac disease vary internationally. We studied the incidence of identified cases of childhood celiac disease in six Dutch provinces that cover 47.9% of the surface area and 67.6% of the total population of The Netherlands. Children with celiac disease aged 0-14 y, diagnosed from January 1975 to January 1991, were traced by 1) contacting all pediatricians in this area, 2) examining the date of the Dutch National Medical Registration, and 3) investigating the membership records of the Dutch Celiac Disease Society. These data were cross-checked by the Dutch Network and National Database of Pathology. Of the 97.9% of pediatricians who answered our inquiry, 46.1% were treating celiac patients. A total of 342 celiac patients were identified. Informed consent that permitted examination of their medical files was given by 97.3% of the parents of the celiac children. The mean crude incidence rate of diagnosed childhood celiac disease, calculated per 1000 live births per year, was 0.18. However, a significant increase in reported incidence was demonstrated from 0.10 in 1976 to 0.32 in 1990. The best estimate, for the years 1985-1990, is 0.22/1000 live births, which is much lower than in most European countries.

Magnetic resonance (MR) imaging has been shown to provide accurate measurements of right ventricular (RV) volumes and myocardial mass. The purpose of this study was to evaluate the reproducibility of MR imaging, which in clinical practice may be as important as its absolute accuracy. The reproducibility of MR imaging measurements of the right ventricle was assessed by analyzing 40 serial functional MR imaging examinations of the right ventricle with variance component analysis. Standard deviations and 95% ranges for change were: for RV myocardial mass, 5.9 and 16 g; and for RV ejection fraction, 6.0% and 16%, respectively. Reproducibility was similar for cine and spin-echo MR imaging. The intraobserver and interobserver errors were especially large, indicating that observer subjectivity is the limiting factor in the interpretation of the MR images. This study suggests that the reproducibility of RV measurements is adequate to detect RV hypertrophy and a low ejection fraction in the individual patient. For accurate follow-up examinations, whereby smaller changes are to be detected, the reproducibility of MR imaging measurements may not be sufficient. More effort is needed to improve the reproducibility of MR imaging measurements.

Coproculture is used in northern Togo and Ghana in the research on Oesophagostomum bifurcum, a common parasite of man in these regions. Prior to a follow-up study to investigate patterns of reinfection in Oesophagostomum and hookworm, it was attempted to evaluate the relevance of counting larvae for the assessment of the intensity of infection at the population level. Of 102 samples, one egg count (Kato-smear) and three coprocultures were carried out. Frequency distributions of counts of larvae of Oesophagostomum and of hookworm isolated in three coprocultures, showed log-normality. There was a highly significant correlation between egg counts and the combined number of Oesophagostomum and hookworm larvae (Spearman rank correlation test, r = 0.74, p < 0.01). It is concluded that the mean larval counts of three coprocultures can be interpreted quantitatively, as normally done for egg counts. A quantitative classification of larval counts is proposed.

In an international collaborative study three candidate reference and the local APTT reagent have been tested with lyophilized plasmas containing heparin added in vitro and fresh plasmas from heparinized patients to determine whether it was possible to standardize APTT heparin monitoring. The APTT responses of patients with thrombosis were much less to the same concentrations of heparin so only these plasmas were used to calibrate the reagents. A calibration constant (b) was determined for each local APTT system from the orthogonal regression slope of the patients' and normals' plasmas. Although the calibration was based on relatively limited numbers of patients' plasmas the results gave no consistent indication that this method of analysis with the reference preparations was incorrect. Two of the three candidate reference reagents performed almost equally well and one of these reagents is recommended as the APTT reference preparation. Use of a single b value for a brand of reagent for all laboratories is not advised. Each laboratory must perform its own local calibration. The adoption of a reference APTT reagent together with the use of orthogonal regression analysis would be a useful step to initiate APTT heparin monitoring standardization and to develop safe and effective local therapeutic ranges.

The ability of technetium-99m-labelled polyclonal human immunoglobulin G (99mTc-IgG) scintigraphy to predict joint destruction in patients with rheumatoid arthritis (RA) was investigated in this study. The progression of radiographically determined joint destruction in wrists, hands and feet was compared with the results of physical and laboratory examination, as well as 99mTc-IgG scintigraphy, measured at the beginning of a year-long study on 30 patients with RA of recent onset. The sensitivity of joint swelling in predicting the progression of radiographically determined joint destruction ranged between 57% and 74%. The sensitivity of 99mTc-IgG scintigraphy ranged between 71% and 100%. The specificity and positive predictive value both of joint swelling and 99mTc-IgG scintigraphy were low. Multiple regression analysis showed that for the total joint score, and for the metacarpophalangeal and forefeet joints, progression of radiographically determined joint destruction was primarily predicted by 99mTc-IgG scintigraphy. Joint swelling, ESR and IgM rheumatoid factor did not contribute to this prediction. We concluded that 99mTc-IgG scintigraphy is superior to conventional clinical and laboratory measurements in RA with respect to prediction of joint destruction.

Objective: To assess differences in activity and immobility during sleep between patients with Parkinson's disease (PD) and healthy subjects and to evaluate the relations of clinical variables with the motor activity measures in patients with PD., Design: Survey, case series., Setting: University hospital outpatient neurology department and urban population in Leiden, the Netherlands. Motor activity was recorded during 6 successive nights at home with a wrist-worn activity monitor., Participants: Eighty-nine patients with PD and 83 age-matched healthy controls., Main Outcome Measures: For each subject, three mean measures reflecting activity or immobility during the nocturnal period were calculated., Results: Compared with the healthy elderly subjects, patients with PD have an elevated nocturnal activity level and an increased proportion of time with movement, indicating a more disturbed sleep. The mean duration of nocturnal immobility periods was similar for both groups. This measure, however, did reflect the self-reported disturbed sleep maintenance in both groups. The daily dose of levodopa or the use of dopamine agonists in patients not receiving levodopa, rather than disease severity, proved to be the best predictors of nocturnal activity., Conclusions: We hypothesize that in mildly to moderately affected patients with PD, levodopa or dopamine agonists cause sleep disruption by their effects on sleep regulation. In more severely affected patients, the beneficial effects of these drugs on nocturnal disabilities that cause sleep disruption in PD prevail.

A tensile test has been developed to test bioactive coating materials. Hydroxylapatite (HA) and fluorapatite (FA) coatings with various roughnesses were tested using sandblasted titanium (Ti) as a control material. Twelve goats received 7 implants each for 6 (2 goats), 12 (5), and 24 (4) week implantation periods. After 12 weeks the mean tensile strength values were highest for polished hydroxylapatite (HAP) followed by HA > FAP (polished fluorapatite) > FA > Ti, and hydroxylapatite type coatings were found to exhibit significantly higher values than fluorapatite type coatings or titanium implants. After 24 weeks no statistically significant differences could be found between any of the implant types. The order of the mean strength values was now HAP > HA > FA > FAP > Ti. Fracture always occurred between the coating and titanium if bone contact had been established. In conclusion, it is suggested that results from different types of test methods cannot be used to compare different types of bioactive coatings.

The ability of scintigraphy with technetium 99m-labelled polyclonal human immunoglobulin G (99mTc-IgG) to detect and quantify arthritis activity was studied in 24 patients with RA and in 10 patients with OA. The results of 99mTc-IgG scintigraphy were compared with those of scintigraphy with 99mTc-labelled hydroxymethylene-diphosphonate (HDP). The mean joint scores of 99mTc-IgG scintigraphy in RA patients with active disease were significantly higher (P < 0.001) than the mean scores in patients with inactive disease. The mean joint scores were also higher in patients with erosions compared to those in patients without erosions (P < 0.05). For 99mTc-HDP scintigraphy no significant differences were found between the mean joint scores of these patient groups. Comparison of scintigraphic results between patients with RA and OA revealed that the mean joint score of 99mTc-IgG scintigraphy was significantly (P < 0.001) higher in the patients with RA than in patients with OA, whereas for 99mTc-HDP scintigraphy this difference was not significant. These results show that 99mTc-IgG scintigraphy, when compared to 99mTc-HDP scintigraphy, is a more specific method of detecting synovitis and, also, shows differentiation between different degrees of arthritis activity in RA.

Purpose: This study investigated the relationship between amplitude and peak velocity of saccadic eye movements (the so-called main sequence) and the intra-individual variability of the main sequence., Methods: Saccadic amplitudes and peak velocities were measured twice in 58 healthy subjects with an infrared reflection technique., Results: Considerable intra-individual variability was found between the first and second recordings., Conclusions: Intra-individual variability of saccadic peak velocity affects the interpretation of changes in repeated recordings of peak velocities, such as before and after medication is administered. Furthermore, considerable intra-individual variability decreases the probability that statistically significant differences between patients and control subjects can be detected, especially when groups are small. Calculating the intraclass correlation coefficient allows the number of subjects in comparative studies to be determined.

The ability of 99Tcm-labelled polyclonal human immunoglobulin G (99Tcm-IgG) scintigraphy to monitor intra-individual variation in arthritis activity was studied in seven patients with rheumatoid arthritis (RA). These patients were treated with an intra-articular injection of 20 mg triamcinolone hexacetonide. The results of semiquantitative 99Tcm-IgG scintigraphy were compared with the degree of joint swelling and the histological changes observed in synovial biopsies before and 14 days after the injection. In all seven patients the local treatment resulted in a decreased arthritis activity of the treated knee as measured clinically or histologically. This decrease was parallelled, in all patients except one, by a lower uptake of 99Tcm-IgG after the injection when compared to uptake prior to treatment. This study shows that 99Tcm-IgG scintigraphy is able to reflect intra-individual variations in arthritis activity in patients with RA.

We studied the influence of dietary protein intake on the plasma level profile of levodopa, carbidopa, and 3-O-methyldopa and clinical efficacy in 12 patients with idiopathic Parkinson's disease after intake of one levodopa-carbidopa 200/50 controlled release tablet (Sinemet CR; LC-CR). The tablet was given 1 h before the protein rich meal on one day (fasted) and together with the meal on an other day (non-fasted). Higher levodopa and carbidopa concentrations were reached when the LC-CR was taken 1 h before the meal, but the plasma level profile for levodopa was flatter in the non-fasted state. The area under the curve for levodopa was slightly higher in the fasted condition. For the clinical variables walking and tapping slightly better clinical results (P = 0.08) were found in the fasted condition with the higher levodopa levels. If the patient on levodopa is in a clinically satisfactory condition, then non-fasted condition could be preferred because of the smooth plasma level profile demonstrated. However, if the initial levodopa concentrations are not in the critical range to be effective for the patient, the advice should be to take the drug in a fasted condition.

Objective: To measure the influence of age on measures of nocturnal activity and immobility in 100 healthy subjects aged 50 to 98 years., Design: Cross-sectional study., Setting: Urban population in Leiden. Recordings were performed at home while the subjects maintained their habitual 24-hour pattern of activities., Participants: 100 subjects without a history of major medical disorders and a normal neurological examination and performance-oriented assessment of gait (Tinetti)., Measurements: Motor activity was recorded during six successive nights with a wrist-worn activity monitor. The occurrence of supra-threshold motor activity was recorded over 15-second epochs. A questionnaire was used to evaluate sleep habits and the occurrence of sleep disturbances. Four mean measures reflecting activity or immobility during the nocturnal period were calculated for each subject., Results: Only one out of four measures, (ie, the nocturnal proportion of time with movement, increased with age for females. For males, no age effects emerged. The mean duration of nocturnal immobility periods was higher in females than in males. Also, for females, the use of hypnotics increased with successive decades. Sex and the use of hypnotics were significantly related to the mean duration of immobility periods., Conclusion: If care is taken not to confound aging with illness, measures of nocturnal activity and immobility reveal only marginal effects of aging.

Wrist motor activity was monitored continuously in 65 patients with Parkinson's disease (PD) to assess the influence of disease severity and excessive fatigue on the diurnal motor activity pattern. Mildly or moderately affected PD patients had a similar diurnal pattern to that of 68 healthy controls, with a late morning peak; however, mean levels of motor activity were lower. The most severely affected patients showed an overall flattened diurnal pattern. Results refute the existence of end of day deterioration, but instead suggest a "depressed morning start" in the most severely affected patients with PD. Excessive fatigue was not reported at a particular time of day and did not influence the diurnal motor activity pattern.

The authors studied the reproducibility of repeated measurements of left ventricular volumes, weight, and wall stress as determined with cine and spin-echo magnetic resonance (MR) imaging. Two observers analyzed 40 serial MR imaging examinations twice, yielding a total of 160 repeated measurements. Estimates of 95% ranges for change were ejection fraction, 10% and 12%; wall mass, 16% and 21%; and wall stress, 22% and 20%, for measurements derived from cine MR imaging and spin-echo MR imaging, respectively. Reproducibility was not significantly different between cine and spin-echo MR imaging. Intraobserver, interobserver, and interexamination errors were quantitated with variance component analysis. Interexamination variability was the single most important contributor to total variance. Reproducibility of left ventricular chamber volume measurements with MR imaging is superior to that of other imaging modalities. In addition, MR imaging can provide reliable estimates of wall mass and wall stress. Efforts to improve reproducibility should be aimed at lowering interexamination variability.

The aim of this study was to assess the internight and intrasubject variability of nocturnal activity and immobility measures of 99 healthy subjects aged 50-98 years. Motor activity was recorded at home during 6 successive nights with a wrist-worn activity monitor. The occurrence of suprathreshold motor activity was recorded over 15-second epochs. For each subject, six mean measures reflecting activity or immobility during sleep and their coefficient of variation were calculated. Our results revealed no first-night effect or day-of-week effect of the activity and immobility measures over the 6 nights across all subjects. On the other hand, for all nocturnal activity and immobility measures, a considerable intrasubject variability across the 6 nights was found. Females had a greater intrasubject variability of the mean duration of immobility periods and the movement index than males. The intrasubject variability of all nocturnal activity and immobility measures across the successive age groups remains stable. These findings emphasize that although a first-night effect may be lacking, the intrasubject variability of activity and immobility measures across several nights may still be considerable.

The aim of this study was to examine the quantitative relationship between activity monitor measures and clinical scores of patients with Parkinson disease (PD). Motor activity was recorded continuously for 5 to 6 days at home with a wrist-worn activity monitor in 69 PD patients and 59 healthy controls. Clinical scores of the patients, age, and sex were submitted to multiple regression analysis to examine the quantitative relationship with measures reflecting the activity level and the proportion of activity and immobility over time. The patients' age, sex, and scores representing hypokinesia and rigidity and resting tremor explained approximately 50% of the variance of the motor activity measures. All motor activity measures declined with age; the rate of decline was similar for the patients and controls. Sex emerged as a predictor of the motor activity measures in the patients only. Male patients with PD showed significantly lower values for all motor activity measures than female patients and controls. Our results show that activity monitoring can be used as an objective quantitative assessment in PD.

The objective of this questionnaire-based survey was to evaluate the prevalence and causes of sleep disturbances in 90 nondepressive patients with Parkinson's disease (PD) and 71 age-matched healthy subjects. We also assessed the prevalence and characteristics of excessive daytime sleepiness (both groups) and excessive fatigue (PD patients). A high prevalence of sleep disturbances in PD patients was found; this is to a large extent probably the result of aging. As compared with controls, patients had a more severely disturbed sleep maintenance because of nycturia, pain, stiffness, and problems with turning in bed. The prevalence of excessive dreaming is similar in both groups, but altered dream experiences almost exclusively occurred in PD. Patients rated themselves more often to be morning-types than controls. This finding may account for the reported adaptation effects in experimental settings and the reduced REM latency in PD patients. The prevalence of daytime sleepiness was similar in both groups. Excessive daytime sleepiness showed a clear diurnal pattern with a peak in the early afternoon. As for excessive fatigue, the majority of the patients did not report a preferential time for this symptom. Our findings further argue against an association of fatigue with any circadian factor, and instead suggest a relationship with the motor deficits of PD.

Plasma-sprayed ceramic coatings of fluorapatite (FA), magnesiumwhitlockite (MW), and hydroxylapatite (HA), and noncoated Ti-6Al-4V alloy (Ti) implants were evaluated histologically and histomorphometrically in a goat animal study. Cylindrical Ti-6Al-4V plugs were plasma-spray-coated with FA, MW, and HA. Noncoated, grit-blasted Ti plugs served as controls. The plugs were implanted into the right femur and left humerus of 20 adult goats. The results were evaluated using descriptive histology and histomorphometry. The histomorphometry consisted of measurements of bone apposition and coating thickness. The results demonstrated that FA showed a high amount of bone apposition without signs of degradation or dissolution. MW showed considerable reduction in thickness and at 12 weeks an adverse tissue reaction. However, at 25 weeks the amount of bone apposition was significantly increased compared with the 12-week implants. HA revealed considerable and progressive reduction in thickness and at 25 weeks a lower amount of bone apposition than FA and MW. At 12 weeks the Ti implants did reveal bone apposition, although frequently localized fibrous tissue was visible. At 25 weeks the Ti implants did not differ in bone apposition from the HA implants. Further studies are necessary on the effect of degradation or dissolution of HA on the compatibility with bone.

The ability of 99mtechnetium labelled nonspecific, polyclonal human immunoglobulin G (99mTc-IgG) scintigraphy to depict and quantify synovial inflammation was studied in 30 patients with rheumatoid arthritis (RA). All patients were injected with 350 MBq 99mTc-IgG and imaging was performed 4 h later. This resulted in excellent images of inflamed synovium. Scores for 99mTc-IgG joint scintigraphy correlated highly with scores for joint swelling and C-reactive protein levels, weakly with pain scores and not with radiographic scores of joint destruction. These results suggest that 99mTc-IgG joint scintigraphy may provide an objective test to detect synovitis and measure the activity of the disease.