Caspase-3 activity as a prognostic factor in colorectal carcinoma.

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.

The relationship between impairments in joint function and disabilities in independent function in children with systemic juvenile idiopathic arthritis.

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.

Endogenous natural killer cells do not play a role in antitumor effects induced by interleukin-2 in a syngeneic rat colon tumor model.

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.

Is there an effect of perioperative blood transfusion on the outcome of radical hysterectomy with lymphadenectomy for cervical cancer in South Africa?

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.

[The ear thermometer; not a good replacement for the rectal thermometer]. / De oorthermometer: geen goede vervanger van de rectale thermometer.

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.

Female sex hormones at the onset of systemic lupus erythematosus affect survival.

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 female 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.

Plasma levels of arginine vasopressin elevated in patients with major depression.

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.

Beneficial effect of enalapril on left ventricular remodelling in patients with a severe residual stenosis after acute anterior wall infarction.

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.

Clozapine versus placebo in Huntington's disease: a double blind randomised comparative study.

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.

Tumour necrosis factor alpha gene polymorphisms in rheumatoid arthritis: association with susceptibility to, or severity of, disease?

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.

Reproducibility of left ventricular size, shape and mass with echocardiography, magnetic resonance imaging and radionuclide angiography in patients with anterior wall infarction. A plea for core laboratories.

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.

An open study of pentoxyfylline and thalidomide as adjuvant therapy in the treatment of rheumatoid arthritis.

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.

Echo planar MRI of the heart on a standard system: validation of measurements of left ventricular function and mass.

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.

Saccadic eye movements in idiopathic blepharospasm.

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.

Pulmonary function and postoperative complications after wedge and flap reconstructions of the main bronchus.

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.

Clinical course of patients with idiopathic Parkinson's disease.

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.

Assessment of left ventricular volume and mass by cine magnetic resonance imaging in patients with anterior myocardial infarction intra-observer and inter-observer variability on contour detection.

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.

Correlation between the antibody response to influenza vaccine and helper T cell subsets in healthy aging.

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.

Enhanced susceptibility of low-density lipoproteins to oxidation in coronary bypass patients with progression of atheroscerosis.

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.