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The glymphatic system is a perivascular fluid clearance system, most active during sleep, considered important for clearing the brain of waste products and toxins. Glymphatic failure is hypothesized to underlie brain protein deposition in neurodegenerative disorders like Alzheimer’s disease. Preclinical evidence suggests that a functioning glymphatic system is also essential for recovery from traumatic brain injury, which involves release of debris and toxic proteins that need to be cleared from the brain. In a cross-sectional observational study, we estimated glymphatic clearance using diffusion tensor imaging along perivascular spaces, an MRI-derived measure of water diffusivity surrounding veins in the periventricular region, in 13 non-injured controls and 37 subjects who had experienced traumatic brain injury ∼5 months previously. We additionally measured the volume of the perivascular space using T2-weighted MRI. We measured plasma concentrations of neurofilament light chain, a biomarker of injury severity, in a subset of subjects. Diffusion tensor imaging along perivascular spaces index was modestly though significantly lower in subjects with traumatic brain injury compared with controls when covarying for age. Diffusion tensor imaging along perivascular spaces index was significantly, negatively correlated with blood levels of neurofilament light chain. Perivascular space volume did not differ in subjects with traumatic brain injury as compared with controls and did not correlate with blood levels of neurofilament light chain, suggesting it may be a less sensitive measure for injury-related perivascular clearance changes. Glymphatic impairment after traumatic brain injury could be due to mechanisms such as mislocalization of glymphatic water channels, inflammation, proteinopathy and/or sleep disruption. Diffusion tensor imaging along perivascular spaces is a promising method for estimating glymphatic clearance, though additional work is needed to confirm results and assess associations with outcome. Understanding changes in glymphatic functioning following traumatic brain injury could inform novel therapies to improve short-term recovery and reduce later risk of neurodegeneration.

BackgroundChoroid plexus (CP) within brain ventricles is well-known to produce CSF. Additional important CP functions are now recognized including critical modulation of inflammation. Recent MRI studies have demonstrated CP enlargement in human diseases including Multiple Sclerosis and Alzheimer’s Disease, and in association with neuroinflammation measured using translocator protein (TSPO) PET. The basis of MRI-visible CP enlargement is unknown.PurposeBased on tissue studies demonstrating CP calcification as a common pathology associated with aging and disease, we hypothesized that previously-unmeasured calcium within CP contributes to MRI-measured CP volume, and may be more specifically associated with neuroinflammation.Materials and MethodsWe performed a retrospective analysis of PET-CT studies performed between 2013-2019 on a single scanner using the TSPO radiotracer 11C-PK11195. Subjects included controls (n=43) and patients diagnosed with several non-inflammatory neuropsychiatric conditions (n=46.) Cortical inflammation / microglial activation was quantified as non-displaceable Binding Potential (BPnd.) CP and ventricle volume were measured using Freesurfer. CP calcium was measured semi-manually via tracing of low-dose CT acquired with PET and automatically using a new CT/MRI method. The contribution of CP calcium, CP overall volume, ventricle volume, subject age, sex and diagnosis to BPnd was assessed using linear regression.Results89 subjects (mean age 54+/-7 years; 52 men) were included. Fully-automated CP calcium quantification was accurate (ICC with semi-manual tracing = .98.) The significant predictors of cortical neuroinflammation were subject age (p=.002) and CP calcium volume (p=.041), but not ventricle or CP volume.ConclusionCP calcium volume can be accurately measured using low-dose CT acquired routinely with PET-CT. CP calcification – but not CP overall volume – was associated with cortical inflammation. Unmeasured CP calcification may be relevant to recent reports of CP enlargement in human inflammatory and other diseases. CP calcification may be a specific and relatively easily-acquired biomarker for neuroinflammation and CP pathology.Key ResultsChoroid plexus (CP) calcification volume can be reliably quantified using semi-manual tracing on low-dose CT acquired with PET-CT, and fully automatically using our new, accurate (ICC with semi-manual tracing = .98) CT/MRI method.CP calcification and age –but not overall CP volume– significantly predicted 11C-PK11195 PET-measured cortical neuroinflammation in 89 subjects.CP calcification is a relatively easily-assessed, previously-overlooked potential biomarker for neuroinflammation and CP pathology.

The glymphatic system is a perivascular fluid clearance system, most active during sleep, considered important for clearing the brain of waste products and toxins. Glymphatic failure is hypothesized to underlie brain protein deposition in neurodegenerative disorders like Alzheimer’s Disease. Preclinical evidence suggests that a functioning glymphatic system is also essential for recovery from traumatic brain injury (TBI), which involves release of debris and toxic proteins that need to be cleared from the brain.We estimated glymphatic clearance using Diffusion Tensor Imaging Along Perivascular Spaces (DTI-ALPS), an MRI-derived measure of water diffusivity surrounding veins, in 13 non-injured controls and 37 subjects with TBI (∼5 months post). We additionally measured plasma concentrations of Neurofilament light chain (NfL), a biomarker of injury severity, in a subset of subjects.DTI-ALPS was significantly lower in TBI subjects compared to controls, after controlling for age, and significantly, negatively correlated with NfL.Glymphatic impairment after TBI could be due to mechanisms such as mis-localization of glymphatic water channels, inflammation, proteinopathy and/or sleep disruption. Additional work, including longitudinal studies, are needed to confirm results and assess glymphatic associations with outcome. Understanding post-TBI glymphatic functioning could inform novel therapies to improve short-term recovery and reduce later risk of neurodegeneration.

Repeated mild Traumatic Brain Injury (TBI) is a risk factor for Chronic Traumatic Encephalopathy (CTE), characterized pathologically by neurofibrillary tau deposition in the depths of brain sulci and surrounding blood vessels. The mechanism by which TBI leads to CTE remains unknown but has been posited to relate to axonal shear injury leading to release and possibly deposition of tau at the time of injury. As part of an IRB-approved study designed to learn how processes occurring acutely after TBI may predict later proteinopathy and neurodegeneration, we performed tau PET using 18F-MK6240 and MRI within 14 days of complicated mild TBI in three subjects. PET radiotracer accumulation was apparent in regions of traumatic hemorrhage in all subjects, with prominent intraparenchymal PET signal in one young subject with a history of repeated sports-related concussions. These results are consistent with off-target tracer binding to blood products as well as possible on-target binding to chronically and/or acutely-deposited neurofibrillary tau. Both explanations are highly relevant to applying tau PET to understanding TBI and CTE. Additional study is needed to assess the potential utility of tau PET in understanding how processes occurring acutely after TBI, such as release and deposition of tau and blood from damaged axons and blood vessels, may relate to development CTE years later.

In rodents, hypothalamic inflammation plays a critical role in aging and age-related diseases. We used Positron Emission Tomography with a radiotracer sensitive to the TSPO molecule expressed by activated microglia to assess, for the first time, human hypothalamic inflammation. We found that women but not men showed age-correlated hypothalamic TSPO expression, and suggest this is relevant to understanding a stark sex difference in human aging, namely, that only women undergo menopause.

Intracranial electrode arrays are routinely used in the pre-surgical evaluation of patients with medically refractory epilepsy, and recordings from these electrodes have been increasingly employed in human cognitive neurophysiology due to their high spatial and temporal resolution. For both researchers and clinicians, it is critical to localize electrode positions relative to the subject-specific neuroanatomy. In many centers, a post-implantation MRI is utilized for electrode detection because of its higher sensitivity for surgical complications and the absence of radiation. However, magnetic susceptibility artifacts surrounding each electrode prohibit unambiguous detection of individual electrodes, especially those that are embedded within dense grid arrays. Here, we present an efficient method to accurately localize intracranial electrode arrays based on pre- and post-implantation MR images that incorporates array geometry and the individual's cortical surface. Electrodes are directly visualized relative to the underlying gyral anatomy of the reconstructed cortical surface of individual patients. Validation of this approach shows high spatial accuracy of the localized electrode positions (mean of 0.96 mm ± 0.81 mm for 271 electrodes across 8 patients). Minimal user input, short processing time, and utilization of radiation-free imaging are strong incentives to incorporate quantitatively accurate localization of intracranial electrode arrays with MRI for research and clinical purposes. Co-registration to a standard brain atlas further allows inter-subject comparisons and relation of intracranial EEG findings to the larger body of neuroimaging literature.

This paper deals with the morphology, fineness and pozzolanic activity of four glass powders: one (GP-fine) from the screening of crushed waste glasses, one (GP-dust) from a dust collector for the glass crushing process and two (GP-4000 and GP-6000) from further grinding of the powder from the dust collector in a ball mill. GP-fine and GP-dust consist mainly of large flaky particles, while GP-4000 and GP-6000 consist mainly of small angular particles. The finenesses of these glass powders are measured by particle size distribution and Blaine fineness method. For a similar particle size distribution, ground glass powder has a higher Blaine specific surface area than Portland cement due to the angular morphology of glass particles. Finely ground glass powders exhibited very high pozzolanic activity. The finer the glass powder is, the higher its pozzolanic reactivity is. An increase in curing temperature accelerates the activation of pozzolanic reactivity of both glass powder and coal fly ash in terms of strength development rate. Mortar cube strength results (ASTM C109) indicated that curing temperature has a greater influence on the glass powder than on fly ash. The rapid mortar bar expansion test (ASTM C1260) results indicate that the replacement of Portland cement with ground glass powder also reduces the expansion due to alkali–aggregate reactions, although it is not as effective as coal fly ash.

Tumor necrosis factor alpha (TNFalpha) is an immunomodulatory and proinflammatory cytokine implicated in neuroinflammation and neuronal damage in response to cerebral ischemia. Tumor necrosis factor-alpha converting enzyme (TACE or ADAM17) is a key sheddase that releases TNFalpha from its inactive cell-bound precursor. Using a selective small molecule inhibitor of TACE, DPH-067517, we tested the hypothesis that inhibition of TNFalpha formation might have a salutary effect in ischemic stroke induced by embolic occlusion of the middle cerebral artery (MCAO). DPH-067517 selectively inhibited TACE enzyme activity in vitro (K(i) = 2.8 nM), and effectively suppressed ischemia-induced increase in soluble TNFalpha in brain tissue after systemic administration. DPH-067517 (3 and 30 mg/kg, i.p. administered 15 min before MCAO) produced 43% (n = 8, p = 0.16) and 58% (n = 8, p0.05) reduction in infarct size and 36% (p0.05) and 23% (p0.05) reduction in neurological deficits, respectively. The salutary effect of DPH-067517 in ischemic brain injury was also observed when the first dose was administrated 60 min after the onset of ischemia. Inhibition of TACE had no effect on apoptosis measured by levels of active caspase-3 expression and DNA fragmentation. Our data suggest that inhibition of TACE might be a potential therapeutic strategy for neuroprotection after focal ischemic stroke.

Background and Purpose— Factor Xa (FXa) is a key coagulation protease and target for novel antithrombotic agents for prevention and treatment of diverse thromboembolic disorders. In the present study we describe the effect of a novel, potent, and selective FXa inhibitor, DPC602, on brain damage and neurobehavioral consequence in a rat thromboembolic model of stroke. Methods— Thromboembolic stroke was induced in rats by placement of an autologous clot into the middle cerebral artery. Results— Laser-Doppler monitoring of cerebral blood flow demonstrated that DPC602 (8 mg/kg, single IV/IP bolus pretreatment) markedly improved cerebral blood flow after thromboembolic stroke by 25% to 160% (n=6; P P P Conclusions— These data suggest that anticoagulation with a selective FXa inhibitor might ameliorate the extent of ischemic brain damage and neurological deficits after a thromboembolic event. Enhanced clot dissolution and early reperfusion may account for the cerebrovascular-protective effect of the drug.

Epidermal growth factor (EGF) up-regulation of glucose absorption via increased Na+/glucose cotransporter (SGLT-1) activity has previously been described in rabbit jejunal brush-border membrane and in differentiated Caco-2 cells. The goal of the present study was to assess the in vitro effect of EGF (200 ng/ml) on glucose uptake in human mucosal specimens, and we describe a simple procedure that uses endoscopic biopsies for short-term gludose uptake measurements. Uptake values for the EGF-treated biopsies ranged from 2.7 to 29.0, with a mean uptake of 10.65, while uptake values for the untreated biopsies ranged from 0.9 to 17.5, with a mean uptake of 7.99 (P < 0.05, paired t test). This early effect of EGF on human enterocytes may have important therapeutic implications. A role in increasing the rate of internal rehydration is suggested.

CD44 is a transmembrane glycoprotein known to be involved in endothelial cell recognition, lymphocyte trafficking, and regulation of cytokine gene expression in inflammatory diseases. In the present study, we demonstrated that the expression of CD44 mRNA was induced in a mouse model of cerebral ischemia. A potential role of CD44 in ischemic brain injury was investigated using CD44-deficient (CD44-/-) mice. Over 50% (p < 0.05, n = 14) and 78% (p < 0.05, n = 10) reduction in ischemic infarct was observed in CD44-/- mice compared with that of wild-type mice following transient (30 min ischemia) and permanent (24 h) occlusion of the middle cerebral artery (MCAO), respectively. Similarly, significant improvement was observed in neurological function in CD44-/- mice as evidenced by spontaneous and forced motor task scores. The marked protection from ischemic brain injury in CD44-/- mice was associated with normal physiological parameters, cytokine gene expression, astrocyte and microglia activation as compared with wild-type mice. However, in CD44-/- mice, significantly lower expression of soluble interleukin-1beta protein was noted after brain ischemia. Our data provide new evidence on the potential role of CD44 in brain tissue in response to ischemia and may suggest that this effect might be associated with selective reduction in inflammatory cytokines such as interleukin-1beta.

Mitogen-activated protein (MAP) kinase-activated protein kinase 2 (MK2) is one of several kinases directly regulated by p38 MAP kinase. A role of p38 MAP kinase in ischemic brain injury has been previously suggested by pharmacological means. In the present study, we provide evidence for a role of MK2 in cerebral ischemic injury using MK2-deficient (MK2(-/-)) mice. MK2(-/-) mice subjected to focal ischemia markedly reduced infarct size by 64 and 76% after transient and permanent ischemia, respectively, compared with wild-type mice. Furthermore, MK2(-/-) mice had significant reduction in neurological deficits. Real-time PCR analysis identified a significantly lower expression in interleukin-1beta mRNA (53% reduction) but not in tumor necrosis factor-alpha mRNA in MK2(-/-) mice over wild-type animals after ischemic injury. The significant reduction in interleukin-1beta was also confirmed in MK2(-/-) mice by enzyme-linked immunosorbent assay. The marked neuroprotection from ischemic brain injury in MK2(-/-) mice was not associated with the alteration of hemodynamic or systemic variables, activation of caspase-3, or apoptosis. Our data provide new evidence for the involvement of MAP kinase pathway in focal ischemic brain injury and suggest that this effect might be associated with the expression of interleukin-1beta in the ischemic brain tissue.

Introduction: The cellular microenvironment plays a key role in the pathogenesis of B-cell malignancies (Amé-Thomas, Blood 2007; Podar, Leukemia 2009). Bone marrow stromal cell interactions can provide survival signals to CLL cells (Kurtova, Blood 2009), and stromal cell gene signatures and markers can predict survival outcomes and add prognostic value, respectively, for patients with DLBCL (Lenz, NEJM 2008; Meyer, Am J Clin Pathol 2011). Ibrutinib (ibr), a first-in-class, oral, once-daily inhibitor of Bruton’s tyrosine kinase, has demonstrated single-agent activity in R/R DLBCL (Wilson, Nat Med 2015). In this study, we established an in vitro coculture system and report the effects of stromal cells on ABC-DLBCL cells and their sensitivity to ibr. Methods: The effect of ibr on cell growth was evaluated by luminescent cell viability assay. Flow cytometry was used to evaluate the effect of ibr on cell death in different cell populations. Live-cell imaging detected drug effects on apoptosis at different time points. Gene expression levels in B lymphoma cells were examined by quantitative PCR and NanoString panels. Human cytokines/chemokines were quantified using MILLIPLEX® MAP Kit. Results: Reduced ibr sensitivity was observed in TMD8 DLBCL cells cocultured with HS-5 bone marrow-derived stromal cells. HS-5 cells protected TMD8 cells from ibr-induced apoptosis. Treatment with ibr induced TNFSF10 expression only in TMD8 cells without HS-5 coculture, providing a survival mechanism for escape of ibr-induced cell death. In addition, coculturing with HS-5 decreased surface expression of CD20 but not CD19. Several cytokines/chemokines showed differential expression in the coculture system (increased CCL22 and IL-10; decreased CCL4 and TNFβ). Reduced expression of BCR signaling-related miR-155 was observed in ABC-DLBCL and CLL cell lines with HS-5 coculture, suggesting downregulation of BCR signaling in these cells. The adhesion molecule, SELL, showed decreased expression in the ABC-DLBCL cells cultured with HS-5 as well as in ibr-resistant TMD8 cells, consistent with our observation that ABC-DLBCL patients with poor responses (PD+SD) to ibr have lower SELL expression in their tumor samples. We further assessed expression levels of amino acid metabolism-related genes and demonstrated significant increases of ASS1 and TDO2 in the TMD8 cells cocultured with HS-5. Expression levels of amino acid metabolism-related genes varied across patients with different responses to ibr, further suggesting the importance of amino acid levels in the tumor microenvironment and ibr response. Conclusions: The changes in ABC-DLBCL cells cocultured with stromal cells identified here may provide new insights into cellular cross-talk in the microenvironment. Further investigation into cell-cell interactions and ibr may help stratify patient populations and provide new therapeutic strategies. Citation Format: Hsu-Ping Kuo, Sidney Hsieh, Mint Sirisawad, Chun-Te Chen, Leo W. Cheung, Karl J. Schweighofer, Chia-Lin Hsu, Chi-Ling Fu, Jing Liu, Shiquan Wu, Karl Eckert, Hugh Wang, Mutiah Apatira, Kamaldeep Dhami, Kevin Kwei, Jeff Hsu, Betty Y. Chang. Interaction of B lymphoma cells with the microenvironment affects ibrutinib sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4197. doi:10.1158/1538-7445.AM2017-4197

The study described in this paper involved a close examination of one of the least-researched cement phases, 4CaO•Al(2)O(3)•Fe(2)O(3) (C(4)AF or ferrite). The two ferrite materials used in this program were: (1) extracted from an industrial clinker free of 3CaO•Al(2)O(3) (C(3)A or aluminate); and (2) a laboratory-synthesized C(4)AF compound. Both ferrite materials were initially characterized using optical microscopy, x-ray diffraction (XRD), and Raman spectroscopy. The hydration kinetics and reactivity of both materials were studied with a calorimetric technique. Similar to aluminate, ferrite also demonstrated a strong early hydration rate. An adequate amount of sulfate (SO(3)) was needed to regulate the ferrite hydration rate. Based on this work, an equivalent aluminate content, C(3)A(eq), is proposed. The hydration of C(3)A(eq) needs to be properly controlled with the appropriate amount of sulfate. The concept, based on equivalent aluminate content for cement sulfate optimization, ensures proper early hydration behavior from both C(3)A and C(4)AF and avoids potential cement-admixture incompatibility probems, especially for the cements containing little or no C(3)A content.

Activation of the extracellular-signal-responsive kinase (ERK 1/2) by MAP kinase/ERK kinase (MEK1/2) following ischemia/reperfusion in the brain has been associated with cell death since inhibition of MEK1/2 provides neuroprotection in cerebral ischemia injury. Since inflammation has been implicated in ischemic brain injury, the present study investigated whether MEK1/2 modifies expression of two key inflammatory cytokines, IL-1beta and TNFalpha, that have been shown to exacerbate ischemic brain injury. A mouse model of transient cerebral ischemia was deployed to test the effect of selective MEK1/2 inhibitor (SL327) on infarct size and cytokine expression. SL327 (100 mg/kg, i.p.) administered 15 min prior to ischemia resulted in 64% reduction in infarct size over controls (n = 8, P < 0.01). Under the same condition, SL327 significantly reduced peak expression of IL-1beta mRNA (59% reduction compared to vehicle, P < 0.01, n = 4) but not TNF-alpha mRNA. A parallel reduction in IL-1beta protein (67%, P < 0.05, n = 6) was also observed using ELISA analysis. These data suggest that the neuroprotective effect of MEK1/2 inhibition may be mediated by suppression of IL-1beta. The study also demonstrates for the first time that these two cytokines are differentially regulated by kinase mediated signaling pathways.

Background and Purpose —CD44 is a transmembrane glycoprotein involved in endothelial cell recognition, lymphocyte trafficking, and regulation of cytokine gene expression in inflammatory diseases. The present report describes the discovery of upregulated CD44 gene expression and its spatial and temporal distribution in the brain after focal stroke. Methods —Rats were subjected to permanent occlusion of the middle cerebral artery (MCAO). Suppression subtractive hybridization (SSH) strategy was used to identify differentially expressed genes. Northern blotting and real-time polymerase chain reaction were used to evaluate the expression of CD44 and hyaluronan synthase 2 (HAS-2) mRNA. Western blotting and immunohistochemistry were used to examine CD44 expression and cellular distribution. Results —CD44 upregulation after focal stroke was discovered by the SSH approach and confirmed by DNA sequencing. Northern blot using a pooled poly(A)+ RNA revealed 3 splice variants of CD44 mRNA, and their inducible expression started at 6 hours (5.3-fold increase over sham operation), peaked at 24 hours (28.6-fold increase), and persisted up to 72 hours (17.8-fold increase) after MCAO. A parallel induction profile of HAS-2 mRNA was observed in the ischemic brain tissue. The levels of CD44 were markedly elevated at 6 hours (1.8-fold increase over sham; n=3), 24 hours (2.9-fold, peak induction; P P Conclusions —The discovery of concomitant induction of CD44 and HAS-2 mRNA expression and the localization of CD44 in the microglia, macrophages, and microvessels of the ischemic brain tissue suggest that an active interaction between CD44 and hyaluronan may occur and play a role in the known inflammatory response and tissue remodeling after stroke.

Septal nuclei, located in basal forebrain, are strongly connected with hippocampi and important in learning and memory, but have received limited research attention in human MRI studies. While probabilistic maps for estimating septal volume on MRI are now available, they have not been independently validated against manual tracing of MRI, typically considered the gold standard for delineating brain structures. We developed a protocol for manual tracing of the human septal region on MRI based on examination of neuroanatomical specimens. We applied this tracing protocol to T1 MRI scans (n=86) from subjects with temporal epilepsy and healthy controls to measure septal volume. To assess the inter-rater reliability of the protocol, a second tracer used the same protocol on 20 scans that were randomly selected from the 72 healthy controls. In addition to measuring septal volume, maximum septal thickness between the ventricles was measured and recorded. The same scans (n=86) were also analyzed using septal probabilistic maps and DARTEL toolbox in SPM. Results show that our manual tracing algorithm is reliable, and that septal volume measurements obtained via manual and automated methods correlate significantly with each other (p

A boy with failure to thrive and isolated pancreatic amylase deficiency is described. Immunoprecipitation confirmed only salivary isoamylase in duodenal fluid at ages 20 and 33 months. Because normal pancreatic amylase messenger RNA was detected by reverse-transcriptase polymerase chain reaction in the fluid, failure of the normal maturation of pancreatic amylase secretion may explain the deficiency.

Epidermal growth factor (EGF) up-regulation of glucose absorption via increased Na+/glucose co-transporter (SGLT-1) activity has previously been described in rabbit jejunal brush-border membrane and in differentiated Caco-2 cells. The goal of the present study was to assess the in vitro effect of EGF (200 ng/ml) on glucose uptake in human mucosal specimens, and we describe a simple procedure that uses endoscopic biopsies for short-term gludose uptake measurements. Uptake values for the EGF-treated biopsies ranged from 2.7 to 29.0, with a mean uptake of 10.65, while uptake values for the untreated biopsies ranged from 0.9 to 17.5, with a mean uptake of 7.99 (P0.05, paired t test). This early effect of EGF on human enterocytes may have important therapeutic implications. A role in increasing the rate of internal rehydration is suggested.

Platelet accretion into arterial thrombus in stenotic arterial vessels involves shear-induced platelet activation and adhesion. The Cone and Plate(let) Analyzer (CPA) is designed to simulate such conditions in vitro under a rotating high shear rate in whole blood. In the present study, we evaluated various experimental conditions (including aspirin, temperature, and calcium concentration) and investigated the effects of small molecules along with peptide glycoprotein IIb/IIIa antagonists on platelet adhesion using the CPA system. Concentration-dependent effect of glycoprotein IIb/IIIa antagonists on shear-induced platelet adhesion showed marked differences in potencies: IC50 = 34, 35, 91, 438, and 606 nM for DPC802 (a specific glycoprotein IIb/IIIa antagonist), roxifiban, sibrafiban, lotrafiban, and orbofiban (free acid forms), respectively, and IC50 values of 43, 430, and 5781 nM for abciximab, tirofiban, and eptifibatide, respectively. Parallel study was also conducted to evaluate the effect of glycoprotein IIb/IIIa inhibitors using optical aggregometry. The potency of fibans in blocking shear-induced platelet adhesion correlated well with their binding affinity to the resting and activated glycoprotein IIb/IIIa receptors, as well as their “off-rates”. Nevertheless, none of these fibans was able to effectively block shear-induced platelet adhesion at targeted clinical dosing regimens except for abciximab. These data suggest that glycoprotein IIb/IIIa antagonists that show similar efficacy in the inhibition of platelet aggregation in a static in vitro assay may differ substantially in a shear-based system of platelet adhesion. The clinical significance of this phenomenon awaits further investigation.

CD44 is a transmembrane glycoprotein known to be involved in endothelial cell recognition, lymphocyte trafficking, and regulation of cytokine gene expression in inflammatory diseases. In the present study, we demonstrated that the expression of CD44 mRNA was induced in a mouse model of cerebral ischemia. A potential role of CD44 in ischemic brain injury was investigated using CD44-deficient (CD44-/-) mice. Over 50% (p0.05, n = 14) and 78% (p0.05, n = 10) reduction in ischemic infarct was observed in CD44-/- mice compared with that of wild-type mice following transient (30 min ischemia) and permanent (24 h) occlusion of the middle cerebral artery (MCAO), respectively. Similarly, significant improvement was observed in neurological function in CD44-/- mice as evidenced by spontaneous and forced motor task scores. The marked protection from ischemic brain injury in CD44-/- mice was associated with normal physiological parameters, cytokine gene expression, astrocyte and microglia activation as compared with wild-type mice. However, in CD44-/- mice, significantly lower expression of soluble interleukin-1beta protein was noted after brain ischemia. Our data provide new evidence on the potential role of CD44 in brain tissue in response to ischemia and may suggest that this effect might be associated with selective reduction in inflammatory cytokines such as interleukin-1beta.

In the present study, an extensive test program is conducted to measure and compare the heat of hydration obtained from both calorimeter and ASTM C186-05 test methods. A statistical analysis is performed to evaluate the variations of the test data. The results indicate that the isothermal conduction calorimeter method is a more reliable, less time-consuming, and less labor-intensive method than the ASTM C186-05 test method. The heat of hydration at 3 days showed the least variation in all calorimeter tests. These suggest that ASTM shall consider adopting the isothermal conduction calorimeter method for measuring the heat of hydration of cement. The 3-day heat of hydration value can be used for specifying the limit of heat release for type II cements.