Search

The aim of this study was to investigate the relationship between stroke lesion location and the resulting somatosensory deficit. We studied exteroceptive and proprioceptive somatosensory symptoms and stroke lesions in 38 patients with first-ever acute stroke. The Erasmus modified Nottingham Sensory Assessment was used to clinically evaluate somatosensory functioning in the arm and hand within the first week after stroke onset. Additionally, more objective measures such as the perceptual threshold of touch and somatosensory evoked potentials were recorded. Non-parametric voxel-based lesion-symptom mapping was performed to investigate lesion contribution to different somatosensory deficits in the upper limb. Additionally, structural connectivity of brain areas that demonstrated the strongest association with somatosensory symptoms was determined, using probabilistic fiber tracking based on diffusion tensor imaging data from a healthy age-matched sample. Voxels with a significant association to somatosensory deficits were clustered in two core brain regions: the central parietal white matter, also referred to as the sensory component of the superior thalamic radiation, and the parietal operculum close to the insular cortex, representing the secondary somatosensory cortex. Our objective recordings confirmed findings from clinical assessments. Probabilistic tracking connected the first region to thalamus, internal capsule, brain stem, postcentral gyrus, cerebellum, and frontal pathways, while the second region demonstrated structural connections to thalamus, insular and primary somatosensory cortex. This study reveals that stroke lesions in the sensory fibers of the superior thalamocortical radiation and the parietal operculum are significantly associated with multiple exteroceptive and proprioceptive deficits in the arm and hand.

Background: Recently, conformational activation of ADAMTS-13 was identified. This mechanism showed the evolution from a condensed conformation, in which the proximal MDTCS and distal T2-CUB2 domains are in close contact with each other, to an activated, open structure due to binding with von Willebrand factor (VWF)., Objectives: Identification of cryptic epitope/exosite exposure after conformational activation and of sites of flexibility in ADAMTS-13., Methods: The activating effect of 25 anti-T2-CUB2 antibodies was studied in the FRETS-VWF73 and the vortex assay. Cryptic epitope/exosite exposure was determined with ELISA and VWF binding assay. The molecular basis for flexibility was hypothesized through rapid automatic detection and alignment of repeats (RADAR) analysis, tested with ELISA using deletion variants and visualized using electron microscopy., Results: Eleven activating anti-ADAMTS-13 antibodies, directed against the T5-CUB2 domains, were identified in the FRETS-VWF73 assay. RADAR analysis identified three linker regions in the distal domains. Interestingly, identification of an antibody recognizing a cryptic epitope in the metalloprotease domain confirmed the contribution of these linker regions to conformational activation of the enzyme. The proof of flexibility around both the T2 and metalloprotease domains, as shown by by electron microscopy, further supported this contribution. In addition, cryptic epitope exposure was identified in the distal domains, because activating anti-T2-CUB2 antibodies increased the binding to folded VWF up to ~3-fold., Conclusion: Conformational activation of ADAMTS-13 leads to cryptic epitope/exosite exposure in both proximal and distal domains, subsequently inducing increased activity. Furthermore, three linker regions in the distal domains are responsible for flexibility and enable the interaction between the proximal and the T8-CUB2 domains., (© 2015 International Society on Thrombosis and Haemostasis.)

Aim: To provide first evidence of construct validity of a semi-quantitative scale for brain structural MRI (sqMRI scale) in children with unilateral cerebral palsy (UCP) secondary to periventricular white matter (PWM) lesions, by examining the relationship with hand sensorimotor function and whole brain structural connectivity., Methods: Cross-sectional study of 50 children with UCP due to PWM lesions using 3 T (MRI), diffusion MRI and assessment of hand sensorimotor function. We explored the relationship of lobar, hemispheric and global scores on the sqMRI scale, with fractional anisotropy (FA), as a measure of brain white matter microstructure, and with hand sensorimotor measures (Assisting Hand Assessment, AHA; Jebsen-Taylor Test for Hand Function, JTTHF; Melbourne Assessment of Unilateral Upper Limb Function, MUUL; stereognosis; 2-point discrimination)., Results: Lobar and hemispheric scores on the sqMRI scale contralateral to the clinical side of hemiplegia correlated with sensorimotor paretic hand function measures and FA of a number of brain structural connections, including connections of brain areas involved in motor control (postcentral, precentral and paracentral gyri in the parietal lobe). More severe lesions correlated with lower sensorimotor performance, with the posterior limb of internal capsule score being the strongest contributor to impaired hand function., Conclusion: The sqMRI scale demonstrates first evidence of construct validity against impaired motor and sensory function measures and brain structural connectivity in a cohort of children with UCP due to PWM lesions. More severe lesions correlated with poorer paretic hand sensorimotor function and impaired structural connectivity in the hemisphere contralateral to the clinical side of hemiplegia. The quantitative structural MRI scoring may be a useful clinical tool for studying brain structure-function relationships but requires further validation in other populations of CP.

Background: The multidomain metalloprotease ADAMTS13 regulates the size of von Willebrand factor (VWF) multimers upon their release from endothelial cells. How the different domains in ADAMTS13 control VWF proteolysis in vivo remains largely unidentified., Methods: Seven C-terminally truncated murine ADAMTS13 (mADAMTS13) mutants were constructed and characterized in vitro. Their ability to cleave VWF strings in vivo was studied in the ADAMTS13(-/-) mouse., Results: Murine MDTCS (devoid of T2-8 and CUB domains) retained full enzyme activity in vitro towards FRETS-VWF73 and the C-terminal T6-8 (del(T6-CUB)) and CUB domains (delCUB) are dispensable under these assay conditions. In addition, mADAMTS13 fragments without the spacer domain (MDT and M) had reduced catalytic efficiencies. Our results hence indicate that similar domains in murine and human ADAMTS13 are required for activity in vitro, supporting the use of mouse models to study ADAMTS13 function in vivo. Interestingly, using intravital microscopy we show that removal of the CUB domains abolishes proteolysis of platelet-decorated VWF strings in vivo. In addition, whereas MDTCS is fully active in vivo, partial (del(T6-CUB)) or complete (delCUB) addition of the T2-8 domains gradually attenuates its activity., Conclusions: Our data demonstrate that the ADAMTS13 CUB and T2-8 domains influence proteolysis of platelet-decorated VWF strings in vivo., (© 2010 International Society on Thrombosis and Haemostasis.)

Background: ADAMTS13 deficiency causes accumulation of unusually large von Willebrand factor molecules, which cross-link platelets in the circulation or on the endothelial surface. This process of intravascular agglutination leads to the microangiopathy thrombotic thrombocytopenic purpura (TTP). Most TTP patients have acquired anti-ADAMTS13 autoantibodies that inhibit enzyme function and/or clear it from the circulation. However, the reason for ADAMTS13 deficiency is not always easily identified in a subset of patients., Objectives: To determine the origin of ADAMTS13 deficiency in a case of acquired TTP., Methods: Western blotting of ADAMTS13 in plasmas from acute and remission phases was used., Results: The ADAMTS13 deficiency was not caused by mutations or (detectable) autoantibodies; however, an abnormal ADAMTS13 truncated fragment (100 kDa) was found in acute-phase but not remission-phase plasma. This fragment resulted from enzymatic proteolysis, as recombinant ADAMTS13 was also cleaved when in the presence of acute-phase but not remission-phase plasma. Inhibitor screening showed that ADAMTS13 was cleaved by a serine protease that could be dose-dependently inhibited by addition of exogenous α₂ -antiplasmin. Examination of the endogenous α₂-antiplasmin antigen and activity confirmed deficiency of α₂ -antiplasmin function in acute-phase but not remission-phase plasma. To investigate the possibility of ADAMTS13 cleavage by plasmin in plasma, urokinase-type plasminogen activator was added to an (unrelated) congenital α₂ -antiplasmin-deficient plasma sample to activate plasminogen. This experiment confirmed cleavage of endogenous ADAMTS13 similar to that observed in our TTP patient., Conclusion: We report the first acquired TTP patient with cleaved ADAMTS13 and show that plasmin is involved., (© 2010 International Society on Thrombosis and Haemostasis.)

Background: ADAMTS-13 proteolytic activity is controlled by the conformation of its substrate, von Willebrand factor (VWF), and changes in the secondary structure of VWF are essential for efficient cleavage. Substrate recognition is mediated through several non-catalytic domains in ADAMTS-13 distant from the active site., Objectives: We hypothesized that not all binding sites for ADAMTS-13 in VWF are cryptic and analyzed binding of native VWF to ADAMTS-13., Methods: Immunoprecipiation of VWF-ADAMTS-13 complexes using anti-VWF antibodies and magnetic beads was used. Binding was assessed by Western blotting and immunosorbent assays., Results: Co-immunoprecipitation demonstrated that ADAMTS-13 binds to native multimeric VWF (K(d) of 79 +/- 11 nmol L(-1)) with no measurable proteolysis. Upon shear-induced unfolding of VWF, binding increased 3-fold and VWF was cleaved. Binding to native VWF was saturable, time dependent, reversible and did not vary with ionic strength (I of 50-200). Moreover, results with ADAMTS-13 deletion mutants indicated that binding to native VWF is mediated through domains distal to the ADAMTS-13 spacer, probably thrombospondin-1 repeats. Interestingly, this interaction occurs in normal human plasma with an ADAMTS-13 to VWF stoichiometry of 0.0040 +/- 0.0004 (mean +/- SEM, n = 10)., Conclusions: ADAMTS-13 binds to circulating VWF and may therefore be incorporated into a platelet-rich thrombus, where it can immediately cleave VWF that is unfolded by fluid shear stress.

Background: The recently discovered plasma enzyme ADAMTS-13 cleaves the A2-domain of von Willebrand factor (VWF). A defective cleaving protease results in unusually large VWF multimers, which cause thrombotic thrombocytopenic purpura (TTP)., Aim: Analysis of the ADAMTS-13 antigen levels in TTP patients compared with normal donors., Methods: An antigen ELISA test was built, based on high affinity anti-ADAMTS-13 monoclonal antibodies, which were generated using genetic immunization., Results: Specificity of the ADAMTS-13 antigen test was confirmed, as (i) plasma from a patient with acquired TTP but presenting without inhibitor did not contain antigen and (ii) the binding of recombinant ADAMTS-13 was inhibited by increasing amounts of normal plasma. The assay is sensitive as it can detect antigen levels as low as 1.6% of normal. The concentration in normal pooled human plasma was determined (1.03 +/- 0.15 microg mL(-1)) and arbitrarily set to 1 U mL(-1). The antigen levels in congenital TTP samples (34 +/- 21 mU mL(-1), n = 2), as well as in samples from patients with acquired TTP (231 +/- 287 mU mL(-1), n = 11), were clearly reduced when compared with normal Caucasian donors (951 +/- 206 mU mL(-1), n = 16). Remarkably, normal Chinese donors have a significantly lower antigen titer (601 +/- 129 mU mL(-1), n = 15), when compared with normal Caucasians., Conclusions: Our results show that acquired TTP patients suffer mainly from ADAMTS-13 antigen depletion, thereby indicating the importance of ADAMTS-13 antigen determination in diagnosis and patient follow-up.

8-Hydroxy-2-(di-n-propylamino)-tetralin hydrobromide (8-OH-DPAT, 2 mg/kg) is used to induce perseverative behavior in rats in a T-maze as a model for obsessive-compulsive disorder (OCD). Using the open-field test, radiant heat test, and the test with von Frey filaments, we examined whether alterations in sensorimotor functioning could contribute to the perseverative tendencies in this model by measuring differences in left versus right hind paw reactions after 8-OH-DPAT administration (2 mg/kg, sc). Also, the effect of repeated 8-OH-DPAT administration on sensorimotor functioning was tested every third day. 8-OH-DPAT administration induced a significantly decreased sensorimotor performance in the open-field test, an increased threshold for noxious thermal stimulation (increased withdrawal latency, WL, and decreased elevation time, ET) in the radiant heat test, and a decreased nociceptive threshold for mechanical stimulation in the test with von Frey filaments. All changes in sensorimotor functioning were similar for left and right hind paws suggesting that, these changes as measured with the tests in the present study, are not likely to contribute to the perseverative behavior of rats in a T-maze. Further, repeated administration of 8-OH-DPAT had no effect in the radiant heat test and the test with the Frey filaments, but produced a tolerance effect in the open-field test.

Background: Urinary incontinence is a common long-term complication after radical prostatectomy. Spontaneous recovery of normal urinary control after surgery can take 1-2 years. We aimed to investigate whether there was any beneficial effect of pelvic-floor re-education for patients with urinary incontinence as a result of radical prostatectomy., Methods: 102 consecutive incontinent patients who had had radical retropubic prostatectomy for clinically localised prostate cancer and who could comply with the ambulatory treatment schedule in our hospital were randomised, after catheter removal, into a treatment group (n=50) and a control group (n=52). Patients in the treatment group took part in a pelvic-floor re-education programme for as long as they were incontinent, and for a maximum of 1 year. The control group received placebo therapy. The primary endpoint was continence rate at 3 months. Incontinence was assessed objectively with the 1 h and 24 h pad tests and subjectively by the visual analogue scale. The groups were analysed on an intention-to-treat basis by ANOVA and chi2-test., Findings: In the treatment group continence was achieved after 3 months in 43 (88%) of 48 patients. In the control group, continence returned after 3 months in 29 (56%) of 52 patients. At 1 year, the difference in proportion between treatment and control group was 14% (95% CI 2-27). In the treatment group improvement in both duration (log-rank test, p=0.0001) and degree of incontinence (Wald test, p=0.0010) was significantly better than in the control group., Interpretation: Pelvic-floor re-education should be considered as a first-line option in curing incontinence after radical prostatectomy.

The effect of several factors on the healing rates of tibial shaft fractures with an intact fibula were examined. Those found to adversely affect healing rates included: 1. Open fractures; 2. Oblique or comminuted fractures; 3. High-velocity injuries; 4. Angulation in the sagittal plane; 5. Displacement. No other factors examined were associated with delayed union. The predictive values for delayed union are estimated for each of these factors in isolation and in combination.

The notes and radiographs of 281 adult tibial shaft fractures were reviewed. In 17 per cent there was an intact fibula. Delayed union rates were lower when the fibula remained intact, thus confirming that this is a good prognostic indicator. This fracture is caused by less severe trauma than fractures where both bones are broken. It is rare over the age of 30 years.