The relationship between hippocampal EEG theta activity and locomotor behaviour in freely moving rats: effects of vigabatrin.

The relationship between hippocampal electroencephalogram (EEG) theta activity and locomotor speed in both spontaneous and forced walking conditions was studied in rats after vigabatrin injection (500 mg/kg i.p.). Vigabatrin increased the percentage of time that rats spent being immobile. During spontaneous walking in the open field, the speed of locomotion was increased by vigabatrin, while theta peak frequency was decreased. Vigabatrin also reduced the theta peak frequency during forced (speed controlled) walking. There was only a weak positive correlation (r=0.22) between theta peak frequency and locomotor speed for the saline condition. Furthermore, vigabatrin abolishes the weak relationship between speed of locomotion and theta peak frequency. Vigabatrin and saline did not differ in the slope of the regression line, but showed different offset points at the theta peak frequency axis. Thus, other factors than speed of locomotion seem to be involved in determination of the theta peak frequency.

Small but significant survival benefit in patients who undergo routine follow-up after colorectal cancer surgery.

BACKGROUND: The benefit of follow-up for patients after resection of primary colorectal cancer is unproven. The aim of this study was to evaluate the value of a standardised follow-up program considering detection of recurrent disease, eligibility for surgical treatment and survival. METHODS: Five hundred and sixty-four patients' records were evaluated. Detection of recurrent disease was distinguished in routine follow up (RF), interval visit (IV) or accidental finding (AF). RESULTS: One hundred and forty-nine patients (26%) had recurrent disease of which 68 were detected by routine follow-up. In 42 patients a resection was performed with curative intent (RF 18, IV 14, AF 10). In 26 patients radical resection (R(0)) was possible (RF 13, IV 5, AF 8), seven of them were long-term survivors. Routine follow-up itself had no significant influence on overall survival (P=0.08), although increased survival was observed if recurrent disease was detected by routine follow-up and resection was performed with curative intent (P=0.006). Median survival after resection was 4.2 years if recurrent disease was detected during routine follow-up and 0.5 years if detected during interval visits. CONCLUSIONS: Patients undergoing resection with curative intent for recurrent disease survive significantly longer if the disease is detected by routine follow-up. Routine follow-up itself did not improve overall survival.

Adherence to the guidelines of the CCCE in the treatment of node-positive breast cancer patients.

Guidelines are tools to improve the quality of care in daily practice. To accomplish adherence, active implementation is needed. The effect of audit, group-oriented feedback and educational activities to increase guideline adherence were investigated in this study. Treatment according to a guideline for premenopausal node-positive breast cancer patients from 1988 to 1992 (P1) and from 1996 to 1998 (P2) was assessed using the following indicators: percentage of patients with breast-conserving surgery, secondary surgery, > or = 10 reported resected axillary lymph nodes, reported tumour differentiation grade, reported hormonal receptor status, chemotherapy received (CT), start of CT < or = 28 days after surgery, Dose Intensity (DI) > or = 85% and completion of CT < or = 1 week beyond the ideal duration of CT. Data were audited from patients' records. The first audit resulted in a quality programme with feedback focused on the delivery of chemotherapy and resected axillary lymph nodes and educational sessions. A Fisher's exact test was used to estimate significant differences between the two time periods. In P1, 323 patients and in P2, 155 patients were eligible for treatment according to the guideline. The percentage of patients with > or = 10 lymph nodes improved from 65.3 to 81.3% (P=0.0004), as did the percentage with a reported oestrogen receptor (ER) status, from 84.8 to 96.8% (P=0.00004), progesterone receptor (PR) status from 82.3% to 97.4% (P<0.000001) and with a DI > or = 85%, from 74.9 to 93.9% (P=0.000003). Adherence varied between the hospitals. In conclusion, significant improvements were observed for the indicators of resected axillary lymph nodes and DI of chemotherapy, which may be attributed to the quality programme. Repeated assessment of the adherence to the guideline is important to observe changes and interhospital variations in order to remain focused on areas for improvement.

Behavioral transitions modulate hippocampal electroencephalogram correlates of open field behavior in the rat: support for a sensorimotor function of hippocampal rhythmical synchronous activity.

A clear relationship exists between moment-to-moment behavioral elements and hippocampal rhythmical synchronous activity (RSA) (theta rhythm). However, behavioral elements are not isolated events but are part of behavioral sequences in a context of behavioral activity. By concurrently monitoring open field behavior and hippocampal EEG, EEG correlates of open field behavior in relation to preceding and following behavior were studied in Sprague Dawley rats to determine whether the behavioral context influences EEG correlates of behavior. Results show that preceding and subsequent behavioral patterns influenced the spectral power correlates of behavior. RSA power was increased when a "type 1 behavior" (voluntary movement) preceded the behavior compared with when a "type 2 behavior" (automatic movement, awake immobility) preceded it. The modulating effect of behavioral transitions was shown for several types of behaviors, and systematic modulation of hippocampal EEG correlates of behavior was demonstrated. The present report shows that the strong and systematic relationship between hippocampal RSA and behavior is modulated by the behavioral-sequential context. Thus, in addition to the well established relationship between RSA and motor activity, a second nonmotor process seems to contribute to hippocampal RSA. A likely candidate is a sensory process, which is in accordance with theories on the sensorimotor function of hippocampal RSA.

Strain differences in hippocampal EEG are related to strain differences in behaviour in rats.

To date, EEG studies towards strain differences have focussed on pharmacologically altered or pathological EEG activity, but only few studies have investigated strain differences and normal EEG activity. A strong relation between behaviour and EEG activity has been demonstrated, especially for hippocampal EEG activity. This relation is known to be similar across species and strains, but no direct comparisons between rat strains within one study have been made. This study compared two rat strains (Sprague-Dawley and Long-Evans) with regard to open-field behaviour and concurrent hippocampal EEG recordings. A detailed behavioural analysis was made and spectral power was calculated for corresponding EEG activity in eight frequency bands. The two strains differed in exploratory activity and in spectral power in the 9-10-Hz frequency band (high frequency rhythmical slow activity [RSA] 6-10 Hz). Long-Evans rats showed higher exploratory activity and higher 9-10 Hz spectral power for voluntary movement and sniffing behaviours. Our results demonstrated these behaviour-specific strain differences in RSA power, although the relation between EEG and behaviour within each strain was similar. The strain differences in EEG were interpreted in relation to strain differences in exploratory behaviour, attributing the differences to a main motor component but also to a smaller sensory component integrated in exploratory behaviour. This is in accordance with theories on the sensory-motor function of the hippocampus and hippocampal theta activity.

The influence of ductal left-to-right shunting during extracorporeal membrane oxygenation.

BACKGROUND/PURPOSE: The aim of this study was to analyze whether a ductal left-to-right (L-R) shunt will prolong extracorporeal membrane oxygenation (ECMO) in neonates with severe pulmonary hypertension. This report discusses the onset and termination of a ductal L-R shunt and its potential influences on ECMO when pulmonary hypertension decreases during venoarterial bypass. METHODS: Twenty-nine neonates were monitored during veno-arterial ECMO, using bedside echocardiography with 12-hour interval observations. RESULTS: Up to 43% of the patients showed this type of shunt already after 12 hours on bypass. In total, this type of ductal shunt was found between 12 and 72 hours on ECMO in 62% of the patients. After 72 hours, the ductal L-R shunt no longer was detected. In 38% of the patients, no ductal L-R shunt was found during ECMO. Comparisons between these 2 patient groups showed a significantly longer ECMO duration in patients with ductal L-R shunt (P <.007). The mean prolongation time was 46 hours. Also, a significant decrease of left atrium to aorta ratio (P <.01) was observed during ECMO in the ductus group after closure of the duct, illustrating the decrease in volume load for the left heart and lungs. CONCLUSIONS: Ductal L-R shunting is related with a substantial prolongation of the ECMO course (mean prolongation of almost 2 days). The authors suggest that on one side, the ductal L-R shunt will lead to pulmonary hypercirculation and on the other side, postductal stealing from the descending aortic circulation will lead to prerenal failure. Possibly because of interactions with pulmonary and renal function, a ductal L-R shunt will, among other factors, interfere with weaning from ECMO, resulting in a prolonged bypass time.

Local staging of prostate cancer using magnetic resonance imaging: a meta-analysis.

Our objective was to determine the influence of patient-, study design-, and imaging protocol characteristics on staging performance of MR imaging in prostate cancer. In an electronic literature search and review of bibliographies (January 1984 to May 2000) the articles selected included data on sensitivity and specificity for local staging. Subgroup analyses examined the influence of age, prostate specific antigen, tumor grade, hormonal pre-treatment, stage distribution, publication year, department of origin, verification bias, time between biopsy and MR imaging; consensus reading, study design, consecutive patients, sample size, histology preparation, imaging planes, fast spin echo, fat suppression, endorectal coil, field strength, resolution, glucagon, contrast agents, MR spectroscopy, and dynamic contrast-enhanced MRI. Seventy-one articles and five abstracts were included, yielding 146 studies. Missing values were highly prevalent for patient characteristics and study design. Publication year, sample size, histologic gold standard, number of imaging planes, turbo spin echo, endorectal coil, and contrast agents influenced staging performance ( p=0.05). Due to poor reporting it was not possible to fully explain the heterogeneity of performance presented in the literature. Our results suggest that turbo spin echo, endorectal coil, and multiple imaging planes improve staging performance. Studies with small sample sizes may result in higher staging performance.

Effects of quality of treatment on prognosis in primary breast cancer patients treated in daily practice.

UNLABELLED: Information on treatment outcome outside clinical trials is sparse. This is the first study that relates surgical and medical quality of care in daily practice with outcome. BACKGROUND: In a previous study we showed, that the quality of chemotherapy as described by a guideline and given in daily practice to premenopausal primary breast cancer patients was suboptimal with only 68% and 53% of the patients receiving chemotherapy with a dose intensity (DI) and relative dose intensity (RDI) of > or = 85%, respectively. Many invalid reasons for delay and dose reductions were identified. PATIENTS AND METHODS: Premenopausal node-positive primary breast cancer patients treated from 1988 to 1992 were traced using two national registries. Relevant data were collected from their records. The following treatment-related variables were correlated with prognosis: type of surgery, number of investigated lymph nodes, radiotherapy, chemotherapy, interval between surgery and start of chemotherapy, DI, duration, delays and dose adjustments of chemotherapy and hospital size. RESULTS: Twenty-four of the 254 traced patients did not receive any chemotherapy, 230 received the recommended schedule of cyclophosphamide (C), methotrexate (M) and 5-fluorouracil (F). The median time of follow-up was 6.7 (range 0.9-10.2) years. The 5-year disease-free survival (DFS) and overall survival (OS) was 61% and 77%, respectively. In an univariate analysis DI < 65% correlated with a worse DFS and OS (p=0.05 and p=0.03, respectively). The use of chemotherapy correlated with a better DFS (p=0.03) than no use. In a multivariate analysis DI between 65 and 85% resulted in a better DFS (p=0.02) than DI > or = 85% and DI < 65%. CONCLUSION: The prognosis of the breast cancer patients in this population was comparable with the results of randomised trials using adjuvant CMF. The only treatment related variable of value for prognosis was DI. Unexpectedly DI between 65% and 85% resulted in the best prognosis in this population. The relevance of this observation remains unclear and warrants further investigation.

Cobalamin supplementation improves cognitive and cerebral function in older, cobalamin-deficient persons.

BACKGROUND: Mild cobalamin (Cbl) deficiency is frequently found in older persons and is associated with cognitive and cerebral abnormalities. The effects of Cbl supplementation on these abnormalities are largely unknown. METHODS: In a single-blind, placebo-controlled intervention study, 16 healthy community-dwelling elderly subjects with low plasma Cbl concentration and no cognitive impairments were studied. Subjects underwent 1 month of treatment with placebo, followed by 5 months of treatment with intramuscular injections of hydroxycobalamin. Before and after measurements of plasma cobalamin, total homocysteine (tHcy), methylmalonic acid (MMA), quantitative electroencephalograph (qEEG), and psychometric tests were taken. RESULTS: After Cbl supplementation, plasma Cbl concentrations increased, and plasma MMA and tHcy concentrations decreased. The performance on the Verbal Word Learning Test, Verbal Fluency and Similarities improved. qEEG showed more fast activity and less slow activity. Lower plasma tHcy concentrations were related to increased fast activity on qEEG on the one hand and improved performance on the Verbal Word Learning Test and Similarities on the other. Increased fast or decreased slow activity on qEEG was associated with improved performance on the Verbal Word Learning Test, Similarities and Verbal Fluency. CONCLUSIONS: Electrographic signs of improved cerebral function and improved cognitive function were found after Cbl supplementation in older subjects with low plasma Cbl concentrations who were free of significant cognitive impairment. These improvements were related to a reduction of plasma tHcy concentration.

Monotherapy versus polytherapy for epilepsy: a multicenter double-blind randomized study.

PURPOSE: Monotherapy has been the gold standard in epilepsy treatment for the last 20 years, partly because of the reputation for increased toxicity of polytherapy. However, monotherapy and polytherapy have not been compared in a double-blind clinical trial. Open trials that compared the two treatments were not optimally designed and compared the two at unequal drug loads (i.e., at nonequivalent dosages). We report on a double-blind clinical trial in which a combination of carbamazepine (CBZ) and valproate (VPA) was compared with CBZ monotherapy. Patients started with equal drug loads, and neurotoxicity was the primary outcome measure. METHODS: The 130 adult patients with untreated generalized tonic-clonic and/or partial seizures were randomized to equal drug loads of either monotherapy (400 mg CBZ per day) or polytherapy (200 mg CBZ plus 300 mg VPA per day). Outcome was measured by seizure counts, clinimetric epilepsy scales, and neuropsychological tests at baseline, at 2 and 12 months, and irregularly between 2 and 12 months. RESULTS: No statistical differences were found between the two treatments in the reduction of seizure frequencies, in overall neurotoxicity, or in overall systemic toxicity. The frequencies and clinimetric scores of certain adverse effects did differ (e.g., more monotherapy patients remained sedated, and more polytherapy patients gained weight). Fewer polytherapy patients withdrew because of adverse effects (14 vs. 22%), although this did not reach statistical significance (p=0.15). Neuropsychological assessment did not show significant differences. CONCLUSIONS: No differences were found in overall neurotoxicity between monotherapy and polytherapy.

Diagnostic performance of biopsy-based methods for determination of Helicobacter pylori infection without a reference standard.

Endoscopic biopsy-based tests are considered to be the reference method for diagnosing Helicobacter pylori infection and monitoring antibiotic treatment, but unbiased data on their diagnostic performance is lacking. In this study we evaluated the diagnostic performance of culture, histology and rapid urease testing of antral biopsies separately and in combination. Antral biopsies were taken from consecutive patients undergoing upper gastrointestinal endoscopies at a single center between January 1995 and May 1997. The biopsies were examined for culture, histology, and CLOtest. The diagnostic performance, i.e., the sensitivity and specificity of the tests was estimated with 7 non-linear equations in 7 unknowns. To determine sources of heterogeneity that may have biased the results, data were stratified for age, gender, and whether they were taken before or after anti-Helicobacter antibiotic treatment. During the study period 631 patients underwent 869 upper gastrointestinal endoscopies. In 122 (14%) of the antral specimens the test results of culture, histology and CLOtest differed. Based on the nonlinear regression techniques we estimated that in 347 tests (40%) H. pylori infection was present. Overall sensitivity, specificity, positive and negative predictive value for each test were as follows: culture 91.4%, 96.3%, 94.2%, 94.4%, respectively; histology 90.3%, 97.8%, 96.4%, 93.8%, respectively; CLOtest 94.9%, 96.7%, 95.0%, 96.6%, respectively. In combination, the three tests provided the definitive diagnosis, either non-infected or infected, in 862 out of the 869 tests. Sensitivity of gastric antral histology was 64.9% (95% CI: 38-86) in females who did and 84.5% (95% CI: 77-90) in females who did not have had recent antibiotic therapy to cure the infection. Approximately 5-10% of H. pylori infected patients, were mis-diagnosed with a single biopsy-based test taken from the gastric antrum. Only a combination of bacterial culture, histological examination and the CLOtest represents an appropriate reference standard for research purposes to identify infected patients.

Neonatal pulmonary hypertension during extracorporeal membrane oxygenation.

OBJECTIVES: This prospective study was designed to monitor severe pulmonary hypertension during extra corporeal membrane oxygenation using echo Doppler variables. BACKGROUND: All neonates treated with extracorporeal membrane oxygenation also have severe pulmonary hypertension. A study which monitors the reaction of the pre-existing pulmonary hypertension during extracorporeal oxygenation by frequent sampling of those variables related to pulmonary pressure is still lacking. Such a study is necessary to analyze the complex haemodynamic changes in patients undergoing extracorporeal membrane oxygenation. METHOD: In 29 neonates, we estimated pulmonary arterial pressure using peakflow velocity of regurgitation across the tricuspid- and pulmonary valve, peakflow velocity of shunting across persistent arterial ductus, and systolic time intervals of the right ventricle. Correlation between the several estimations of pulmonary arterial pressure were analysed with the Spearman correlation coefficient. RESULTS: Systolic pulmonary arterial pressure measured by the velocity of tricuspid regurgitation illustrated severe pulmonary hypertension prior to extra corporeal membrane oxygenation (mean 63 mmHg, sd 20). Similar levels for the systolic pulmonary arterial pressure could be derived (mean 73 mmHg, sd 17) from ductal shunting. A fair correlation of 0.76 (p< 0.002) could be demonstrated. Pulmonary hypertension responded well and quickly to treatment by extra corporeal membrane oxygenation, with reductions within 24 hours to mean systolic levels of 35 mmHg, sd 23. This very early reaction has not previously been demonstrated and could be of importance in defining parameters for weaning from cardiopulmonary bypass. Diastolic pulmonary arterial pressure was investigated because of its relation to vascular resistance. It proved more difficult to measure because of the low incidence of pulmonary regurgitation. Derived diastolic pressures did not show any good correlations. CONCLUSION: Pulmonary hypertension is well documented prior to extra corporeal membrane oxygenation and response very quickly to the institution of treatment. Ultra sound techniques are indicated at the bedside, and prove useful in monitoring pulmonary blood pressure during the procedure.

Natural history of congenital pulmonary valvar stenosis: an echo and Doppler cardiographic study.

Doppler echocardiography allows accurate serial assessment of pulmonary valvar stenosis by measuring the velocity of the jet stream through the pulmonary valve. Between 1979 and 1997, we saw 174 patients with isolated pulmonary valvar stenosis. At admission their ages ranged from 9 days to 22.5 years. We measured the velocity over the pulmonary valve, and the thickness of the anterior wall of the right ventricle, and made a study of their electrocardiograms. We found that rapid increases and decreases occurred in almost every age-group. For patients with a trivial, mild or moderate level of stenosis, severe stenosis developed in 3, 10 and 9%, respectively. In most of the patients, 122 (90%), in whom there was more than one examination, a change in pressure gradient between -12 mmHg/year and +3 mmHg/year was found. Only 7 patients had an increase of more than 10 mmHg per year. In contrast with our patients having aortic stenosis, these with stenosis of the pulmonary valve showed no rapid increase in early childhood. Indeed, in 58% the severity of the stenosis decreased. No correlation was found when comparing the echocardiographic measurements of the thickness of the anterior wall of the right ventricle with the voltages on the electrocardiogram. A significant relation was found however, between an increasing pressure gradient and thickened valvar leaflets (p=0.017).

Plasma patterns of tumor necrosis factor-alpha (TNF) and TNF soluble receptors during acute meningococcal infections and the effect of plasma exchange.

In 39 patients with acute meningococcal infections, the plasma concentrations of tumor necrosis factor-alpha (TNF) and its soluble receptors (sRs) TNFsR-p55 and TNFsR-p75 were measured from admission till recovery. At admission, patients with shock had significantly higher TNF, TNFsR-p55, and TNFsR-p75 values than patients without shock. In addition, during the first 24 hours, patients with shock had higher TNFsR-p75 to TNFsR-p55 ratios, indicating that in shock the increase of TNFsR-p75 exceeds that of TNFsR-p55. TNF measured more than 12 hours after admission failed to differentiate between shock and nonshock because TNF concentrations normalized within 12-24 hours. However, because concentrations of TNFsRs remained elevated for 5-6 days, at that time plasma TNFsRs still differentiated between shock and nonshock. Plasma exchange or whole blood exchange (PEBE), performed in 20 patients with shock, accelerated the decrease of plasma TNFsRs. However, because of a rebound after each PEBE session, the overall half-lives of both TNFsRs were not affected by PEBE.

Fever of unknown origin (FUO). II. Diagnostic procedures in a prospective multicenter study of 167 patients. The Netherlands FUO Study Group.

From January 1992 until January 1994, we used a standardized diagnostic protocol for the 167 immunocompetent patients with fever of unknown origin (FUO) admitted on the internal medicine wards in all 8 university hospitals in the Netherlands. This protocol consisted of a standardized coded history and standardized physical examination for all 167 patients. A number of additional obligatory investigations had to be performed in the first week of admission for all patients, and all potentially diagnostic clues (PDCs) thus retrieved had to be registered. In the presence of PDCs, specific investigations had to be performed based on the differential diagnosis. In the absence of PDCs or in the presence of only misleading PDCs, patients underwent a screening 2-staged diagnostic protocol. In 162 (97%) patients, PDCs were present after 1 week of admission. In 61 patients these PDCs were all misleading. The likelihood of reaching a diagnosis in patients with PDCs was not significantly higher than that in patients without PDCs, probably because of the high proportion of misleading PDCs. The likelihood of establishing a diagnosis was significantly lower (< 10%) only for patients with recurrent fever, normal erythrocyte sedimentation rate (ESR), and normal hemoglobin. All other PDCs were not significantly different in patients with a diagnosis compared with patients without a diagnosis. The screening 2-staged diagnostic protocol proved useful in 10 of 43 patients in whom it was used. The screening value of immunologic and microbiologic serology and endocrine investigations was nil; these investigations probably should be performed only when PDCs for the disease searched for are present. Scintigraphic techniques, echocardiography, and other imaging procedures were never helpful in our population in the absence of PDCs. Many patients with FUO had nonspecific anemia and disturbed liver chemistry. In the presence of these findings alone, without other more specific PDCs, the likelihood of reaching a diagnosis with help of bone marrow aspiration was nil, and with help of liver biopsy, it was low. Enteric biopsy was never helpful. If lymphadenopathy was confined to the cervical or inguinal region (with negative chest X-ray and abdominal ultrasound), lymph node biopsy was not helpful, in contrast to patients having generalized lymphadenopathy, in whom the technique had a yield of 79%. As shown in this study, the search for PDCs remains an important tool for establishing the diagnosis in patients with FUO, although in many cases these PDCs appear to be misleading. Directed diagnostic workup--using the PDCs retrieved by repeated, meticulous history taking and physical examination--remains the most efficient and intellectually satisfactory way to solve the problem of FUO in the individual patient. A standard protocol in patients with FUO in whom the obligatory investigations, as used by us, do not lead to the diagnosis can be limited to the tests that proved to be of some use as screening procedure: temporal biopsy in patients older than 55 years; fundoscopy; serology (Western blot) for Yersinia enterocolitica; serum for cryoglobulin at an early stage of the diagnostic process; and bone biopsy, liver biopsy, abdominal computed tomography (CT), and chest CT at a later stage. Repeating a thorough history-taking, physical examination, and obligatory investigations and waiting for PDCs to appear probably is better than ordering more screening investigations in the hope that something abnormal will come up. Supportive treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) can be helpful at this stage. Only rarely do patients deteriorate while using NSAIDs without presenting new PDCs. In these rare patients, further diagnostic workup should be performed or a therapeutic trial with, for example, antibiotics, steroids, or antituberculous agents started.

Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial.

In this study, methotrexate (MTX) was compared with placebo in the treatment of systemic sclerosis (scleroderma, SSc) in a 24 week randomized double-blind trial, followed by an observational trial of 24 weeks duration. Twenty-nine scleroderma patients were allocated to receive weekly injections of either 15 mg MTX or placebo. Patients who responded favourably after 24 weeks continued with the same regimen for a further 24 weeks; those who showed a poor response on placebo were allocated to further treatment with 15 mg MTX weekly, and those who responded poorly to treatment with 15 mg MTX had their doses increased to 25 mg. A favourable response was defined as an improvement of total skin score (TSS) by > or = 30%, of single breath diffusion capacity (DLCO) by > or = 15%, or of the score on a visual analogue scale of general well-being (VAS) by > or = 30%, provided that such improvements were not accompanied by persistent digital ulcerations or worsening of DLCO > or = 15%. Seventeen patients were allocated to MTX treatment and 12 to treatment with placebo. After 24 weeks, a significantly larger number of patients receiving MTX (n = 8, 53%) who completed the first 24 weeks of the study had responded favourably compared to patients receiving placebo (n = 1, 10%, P = 0.03). Comparison of separate variables between the two treatment groups by intention-to-treat analysis at week 24 showed improvement in the MTX group of TSS (P = 0.06) and creatinine clearance (P = 0.07). At week 48, 13 patients received MTX from the start of the study and nine during 24 weeks. From these 22 patients, 15(68%) responded favourably and compared with the start of the study they showed significant improvement of TSS (P = 0.04), VAS (P = 0.02), grip strength of the right hand (P = 0.02) and ESR (P = 0.01). Although the number of patients enrolled in this study is small, these results suggest that in a group of patients with active systemic sclerosis, low-dose MTX seems to be more effective than placebo according to pre-defined response criteria.

Crossover trials with a binary response: a powerful method despite the carryover effect.

The two-period crossover trial has the evident advantage that, by use of within-patient comparisons, the usual large between-patient variability is not used as a measure to compare treatments. A prerequisite, however, is that the order of the treatments does not substantially influence the outcome of the treatment. Crossover studies with a binary response (such as yes/no or present/absent), although widely used for initial screening of new compounds, have not previously been studied for such order effects. This study uses a mathematical model based on standard statistical tests to study to what extent such order effects, here identical to carryover effects, may reduce the power of detecting a treatment effect. It is concluded that, despite large carryover effects, the crossover study with a binary response remains a powerful method and that testing for carryover effects makes sense only if the null hypothesis of no treatment effect cannot be rejected.

Neither dosage nor serum levels of antiepileptic drugs are predictive for efficacy and adverse effects.

In order to assess whether doses or serum levels are predictive for the efficacy and adverse effects of antiepileptic drugs (AEDs), measures for exposure to drug combinations have to be used. For doses, the ratio of the observed prescribed daily dose (PDD) and the average defined daily dose (DDD) considered effective for the main indication of the drug was used. In analogy for serum levels, the OSL/ATL ratio, i.e. the ratio of the observed serum level and the average therapeutic level was used. In polypharmacy these ratios can be summed as the are normalized measures of strength. The correlations of these ratios with outcome measures were studied in 200 patients attending out-patient clinics of special centres for epilepsy; half of these patients were treated with monopharmacy and half with polypharmacy. As outcome measures the following indices were used: the index of seizures, which quantifies seizure type and frequency, the seizure activity index, the neurotoxicity score, the systemic toxicity score, and the composite index of impairments, which is the sum of the seizure activity index and the neurotoxicity score and the systemic toxicity score. When all data were pooled, the correlation coefficient between the PDD/DDD ratio and the OSL/ATL ratio was 0.77. However, when the data were examined separately for the monopharmacy and polypharmacy groups, the correlation was 0.31 for the monopharmacy group and 0.50 for the polypharmacy group. Neither the PDD/DDD ratio nor the OSL/ATL ratio correlated with the composite index of impairments or with any of the individual indices. Factors such as the difficulty of titrating the endpoint of seizure suppression and the development of tolerance to adverse drug effects may perhaps be responsible for these findings. This observational study signals the problem.

Monotherapy or polytherapy for epilepsy revisited: a quantitative assessment.

Some investigators argue that treating epilepsy with several antiepileptic drugs (AEDs) simultaneously (polytherapy) may give rise to more adverse effects than monotherapy, but this argument lacks supporting quantitative data. To reexamine this issue, we recruited a cohort of patients from the outpatients of the Special Centres for Epilepsy in The Netherlands and from the outpatients of the Department of Neurology, Nijmegen University, The Netherlands. Two tools were used for analysis. All daily doses of antiepileptic drugs (AEDs) were standardized by the ratio of prescribed daily dose to defined daily dose (PDD/DDD). The DDD is the assumed average effective daily dose for a drug used for its main indication in adults. The assignment of DDD values is the task of the World Health Organization (WHO) Collaborating Centre for Drugs Statistics Methodology and Nordic Council on Medicines, which regularly publishes Guidelines for Defined Daily Doses. The severity of adverse effects (AE) was assessed by using the Neurotoxicity Index and the Systemic Toxicity Index as developed by the VA Cooperative Study Group for their recent studies comparing the efficacy and tolerability of AEDs. One hundred sixty-one patients received monotherapy; all had a PDD/DDD ratio < or = 2/day; 128 of 262 patients receiving polytherapy also had < or = 2 PDD/DDD ratios/day. The mono- and polytherapy groups were stratified according to the PDD/DDD ratio. The prevalence of neurological AE for patients with similar PDD/DDD ratios was 50-80% for monotherapy patients and 50-82% for polytherapy patients. The difference between the mono- and polytherapy groups was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of intrabrachial and finger blood pressure in healthy elderly volunteers.

This study was performed to compare continuous Finapres (FIN) and intrabrachial (IAP) blood pressure in healthy elderly volunteers. Fifteen elderly subjects (age 71 to 83) without cardiovascular disease and an intraarterial mean (range) systolic and diastolic blood pressure of 162 (122 to 195) and 73 (62 to 88) mm Hg, respectively, participated in the study. A 10-min head-up tilt, 10 min active standing, a 15-sec Valsalva, and a 5-min mental arithmetic were performed in random order. Beat-to-beat values of systolic, diastolic, and mean arterial pressure were analyzed. At rest, FIN underestimated IAP by 16.8 +/- 2.6 (SE), 10.8 +/- 1.5, and 17.5 +/- 1.6 mm Hg for systolic, diastolic, and mean arterial blood pressure, respectively (P < .05). During head-up tilt, FIN overestimated the intraarterial systolic blood pressure response by 7.2 +/- 1.6 (SE) mm Hg (P < .05). Group-averaged changes in diastolic and mean arterial IAP were followed closely by FIN. During standing, Finapres closely followed intraarterial diastolic and mean arterial pressure but the increase in systolic blood pressure was higher at the finger as compared to intrabrachial recordings, resembling the results of head-up tilt. During the Valsalva maneuver, maximal responses in systolic, diastolic, and mean arterial pressure were underestimated by FIN by 12.1 +/- 3.3 (SE), 6.8 +/- 2.7, and 7.1 +/- 1.7 mm Hg, respectively (P < .05 for all parameters). During mental arithmetic, FIN underestimated the intraarterial systolic blood pressure response by 6.1 +/- 2.7 (SE) mm Hg (P < .05), while diastolic and mean arterial pressure responses were followed correctly by FIN. It is concluded that apart from systolic blood pressure, FIN closely follows intraarterial blood pressure responses for the orthostatic maneuvers and mental arithmetic. During Valsalva, the rapid changes in blood pressure were followed in direction but not in magnitude.