Utility of serological markers in predicting the early occurrence of complications and surgery in pediatric Crohn's disease patients

BACKGROUND AND OBJECTIVES: Many Crohn's disease (CD) patients develop complications (fistulae and abscesses), and require surgery, often repeatedly and at variable instances. Identifying serological markers that determine their early or repeated manifestation can enable implementing more aggressive preventive strategies. Our objective was to study the ability of serological markers for predicting development of early (first) and recurrent complications or requirement for surgery. METHODS: Serum anti-Saccharomyces cervisiae (ASCA) (IgA & IgG) and perinuclear antineutrophil cytoplasmic antibodies (pANCA) were assayed close to diagnosis in a pediatric cohort of CD patients identified between 1996 and 1998. At diagnosis and follow-up, information was acquired on demographic and clinical features of disease. Relation between ASCA and clinical events was studied using adjusted Cox-proportional hazards modeling. The relative rates of recurrent clinical events according to the marker measures were compared. RESULTS: The mean age (SD) at diagnosis was 11.2 (3.4) yr. Among 139 patients, 35 (25.9%) and 31 (22.3%) acquired one or more CD related surgery or complication, respectively. Time to occurrence of the first complication was lower among patients ASCA+ (IgA or IgG) (hazards ratio (HR) = 2.33; 95% confidence interval (CI) = 0.99-5.50) and among those with higher ASCA-IgA titers (HR = 1.20; 95% CI = 1.08-1.34). The rates of recurrent complications were higher among those positive or with higher ASCA titers. ASCA did not predict time to undergoing surgery independent of complications, and was unrelated to the occurrence of recurrent surgeries. CONCLUSIONS: Our study shows that serum ASCA measured close to diagnosis can determine the occurrence of early complications in pediatric CD. Preventive treatment targeted toward these susceptible patients could potentially modify the disease course.     

Clinically active Crohn's disease in the presence of a low C-reactive protein

OBJECTIVE: Clinical interest in C-reactive protein (CRP) -- a component of the innate immune system -- has focused mainly on its worth as an indicator of disease activity. There has been a resurgence of interest in CRP in the Crohn's disease (CD) literature because several trials of new treatments for active CD have been characterized by both a large proportion of patients with low CRP (<10 mg/l) at entry to the trials and by a negative therapeutic outcome. It is therefore of interest to study the clinical characteristics of patients who are thought to have at the same time both active CD and a low CRP. MATERIAL AND METHODS: Patients were prospectively recruited as part of the Brisbane IBD clinical and research programme. Subjects were included in the low CRP group only if there were complete datasets for CRP on all occasions of active CD, and CRP was < 10 mg/l. Active disease was defined as CD activity index (CDAI)>200. The low CRP group was compared with patients in the raised CRP group for a range of clinical variables as well as the major NOD2 variants. RESULTS: There were data sets for 223 CD patients, with a mean disease duration of 12 years. Of these, 22 patients fulfilled the criteria for low CRP. The low CRP group (group 1) showed significant differences for disease site (p<0.01) and for BMI (p=0.006) compared to the raised CRP group (group 2). Specifically, group 1 had a predominance of pure ileal disease (95% versus 53%) and lack of pure colonic disease (0% versus 24%) compared to group 2, and their BMI was significantly lower (20.3 kg/m(2) versus 25.0 kg/m(2)). Groups 1 and 2 did not differ with respect to Vienna behaviour at diagnosis, smoking, appendicectomy, extra-intestinal manifestations of CD, or NOD2 SNP variants. There was a trend for low CRP patients with previous ileal resection to evolve to a stricturing phenotype. Fat wrapping was noted in 11/13 (85%) of low CRP patients undergoing ileal resections. CONCLUSIONS: Patients with CD and a persistently low CRP in the face of active disease were characterized by an almost exclusive ileal disease distribution and a low BMI, compared to those with a raised CRP. These patients had a similar frequency and distribution of NOD2/CARD15 variants. Stricturing (v inflammatory or penetrating) behaviour may explain some low CRP. Despite the abnormally low BMI, fat wrapping was noted in the majority of low CRP patients undergoing ileal resection.     

The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2

The majority of patients with MELAS (mitochondrial encephalomyophathy, lactic acidosis, stroke-like episodes) carry a heteroplasmic A3243G mutation in the mitochondrial tRNA(Leu(UUR)). The mutation prevents modification of the wobble U base, impairing translation at UUA and UUG codons; however, whether this results in amino acid misincorporation in the mitochondrial translation products remains controversial. We tested this hypothesis in homoplasmic mutant myoblasts isolated from a MELAS patient and investigated whether overexpression of the mitochondrial translation elongation factors could suppress the translation defect. Blue-Native gel electrophoretic analysis demonstrated an almost complete lack of assembly of respiratory chain complexes I, IV and V in MELAS myoblasts. This phenotype could be partially suppressed by overexpression of EFTu or EFG2 but not EFTs or EFG1. Despite the severity of the assembly defect, overall mitochondrial protein synthesis was only moderately affected, but some anomalously migrating translation products were present. Pulse-chase labeling showed reduced stability of all mitochondrial translation products consistent with the assembly defect. Labeling patterns of the translation products were similar with [(3)H]-leucine or [(3)H]-phenylalanine, showing that loss of the wobble U modification did not permit decoding of UUY codons; however, endoproteinase fingerprint analysis showed clear evidence of amino acid misincorporation in three polypeptides: CO III, CO II and ATP6. Taken together, these data demonstrate that the A3243G mutation produces both loss- and gain-of-function phenotypes, explaining the apparent discrepancy between the severity of the translation and respiratory chain assembly defects, and suggest a function for EFG2 in quality control of translation elongation.     

An EPID response calculation algorithm using spatial beam characteristics of primary, head scattered and MLC transmitted radiation

We have developed an independent algorithm for the prediction of electronic portal imaging device (EPID) response. The algorithm uses a set of images [open beam, closed multileaf collimator (MLC), various fence and modified sweeping gap patterns] to separately characterize the primary and head-scatter contributions to EPID response. It also characterizes the relevant dosimetric properties of the MLC: Transmission, dosimetric gap, MLC scatter [P. Zygmansky et al., J. Appl. Clin. Med. Phys. 8(4) (2007)], inter-leaf leakage, and tongue and groove [F. Lorenz et al., Phys. Med. Biol. 52, 5985-5999 (2007)]. The primary radiation is modeled with a single Gaussian distribution defined at the target position, while the head-scatter radiation is modeled with a triple Gaussian distribution defined downstream of the target. The distances between the target and the head-scatter source, jaws, and MLC are model parameters. The scatter associated with the EPID is implicit in the model. Open beam images are predicted to within 1% of the maximum value across the image. Other MLC test patterns and intensity-modulated radiation therapy fluences are predicted to within 1.5% of the maximum value. The presented method was applied to the Varian aS500 EPID but is designed to work with any planar detector with sufficient spatial resolution.     

Impact of a Computer-Aided Detection (CAD) System Integrated into a Picture Archiving and Communication System (PACS) on Reader Sensitivity and Efficiency for the Detection of Lung Nodules in Thoracic CT Exams

The objective of this study is to assess the impact on nodule detection and efficiency using a computer-aided detection (CAD) device seamlessly integrated into a commercially available picture archiving and communication system (PACS). Forty-eight consecutive low-dose thoracic computed tomography studies were retrospectively included from an ongoing multi-institutional screening study. CAD results were sent to PACS as a separate image series for each study. Five fellowship-trained thoracic radiologists interpreted each case first on contiguous 5 mm sections, then evaluated the CAD output series (with CAD marks on corresponding axial sections). The standard of reference was based on three-reader agreement with expert adjudication. The time to interpret CAD marking was automatically recorded. A total of 134 true-positive nodules, measuring 3 mm and larger were included in our study; with 85 ≥ 4 and 50 ≥ 5 mm in size. Readers detection improved significantly in each size category when using CAD, respectively, from 44 to 57 % for ≥3 mm, 48 to 61 % for ≥4 mm, and 44 to 60 % for ≥5 mm. CAD stand-alone sensitivity was 65, 68, and 66 % for nodules ≥3, ≥4, and ≥5 mm, respectively, with CAD significantly increasing the false positives for two readers only. The average time to interpret and annotate a CAD mark was 15.1 s, after localizing it in the original image series. The integration of CAD into PACS increases reader sensitivity with minimal impact on interpretation time and supports such implementation into daily clinical practice.     

Test-retest stability of calibrated BOLD-fMRI in HIV- and HIV+ subjects

Subject performance, scanner hardware, or biological factors can affect single session neuroimaging measures. Stability studies using calibrated blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) have been performed in health but not disease. We utilized calibrated BOLD-fMRI to determine the effects of HIV on neurovascular coupling. Six clinically stable HIV-infected patients (HIV+) and 10 seronegative controls (HIV-) were scanned at two separate sessions approximately 3 months apart. Both mild hypercapnia (5% CO(2)) exposure and a visual functional activation task were performed. Intraclass correlation coefficients (ICC) and inter-subject variance were determined for calibrated BOLD-fMRI measures (baseline cerebral blood flow (CBF), functional CBF, BOLD, and cerebral metabolic rate of oxygen consumption (CMRO(2)) changes) for HIV+ and HIV- subjects. The two groups did not differ in age, sex, or education. HIV+ subjects had lower mean baseline CBF (p<0.04, Cohen's d=-1.07) and functional BOLD responses (p<0.001, Cohen's d=-2.47) and a trend towards a decrease in mean functional CBF responses (p=0.07, Cohen's d=-0.92) despite similar mean functional CMRO(2) changes (p=0.71, Cohen's d=0.19). The stability of each calibrated BOLD-fMRI measure, as assessed by ICC, was significantly lower for HIV+ subjects. In addition, HIV+ participants had greater inter-subject variability for baseline CBF (p<0.02), functional BOLD (p<0.001), CBF (p<0.001), and CMRO(2) (p<0.002) responses. Our results demonstrate that calibrated BOLD-fMRI measures have excellent stability within healthy controls. In contrast, these values have greater variability in clinically stable HIV+ subjects and may reflect alterations in coupling between CBF and CMRO(2) with disease.     

Effects of Marathi-Hindi bilingualism on neuropsychological performance

The present study aimed to examine if bilingualism affects executive functions and verbal fluency in Marathi and Hindi, two major languages in India, with a considerable cognate (e.g., activity is actividad in Spanish) overlap. A total of 174 native Marathi speakers from Pune, India, with varying levels of Hindi proficiency were administered tests of executive functioning and verbal performance in Marathi. A bilingualism index was generated using self-reported Hindi and Marathi proficiency. After controlling for demographic variables, the association between bilingualism and cognitive performance was examined. Degree of bilingualism predicted better performance on the switching (Color Trails-2) and inhibition (Stroop Color-Word) components of executive functioning; but not for the abstraction component (Halstead Category Test). In the verbal domain, bilingualism was more closely associated with noun generation (where the languages share many cognates) than verb generation (which are more disparate across these languages), as predicted. However, contrary to our hypothesis that the bilingualism "disadvantage" would be attenuated on noun generation, bilingualism was associated with an advantage on these measures. These findings suggest distinct patterns of bilingualism effects on cognition for this previously unexamined language pair, and that the rate of cognates may modulate the association between bilingualism and verbal performance on neuropsychological tests.     

The ecological risk of heavy metals in sediment from the Danube Delta

The objectives of this study were to assess the sediment contamination with heavy metals and to investigate accordingly the ecological risk posed in the SE of the Danube Delta. Sediments are important in assessing the contamination as they act as reservoirs, transporters and contamination sources. Sediment samples were collected and analysed for lead, cadmium, arsenic and mercury, revealing levels higher than the background, especially for cadmium and mercury (Pb > As > Cd > Hg). Concentrations exceeding the probable effect limit were noticed for arsenic and mercury. The contamination indexes describe the study area as having almost half of the samples as contaminated (pollution load index-PLI 1.04), however the contamination is mostly low-to moderate (modified contamination degree-mCd 1.36). The sediment contamination poses mostly a low ecological risk (RI 94.8). The sediment quality guideline quotient (SQG-Q 0.29) describes a moderate impact, while the probable effect concentration quotient (PEC-Q 0.16) confirms that there are no levels likely to affect the aquatic biota. In our study area, the main Branch of the Danube River and the Secondary Delta are the most affected by contamination, while the narrow, reed abundant channels as the preferred habitat of most aquatic organisms, have a low contamination level.