Risk factors for recurrent venous thromboembolism in the European collaborative paediatric database on cerebral venous thrombosis: a multicentre cohort study

BACKGROUND: The relative importance of previous diagnosis and hereditary prothrombotic risk factors for cerebral venous thrombosis (CVT) in children in determining risk of a second cerebral or systemic venous thrombosis (VT), compared with other clinical, neuroimaging, and treatment variables, is unknown. METHODS: We followed up the survivors of 396 consecutively enrolled patients with CVT, aged newborn to 18 years (median 5.2 years) for a median of 36 months (maximum 85 months). In accordance with international treatment guidelines, 250 children (65%) received acute anticoagulation with unfractionated heparin or low-molecular weight heparin, followed by secondary anticoagulation prophylaxis with low-molecular weight heparin or warfarin in 165 (43%). RESULTS: Of 396 children enrolled, 12 died immediately and 22 (6%) had recurrent VT (13 cerebral; 3%) at a median of 6 months (range 0.1-85). Repeat venous imaging was available in 266 children. Recurrent VT only occurred in children whose first CVT was diagnosed after age 2 years; the underlying medical condition had no effect. In Cox regression analyses, non-administration of anticoagulant before relapse (hazard ratio [HR] 11.2 95% CI 3.4-37.0; p<0.0001), persistent occlusion on repeat venous imaging (4.1, 1.1-14.8; p=0.032), and heterozygosity for the G20210A mutation in factor II (4.3, 1.1-16.2; p=0.034) were independently associated with recurrent VT. Among patients who had recurrent VT, 70% (15) occurred within the 6 months after onset. CONCLUSION: Age at CVT onset, non-administration of anticoagulation, persistent venous occlusion, and presence of G20210A mutation in factor II predict recurrent VT in children. Secondary prophylactic anticoagulation should be given on a patient-to-patient basis in children with newly identified CVT and at high risk of recurrent VT. Factors that affect recanalisation need further research.     

Therapy insight: stroke risk and its management in patients with sickle cell disease

Children with sickle cell disease, a chronic hemolytic anemia, present with a wide variety of neurological syndromes, including ischemic and hemorrhagic stroke, transient ischemic attacks, 'soft neurological signs', seizures, headache, coma, visual loss, altered mental status, cognitive difficulties, and covert or 'silent' infarction. Those with ischemic stroke usually have stenosis or occlusion of the distal internal carotid and proximal middle cerebral arteries. Indefinite transfusion prevents recurrence in most patients who have had a stroke, and can prevent first stroke in those with high transcranial Doppler velocities. High white cell count, low hemoglobin and oxyhemoglobin desaturation predict neurological complications. Other risk factors for overt ischemic stroke include hypertension, previous transient ischemic attack, covert infarction and chest crisis. For hemorrhagic stroke, aneurysms are common in adults but not children, who often present with hypertension after transfusion or corticosteroids. Seizures are particularly common in patients with cerebrovascular disease and covert infarction; the latter is also associated with hyposplenism and infrequent pain. Factors associated with cognitive difficulties include thrombocytosis, infarction, large-vessel disease, and perfusion abnormality on neuroimaging. As well as investigating the role of genes and the possibility that hydroxyurea or blood pressure control reduce neurological complications, we should explore the modifiable effects of poor nutrition, chronic infection, hemolysis and oxyhemoglobin desaturation on stroke risk.     

Translating efficacious behavioral principles for diabetes prevention into practice

This case study describes the process of translating efficacy-based Diabetes Prevention Program principles into a practical format for delivery within a managed care organization. Using Rogers' innovation-decision process model, the authors tracked the adoption, implementation, and short-term effectiveness of a clinical program. Effectiveness was documented using a pre-post design to detect changes in physical activity and dietary habits. Participants (N = 298) were Kaiser Permanente of Colorado patients enrolled in diabetes-prevention classes. Changes were analyzed using paired-samples t tests and one-way analysis of variance. Participants significantly increased reported minutes of moderate (p < .001, mu = 84.52, CI: 58.44-110.61) and vigorous (t = 2.220, p = .028, mu = 19.05, CI: 2.10-36.00) physical activity and their daily servings of fruits and vegetables (p < .001, mu = 0.20, CI: 0.13-0.27). By identifying the underlying strategies that led to efficacy, professionals can implement sound diabetes-prevention programs that fit within their context.     

A New Computerised Advanced Theory of Mind Measure for Children with Asperger Syndrome: The ATOMIC

This study examined the ability of children with Asperger Syndrome (AS) to attribute mental states to characters in a new computerised, advanced theory of mind measure: The Animated Theory of Mind Inventory for Children (ATOMIC). Results showed that children with AS matched on IQ, verbal comprehension, age and gender performed equivalently on central coherence questions, but more poorly on the theory of mind questions compared with controls. A significant relationship was found between performance on ATOMIC and accuracy of mental state explanations provided on (Happé’s, Journal of Autism and Developmental Disorders, 24, 129–154, 1994) Strange Stories Task, supporting the validity of the new measure. Limitations of the study and suggestions for future research are discussed.     

In vitro analysis of anterior and posterior fixation in an experimental unstable burst fracture model

STUDY DESIGN: A biomechanical comparison of fixation constructs in an experimental fracture model. OBJECTIVE: To determine the relative postoperative stability of anterior graft and plating with that of posterior or combined fixation constructs in an unstable thoracolumbar burst fracture model. SUMMARY OF BACKGROUND DATA: Several treatment modalities have been proposed for unstable thoracolumbar burst fractures, but the optimal technique is unclear. Previous cadaveric biomechanical studies in unstable burst fracture models have not considered the commonly used posterior (interpedicular) and anterior (plate) constructs. METHODS: Nine human spine segments (T11-L3) were potted in epoxy and scanned using dual energy x-ray absorptiometry and computed tomography. Intact specimens had baseline flexibility testing. Unstable L1 burst fractures as verified by computed tomography were created using an impulse load and posterior surgical osteoligamentous destabilization (ie, transection of the lamina, interspinous ligaments, facet capsules, and ligamentum flavum). Specimens were instrumented posteriorly with pedicle screws and rods and tested to 6 Nm in flexion-extension, lateral bending, and torsion. Corpectomy and strut grafting were then performed, and testing was repeated in varying order with posterior fixation, anterior plating and circumferential fixation. Range of motion (ROM) and neutral zone was calculated for each test and fixation groups were compared using analysis of variance. RESULTS: All specimens had AO B1.2 (unstable burst) fractures. Mean ROM for posterior-only constructs was significantly less than that of the intact in lateral bending, flexion, and extension (P<0.001). Anterior-only constructs after corpectomy and strut grafting generally resulted in a smaller ROM versus intact in flexion (NS: P=0.1) and lateral bending (P<0.001). In contrast, all anterior-only and posterior constructs had greater ROM than intact in torsion (all at P<0.05). Circumferential fixation resulted in statistically smaller ROM compared with all other constructs (P< or =0.04), and reached that of the intact specimen in torsion. Increased ROM was correlated with greater fracture comminution for posterior-only fixation (P<0.05), and was weakly correlated with lower dual energy x-ray absorptiometry score (R=0.3) for anterior-only fixation. CONCLUSIONS: Circumferential instrumentation provided the most rigid fixation, followed by posterior fixation with anterior strut grafting, posterior fixation alone, and by anterior fixation with strut grafting. These results were dependent on bone quality and the comminution severity of the fracture. These results should aid surgical decision making in addition to other factors in the overall clinical situation.     

In vitro cytotoxicity of nelarabine, clofarabine and flavopiridol in paediatric acute lymphoblastic leukaemia

The in vitro efficacies of three new drugs--clofarabine (CLOF), nelarabine (NEL) and flavopiridol (FP) - were assessed in a panel of acute lymphoblastic leukaemia (ALL) cell lines. The 50% inhibitory concentration (IC50) for CLOF across all lines was 188-fold lower than that of NEL. B-lineage, but not T-lineage lines, were >7-fold more sensitive to CLOF than cytosine arabinoside (ARAC). NEL IC50 was 25-fold and 113-fold higher than ARAC in T- and B-lineage, respectively. T-ALL cells were eightfold more sensitive to NEL than B-lineage but there was considerable overlap. FP was more potent in vitro than glucocorticoids and thiopurines and at doses that recent phase I experience predicts will translate into clinical efficacy. Potential cross-resistance of CLOF, NEL and FP was observed with many front-line ALL therapeutics but not methotrexate or thiopurines. Methotrexate sensitivity was inversely related to that of NEL and FP. Whilst NEL was particularly effective in T-ALL, a subset of patients with B-lineage ALL might also be sensitive. CLOF appeared to be marginally more effective in B-lineage than T-ALL and has a distinct resistance profile that may prove useful in combination with other compounds. FP should be widely effective in ALL if sufficient plasma levels can be achieved clinically.     

Cortical α-synuclein load is associated with amyloid-β plaque burden in a subset of Parkinson’s disease patients

Amyloid-β (Aβ) peptide pathology in Alzheimer’s disease (AD) comprises extracellular plaques and cerebral amyloid angiopathy (CAA). In Parkinson’s disease (PD), α-synuclein forms intraneuronal Lewy bodies (LBs), and cortical LBs are thought to play a major role in cognitive decline designated as PD with dementia. As there is increasing evidence that Aβ may also promote α-synuclein fibrillization, we assessed the relationship between LB pathology and Aβ deposition in 40 cases of PD and 20 age-matched controls. In five cortical areas, we established the severity of Aβ plaque load using an approach similar to that recommended by CERAD in AD. LB densities were determined using a morphometric approach. CAA was graded using previously described scales. The APOE genotype was established in 38 PD and 19 control cases. We have found that the overall Aβ plaque burden and, in particular, the diffuse plaque load shows a statistically significant ‘large’ correlation with the overall cortical LB burden. The strength of this correlation further increases in PD cases (about 50% of the cases) with moderate to high Aβ plaque load. The APOE ε4 allele is over-represented in this subgroup. Our data indicate a strong association between pathologically identifiable Aβ plaque burden and α-synuclein load in cerebral cortex and provide indirect evidence that Aβ pathology is likely to be an important factor contributing to cognitive decline in a subgroup of PD patients.     

Oxidative stress and steroid resistance in asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy

Insensitivity to corticosteroid treatment in inflammatory conditions, such as asthma and chronic obstructive pulmonary disease, present considerable management problems and cost burdens to health services. Oxidative stress is a major component of chronic inflammation and can have a significant suppressive effect on corticosteroid efficacy. Recent advances in the understanding of both the mechanisms of corticosteroid action and corticosteroid insensitivity have provided hope for a therapeutic strategy of restoring corticosteroid sensitivity. Histone deacetylase 2 (HDAC-2) plays a pivotal role in corticosteroid action and is reduced in many cases of steroid insensitivity. Moreover, it has shown that oxidative stress can be responsible for this reduction in HDAC-2 activity. Two structurally different compounds; methyl-xanthine theophylline and polyphenol curcumin restore HDAC activity, thereby restoring corticosteroid function. Low, subbronchodilator doses of theophylline can also act as corticosteroid-sparing drugs in asthmatics. Although these compounds appear to restore corticosteroid function and may initially provide therapeutic potential, they lack specificity and the mechanism of their action is unknown. Once their mechanisms of action are established, it is likely that derivatives of these compounds may be used as a therapeutic strategy to restore corticosteroid insensitivity in the future.