Validation of mean upper cervical cord area (MUCCA) measurement techniques in multiple sclerosis (MS): High reproducibility and robustness to lesions, but large software and scanner effects.

INTRODUCTION: Atrophy of the spinal cord is known to occur in multiple sclerosis (MS). The mean upper cervical cord area (MUCCA) can be used to measure this atrophy. Currently, several (semi-)automated methods for MUCCA measurement exist, but validation in clinical magnetic resonance (MR) images is lacking. METHODS: Five methods to measure MUCCA (SCT-PropSeg, SCT-DeepSeg, NeuroQLab, Xinapse JIM and ITK-SNAP) were investigated in a predefined upper cervical cord region. First, within-scanner reproducibility and between-scanner robustness were assessed using intra-class correlation coefficient (ICC) and Dice's similarity index (SI) in scan-rescan 3DT1-weighted images (brain, including cervical spine using a head coil) performed on three 3 T MR machines (GE MR750, Philips Ingenuity, Toshiba Vantage Titan) in 21 subjects with MS and 6 healthy controls (dataset A). Second, sensitivity of MUCCA measurement to lesions in the upper cervical cord was assessed with cervical 3D T1-weighted images (3 T GE HDxT using a head-neck-spine coil) in 7 subjects with MS without and 14 subjects with MS with cervical lesions (dataset B), using ICC and SI with manual reference segmentations. RESULTS: In dataset A, MUCCA differed between MR machines (p < 0.001) and methods (p < 0.001) used, but not between scan sessions. With respect to MUCCA values, Xinapse JIM showed the highest within-scanner reproducibility (ICC absolute agreement = 0.995) while Xinapse JIM and SCT-PropSeg showed the highest between-scanner robustness (ICC consistency = 0.981 and 0.976, respectively). Reproducibility of segmentations between scan sessions was highest in Xinapse JIM and SCT-PropSeg segmentations (median SI ≥ 0.921), with a significant main effect of method (p < 0.001), but not of MR machine or subject group. In dataset B, SI with manual outlines did not differ between patients with or without cervical lesions for any of the segmentation methods (p > 0.176). However, there was an effect of method for both volumetric and voxel wise agreement of the segmentations (both p < 0.001). Highest volumetric and voxel wise agreement was obtained with Xinapse JIM (ICC absolute agreement = 0.940 and median SI = 0.962). CONCLUSION: Although MUCCA is highly reproducible within a scanner for each individual measurement method, MUCCA differs between scanners and between methods. Cervical cord lesions do not affect MUCCA measurement performance.

Long-term disease activity and disability progression in relapsing-remitting multiple sclerosis patients on natalizumab.

BACKGROUND: Natalizumab is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). Data on clinical and imaging measures predictive of disease activity and progression during treatment is limited. OBJECTIVE: To determine clinical and imaging predictors of long-term inflammatory disease activity and disability progression in RRMS patients on natalizumab. METHODS: Patients (n = 135) were selected from our prospective observational natalizumab cohort and monitored using brain MRI and extensive clinical testing. Progression and improvement on the Expanded Disability Status Scale (EDSS), no evidence of disease activity (NEDA) and no evidence of progression or active disease (NEPAD) status were determined using measurements after the initial phase of inflammation and the early anti-inflammatory impact of natalizumab. RESULTS: EDSS progression was seen in 43.7% of patients and EDSS improvement in 17.8%. Median follow-up was 4.9 years (IQR 3.6-6.0). Patients with a longer disease duration at natalizumab initiation have a higher hazard for earlier EDSS progression (HR 1.05, CI 1.00-1.09, p = 0.037) and a higher pre-baseline relapse rate predicted a longer NEPAD status (HR 1.70, CI 1.06-2.72, p = 0.028). CONCLUSION: The results suggest that starting natalizumab early, during active inflammatory disease results in a more favourable outcome. When taking into account early inflammation and the impact of natalizumab on disease activity during the initial treatment phase, a higher than expected proportion of patients showed disability progression.

Predicting clinical progression in multiple sclerosis after 6 and 12 years.

BACKGROUND AND PURPOSE: To predict disability and cognition in multiple sclerosis (MS) after 6 and 12 years, using early clinical and imaging measures. METHODS: A total of 115 patients with MS were selected and followed up after 2 and 6 years, with 79 patients also being followed up after 12 years. Disability was measured using the Expanded Disability Status Scale (EDSS); cognition was measured only at follow-up using neuropsychological testing. Predictors of interest included EDSS score, baseline brain and lesion volumes and their changes over 2 years, baseline age, clinical phenotype, sex and educational level. RESULTS: Higher 6-year EDSS score was predicted by early EDSS score and whole-brain volume changes and baseline diagnosis of primary progressive MS (adjusted R2  = 0.56). Predictors for 12-year EDSS score included larger EDSS score changes and higher T1-hypointense lesion volumes (adjusted R2  = 0.38). Year 6 cognition was predicted by primary progressive MS phenotype, lower educational level, male sex and early whole-brain atrophy (adjusted R2  = 0.26); year 12 predictors included male sex, lower educational level and higher baseline T1-hypointense lesion volumes (adjusted R2  = 0.14). CONCLUSIONS: Patients with early signs of neurodegeneration and a progressive disease onset were more prone to develop both disability progression and cognitive dysfunction. Male sex and lower educational level only affected cognitive dysfunction, which remains difficult to predict and probably needs more advanced imaging measures.

Comparison of the GRACE, HEART and TIMI score to predict major adverse cardiac events in chest pain patients at the emergency department.

BACKGROUND: The performance of the GRACE, HEART and TIMI scores were compared in predicting the probability of major adverse cardiac events (MACE) in chest pain patients presenting at the emergency department (ED), in particular their ability to identify patients at low risk. METHODS: Chest pain patients presenting at the ED in nine Dutch hospitals were included. The primary outcome was MACE within 6weeks. The HEART score was determined by the treating physician at the ED. The GRACE and TIMI score were calculated based on prospectively collected data. Performance of the scores was compared by calculating AUC curves. Additionally, the number of low-risk patients identified by each score were compared at a fixed level of safety of at least 95% or 98% sensitivity. RESULTS: In total, 1748 patients were included. The AUC of GRACE, HEART, and TIMI were 0.73 (95% CI: 0.70-0.76%), 0.86 (95% CI: 0.84-0.88%) and 0.80 (95% CI: 0.78-0.83%), respectively (all differences in AUC highly statistically significant). At an absolute level of safety of at least 98% sensitivity, the GRACE score identified 231 patients as "low risk" in which 2.2% a MACE was missed; the HEART score identified 381 patients as "low risk" with 0.8% missed MACE. The TIMI score identified no "low risk" patients at this safety level. CONCLUSIONS: The HEART score outperformed the GRACE and TIMI scores in discriminating between those with and without MACE in chest pain patients, and identified the largest group of low-risk patients at the same level of safety.

Neuropsychological outcome after deep brain stimulation for Parkinson disease.

OBJECTIVE: To assess the neuropsychological outcome 12 months after bilateral deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) or subthalamic nucleus (STN) for advanced Parkinson disease. METHODS: We randomly assigned patients to receive either GPi DBS or STN DBS. Standardized neuropsychological tests were performed at baseline and after 12 months. Patients and study assessors were masked to treatment allocation. RESULTS: Univariate analysis of change scores indicated group differences on Stroop word reading and Stroop color naming (confidence interval [CI] 1.9-10.0 and 2.1-8.8), on Trail Making Test B (CI 0.5-10.3), and on Wechsler Adult Intelligence Scale similarities (CI -0.01 to 1.5), with STN DBS showing greater negative change than GPi DBS. No differences were found between GPi DBS and STN DBS on the other neuropsychological tests. Older age and better semantic fluency at baseline predicted cognitive decline after DBS. CONCLUSIONS: We found no clinically significant differences in neuropsychological outcome between GPi DBS and STN DBS. No satisfactory explanation is available for the predictive value of baseline semantic fluency for cognitive decline. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that there is no large difference in neuropsychological outcome between GPi DBS and STN DBS after 12 months. The study lacks the precision to exclude a moderate difference in outcomes.

Protein-enriched 'regular products' and their effect on protein intake in acute hospitalized older adults; a randomized controlled trial.

BACKGROUND & AIMS: Especially in older adults, maintaining muscle mass is essential to perform activities of daily living. This requires a sufficient protein intake. However, protein intake in hospitalized older adults is often insufficient. Thus far different nutrition intervention strategies have failed to show success in reaching sufficient protein intake in hospitalized older adults. The effect of recently developed protein-enriched bread and drinking yoghurt on protein intake is still unknown. Therefore, the objective of this study was to examine the effect of protein-enriched bread and drinking yoghurt on the protein intake of acute hospitalized older adults (≥55 years). METHODS: This study was performed as a single blind randomized controlled trial in 47 hospitalized elderly acutely admitted to a university hospital. During three consecutive days participants received either ad libitum protein-enriched bread and drinking yoghurt or normal, non-enriched products as part of their daily meals. The protein-enriched bread contained 6.9 g of protein per serving and the normal bread 3.8 g of protein. For drinking yoghurt this was 20.0 g and 7.5 g of protein per serving respectively. The products were almost isocaloric. Food intake of participants was measured and nutritional values were calculated according to the Dutch Food Composition Table. An independent sample t-test was used to compare protein intake between the intervention and control group. RESULTS: Analyses illustrate a protein intake in the intervention group of 75.0 ± 33.2 g per day versus 58.4 ± 14.5 g in the control group (p = 0.039). Intervention patients had a mean protein intake of 1.1 g/kg/day, with 36% of the patients reaching the minimum requirement of 1.2 g/kg/day; in control patients this was 0.9 g/kg/day (p = 0.041) and 8% (p = 0.030). Bread and drinking yoghurt contributed almost equally to the increased intake of protein in the intervention group. CONCLUSIONS: The use of protein-enriched bread and drinking yoghurt, consumed as part of regular meals, is a promising and feasible solution to increase the protein intake of acutely ill patients. It needs to be confirmed whether the use of these products will also result in a better clinical outcome. ClinicalTrials.gov ID number: NCT01907152.

Impulse control behaviours in patients with Parkinson's disease after subthalamic deep brain stimulation: de novo cases and 3-year follow-up.

OBJECTIVE: To document the occurrence of impulse control behaviours (ICBs) in patients with Parkinson's disease after 3 years of continuous deep brain stimulation (DBS) of the subthalamic nucleus (STN). METHODS: Detailed neurological and ICB assessments were performed before STN DBS and up to 3 years after implant. RESULTS: 13 out of 56 patients (23.2%) had ICBs at baseline; they took higher doses of dopamine agonists (DAA). Three years after implant 11 had fully remitted with a 60.8% reduction of DAA medication; the remaining two, who had a similar medication reduction, had only compulsive eating, having recovered from hypersexuality. Six of the 43 patients without ICBs at baseline (14%) developed transient de novo ICBs after implant; none of them had ICBs at the 3-year observation. CONCLUSIONS: ICBs were abolished in patients 3 years after STN DBS and DAA dosages were lowered. New ICBs may occur after implant and are transient in most cases. Compulsive eating may be specifically related to STN stimulation.

What contributes to internists' willingness to disclose medical errors?

BACKGROUND: The release of the report 'To err is human' put medical safety and the disclosure of errors to the forefront of the health care agenda. Disclosure of medical errors by physicians is vital in this process. We studied the role of background and social psychological factors in internists' willingness to report medical errors. METHODS: Survey among a random sample of internists from five teaching hospitals in the Netherlands, all internists and internists in training at the Departments of Internal Medicine of the participating hospitals. RESULTS: Questionnaires were received from 115 participants (response 51%). The willingness to disclose was related to the severity of the error, with the majority of near misses not reported to the head of department or the hospital error committees. Errors were more often reported to colleagues. Positive factors in favour of disclosing were reported more often than negative ones prohibiting disclosure. Motivation, behavioural control and social barriers were related to the disclosure of errors. CONCLUSION: Personal and social issues contributing to the will and addressed properly to stimulate disclosure. The creation of an atmosphere where disclosing errors is routine seems vital. In addition, it is essential to create a departmental culture where medical errors are discussed in a non-judgmental, safe environment. In order to improve reporting of medical errors, more emphasis should be placed on the individual barriers that preclude adequate reporting.

Cerebral blood flow velocity wave form as an indicator of neonatal left ventricular heart function.

OBJECTIVE: To investigate the relationship between cerebral blood flow velocity wave form (CBFV-WF) parameters and myocardial contractility indices in healthy and sick preterm and term newborns. METHODS: Total group of 82 babies was divided into four subgroups: prematures with gestational age <34 weeks with (n=20) and without (n=14) respiratory distress syndrome (RDS) and infants with gestational age of >33 weeks with (n=18) and without (n=30) asphyxia. On day 1, 2, 3, 6 and 14, the acceleration time, Q(ECG)-peak(flow) time and preejection period of CBFV-WF (internal carotid artery) were measured through the anterior fontanel by Doppler ultrasonography. Simultaneously cardiac output, fractional shortening, systolic time intervals and their ratio were determined echocardiographically. RESULTS: RDS-babies had higher cardiac output and better myocardial performance then non-RDS-babies. Asphyxiated babies had lower cardiac output as compared to healthy babies, improving over time. Correlations were found between CBFV-WF parameters and several myocardial function indicators, but preejection period of cerebral blood flow velocity correlated closest with the same period measured echocardiographically (r=0.67, P<0.0001). Multiple linear regression revealed no influence of gestational age or clinical condition on this relationship. Assessment of agreement indicated that only substantial changes in myocardial performance could be monitored using preejection period of CBFV. CONCLUSION: Although a relationship was detected between the preejection period of CBFV and left ventricular systolic time interval (used as indicator of changes in left ventricular function), only rather large changes in left ventricular performance can be reliably detected using the preejection period of CBFV.

Personal and organizational predictors of workplace sexual harassment of women by men.

The authors investigated the predictors of workplace sexual harassment in 278 male university faculty and staff (M age = 45 years). Workplace variables (perceptions of organizational sanctions against harassment and perceptions of a sexualized workplace) and personal variables (adversarial sexual beliefs, sexual harassment beliefs, perspective taking, and self-esteem) were studied as predictors of sexualized and gender harassment. Social desirability was controlled. Both organizational variables and beliefs about sexual harassment predicted gender harassment and sexualized harassment. Perspective taking, adversarial sexual beliefs, and sexual harassment beliefs moderated the effects of perceived organizational sanctions against harassment on sexualized harassment. Findings are discussed as they relate to organizational efforts to reduce or prevent sexual harassment.

Antioxidant levels in the nasal mucosa of patients with chronic sinusitis and healthy controls.

BACKGROUND: Imbalances between oxidant formation and antioxidative defense are associated with the pathogenesis of several chronic inflammatory disorders of the respiratory tract. Therefore, a role of oxidative stress in chronic upper airway tract infections can be anticipated. OBJECTIVE: To determine if patients with chronic sinusitis demonstrate a reduced antioxidative tissue status. DESIGN: The levels of 3 biologically important antioxidants, reduced glutathione and oxidized glutathione, uric acid, and vitamin E, were determined biochemically in mucosal biopsy specimens from the uncinate process of patients with chronic sinusitis and healthy controls. SUBJECTS: Inflamed mucosa samples were obtained from 9 patients with chronic sinusitis during functional endoscopic sinus surgery. Normal mucosa samples were collected from 10 healthy controls during surgery for nasal obstruction. RESULTS: The data (presented as mean +/- SD) show a significant reduction (P < or = .05) of reduced glutathione levels (0.3 +/- 0.1 mumol/g wet weight) and uric acid levels (2.7 +/- 0.4 mumol/g wet weight) in mucosa samples obtained from patients with chronic sinusitis compared with healthy controls (0.6 +/- 0.2 and 3.4 +/- 0.6 mumol/g wet weight, respectively). No difference was found in oxidized glutathione (24 +/- 8 vs 25 +/- 15 nmol/g wet weight) and vitamin E (20.5 +/- 7.9 vs 22.5 +/- 6.9 nmol/g wet weight) levels between both groups. CONCLUSIONS: Decreased levels of both reduced glutathione and uric acid in patients with chronic sinusitis lead to a diminished antioxidant defense, which may be associated with the pathogenesis of upper respiratory tract disorders. The vitamin E level seems less important. This finding may offer perspectives for pharmacotherapeutic intervention with antioxidants.

Age-related differences in outcome and severity of DIC in children with septic shock and purpura.

We studied the influence of age on mortality and severity of clotting abnormalities in 79 children (median age: 3.1 years) with meningococcal sepsis. Parameters of coagulation and fibrinolysis and plasma levels of cytokines were prospectively measured on admission. The mortality rate was 27%. The age of survivors was significantly different from that of non-survivors (p = 0.013). With the exception of FVII, vWF and t-PA, parameters of coagulation and fibrinolysis, as well as plasma cytokine levels were related to outcome. Patients were divided in two groups: younger and older than median age. The mortality in children < or = 3.1 years was 40% versus 13% in children > 3.1 years (p = 0.006). In contrast to cytokine levels, which were not different between the two age groups, fibrinogen, prothrombin, factors V, VII, VIII, vWF, protein C, antithrombin, FDP, and the ratio PA1-1/t-PA were related to age, indicating a more severe coagulopathy in children < or = 3.1 years despite a similar degree of inflammatory response. A relative deficiency of coagulation factors due to an immature state of the clotting system, as well as an inadequate fibrinolytic response, both related to age may have caused this more severe coagulative response in younger children, and may have contributed to the higher mortality rate.

Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease.

An imbalance between oxidative stress and antioxidative capacity is thought to play an important role in the development and progression of chronic obstructive pulmonary disease (COPD). To assess the lung oxidative status in patients with COPD, we studied whether exhaled hydrogen peroxide (H2O2) is increased in breath condensate of patients with stable COPD (n = 12, mean FEV1 51% pred) and in patients with exacerbated COPD (n = 19, actual FEV1 36% pred) compared with a healthy control group (n = 10, FEV1 108% pred). Expired breath condensate during 15 min of tidal breathing was collected by cooling. The concentration of H2O2 was measured spectrophotometrically by means of horse radish peroxidase-catalyzed oxidation of tetramethylbenzidine. Concentrations of H2O2 (mean +/- SEM) were significantly elevated at 0.205 +/- 0.054 microM in patients with stable COPD compared with 0.029 +/- 0.012 microM in the control group (p < 0.05) and were further increased to 0.600 +/- 0.075 microM in patients with acutely exacerbated COPD (p < 0.001 compared with patients with stable COPD). Patients with pulmonary infiltrates on chest radiograph showed similar values compared with patients without obvious infiltrates. These findings demonstrate that patients with stable COPD exhibit increased oxidant production in the airways and that oxidant production increases further during exacerbations.

Elevated estrogen receptor expression in human prostatic stromal cells by androgen ablation therapy.

PURPOSE: The presence of estrogen receptors (ER) in human prostatic tissue is a longstanding, controversial issue. In a few experimental animal models androgen deprivation was shown to be associated with a spontaneous increased ER expression in prostatic tissue. We intended to study whether these observations also apply to human prostatic tissue. MATERIALS AND METHODS: Estrogen receptor expression by stromal and glandular cells was studied by immunohistochemistry in prostatectomy specimens of 21 patient with prostate cancer, treated for 3 months with a luteinizing hormone-releasing hormone (LHRH) agonist and flutamide. In addition 2 patients treated with estrogens were also examined. For comparison, ER expression was also studied in a series of 18 prostatectomy specimens of untreated patients. RESULTS: The specimens of patients treated with androgen blockade showed atrophic changes of the gland as well as basal cell hyperplasia, features characteristic for this therapy. Although stromal cells of prostatectomy specimens from untreated patients were largely ER negative, those of patients exposed to androgen ablation therapy or estrogen therapy had an intense nuclear ER expression in a great number of stromal cells around prostatic glands. Sporadic epithelial cells lining the glands displayed some nuclear ER expression. Prostatic glands from treated patients with basal cell hyperplasia lacked ER expression. In all treated and untreated cases the carcinoma cells were ER negative. CONCLUSIONS: Androgen deprivation leads to an upregulation of stromal ER expression in human prostate. Estrogen-induced morphological epithelial changes could be explained by a paracrine interaction between stromal and epithelial cells.

Acquired Von Willebrand disease in children with a Wilms' tumor.

The association between acquired von Willebrand disease and Wilms' tumor has been reported in eight cases: four cases reports and one prospective study of Coppes et al. (J. Clin Oncol 10:422-427, 1992) who found this in four out of 50 patients. We retrospectively studied 73 children who were diagnosed with a Wilms' tumor between 1970 and 1993. All patients were treated according to the running international SIOP protocol. According to our local diagnostic workup protocol, blood samples for screening coagulation tests were obtained at diagnosis and during preoperative chemotherapy. Since 1984, factor VIII analysis was added. In four patients, no coagulation screen was done. Bleeding time and screening tests apart from APTT were normal in all 69 children tested before or within 2 days after starting therapy. In 47 out of 73 patients, an APTT was performed before starting therapy. In 19 patients (40%), it was prolonged (>33 sec). In 8 of them (17%), the prolongation was severe (> or = 40 sec). In 11 out of the 19 patients, factor VIIIc, factor VIIIag, and factor VIII RcoF determinations were done. In two children, all three factors were decreased suggestive for von Willebrand disease. One of the 19 patients with a prolonged APTT had hematuria. The others had no increased bleeding tendency or signs of bleeding in the tumor. In all patients, the prolonged APTT normalised during preoperative chemotherapy within 6 weeks. Frequent blood samples were obtained of the two children with acquired von Willebrand disease and showed normalisation of the coagulation disorder after 1 and 2 weeks, respectively. No specific therapy to correct the coagulation abnormalities was given to any patient.

Expression of the ubiquitin-conjugating DNA repair enzymes HHR6A and B suggests a role in spermatogenesis and chromatin modification.

RAD6, a member of the expanding family of ubiquitin-conjugating (E2) enzymes, functions in the so-called "N-rule" protein breakdown pathway of Saccharomyces cerevisiae. In vitro, the protein can attach one or multiple ubiquitin (Ub) moieties to histones H2A and B and trigger their E3-dependent degradation. Rad6 mutants display a remarkably pleiotropic phenotype, implicating the protein in DNA damage-induced mutagenesis, postreplication repair, repression of retrotransposition, and sporulation. RAD6 transcription is strongly induced upon UV exposure and in meiosis, suggesting that it is part of a damage-induced response pathway and that it is involved in meiotic recombination. It is postulated that the protein exerts its functions by modulating chromatin structure. Previously, we have cloned two human homologs of this gene (designated HHR6A and HHR6B) and demonstrated that they partially complement the yeast defect. Here we present a detailed characterisation of their expression at the transcript and protein levels. Both HHR6 proteins, resolved by 2-dimensional immunoblot analysis, are expressed in all mammalian tissues and cell types examined, indicating that both genes are functional and constitutively expressed. Although the proteins are highly conserved, the UV induction present in yeast is not preserved, pointing to important differences in damage response between yeast and mammals. Absence of alterations in HHR6 transcripts or protein upon heat shock and during the cell cycle suggests that the proteins are not involved in stress response or cell cycle regulation. Elevated levels of HHR6 transcripts and proteins were found in testis. Enhanced HHR6 expression did not coincide with meiotic recombination but with the replacement of histones by transition proteins. Immunohistochemistry demonstrated that the HHR6 proteins are located in the nucleus, consistent with a functional link with chromatin. Electron microscopy combined with immunogold labeling revealed a preferential localisation of HHR6 in euchromatin areas, suggesting that the protein is associated with transcriptionally active regions. Our findings support the idea that both HHR6 genes have overlapping, constitutive functions related to chromatin conformation and that they have a specific role in spermatogenesis, involving Ub-mediated histone degradation.

Anti-oxidant actions of oxymethazoline and xylomethazoline.

Anti-oxidant actions of oxymethazoline and xylomethazoline were investigated by measuring inhibition of microsomal lipid peroxidation and hydroxyl radical scavenging activity. Oxymethazoline was shown to be a potent inhibitor of lipid peroxidation (IC50 = 4.9 microM at t = 15 min, IC50 = 8.1 microM at t = 30 min), in contrast to xylomethazoline. Both compounds were excellent hydroxyl radical scavengers. Their rate constants (ks = 1.1 x 10(12) M-1 s-1 for oxymethazoline and ks = 4.7 x 10(10) M-1 s-1 for xylomethazoline) exceeded the rate constant of a known powerful scavenger cimetidine (ks = 1.8 x 10(10) M-1 s-1). The difference in inhibiting lipid peroxidation might be explained by the fact that only oxymethazoline has a hydroxy group which can donate a hydrogen atom and terminate the chain reaction of lipid peroxidation. The mechanism of hydroxyl radical scavenging activity is still unclear. Moreover oxymethazoline seems to have a different mode of action in scavenging hydroxyl radicals than xylomethazoline and cimetidine which results in an extremely high rate constant. Because oxidants play a role in tissue damage in inflammation, it was hypothesized that especially oxymethazoline and to a lesser extent xylomethazoline may have an additional beneficial effect, due to their anti-oxidant properties, in the topical treatment of nasal inflammation.

The widely used anesthetic agent propofol can replace alpha-tocopherol as an antioxidant.

The cell membrane is protected against lipid peroxidation through endogenous antioxidants such as the lipid soluble alpha-tocopherol. The anesthetic agent propofol (2,6-diisopropylphenol) has a chemical structure which is similar to alpha-tocopherol, since it also contains a phenolic OH-group. The transient protection of GSH against lipid peroxidation in control liver microsomes is not observed in microsomes deficient in alpha-tocopherol. Introducing propofol (2 and 5 microM) restored the protective effect of GSH. Similar to the control microsomes the GSH-protective effect did not occur in previously heated microsomes. These results suggest that propofol acts similarly to alpha-tocopherol as a chain breaking antioxidant in liver microsomal membranes.

12p chromosomal aberrations in precursor B childhood acute lymphoblastic leukemia predict an increased risk of relapse in the central nervous system and are associated with typical blast cell morphology.

Recently we reported cytogenetic, clinical, and immunologic data of 135 childhood ALL patients, who were diagnosed and treated in The Sophia Children's Hospital between January 1, 1980 and November 1, 1990. An increased risk for a first relapse in the central nervous system (CNS) was detected in a subgroup of childhood ALL patients with common ALL or pre-B ALL phenotype and chromosomal aberrations of the short arm of chromosome 12. In this paper we report clinical, cytogenetic, immunologic, morphologic and cytochemical data on these eight childhood ALL patients with aberrations of the short arm of chromosome 12 and of an additional four cases that were diagnosed and treated between November 1, 1990 and February 1, 1992. We found that three out of six common ALL, two out of three pre-B ALL and one out of three T-ALL patients with 12p chromosomal rearrangements developed a first relapse in the CNS. On the contrary, the frequency of CNS relapse in our childhood ALL patients without 12p aberrations was 10%. Furthermore, morphologic and cytochemical analysis of the bone marrow smears of these 12 patients with aberrations of the short arm of chromosome 12 revealed that the nine cases with pre-B or common ALL phenotype had typical morphologic characteristics that are unusual for newly diagnosed childhood ALL. Typical for this subtype is the presence of large polymorphic blast cells without nucleoli. The nuclei are irregularly shaped showing folds and clefts and a stripy pattern. The nucleus and cytoplasm are often abundantly vacuolated. The cytoplasm has a foamy light-blue appearance.

Minimal effects of E. coli and Erwinia asparaginase on the coagulation system in childhood acute lymphoblastic leukemia: a randomized study.

A randomized study was done in twenty newly diagnosed children with acute lymphoblastic leukemia. Ten children were treated with Escherichia coli L-asparaginase, and ten with Erwinia chrysanthemi L-asparaginase. L-asparaginase (ASP) treatment started halfway during ALL-induction treatment with vincristine, prednisone, daunorubicin and intrathecal methotrexate. The mean activated partial thromboplastin time (APTT) level in all children demonstrated a significant fall (P < 0.001) from 28.25 sec at diagnosis to 23.0 sec at the start of ASP treatment. In this same time interval, the mean fibrinogen level declined markedly from 3 g/l to 1.2 g/l (P < 0.001), probably due to prednisone therapy. The APTT stayed shortened during ASP therapy, whereas the hypofibrinogenemia recovered significantly faster in the Erwinia group (P < or = 0.01). Factors (F) II, V, VII and X stayed within the normal range, while F VIII and F IX were elevated. During the entire period of induction therapy, the ATIII activity remained within the normal range in both treatment groups. The protein C values, however, demonstrated a steady decline from 140% at start of ASP treatment to a mean of 81% and 93%, respectively, at the end of the ASP therapy in the E. coli and Erwinia group. Five of the ten children treated with E. coli ASP demonstrated protein C levels below 70% at the end of ASP therapy, opposed to none of the Erwinia treated patients (P = 0.03). We suggest that the effect of ASP resulting in decreased coagulation factor synthesis is in part counterbalanced by the effect of prednisone on the coagulation system, when ASP is administered at the end of ALL induction treatment. The overall effect of ASP either of E. coli or of Erwinia on the hemorrhagic system reveals a slight imbalance towards thrombosis, mainly because of a gradual decrease in protein C activity. This imbalance is less pronounced in the Erwinia group.