Vascular cognitive impairment: Advances and trends.

The presence of vascular neurocognitive impairment (whatever the severity) is always associated with a functional impact and increased risk of dependency and institutionalization. However, vascular cognitive impairment remains underdiagnosed, and the mechanisms underlying post-stroke cognitive disorders are still poorly understood. However, the advent of new criteria and a standardized international neuropsychological battery is expected to lead to improved diagnosis and management, and the development of novel techniques (such as brain imaging and amyloid PET) should improve our understanding of the mechanisms underlying vascular cognitive impairment and help to identify potential targets for therapy.

Dose reduction in paediatric cranial CT via iterative reconstruction: a clinical study in 78 patients.

AIM: To assess how adaptive statistical iterative reconstruction (ASIR) contributes to dose reduction and affects image quality of non-contrast cranial computed tomography (cCT) in children. MATERIALS AND METHODS: Non-contrast cranial CT acquired in 78 paediatric patients (age 0-12 years) were evaluated. The images were acquired and processed using four different protocols: Group A (control): 120 kV, filtered back projection (FBP), n=18; Group B: 100 kV, FBP, n=22; Group C: 100 kV, scan and reconstruction performed with 20% ASIR, n=20; Group D1: 100 kV, scan and reconstruction performed with 30% ASIR, n=18; Group D2: raw data from Group D1 reconstructed using a blending of 40% ASIR and 60% FBP, n=18. The effective dose was calculated and the image quality was assessed quantitatively and qualitatively. RESULTS: Compared to Group A, Groups C and D1/D2 showed a significant reduction of the dose-length product (DLP) by 34.4% and 64.4%, respectively. All experimental groups also showed significantly reduced qualitative levels of noise, contrast, and overall diagnosability. Diagnosis-related confidence grading showed Group C to be adequate for everyday clinical practice. Quantitative measures of Groups B and C were comparable to Group A with only few parameters compromised. Quantitative scores in Groups D1 and D2 were mainly lower compared to Group A, with Group D2 performing better than Group D1. Group D2 was considered adequate for follow-up imaging of severe acute events such as bleeding or hydrocephalus. DISCUSSION: The use of ASIR combined with low tube voltage may reduce radiation significantly while maintaining adequate image quality in non-contrast paediatric cCT.

Reducing Radiation Dose in Adult Head CT using Iterative Reconstruction - A Clinical Study in 177 Patients.

PURPOSE: To assess how ASIR (adaptive statistical iterative reconstruction) contributes to dose reduction and affects image quality of non-contrast cranial computed tomography (cCT). MATERIALS AND METHODS: Non-contrast emergency CT scans of the head acquired in 177 patients were evaluated. The scans were acquired and processed using four different protocols: Group A (control): 120 kV, FBP (filtered back projection) n = 71; group B1: 120 kV, scan and reconstruction performed with 20 % ASIR (blending of 20 % ASIR and 80 % FBP), n = 86; group B2: raw data from group B1 reconstructed using a blending of 40 % ASIR and 60 % FBP, n = 74; group C1: 120 kV, scan and reconstruction performed with 30 % ASIR, n = 20; group C2: raw data from group C1 reconstructed using a blending of 50 % ASIR and 50 % FBP, n = 20. The effective dose was calculated. Image quality was assessed quantitatively and qualitatively. RESULTS: Compared to group A, groups B1/2 and C1/2 showed a significantly reduced effective dose of 40.4 % and 73.3 % (p < 0.0001), respectively. Group B1 and group C1/2 also showed significantly reduced quantitative and qualitative image quality parameters. In group B2, quantitative measures were comparable to group A, and qualitative scores were lower compared to group A but higher compared to group B1. Diagnostic confidence grading showed groups B1/2 to be adequate for everyday clinical practice. Group C2 was considered acceptable for follow-up imaging of severe acute events such as bleeding or subacute stroke. CONCLUSION: Use of ASIR makes it possible to reduce radiation significantly while maintaining adequate image quality in non-contrast head CT, which may be particularly useful for younger patients in an emergency setting and in follow-up. KEY POINTS: ASIR may reduce radiation significantly while maintaining adequate image quality. cCT protocol with 20 % ASIR and 40 %ASIR/60 %FBP blending is adequate for everyday clinical use. cCT protocol with 30 % ASIR and 50 %ASIR/50 %FBP blending is adequate for follow-up imaging

Outcome prediction in patients after cardiac arrest: a simplified method for determination of gray-white matter ratio in cranial computed tomography.

PURPOSE: Out-of-hospital cardiac arrest is a frequent cause of death in Europe. Hypoxic ischemic encephalopathy (HIE) often develops in initial survivors, and the question of treatment limitation arises in severely affected patients. To establish a poor prognosis with a high level of certainty, the use of a combination of prognostic parameters such as neurological examination, somatosensory evoked potentials, and neuron-specific enolase is common practice. A few recent studies suggest that gray-white matter ratio (GWR) determined from cranial computed tomography (CT) scans is an additional reliable predictor of poor prognosis. The standard GWR determination method involves measurements of 16 different regions of interest (ROIs). We tested whether a simplified method to obtain GWR has equivalent reliability for poor outcome prediction. MATERIALS AND METHODS: We retrospectively analyzed 98 patients after cardiac arrest who had been treated with hypothermia. CT scans were obtained within the first 7 days after cardiac arrest. Neurological outcome was determined at intensive care unit discharge. Four different methods to obtain GWR were compared in a receiver-operating characteristic curve analysis with respect to their prognostic value for poor outcome prediction. RESULTS: The simplest method using only four ROIs (putamen and internal capsule bilaterally) had the same prognostic value compared with the standard method using 16 ROIs. The simplified GWR predicted poor outcome with a sensitivity of 44 % at 100 % specificity. CONCLUSION: Our results indicate that for poor outcome prediction in survivors of cardiac arrest, a simplified GWR determination is feasible and has the same reliability as the complex standard procedure.

Meningioma of the skull base: long-term outcome after image-guided stereotactic radiotherapy.

PURPOSE: The purpose of this study was to analyse the feasibility, safety, and long-term efficacy of linear accelerator-based fractionated stereotactic radiotherapy for meningiomas of the skull base. We evaluated the long-term clinical outcome of patients and identified prognostic factors after fractionated stereotactic radiotherapy. PATIENTS AND METHODS: Between 10/1995 and 03/2009, 136 patients with a median age of 57 years with skull base meningioma received fractionated stereotactic radiotherapy. A total of 34 patients had a grade I meningioma, in 102 cases no histology was obtained (grade 0). Fractionated stereotactic radiotherapy was delivered as primary treatment for 57 patients and postoperatively for 79. The patients received a mean total dose of 56.95 (min/max 32.4/63)Gy. RESULTS: Median follow-up was 44.9 months. Overall progression-free survival was 96.9% after 3 years, 93.8% after 5 years, and 91.5% after 10 years. Patients with unknown histology showed progression-free survival rates of 100%, 98.7%, and 93.5% at 3, 5, and 10 years and patients with biopsy-proven grade I meningioma showed rates of 100% after 3 years, 91.7% after 5 years and 85.9% after 10 years. Patients with adjuvant radiotherapy showed significantly worse progression-free survival rates than patients who had been treated with primary radiotherapy (P=0.043), progression-free survival rates were independent of tumour size. The most common acute grade I symptoms were headache, fatigue, and local alopecia. The most common chronic grade I symptoms were fatigue and headache. CONCLUSIONS: This large study showed that fractionated stereotactic radiotherapy is an effective and safe treatment modality with high progression-free survival rates for intracranial meningioma. We identified "prior surgery" as significant poor prognostic factor.

Image-guided stereotactic radiotherapy for patients with vestibular schwannoma. A clinical study.

INTRODUCTION: Local tumor control and functional outcome after linac-based stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) for vestibular schwannoma (VS) were assessed. METHODS: In all, 250 patients with VS were treated: 190 patients with tumors < 2 cm diameter underwent SRS and 60 patients with tumors >2 to 3.5 cm underwent FSRT. Dose prescription for all cases with SRS (n = 190, 76 %) was 13.5 Gy. For FSRT, mainly two hypofractionated schedules (n = 60, 24 %) with either 7 fractions of 5 Gy (total dose: 35 Gy; n = 35) or 11 fractions of 3.8 Gy (total dose: 41.8 Gy; n = 16) were used. The primary endpoint was local tumor control. Secondary endpoints were symptomatic control and morbidity. RESULTS: The median follow-up was 33.8 months. The 3-year local tumor control was 88.9 %. Local control for SRS and FSRT was 88 and 92 %, respectively. For FSRT with 35 and 41.8 Gy, local control was 90 and 100 %, respectively. There were no acute reactions exceeding grade I. In 61 cases (24.4 % of the entire cohort), trigeminal neuralgia was reported prior to treatment. At last follow-up, 16.3 % (10/61) of those patients reported relief of pain. Regarding facial nerve dysfunction, 45 patients (18 %) presented with symptoms prior to RT. At the last follow-up, 13.3% (6/45) of those patients reported a relief of dysesthesia. CONCLUSION: Using SRS to treat small VS results in good local control rates. FSRT for larger lesions also seems effective. Severe treatment-related complications are not frequent. Therefore, image-guided stereotactic radiotherapy is an appropriate alternative to microsurgery for patients with VS.

Volumetric assessment of optic nerve sheath and hypophysis in idiopathic intracranial hypertension.

BACKGROUND AND PURPOSE: Idiopathic intracranial hypertension is a headache syndrome characterized by increased CSF pressure. Compression of the hypophysis and distension of the optic nerve sheath are reliable imaging signs. The purpose of the study was to validate, in patients with idiopathic intracranial hypertension, MR imaging-based volumetric measurements of the optic nerve sheath and hypophysis as an objective observation method for more accurate diagnosis and posttreatment follow-up. MATERIALS AND METHODS: Twenty-three patients with idiopathic intracranial hypertension as well as age-, sex-, and body mass index-matched controls underwent volumetric measurements of the optic nerve, optic nerve sheath, and hypophysis on high-resolution T2-weighted MR images by using a 7-cm surface coil, followed by correlation with CSF opening pressures and clinical symptom scores of visual disturbances and headache. RESULTS: Mean values of optic nerve sheath (341.86 ± 163.69 mm(3) versus 127.56 ± 53.17 mm(3), P < .001) and hypophysis volumes (554.59 ± 142.82 mm(3) versus 686.60 ± 137.84 mm(3), P < .05) differed significantly between healthy and diseased subjects. No significant differences between mean optic nerve volumes were observed. Receiver operating characteristic analysis showed optic nerve sheath volumes of >201.30 mm(3) (sensitivity, 86.96%; specificity, 91.30%) and hypophysis volumes of <611.21 mm(3) (sensitivity, 78.26%; specificity, 69.57%) to be indicative of idiopathic intracranial hypertension diagnosis. In patients with idiopathic intracranial hypertension, no correlations were found between optic nerve sheath and hypophysis volumes and CSF opening pressures or clinical scores of visual disturbances and headache. CONCLUSIONS: Semiautomated volumetric measurement of optic nerve sheath and hypophysis has the potential to more accurately diagnose and follow patients with idiopathic intracranial hypertension.

The purinergic P2Y14 receptor axis is a molecular determinant for organism survival under in utero radiation toxicity.

In utero exposure of the embryo and fetus to radiation has been implicated in malformations or fetal death, and often produces lifelong health consequences such as cancers and mental retardation. Here we demonstrate that deletion of a G-protein-coupled purinergic receptor, P2Y14, confers potent resistance to in utero radiation. Intriguingly, a putative P2Y14 receptor ligand, UDP-glucose, phenocopies the effect of P2Y14 deficiency. These data indicate that P2Y14 is a receptor governing in utero tolerance to genotoxic stress that may be pharmacologically targeted to mitigate radiation toxicity in pregnancy.

Glioblastoma multiforme versus solitary supratentorial brain metastasis: differentiation based on morphology and magnetic resonance signal characteristics.

PURPOSE: To evaluate the diagnostic potential of a multi-factor analysis of morphometric parameters and magnetic resonance (MR) signal characteristics of a mass and peritumoral area to distinguish solitary supratentorial metastasis from glioblastoma multiforme (GBM). MATERIALS AND METHODS: MR examinations of 51 patients with histologically proven GBM and 44 with a single supratentorial metastasis were evaluated. A large variety of morphologic criteria and MR signal characteristics in different sequences were analyzed. The data were subjected to logistic regression to investigate their ability to discriminate between GBM and cerebral metastasis. Receiver-operating characteristic (ROC) analysis was used to select an optimal cut-off point for prediction and to assess the predictive value in terms of sensitivity, specificity, and accuracy of the final model. RESULTS: The logistic regression analysis revealed that the ratio of the maximum diameter of the peritumoral area measured on T2-weighted images (d T2) to the maximum diameter of the enhancing mass area (d T1, post-contrast) is the only useful criterion to distinguish single supratentorial brain metastasis from GBM with a lower ratio favoring GBM (accuracy 68 %, sensitivity 84 % and specificity 45 %). The cut-off point for the ratio d T2/d T1 post-contrast was calculated as 2.35. CONCLUSION: Measurement of maximum diameters of the peritumoral area in relation to the enhancing mass can be evaluated easily in the clinical routine to discriminate GBM from solitary supratentorial metastasis with an accuracy comparable to that of advanced MRI techniques.

A new approach for corticospinal tract reconstruction based on navigated transcranial stimulation and standardized fractional anisotropy values.

PURPOSE: To establish a novel approach for fiber tracking based on navigated transcranial magnetic stimulation (nTMS) mapping of the primary motor cortex and to propose a new algorithm for determination of an individualized fractional anisotropy value for reliable and objective fiber tracking. METHODS: 50 patients (22 females, 28 males, median age 58 years (20-80)) with brain tumors compromising the primary motor cortex and the corticospinal tract underwent preoperative MR imaging and nTMS mapping. Stimulation spots evoking muscle potentials (MEP) closest to the tumor were imported into the fiber tracking software and set as seed points for tractography. Next the individual FA threshold, i.e. the highest FA value leading to visualization of tracts at a predefined minimum fiber length of 110 mm, was determined. Fiber tracking was then performed at a fractional anisotropy value of 75% and 50% of the individual FA threshold. In addition, fiber tracking according to the conventional knowledge-based approach was performed. Results of tractography of either method were presented to the surgeon for preoperative planning and integrated into the navigation system and its impact was rated using a questionnaire. RESULTS: Mapping of the motor cortex was successful in all patients. A fractional anisotropy threshold for corticospinal tract reconstruction could be obtained in every case. TMS-based results changed or modified surgical strategy in 23 of 50 patients (46%), whereas knowledge-based results would have changed surgical strategy in 11 of 50 patients (22%). Tractography results facilitated intraoperative orientation and electrical stimulation in 28 of 50 (56%) patients. Tracking at 75% of the individual FA thresholds was considered most beneficial by the respective surgeons. CONCLUSIONS: Fiber tracking based on nTMS by the proposed standardized algorithm represents an objective visualization method based on functional data and provides a valuable instrument for preoperative planning and intraoperative orientation and monitoring.

Traumatic middle meningeal artery pseudoaneurysms: diagnosis and endovascular treatment of two cases and review of the literature.

Intracranial pseudoaneurysms are rare and mostly associated with a history of head trauma. Only little is known about their natural development. They are characterized by an unpredictable course with a possibility of causing secondary intracranial hemorrhage with significant morbidity and mortality. We present two cases of traumatic pseudoaneurysms of the middle meningeal artery (MMA) treated via endovascular coil occlusion and review of literature. Pseudoaneurysms of the middle meningeal artery carry a potential risk of rupture. They can be detected via a computed tomography angiogram (CT-A). An endovascular embolization followed by catheter angiography may represent a safe treatment of traumatic middle meningeal artery pseudoaneurysms. Considering the risk of secondary rupture and the potentially catastrophic consequences, we recommend a CT-A in all patients with skull base fractures and intracranial hemorrhage.

The influence of collagen network integrity on the accumulation of gadolinium-based MR contrast agents in articular cartilage.

PURPOSE: Delayed gadolinium-enhanced MR imaging of cartilage is used to quantify the proteoglycan loss in early osteoarthritis. It is assumed that T1 after Gd-DTPA administration in the near equilibrium state reflects selective proteoglycan loss from cartilage. To investigate the influence of the collagen network integrity on contrast accumulation, the relaxation rates ΔR(1) and ΔR(2) were compared after Gd-DTPA administration in a well established model of osteoarthritis. MATERIALS AND METHODS: Collagen or proteoglycan depletion was induced by the proteolytic enzymes papain and collagenase in healthy bovine patellar cartilage. Using a dedicated MRI sequence, T(1) and T(2) maps were simultaneously acquired before and 11 h after Gd-DTPA administration. Depth-dependent profiles of ΔR(1) and ΔR(2) were calculated in healthy, proteoglycan and collagen-depleted articular cartilage and the mean values of different cartilage layers were compared using the Mann-Whitney-U test. RESULTS: In superficial layers (1 mm) there was no significant difference (p > 0.05) in either ΔR(1) or ΔR(2) between proteoglycan-depleted (16.6 ± 1.2 s(-1), 15.9 ± 1.0 s(-1)) and collagen-depleted articular cartilage (15.3 ± 0.9 s(-1), 15.5 ± 0.9 s(-1)). In deep layers (3 mm) both parameters were significantly higher (p = 0.005, 0.03) in proteoglycan-depleted articular cartilage (12.3 ± 1.1 s(-1), 9.8 ± 0.8 s(-1)) than in collagen-depleted articular cartilage (9.1 ± 1.1 s(-1), 8.7 ± 0.7 s(-1)). CONCLUSION: Both proteoglycan loss and alterations in the collagen network influence the accumulation of Gd-DTPA in articular cartilage with significant differences between superficial and deep cartilage layers.

Spatial variation in T1 of healthy human articular cartilage of the knee joint.

The longitudinal relaxation time T(1) of native cartilage is frequently assumed to be constant. To redress this, the spatial variation of T(1) in unenhanced healthy human knee cartilage in different compartments and cartilage layers was investigated. Knees of 25 volunteers were examined on a 1.5 T MRI system. A three-dimensional gradient-echo sequence with a variable flip angle, in combination with parallel imaging, was used for rapid T(1) mapping of the whole knee. Regions of interest (ROIs) were defined in five different cartilage segments (medial and lateral femoral cartilage, medial and lateral tibial cartilage and patellar cartilage). Pooled histograms and averaged profiles across the cartilage thickness were generated. The mean values were compared for global variance using the Kruskal-Wallis test and pairwise using the Mann-Whitney U-test. Mean T(1) decreased from 900-1100 ms in superficial cartilage to 400-500 ms in deep cartilage. The averaged T(1) value of the medial femoral cartilage was 702+/-68 ms, of the lateral femoral cartilage 630+/-75 ms, of the medial tibial cartilage 700+/-87 ms, of the lateral tibial cartilage 594+/-74 ms and of the patellar cartilage 666+/-78 ms. There were significant differences between the medial and lateral compartment (p<0.01). In each cartilage segment, T(1) decreased considerably from superficial to deep cartilage. Only small variations of T(1) between different cartilage segments were found but with a significant difference between the medial and lateral compartments.

Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) of cadaveric shoulders: comparison of contrast dynamics in hyaline and fibrous cartilage after intraarticular gadolinium injection.

BACKGROUND: Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) is a novel method to investigate cartilaginous and fibrocartilaginous structures. PURPOSE: To investigate the contrast dynamics in hyaline and fibrous cartilage of the glenohumeral joint after intraarticular injection of gadopentetate dimeglumine. MATERIAL AND METHODS: Transverse T(1) maps were acquired on a 1.5T scanner before and after intraarticular injection of 2.0 mmol/l gadopentetate dimeglumine in five cadaveric shoulders using a dual flip angle three-dimensional gradient echo (3D-GRE) sequence. The acquisition time for the T(1) maps was 5 min 5 s for the whole shoulder. Measurements were repeated every 15 min over 2.5 hours. Regions of interest (ROIs) covering the glenoid cartilage and the labrum were drawn to assess the temporal evolution of the relaxation parameters. RESULTS: T(1) of unenhanced hyaline cartilage of the glenoid was 568+/-34 ms. T(1) of unenhanced fibrous cartilage of the labrum was 552+/-38 ms. Significant differences (P=0.002 and 0.03) in the relaxation parameters were already measurable after 15 min. After 2 to 2.5 hours, hyaline and fibrous cartilage still demonstrated decreasing relaxation parameters, with a larger range of the T(1)(Gd) values in fibrous cartilage. T(1) and triangle Delta R(1) values of hyaline and fibrous cartilage after 2.5 hours were 351+/-16 ms and 1.1+/-0.09 s(-1), and 332+/-31 ms and 1.2+/-0.1 s(-1), respectively. CONCLUSION: A significant decrease in T(1)(Gd) was found 15 min after intraarticular contrast injection. Contrast accumulation was faster in hyaline than in fibrous cartilage. After 2.5 hours, contrast accumulation showed a higher rate of decrease in hyaline cartilage, but neither hyaline nor fibrous cartilage had reached equilibrium.

Evaluation of reconstructed orbital wall fractures: high-resolution MRI using a microscopy surface coil versus 16-slice MSCT.

We evaluated high-resolution magnetic resonance imaging (MR) using a 47-mm microscopy surface coil in comparison to 16-slice multislice CT (MSCT) for postsurgical imaging of reconstructed orbital walls. Twenty-five patients with 27 internal orbital wall fractures were imaged prospectively after reconstruction with resorbable polydioxanone sulfate (PDS) sheets. Coronal high-quality T1- and T2-weighted MR images were obtained with an in-plane resolution of 350 microm within a measure time of 6-7 min for each sequence. Nineteen symptomatic patients underwent MSCT as the current gold standard. In MRI the PDS foil appears in T1- and T2-weighted images as a thin, low-signal-intensity linear structure. In CT it appears hyperdense in comparison to soft tissue and slightly hypodense in comparison to cortical bone. PDS foils could be clearly depicted in 20 out of 25 patients (80%) with MRI and in 13 out of 19 patients (68%) with MSCT. An inadequate foil position or size could be diagnosed in eight patients with MRI and in only three patients with MSCT. In ten symptomatic patients secondary surgery could be avoided because of regular MRI findings except mild hematoma and muscle edema. High-resolution MRI of the orbit using a 47-mm microscopy coil is a promising method to accurately demonstrate normal and pathologic conditions in symptomatic patients after orbital wall reconstruction with PDS foils.

A nanotechnology-based analog of monoclonal antibodies for targeted delivery of diagnostic and therapeutic agents.

The goal of our research is in vivo molecular and cellular imaging. This includes but is not limited to the imaging of protein expression. Dendrimers are an extremely monodisperse polymer used in many types of targeted delivery. Dendrimer families currently used have only one type of surface functional group. Thus when adding both targeting and reporter molecules one gets an ensemble of dendrimer based agents with different avidities. This is analogous to the production of polyclonal antibodies which are a solution of different proteins that bind to the same target with different affinities, and avidities. Using tris-ester protected acids and alpha,omega-protected triamine building blocks we created a dendrimer family with two or more different types of surface functional groups and different protecting groups. This framework technology allows the independent and quantitative addition of targeting, reporter, and/or therapeutic molecules. This provides a solution of identical molecules all with the same avidity and affinity for the target, much like monoclonal antibodies.

Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat.

Plastic changes in motor cortex capillary structure and function were examined in three separate experiments in adult rats following prolonged exercise. The first two experiments employed T-two-star (T(2)*)-weighted and flow-alternating inversion recovery (FAIR) functional magnetic resonance imaging to assess chronic changes in blood volume and flow as a result of exercise. The third experiment used an antibody against the CD61 integrin expressed on developing capillaries to determine if motor cortex capillaries undergo structural modifications. In experiment 1, T(2)*-weighted images of forelimb regions of motor cortex were obtained following 30 days of either repetitive activity on a running wheel or relative inactivity. The proton signal intensity was markedly reduced in the motor cortex of exercised animals compared with that of controls. This reduction was not attributable to alterations of vascular iron levels. These results are therefore most consistent with increased capillary perfusion or blood volume of forelimb regions of motor cortex. FAIR images acquired during experiment 2 under normocapnic and hypercapnic conditions indicated that resting cerebral blood flow was not altered under normal conditions but was elevated in response to high levels of CO(2), suggesting that prolonged exercise increases the size of a capillary reserve. Finally, the immunohistological data indicated that exercise induces robust growth of capillaries (angiogenesis) within 30 days from the onset of the exercise regimen. Analysis of other regions failed to find any changes in perfusion or capillary structure suggesting that this motor activity-induced plasticity may be specific to motor cortex.These data indicate that capillary growth occurs in motor areas of the cerebral cortex as a robust adaptation to prolonged motor activity. In addition to capillary growth, the vascular system also experiences heightened flow under conditions of activation. These changes are chronic and observable even in the anesthetized animal and are measurable using noninvasive techniques.

Anti-HPA-1a-mediated platelet phagocytosis by monocytes in vitro and its inhibition by Fc gamma receptor (FcgammaR) reactive reagents.

The study was undertaken to delineate mechanisms of platelet destruction by phagocytosis during fetal/neonatal alloimmune thrombocytopenia (FAIT/NAIT) because of maternal antibodies against human platelet antigen 1a (HPA-1a). By employing a platelet phagocytosis assay based on the ORPEGEN flow cytometric bacterial phagocytosis test, we measured monocyte ingestion of platelets mediated by anti-HPA-1a antibodies. Moreover, we tested, as potential therapeutic agents, FcgammaR reactive reagents, for their inhibition of this process. Four of six anti-HPA-1a sera tested mediated phagocytosis of HPA-1a-positive platelets in a concentration-dependent manner. Monocyte ingestion of platelets was almost completely inhibited by cytochalasin D. No anti-HPA-1a-mediated phagocytosis was observed with anti-HPA-1a-negative platelets. The humanised anti-FcgammaRI monoclonal antibody H22 at concentrations 1-100 microg/ml, completely inhibited anti-HPA-1a-mediated phagocytosis as did similar concentrations of ivIg. By contrast, a mouse monoclonal anti-FcgammaRII (IV.3, Fab) at 10 microg/ml caused little or no suppression of platelet phagocytosis mediated by two anti-HPA-1 sera. Furthermore, the addition of anti-FcgammaRII (10 microg/ml) to sub-optimal concentrations of H22 did not significantly increase the inhibitory effect of the latter compound. Monomeric IgG (0.1-10 microg/ml) failed to suppress anti-HPA-1 mediated platelet ingestion by the phagocytes, as did anti-FcgammaRIII. To our knowledge this is a rare example of an assay that measures platelet phagocytosis in vitro. The results suggest that FcgammaRI plays a major role in anti-HPA-1a-mediated platelet phagocytosis by monocytes while FcgammaRIIa, is of little or minor importance only. Moreover, the findings indicate the use of H22 as an alternative to interavenous Ig (ivIg) in the management of FAIT/NAIT.

Lessons learned from a failed multi-institutional randomized controlled study.

BACKGROUND/PURPOSE: In 1996, the Surgical Sections of the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) received National Cancer Institute funding to conduct a prospective, randomized, controlled, surgeon-directed study to evaluate the role of minimally invasive surgery (MIS) in children with cancer. Because of lack of patient accrual, the study was closed in 1998. The purpose of this study is to evaluate and describe those factors that impacted on study failure to ensure future successful clinical trials. METHODS: One hundred forty surgeons representing the surgical membership of CCG and POG as well as 111 institutions within CCG and POG were asked to complete a questionnaire about the failed clinical trial. The questionnaire focused on study objectives, organization, and institutional review board (IRB) submission. It also examined the surgeon's ability to perform the minimal access operation, the influence of the pediatric oncologist, and the existence of preconceived biases by surgeons, oncologists, and families. Statistical analysis was performed as appropriate. RESULTS: Eighty-six of 140 (62%) surgeons responded to the questionnaire. Only 23% of the potential protocols were submitted for IRB approval. Of responding surgeons, 39% were not actively performing MIS when the study opened. A surgeon's support of the study was directly related to when the surgeon received the protocols (P <.001) and whether the participating surgeon was actively participating in MIS (P <.016). The oncologist's knowledge and support of the study affected IRB submission and approval (P <.02) and was influenced by whether MIS was practiced at the institution (P <.05). The majority of responding surgeons believed the experimental question was relevant (P <.05). However, responding surgeons believed that a preconceived bias existed within both their local surgical and oncology communities favoring a particular surgical approach (P <.001), but this bias did not extend to the families (P >.05). CONCLUSION: The study failed because of lack of accrual for a variety of reasons: failure to submit to the institution's IRB, lack of surgical expertise with MIS procedures, and preconceived surgeon bias toward either an endoscopic or traditional open approach.

Which patients with microscopic disease and rhabdomyosarcoma experience relapse after therapy? A report from the soft tissue sarcoma committee of the children's oncology group.

PURPOSE: To identify which patients with rhabdomyosarcoma and microscopic residual disease (group II) are likely to not respond to therapy. PATIENTS AND METHODS: Six hundred ninety-five patients with group II tumors received chemotherapy and 90% received radiation therapy on Intergroup Rhabdomyosarcoma Study (IRS)-I to IRS-IV (1972 to 1997). Tumors were subgrouped depending on the presence of microscopic residual disease only (subgroup IIa), resected positive regional lymph nodes, (subgroup IIb), or microscopic residual disease and resected positive regional lymph nodes (subgroup IIc). RESULTS: Overall, the 5-year failure-free survival rate (FFSR) was 73%, and patients with embryonal rhabdomyosarcoma treated on IRS-IV fared especially well (5-year FFSR, 93%; n = 90). Five-year FFSRs differed significantly by subgroup (IIa, 75% and n = 506; IIb, 74% and n = 101; IIc, 58% and n = 88; P = .0037) and treatment (IRS-I, 68%; IRS-II, 67%; IRS-III, 75%; IRS-IV, 87%; P < .001). Multivariate analysis revealed positive associations between primary site (favorable), histology (embryonal), subgroup IIa or IIb, treatment (IRS-III/IV), and better FFSRs. Patterns of treatment failure revealed local failure to be 8%, regional failure, 4%, and distant failure, 14%. The relapse pattern noted over the course of IRS-I to IRS-IV shows a decrease in the systemic relapse rates, particularly for patients with embryonal histology, suggesting that improvement in FFSRs is primarily a result of improved chemotherapy. CONCLUSION: Group II rhabdomyosarcoma has an excellent prognosis with contemporary therapy as used in IRS-III/IV, and those less likely to respond can be identified using prognostic factors: histology, subgroup, and primary site. Patients with embryonal rhabdomyosarcoma are generally cured, although patients with alveolar rhabdomyosarcoma or undifferentiated sarcoma, particularly subgroup IIc at unfavorable sites, continue to need better therapy.