Bruton’s tyrosine kinase (BTK) is involved in the regulation of B-cell growth, migration, and adhesion. The importance of BTK in cell trafficking is emphasized by the clonal contraction proceeded by lymphocytosis typical for the enzyme inhibitor, ibrutinib,in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Here, we investigated BTK regulation of leukemic B-cell trafficking in a mouse model of aggressive TCL1 CLL-like disease. Inhibiting BTK by ibrutinib reduced surface membrane (sm) levels of CXCR4 but not CXCR5, CD49d, and other adhesion/homing receptors. Decreased smCXCR4 levels resulted from blocking receptor signal transduction, which in turn aborted cycling from and to the membrane. This resulted in rapid re-distribution of CLL cells from spleens and lymph nodes into the circulation. CLL cells with impaired smCXCR4 from BTK-inhibition failed to home to spleens. These functional changes mainly resulted from inhibition of CXCR4 phosphorylation at Ser339, mediated directly by blocking BTK enzymatic activity and indirectly by affecting the function of downstream targets PLCγ2 and PKCμ, and eventually synthesis of PIM-1 and BTK itself. Our data identify CXCR4 as a key regulator in BTK-mediated CLL cell retention and have elucidated a complex set of not previously described mechanisms responsible for these effects.
Endoscopic corpus callosotomy and hemispherotomy are surgically feasible procedures associated with minimal blood loss, minimal risk, and excellent visualization.
Objective: Exaggerated nocturnal intracranial pressure (ICP) dynamics are commonly observed in hydrocephalic children with a compromise of CSF compensatory reserve capacity. Successful shunting restores this cerebrospinal reserve. We used ICP overnight monitoring combined with positional maneuvers in complex hydrocephalic children with a suspected shunt malfunction for the assessment of shunt function. Methods: In 32 hydrocephalic children, we performed 65 computerized overnight recordings and 25 positional maneuvers. Baseline ICP was considered abnormal if it exceeded the operating pressure of the shunt by more than 2.5 mm Hg. The maximum ICP (normal = <25 mm Hg), RAP coefficient (the correlation coefficient between pulse amplitude and mean intracranial pressure, which indicates pressure volume compensatory reserve; normal = <0.6), magnitude of slow waves (SLOW) and ICP pulse amplitude (AMP) were calculated for each night. Results: Using baseline ICP, maximum ICP and RAP, 19 recordings were classified as ‘normal’ (group 1), 13 as ‘questionable’ (group 2), and 33 as ‘pathological’ (group 3) indicating shunt dysfunction or active hydrocephalus. ICP, AMP, RAP and SLOW were significantly different between groups and significantly elevated in group 3 compared to group 1. Positional tests identified shunt overdrainage in 5 of 25 occasions. In patients of group 1, who underwent revision, shunts turned out to be functional. All patients of group 3 eventually underwent shunt revision with improvement of symptoms thereafter. Conclusion: Computerized ICP monitoring can benefit the assessment of shunt function, and can accurately characterize the status of CSF compensation in shunted children with a complex presentation.
The purpose of this article is to describe outcomes of intrathecal baclofen therapy for 29 patients with cerebral palsy, focusing on impairments, functional limitations, and disability. Patients received individualized rehabilitation and were followed up to 24 months. The primary outcome measures were the Ashworth Scale and the functional skills and caregiver assistance scales of the Pediatric Evaluation of Disability Inventory (PEDI). Ashworth Scale scores were significantly reduced (P < or = .0005). All areas of functional skills and caregiver assistance improved. Comparing groups of adults and patients less than 18 years, there were no significant differences, but there was a relationship between age and dose. Comparing groups of patients in high and low levels of independent functional mobility, no significant differences were found. These results provide suggestive evidence that the combination of intrathecal baclofen therapy and rehabilitation has positive effects across the dimensions of disablement. This study serves as a basis for high-level scientific studies of these effects.
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