Molecular Insights in MLL Rearranged Acute Leukemia

Acute lymphoblastic leukemia (ALL) in infants (<1 year of age) is characterized by a high incidence (~80%) of rearrangements of the MLL gene, resistance to several important chemotherapeutic drugs, and a poor treatment outcome. With overall survival rates for infant ALL not exceeding 50%, current chemotherapeutic regime

The difference between actual and prescribed weight bearing of total hip patients with a trochanteric osteotomy: long-term vertical force measurements inside and outside the hospital

OBJECTIVE: To determine whether patients load the operated leg at a prescribed weight-bearing target load during postoperative recovery. DESIGN: A descriptive prospective study. SETTING: Orthopedic clinic and patients' homes. PARTICIPANTS: Fifty patients who had undergone total hip arthroplasty (THA) with trochanteric osteotomy. INTERVENTION: Patients were verbally instructed by a physical therapist to perform partial weight bearing at a 10% body weight (BW) target load (n=33) or at a 50% BW target load (n=17). MAIN OUTCOME MEASURES: Mean peak load (%BW) and percentage of patients and mean percentage of steps below, equal to, and above the target load. Weight bearing was measured when patients walked with (condition 1) and without (condition 2) a physical therapist in the hospital and walked at home (condition 3). RESULTS: The mean peak load was significantly higher than the target in the 10% BW group for all 3 conditions (condition 1, 19.2% BW; condition 2, 20.0% BW; condition 3, 26.8% BW). In the 50% BW group, the mean peak load was significantly lower than the target in conditions 1 (28.1% BW) and 2 (32.5% BW). No significant difference in weight bearing was found when walking with or without a physical therapist (change in 10% BW, -0.1% BW; change in 50% BW, -3.17% BW). At home, the mean peak load was significantly larger compared with walking without a physical therapist in the hospital (change in 10% BW, -7.0% BW; change in 50% BW, -11.5% BW). CONCLUSIONS: Partial weight bearing at a specific target load was not achieved by patients with a THA when given verbal instructions. Especially when using a low target load and when walking at home with no supervision of a physical therapist, patients loaded the operated leg higher and more frequently above the target load. Other training methods (eg, biofeedback) have to be evaluated to use as training tools for partial weight bearing at specific target loads

Rigidity of unilateral external fixators - A biomechanical study

Introduction: External fixation is the primary choice of temporary fracture stabilisation for specific polytrauma patients. Adequate initial fracture healing requires sufficient stability at the fracture site. The purpose of this study was to compare the rigidity of the Dynafix DFS®Standard Fixator (4 joints) with the Orthofix ProCallus Fixator®(2 joints), which differ in possibilities for adapting the configuration for clinical needs. Materials and methods: Both devices were tested 10 times in a standardised model. In steps of 10 N, loading was increased to a maximum of 160 N in parallel, transversal and axial direction (distraction and compression). Translation resultant and rotation resultant were calculated. Results: With a force of 100 N in parallel direction the mean translation resultant (Trmean) of the Dynafix DFS®Standard Fixator (6.65 ± 1.43 mm) was significantly higher than the ProCallus Fixator®(3.29 ± 0.83 mm, p < 0.001; Student's t-test). With a maximum load of 60 N in transverse direction the Trmeanof the Dynafix DFS®Standard Fixator was significantly lower (8.14 ± 1.20 mm versus 9.83 ± 0.63 mm, p < 0.005). Translation was significantly higher with the Dynafix DFS®Standard Fixator, for both distraction (2.13 ± 0.32 mm versus 1.69 ± 0.44 mm, p < 0.05) and compression (1.55 ± 1.08 mm versus 0.15 ± 0.33 mm, p < 0.005). The mean rotation resultant (Rrmean) at 160 N distraction was lower for the Dynafix DFS®Standard Fixator (0.70 ± 0.17° versus 0.97 ± 0.21°, p < 0.005). Conclusions: Both fixators were most sensitive to transverse forces. The Dynafix DFS®Standard Fixator was less rigid with parallel and axial forces, whereas transverse forces and rotation at distraction forces favoured the Dynafix DFS®Standard Fixator. Repeated heavy loading did not influence the rigidity of both devices

Atom lithography of Fe

Direct write atom lithography is a technique in which nearly resonant light is used to pattern an atom beam. Nanostructures are formed when the patterned beam falls onto a substrate. We have applied this lithography scheme to a ferromagnetic element, using a 372 nm laser light standing wave to pattern a beam of iron atoms. In this proof-of-principle experiment, we have deposited a grid of 50-nm-wide lines 186 nm apart. These ultraregular, large-scale, ferromagnetic wire arrays may generate exciting new developments in the fields of spintronics and nanomagnetics. (C) 2004 American Institute of Physics

Stronger relation between impairment and manual capacity in the non-dominant hand than the dominant hand in congenital hand differences; Implications for surgical and therapeutic interventions

Objectives To evaluate manual activity capacity (i.e. activity capacity to perform hand activities) and its relation with body functions of the hand and forearm in children with congenital hand differences (CHD) Methods We assessed 10-14 year-old children with CHD (N = 106) using a functional handgrips test. Measurements of body functions included joint mobility and muscle strength. Patient characteristics were hand dominance and severity. Results We found a stronger relation between body functions and manual activity capacity in non-dominant hands than dominant hands. Dominant hands scored significantly higher on manual activity capacity than nondominant hands that were similarly impaired at body functions level. Severity of the CHD and body functions had only small effects on manual activity capacity. Conclusion The relation between body functions and manual activity capacity is stronger in non-dominant hands than dominant hands, indicating that improvement in body functions lead to larger changes in manual activity capacity in the non-dominant hand. This may suggest that in bilaterally-affected children surgery should be done at the non-dominant hand first since this hand would benefit most from surgery-induced body functions improvement

MEK inhibition is a promising therapeutic strategy for MLL-rearranged infant acute lymphoblastic leukemia patients carrying RAS mutations

Acute lymphoblastic leukemia (ALL) in infants is an aggressive malignancy with a poor clinical outcome, and is characterized by translocations of the Mixed Lineage Leukemia (MLL) gene. Previously, we identified RAS mutations in 14-24% of infant ALL patients, and showed that the presence of a RAS mutation decreased the survival chances even further. We hypothesized that targeting the RAS signaling pathway could be a therapeutic strategy for RAS-mutant infant ALL patients. Here we show that the MEK inhibitors Trametinib, Selumetinib and MEK162 severely impair primary RAS-mutant MLL-rearranged infant ALL cells in vitro. While all RAS-mutant samples were sensitive to MEK inhibitors, we found both sensitive and resistant samples among RAS-wildtype cases. We confirmed enhanced RAS pathway signaling in RASmutant samples, but found no apparent downstream over-activation in the wildtype samples. However, we did confirm that MEK inhibitors reduced p-ERK levels, and induced apoptosis in the RAS-mutant MLL-rearranged ALL cells. Finally, we show that MEK inhibition synergistically enhances prednisolone sensitivity,

Development and validation of a clinically applicable ARM use monitor for people after stroke

Objective: To develop and validate a clinically applicable and easy-to-use accelerometry-based device to measure arm use in people after stroke; the Ac-tiv8 arm use monitor (Activ8-AUM). Design: Development and validation study. Patients: A total of 25 people at different stages of rehabilitation after stroke were included in this study. Methods: The Activ8-AUM consists of 3 single-sensor Activ8s: one on the unaffected thigh and one on each wrist. Arm use was calculated by combining movement intensity of the arms with data from body posture and movements on the leg sensor. Data were divided into 2 sets: one for determining situation-specific movement intensity thresholds for arm use, and the other to validate the Activ8-AUM using video recordings. Results: Overall agreement between the Activ8-AUM and video recordings was 75%, sensitivity was 73% and specificity was 77%. Agreement between the different categories of arm use ranged from 42% to 93% for the affected arm and from 24% to 82% for the unaffected arm. Conclusion: By combining the movement intensity threshold with body posture and movements, good agreement was reached between the Activ8-AUM and video recordings. This result, together with the easy-to-use configuration, makes the Activ8-AUM a promising device to measure arm use in people after stroke

Partner independent fusion gene detection by multiplexed CRISPR-Cas9 enrichment and long read nanopore sequencing

Fusion genes are hallmarks of various cancer types and important determinants for diagnosis, prognosis and treatment. Fusion gene partner choice and breakpoint-position promiscuity restricts diagnostic detection, even for known and recurrent configurations. Here, we develop FUDGE (FUsion Detection from Gene Enrichment) to accurately and impartially identify fusions. FUDGE couples target-selected and strand-specific CRISPR-Cas9 activity for fusion gene driver enrichment - without prior knowledge of fusion partner or breakpoint-location - to long read nanopore sequencing with the bioinformatics pipeline NanoFG. FUDGE has flexible target-loci choices and enables multiplexed enrichment for simultaneous analysis of several genes in multiple samples in one sequencing run. We observe on-average 665 fold breakpoint-site enrichment and identify nucleotide resolution fusion breakpoints within 2 days. The assay identifies cancer cell line and tumor sample fusions irrespective of partner gene or breakpoint-position. FUDGE is a rapid and versatile fusion detection assay for diagnostic pan-cancer fusion detection