Prediction of Outcome Using Quantified Blood Volume in Aneurysmal SAH.

BACKGROUND AND PURPOSE: In patients with SAH, the amount of blood is strongly associated with clinical outcome. However, it is commonly estimated with a coarse grading scale, potentially limiting its predictive value. Therefore, we aimed to develop and externally validate prediction models for clinical outcome, including quantified blood volumes, as candidate predictors. MATERIALS AND METHODS: Clinical and radiologic candidate predictors were included in a logistic regression model. Unfavorable outcome was defined as a modified Rankin Scale score of 4-6. An automatic hemorrhage-quantification algorithm calculated the total blood volume. Blood was manually classified as cisternal, intraventricular, or intraparenchymal. The model was selected with bootstrapped backward selection and validated with the R 2, C-statistic, and calibration plots. If total blood volume remained in the final model, its performance was compared with models including location-specific blood volumes or the modified Fisher scale. RESULTS: The total blood volume, neurologic condition, age, aneurysm size, and history of cardiovascular disease remained in the final models after selection. The externally validated predictive accuracy and discriminative power were high (R 2 = 56% ± 1.8%; mean C-statistic = 0.89 ± 0.01). The location-specific volume models showed a similar performance (R 2 = 56% ± 1%, P = .8; mean C-statistic = 0.89 ± 0.00, P = .4). The modified Fisher models were significantly less accurate (R 2 = 45% ± 3%, P < .001; mean C-statistic = 0.85 ± 0.01, P = .03). CONCLUSIONS: The total blood volume-based prediction model for clinical outcome in patients with SAH showed a high predictive accuracy, higher than a prediction model including the commonly used modified Fisher scale.

Follow-up infarct volume as a mediator of endovascular treatment effect on functional outcome in ischaemic stroke.

OBJECTIVE: The putative mechanism for the favourable effect of endovascular treatment (EVT) on functional outcome after acute ischaemic stroke is preventing follow-up infarct volume (FIV) progression. We aimed to assess to what extent difference in FIV explains the effect of EVT on functional outcome in a randomised trial of EVT versus no EVT (MR CLEAN). METHODS: FIV was assessed on non-contrast CT scan 5-7 days after stroke. Functional outcome was the score on the modified Rankin Scale at 3 months. We tested the causal pathway from intervention, via FIV to functional outcome with a mediation model, using linear and ordinal regression, adjusted for relevant baseline covariates, including stroke severity. Explained effect was assessed by taking the ratio of the log odds ratios of treatment with and without adjustment for FIV. RESULTS: Of the 500 patients included in MR CLEAN, 60 died and four patients underwent hemicraniectomy before FIV was assessed, leaving 436 patients for analysis. Patients in the intervention group had better functional outcomes (adjusted common odds ratio (acOR) 2.30 (95% CI 1.62-3.26) than controls and smaller FIV (median 53 vs. 81 ml) (difference 28 ml; 95% CI 13-41). Smaller FIV was associated with better outcome (acOR per 10 ml 0.60, 95% CI 0.52-0.68). After adjustment for FIV the effect of intervention on functional outcome decreased but remained substantial (acOR 2.05, 95% CI 1.44-2.91). This implies that preventing FIV progression explains 14% (95% CI 0-34) of the beneficial effect of EVT on outcome. CONCLUSION: The effect of EVT on FIV explains only part of the treatment effect on functional outcome. KEY POINTS: • Endovascular treatment in acute ischaemic stroke patients prevents progression of follow-up infarct volume on non-contrast CT at 5-7 days. • Follow-up infarct volume was related to functional outcome, but only explained a modest part of the effect of intervention on functional outcome. • A large proportion of treatment effect on functional outcome remains unexplained, suggesting FIV alone cannot be used as an early surrogate imaging marker of functional outcome.

Impact of Ischemic Lesion Location on the mRS Score in Patients with Ischemic Stroke: A Voxel-Based Approach.

BACKGROUND AND PURPOSE: Previous studies indicated that ischemic lesion volume might be a useful surrogate marker for functional outcome in ischemic stroke but should be considered in the context of lesion location. In contrast to previous studies using the ROI approach, which has several drawbacks, the present study aimed to measure the impact of ischemic lesion location on functional outcome using a more precise voxelwise approach. MATERIALS AND METHODS: Datasets of patients with acute ischemic strokes from the Multicenter Randomized Clinical Trial of Endovascular Therapy for Acute Ischemic Stroke in the Netherlands (MR CLEAN) were used. Primary outcome was functional outcome as assessed by the modified Rankin Scale 3 months after stroke. Ischemic lesion volume was determined on CT scans 3-9 days after stroke. Voxel-based lesion-symptom mapping techniques, including covariates that are known to be associated with functional outcome, were used to determine the impact of ischemic lesion location for outcome. RESULTS: Of the 500 patients in the MR CLEAN trial, 216 were included for analysis. The mean age was 63 years. Lesion-symptom mapping with inclusion of covariates revealed that especially left-hemispheric lesions in the deep periventricular white matter and adjacent internal capsule showed a great influence on functional outcome. CONCLUSIONS: Our study confirms that infarct location has an important impact on functional outcome of patients with stroke and should be considered in prediction models. After we adjusted for covariates, the left-hemispheric corticosubcortical fiber tracts seemed to be of higher functional importance compared with cortical lesions.

Association of Quantified Location-Specific Blood Volumes with Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia is a severe complication of aneurysmal SAH and is associated with a high case morbidity and fatality. The total blood volume and the presence of intraventricular blood on CT after aneurysmal SAH are associated with delayed cerebral ischemia. Whether quantified location-specific (cisternal, intraventricular, parenchymal, and subdural) blood volumes are associated with delayed cerebral ischemia has been infrequently researched. This study aimed to associate quantified location-specific blood volumes with delayed cerebral ischemia. MATERIALS AND METHODS: Clinical and radiologic data were collected retrospectively from consecutive patients with aneurysmal SAH with available CT scans within 24 hours after ictus admitted to 2 academic centers between January 2009 and December 2011. Total blood volume was quantified using an automatic hemorrhage-segmentation algorithm. Segmented blood was manually classified as cisternal, intraventricular, intraparenchymal, or subdural. Adjusted ORs with 95% confidence intervals for delayed cerebral ischemia per milliliter of location-specific blood were calculated using multivariable logistic regression analysis. RESULTS: We included 282 patients. Per milliliter increase in blood volume, the adjusted OR for delayed cerebral ischemia was 1.02 (95% CI, 1.01-1.04) for cisternal, 1.02 (95% CI, 1.00-1.04) for intraventricular, 0.99 (95% CI, 0.97-1.02) for intraparenchymal, and 0.96 (95% CI, 0.86-1.07) for subdural blood. CONCLUSIONS: Our findings suggest that in patients with aneurysmal subarachnoid hemorrhage, the cisternal blood volume has a stronger relation with delayed cerebral ischemia than the blood volumes at other locations in the brain.

Value of Quantitative Collateral Scoring on CT Angiography in Patients with Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Many studies have emphasized the relevance of collateral flow in patients presenting with acute ischemic stroke. Our aim was to evaluate the relationship of the quantitative collateral score on baseline CTA with the outcome of patients with acute ischemic stroke and test whether the timing of the CTA acquisition influences this relationship. MATERIALS AND METHODS: From the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) data base, all baseline thin-slice CTA images of patients with acute ischemic stroke with intracranial large-vessel occlusion were retrospectively collected. The quantitative collateral score was calculated as the ratio of the vascular appearance of both hemispheres and was compared with the visual collateral score. Primary outcomes were 90-day mRS score and follow-up infarct volume. The relation with outcome and the association with treatment effect were estimated. The influence of the CTA acquisition phase on the relation of collateral scores with outcome was determined. RESULTS: A total of 442 patients were included. The quantitative collateral score strongly correlated with the visual collateral score (ρ = 0.75) and was an independent predictor of mRS (adjusted odds ratio = 0.81; 95% CI, .77-.86) and follow-up infarct volume (exponent ß = 0.88; P < .001) per 10% increase. The quantitative collateral score showed areas under the curve of 0.71 and 0.69 for predicting functional independence (mRS 0-2) and follow-up infarct volume of >90 mL, respectively. We found significant interaction of the quantitative collateral score with the endovascular therapy effect in unadjusted analysis on the full ordinal mRS scale (P = .048) and on functional independence (P = .049). Modification of the quantitative collateral score by acquisition phase on outcome was significant (mRS: P = .004; follow-up infarct volume: P < .001) in adjusted analysis. CONCLUSIONS: Automated quantitative collateral scoring in patients with acute ischemic stroke is a reliable and user-independent measure of the collateral capacity on baseline CTA and has the potential to augment the triage of patients with acute stroke for endovascular therapy.

Topographic distribution of cerebral infarct probability in patients with acute ischemic stroke: mapping of intra-arterial treatment effect.

BACKGROUND: Since proof emerged that IA treatment (IAT) is beneficial for patients with acute ischemic stroke, it has become the standard method of care. Despite these positive results, recovery to functional independence is established in only about one-third of treated patients. The effect of IAT is commonly assessed by functional outcome, whereas its effect on brain tissue salvage is considered a secondary outcome measure (at most). Because patient and treatment selection needs to be improved, understanding the treatment effect on brain tissue salvage is of utmost importance. OBJECTIVE: To introduce infarct probability maps to estimate the location and extent of tissue damage based on patient baseline characteristics and treatment type. METHODS: Cerebral infarct probability maps were created by combining automatically segmented infarct distributions using follow-up CT images of 281 patients from the MR CLEAN trial. Comparison of infarct probability maps allows visualization and quantification of probable treatment effects. Treatment impact was calculated for 10 Alberta Stroke Program Early CT Score (ASPECTS) and 27 anatomical regions. RESULTS: The insular cortex had the highest infarct probability in both control and IAT populations (47.2% and 42.6%, respectively). Comparison showed significant lower infarct probability in 4 ASPECTS and 17 anatomical regions in favor of IAT. Most salvaged tissue was found within the ASPECTS M2 region, which was 8.5% less likely to infarct. CONCLUSIONS: Probability maps intuitively visualize the topographic distribution of infarct probability due to treatment, which makes it a promising tool for estimating the effect of treatment.

Assessment of Collateral Status by Dynamic CT Angiography in Acute MCA Stroke: Timing of Acquisition and Relationship with Final Infarct Volume.

BACKGROUND AND PURPOSE: Dynamic CTA is a promising technique for visualization of collateral filling in patients with acute ischemic stroke. Our aim was to describe collateral filling with dynamic CTA and assess the relationship with infarct volume at follow-up. MATERIALS AND METHODS: We selected patients with acute ischemic stroke due to proximal MCA occlusion. Patients underwent NCCT, single-phase CTA, and whole-brain CT perfusion/dynamic CTA within 9 hours after stroke onset. For each patient, a detailed assessment of the extent and velocity of arterial filling was obtained. Poor radiologic outcome was defined as an infarct volume of ≥70 mL. The association between collateral score and follow-up infarct volume was analyzed with Poisson regression. RESULTS: Sixty-one patients with a mean age of 67 years were included. For all patients combined, the interval that contained the peak of arterial filling in both hemispheres was between 11 and 21 seconds after ICA contrast entry. Poor collateral status as assessed with dynamic CTA was more strongly associated with infarct volume of ≥70 mL (risk ratio, 1.9; 95% CI, 1.3-2.9) than with single-phase CTA (risk ratio, 1.4; 95% CI, 0.8-2.5). Four subgroups (good-versus-poor and fast-versus-slow collaterals) were analyzed separately; the results showed that compared with good and fast collaterals, a similar risk ratio was found for patients with good-but-slow collaterals (risk ratio, 1.3; 95% CI, 0.7-2.4). CONCLUSIONS: Dynamic CTA provides a more detailed assessment of collaterals than single-phase CTA and has a stronger relationship with infarct volume at follow-up. The extent of collateral flow is more important in determining tissue fate than the velocity of collateral filling. The timing of dynamic CTA acquisition in relation to intravenous contrast administration is critical for the optimal assessment of the extent of collaterals.

Association of Automatically Quantified Total Blood Volume after Aneurysmal Subarachnoid Hemorrhage with Delayed Cerebral Ischemia.

BACKGROUND AND PURPOSE: The total amount of extravasated blood after aneurysmal subarachnoid hemorrhage, assessed with semiquantitative methods such as the modified Fisher and Hijdra scales, is known to be a predictor of delayed cerebral ischemia. However, prediction rates of delayed cerebral ischemia are moderate, which may be caused by the rough and observer-dependent blood volume estimation used in the prediction models. We therefore assessed the association between automatically quantified total blood volume on NCCT and delayed cerebral ischemia. MATERIALS AND METHODS: We retrospectively studied clinical and radiologic data of consecutive patients with aneurysmal SAH admitted to 2 academic hospitals between January 2009 and December 2011. Adjusted ORs with associated 95% confidence intervals were calculated for the association between automatically quantified total blood volume on NCCT and delayed cerebral ischemia (clinical, radiologic, and both). The calculations were also performed for the presence of an intraparenchymal hematoma and/or an intraventricular hematoma and clinical delayed cerebral ischemia. RESULTS: We included 333 patients. The adjusted OR of total blood volume for delayed cerebral ischemia (clinical, radiologic, and both) was 1.02 (95% CI, 1.01-1.03) per milliliter of blood. The adjusted OR for the presence of an intraparenchymal hematoma for clinical delayed cerebral ischemia was 0.47 (95% CI, 0.24-0.95) and of the presence of an intraventricular hematoma, 2.66 (95% CI, 1.37-5.17). CONCLUSIONS: A higher total blood volume measured with our automated quantification method is significantly associated with delayed cerebral ischemia. The results of this study encourage the use of rater-independent quantification methods in future multicenter studies on delayed cerebral ischemia prevention and prediction.

Discovery of new methylation markers to improve screening for cervical intraepithelial neoplasia grade 2/3.

BACKGROUND: Assessment of DNA promoter methylation markers in cervical scrapings for the detection of cervical intraepithelial neoplasia (CIN) and cervical cancer is feasible, but finding methylation markers with both high sensitivity as well as high specificity remains a challenge. In this study, we aimed to identify new methylation markers for the detection of high-grade CIN (CIN2/3 or worse, CIN2+) by using innovative genome-wide methylation analysis (MethylCap-seq). We focused on diagnostic performance of methylation markers with high sensitivity and high specificity considering any methylation level as positive. RESULTS: MethylCap-seq of normal cervices and CIN2/3 revealed 176 differentially methylated regions (DMRs) comprising 164 genes. After verification and validation of the 15 best discriminating genes with methylation-specific PCR (MSP), 9 genes showed significant differential methylation in an independent cohort of normal cervices versus CIN2/3 lesions (p < 0.05). For further diagnostic evaluation, these 9 markers were tested with quantitative MSP (QMSP) in cervical scrapings from 2 cohorts: (1) cervical carcinoma versus healthy controls and (2) patients referred from population-based screening with an abnormal Pap smear in whom also HPV status was determined. Methylation levels of 8/9 genes were significantly higher in carcinoma compared to normal scrapings. For all 8 genes, methylation levels increased with the severity of the underlying histological lesion in scrapings from patients referred with an abnormal Pap smear. In addition, the diagnostic performance was investigated, using these 8 new genes and 4 genes (previously identified by our group: C13ORF18, JAM3, EPB41L3, and TERT). In a triage setting (after a positive Pap smear), sensitivity for CIN2+ of the best combination of genes (C13ORF18/JAM3/ANKRD18CP) (74 %) was comparable to hrHPV testing (79 %), while specificity was significantly higher (76 % versus 42 %, p ≤ 0.05). In addition, in hrHPV-positive scrapings, sensitivity and specificity for CIN2+ of this best-performing combination was comparable to the population referred with abnormal Pap smear. CONCLUSIONS: We identified new CIN2/3-specific methylation markers using genome-wide DNA methylation analysis. The diagnostic performance of our new methylation panel shows higher specificity, which should result in prevention of unnecessary colposcopies for women referred with abnormal cytology. In addition, these newly found markers might be applied as a triage test in hrHPV-positive women from population-based screening. The next step before implementation in primary screening programs will be validation in population-based cohorts.

Characteristics of Misclassified CT Perfusion Ischemic Core in Patients with Acute Ischemic Stroke.

BACKGROUND: CT perfusion (CTP) is used to estimate the extent of ischemic core and penumbra in patients with acute ischemic stroke. CTP reliability, however, is limited. This study aims to identify regions misclassified as ischemic core on CTP, using infarct on follow-up noncontrast CT. We aim to assess differences in volumetric and perfusion characteristics in these regions compared to areas that ended up as infarct on follow-up. MATERIALS AND METHODS: This study included 35 patients with >100 mm brain coverage CTP. CTP processing was performed using Philips software (IntelliSpace 7.0). Final infarct was automatically segmented on follow-up noncontrast CT and used as reference. CTP and follow-up noncontrast CT image data were registered. This allowed classification of ischemic lesion agreement (core on CTP: rMTT≥145%, aCBV<2.0 ml/100g and infarct on follow-up noncontrast CT) and misclassified ischemic core (core on CTP, not identified on follow-up noncontrast CT) regions. False discovery ratio (FDR), defined as misclassified ischemic core volume divided by total CTP ischemic core volume, was calculated. Absolute and relative CTP parameters (CBV, CBF, and MTT) were calculated for both misclassified CTP ischemic core and ischemic lesion agreement regions and compared using paired rank-sum tests. RESULTS: Median total CTP ischemic core volume was 49.7ml (IQR:29.9ml-132ml); median misclassified ischemic core volume was 30.4ml (IQR:20.9ml-77.0ml). Median FDR between patients was 62% (IQR:49%-80%). Median relative mean transit time was 243% (IQR:198%-289%) and 342% (IQR:249%-432%) for misclassified and ischemic lesion agreement regions, respectively. Median absolute cerebral blood volume was 1.59 (IQR:1.43-1.79) ml/100g (P<0.01) and 1.38 (IQR:1.15-1.49) ml/100g (P<0.01) for misclassified ischemic core and ischemic lesion agreement, respectively. All CTP parameter values differed significantly. CONCLUSION: For all patients a considerable region of the CTP ischemic core is misclassified. CTP parameters significantly differed between ischemic lesion agreement and misclassified CTP ischemic core, suggesting that CTP analysis may benefit from revisions.

Automatic quantification of subarachnoid hemorrhage on noncontrast CT.

BACKGROUND AND PURPOSE: Quantification of blood after SAH on initial NCCT is an important radiologic measure to predict patient outcome and guide treatment decisions. In current scales, hemorrhage volume and density are not accounted for. The purpose of this study was to develop and validate a fully automatic method for SAH volume and density quantification. MATERIALS AND METHODS: The automatic method is based on a relative density increase due to the presence of blood from different brain structures in NCCT. The method incorporates density variation due to partial volume effect, beam-hardening, and patient-specific characteristics. For validation, automatic volume and density measurements were compared with manual delineation on NCCT images of 30 patients by 2 radiologists. The agreement with the manual reference was compared with interobserver agreement by using the intraclass correlation coefficient and Bland-Altman analysis for volume and density. RESULTS: The automatic measurement successfully segmented the hemorrhage of all 30 patients and showed high correlation with the manual reference standard for hemorrhage volume (intraclass correlation coefficient = 0.98 [95% CI, 0.96-0.99]) and hemorrhage density (intraclass correlation coefficient = 0.80 [95% CI, 0.62-0.90]) compared with intraclass correlation coefficient = 0.97 (95% CI, 0.77-0.99) and 0.98 (95% CI, 0.89-0.99) for manual interobserver agreement. Mean SAH volume and density were, respectively, 39.3 ± 31.5 mL and 62.2 ± 5.9 Hounsfield units for automatic measurement versus 39.7 ± 32.8 mL and 61.4 ± 7.3 Hounsfield units for manual measurement. The accuracy of the automatic method was excellent, with limits of agreement of -12.9-12.1 mL and -7.6-9.2 Hounsfield units. CONCLUSIONS: The automatic volume and density quantification is very accurate compared with manual assessment. As such, it has the potential to provide important determinants in clinical practice and research.

DNA methylation analysis in self-sampled brush material as a triage test in hrHPV-positive women.

BACKGROUND: Primary high-risk human papillomavirus (hrHPV) testing in cervical cancer screening shows relatively low specificity, which makes triage testing necessary. In this study, DNA methylation analysis was compared with cytology for triage testing in hrHPV-positive women. Moreover, feasibility of DNA methylation analysis directly on brush-based self-sampled specimens was assessed. METHODS: Non-responding women from population-based screening were invited to self-collect a cervico-vaginal specimen for hrHPV testing; hrHPV-positive women were referred to a physician for triage liquid-based cytology. DNA methylation analysis was performed on 128 hrHPV-positive physician-collected triage samples and 50 matched brush self-samples with QMSP for C13ORF18, EPB41L3, JAM3 and TERT. RESULTS: In physician-taken triage material, DNA methylation analysis of JAM3 showed the highest combined specificity (88%) and sensitivity (82%) for detection of CIN3+, whereas cytology showed a specificity of 48% and a sensitivity of 91%. Out of 39 women with abnormal cytology and normal histology (false-positive by cytology), 87% were negative for JAM3 and 90% for C13ORF18 methylation. Agreement between DNA methylation analysis performed directly on the matched self-sampled material and physician-taken samples was 88% for JAM3 (κ=0.75, P<0.001) and 90% for C13ORF18 (κ=0.77; P<0.001). CONCLUSIONS: DNA methylation analysis as a triage test in hrHPV-positive women is an attractive alternative to cytology. Furthermore, DNA methylation is feasible directly on brush-based self-samplers and showed good correlation with matched physician-taken samples. Direct molecular triage on self-collected specimens could optimise the screening program, especially for non-responders, as this would eliminate the need for an additional physician-taken scraping for triage testing.

Automated cerebral infarct volume measurement in follow-up noncontrast CT scans of patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Cerebral infarct volume as observed in follow-up CT is an important radiologic outcome measure of the effectiveness of treatment of patients with acute ischemic stroke. However, manual measurement of CIV is time-consuming and operator-dependent. The purpose of this study was to develop and evaluate a robust automated measurement of the CIV. MATERIALS AND METHODS: The CIV in early follow-up CT images of 34 consecutive patients with acute ischemic stroke was segmented with an automated intensity-based region-growing algorithm, which includes partial volume effect correction near the skull, midline determination, and ventricle and hemorrhage exclusion. Two observers manually delineated the CIV. Interobserver variability of the manual assessments and the accuracy of the automated method were evaluated by using the Pearson correlation, Bland-Altman analysis, and Dice coefficients. The accuracy was defined as the correlation with the manual assessment as a reference standard. RESULTS: The Pearson correlation for the automated method compared with the reference standard was similar to the manual correlation (R = 0.98). The accuracy of the automated method was excellent with a mean difference of 0.5 mL with limits of agreement of -38.0-39.1 mL, which were more consistent than the interobserver variability of the 2 observers (-40.9-44.1 mL). However, the Dice coefficients were higher for the manual delineation. CONCLUSIONS: The automated method showed a strong correlation and accuracy with the manual reference measurement. This approach has the potential to become the standard in assessing the infarct volume as a secondary outcome measure for evaluating the effectiveness of treatment.

Disease-modifying anti-rheumatic drug usage, prescribing patterns and disease activity in rheumatoid arthritis patients in community-based practice.

AIMS: Our aim was to examine the spectrum of disease activity and usage of disease-modifying anti-rheumatic drugs (DMARD) in rheumatoid arthritis (RA) patients seen over a period of 12 months in community-based rheumatology practice. METHODS: Data were prospectively collected on 1059 consecutive RA patients who attended two private, community-based rheumatology clinics from 1 May 2007 to 1 May 2008. Information on patient demographics, medication history and disease activity was collected. Life table graphs were developed to track medication retention over time. Statistical significance was determined by log-rank tests. RESULTS: One thousand and fifty-nine patients with RA were entered into the database over a 12-month period. Eight hundred and twenty-six patients (85%) were treated with single or combination conventional DMARD compared with 159 patients (15%) on a biologic DMARD either alone or in combination. Methotrexate monotherapy was the most commonly prescribed DMARD, used in 41% of patients studied. Almost half (47%) were on combination DMARD therapy. Methotrexate and tumour necrosis factor inhibitors had the highest retention rate over 12 and 30 months since first prescription. A large proportion of patients (47%) had moderate disease activity. CONCLUSION: Rates of biologic DMARD usage were similar to other studies and the predominance of methotrexate use was also in keeping with current recommendations for management of RA. There appears to be a significant unmet need for improved disease control among RA patients with moderate disease activity, which requires further investigation.

Ankylosing spondylitis: an Australian experience.

BACKGROUND: The purpose of this study was to characterize an Australian cohort of ankylosing spondylitis (AS) patients and examine predictors of important disease outcomes. METHODS: Cross-sectional study of first visit data among patients referred to the Austin Spondylitis Clinic from rheumatology or general practices. We obtained clinical and laboratory data and validated composite indices through self-reported questionnaire. RESULTS: Delay in AS diagnosis averaged 8.1 years and was higher among women and younger-onset disease. Cervicothoracic mobility was better in women although they showed more entheseal tender points and greater impairment of quality of life. Those with long-standing AS had similar disease activity to recent onset disease but had greater functional disability. Current smoking was associated with worse outcomes although there was no association between cumulative exposure and AS outcomes. CONCLUSION: The clinical expression of AS in this first-described Australian cohort is similar to previously described cohorts. We observed greater cervicothoracic mobility and a higher enthesitis index among women perhaps contributing to longer delay to diagnosis.

[A multidisciplinary approach is necessary in the neonatal withdrawal syndrome]. / Multidisciplinaire benadering nodig bij neonataal abstinentiesyndroom.

Two baby boys, born of mothers that were abusing drugs, were restless and hypertonic, typical symptoms of the neonatal withdrawal syndrome. The symptoms disappeared during treatment with phenobarbital and methadone. The children were then placed in a foster home. Symptoms of the neonatal withdrawal syndrome are excitation of the central nervous system, the gastrointestinal tract and the respiratory tract. For both legal and medical reasons it is essential to test the urine of the neonate for drugs. The Finnegan score is a useful tool to decide whether medical treatment is indicated. Medical treatment consists of the administration of phenobarbital and or methadone. The Child Protection Agency of the Ministry of Justice is notified of the child's birth. If parents that are abusing drugs have been shown not to be able to look after their children, they are limited in their right to parenthood.

Final height and hormonal function after bone marrow transplantation in children.

AIM: To analyze final height and hormonal function in long-term survivors of bone marrow transplantation (BMT). PATIENTS: Group 1 consisted of 16 patients (10 boys) with a hematologic malignancy, mostly leukemia, conditioned for BMT with total body irradiation (TBI), 7.5 to 12 Gy, and cyclophosphamide. Group 2 consisted of 14 patients (9 boys) with severe aplastic anemia, conditioned with chemotherapy only. RESULTS: In group 1, patients achieved a reduced final height after BMT. The difference between the height standard deviation score (SDS) at BMT and the height SDS at final height was -1.96 (0.82) SDS in boys and -0.92 (0.71) SDS in girls (p = 0.0001, and p = 0.02 respectively). Final height was also lower than target height (boys, p = 0.01; girls, p = 0.03). Prepubertal growth in the first 3 years after BMT was normal but pubertal height gain was decreased. The patients in group 2 achieved normal height. Thyroid function and adrenal function were normal in all patients, and no growth hormone deficiency was detected. Serum follicle-stimulating hormone values after BMT were increased in all group 1 patients, with return to normal in two patients. Serum luteinizing hormone values were increased in all group 1 girls, with recovery in one girl. Normal serum luteinizing hormone values and spontaneous puberty were found in all group 1 boys. In group 2, disturbances in gonadotropins were seen only in three boys and two girls. CONCLUSION: In patients treated in childhood with BMT after chemotherapy and TBI with 7.5 Gy or more, final height is compromised because of blunted growth in puberty. Patients who had not received TBI suffered no height loss. In the majority of patients, the combination of chemotherapy and TBI also resulted in irreversible disturbances of gonadal function.

Phosphatidylinositol and not phosphatidylglycerol is the important minor phospholipid in rhesus-monkey surfactant.

Pulmonary surfactant was isolated from lung tissue and alveolar washes of lungs of adult rhesus monkeys (Macaca mulatta). The phospholipid composition was determined and compared to the composition of human surfactant fractions. Contrary to human surfactant, phosphatidylinositol is the major acidic phospholipid, whereas phosphatidylglycerol is only a minor component in rhesus-monkey surfactant. These differences are not caused by a difference in plasma myo-inositol concentrations between the two species.