Magnetic resonance imaging indicators of blood-brain barrier and brain water changes in young rats with kaolin-induced hydrocephalus

<p>Abstract</p> <p>Background</p> <p>Hydrocephalus is associated with enlargement of cerebral ventricles. We hypothesized that magnetic resonance (MR) imaging parameters known to be influenced by tissue water content would change in parallel with ventricle size in young rats and that changes in blood-brain barrier (BBB) permeability would be detected.</p> <p>Methods</p> <p>Hydrocephalus was induced by injection of kaolin into the cisterna magna of 4-week-old rats, which were studied 1 or 3 weeks later. MR was used to measure longitudinal and transverse relaxation times (T1 and T2) and apparent diffusion coefficients in several regions. Brain tissue water content was measured by the wet-dry weight method, and tissue density was measured in Percoll gradient columns. BBB permeability was measured by quantitative imaging of changes on T1-weighted images following injection of gadolinium diethylenetriamine penta-acetate (Gd-DTPA) tracer and microscopically by detection of fluorescent dextran conjugates.</p> <p>Results</p> <p>In nonhydrocephalic rats, water content decreased progressively from age 3 to 7 weeks. T1 and T2 and apparent diffusion coefficients did not exhibit parallel changes and there was no evidence of BBB permeability to tracers. The cerebral ventricles enlarged progressively in the weeks following kaolin injection. In hydrocephalic rats, the dorsal cortex was more dense and the white matter less so, indicating that the increased water content was largely confined to white matter. Hydrocephalus was associated with transient elevation of T1 in gray and white matter and persistent elevation of T2 in white matter. Changes in the apparent diffusion coefficients were significant only in white matter. Ventricle size correlated significantly with dorsal water content, T1, T2, and apparent diffusion coefficients. MR imaging showed evidence of Gd-DTPA leakage in periventricular tissue foci but not diffusely. These correlated with microscopic leak of larger dextran tracers.</p> <p>Conclusions</p> <p>MR characteristics cannot be used as direct surrogates for water content in the immature rat model of hydrocephalus, probably because they are also influenced by other changes in tissue composition that occur during brain maturation. There is no evidence for widespread persistent opening of BBB as a consequence of hydrocephalus in young rats. However, increase in focal BBB permeability suggests that periventricular blood vessels may be disrupted.</p

Leukocyte- and Platelet-Derived Microvesicle Interactions following In Vitro and In Vivo Activation of Toll-Like Receptor 4 by Lipopolysaccharide

BACKGROUND: Pro-coagulant membrane microvesicles (MV) derived from platelets and leukocytes are shed into the circulation following receptor-mediated activation, cell-cell interaction, and apoptosis. Platelets are sentinel markers of toll-like receptor 4 (TLR4) activation. Experiments were designed to evaluate the time course and mechanism of direct interactions between platelets and leukocytes following acute activation of TLR4 by bacterial lipopolysaccharide (LPS). METHODOLOGY/PRINCIPAL FINDINGS: Blood from age-matched male and female wild type (WT) and TLR4 gene deleted (dTLR4) mice was incubated with ultra-pure E. coli LPS (500 ng/ml) for up to one hour. At designated periods, leukocyte antigen positive platelets, platelet antigen positive leukocytes and cell-derived MV were quantified by flow cytometry. Numbers of platelet- or leukocyte-derived MV did not increase within one hour following in vitro exposure of blood to LPS. However, with LPS stimulation numbers of platelets staining positive for both platelet- and leukocyte-specific antigens increased in blood derived from WT but not dTLR4 mice. This effect was blocked by inhibition of TLR4 signaling mediated by My88 and TRIF. Seven days after a single intravenous injection of LPS (500 ng/mouse or 20 ng/gm body wt) to WT mice, none of the platelets stained for leukocyte antigen. However, granulocytes, monocytes and apoptotic bodies stained positive for platelet antigens. CONCLUSIONS/SIGNIFICANCE: Within one hour of exposure to LPS, leukocytes exchange surface antigens with platelets through TLR4 activation. In vivo, leukocyte expression of platelet antigen is retained after a single exposure to LPS following turn over of the platelet pool. Acute expression of leukocyte antigen on platelets within one hour of exposure to LPS and the sustained expression of platelet antigen on leukocytes following a single acute exposure to LPS in vivo explains, in part, associations of platelets and leukocytes in response to bacterial infection and changes in thrombotic propensity of the blood

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

IMPROVED DYNAMIC-MODEL OF THE HUMAN KNEE-JOINT AND ITS RESPONSE TO IMPACT LOADING ON THE LOWER LEG

Almost a decade ago, three-dimensional formulation for the dynamic modeling of an articulating human joint was introduced. Two-dimensional version of this fomulation was subsequently applied to the knee joint. However, because of the iterative nature of the solution technique, this model cannot handle impact conditions. In this paper, alternative solution methods are introduced which enable investigation of the response of the human knee to impact loading on the lower leg via an anatomically based model. In addition, the classical impact theory is applied to the same model and a closed-form solution is obtained. The shortcomings of the classical impact theory as applied to the impact problem of the knee joint are delineated

3-BODY SEGMENT DYNAMIC-MODEL OF THE HUMAN KNEE

In this paper, a two-dimensional, three-body segment dynamic model of the human knee is introduced. The model includes tibio-femoral and patello-femoral articulations, and anterior cruciate, posterior cruciate, medial collateral, lateral collateral and patellar ligaments. It enables one to obtain dynamic response of the knee joint to any one or combination of quadriceps femoris, hamstrings, and gastrocnemius muscle actions, as well as any externally applied forces on the lower leg. A specially developed human knee animation program is utilized in order to fine tune some model parameters. Numerical results are presented for knee extension under the impulsive action of the quadriceps femoris muscle group to simulate a vigorous lower limb activity such as kicking. The model shows that the patella can be subjected to very large transient patello-femoral contact force during a strenuous lower limb activity even under conditions of small knee-flexion angles. The results are discussed and compared with limited data reported in the literature

Evolution of Task Partitioning in Swarm Robotics

status: publishe

ARCHITECTURE OF LATE OROGENIC QUATERNARY BASINS IN NORTHEASTERN MEDITERRANEAN-SEA

In the northeastern Mediterranean Sea, Pliocene to Quaternary depocentres have formed in extensional basins bounded by splays of the East Anatolian Transform Fault. This tectonic regime is superimposed on a Miocene and older back-arc environment, that experienced late Miocene compression along the Misis-Kyrenia thrust, which now lies in the middle of the extensional zone. The thrust zone is now represented by a narrow horst that appears to be bounded by strike-slip faults. Pliocene-Quaternary extension took place on listric fault fans that are orthogonal to the bounding transform splays and sole at a Messinian evaporite horizon, and on some deeper-soling listric faults parallel to and near the bounding faults. The rapid extension has resulted in progressive landward migration of paleoshorelines and low depositional gradients. Glacio-eustatic fluctuations in shoreline positions strongly influenced sediment distribution. Most sediment dispersion was from deltaic plumes, with turbidites of minor significance. Depocentres landward of the maximum seaward extent of paleoshorelines were formed almost entirely by tectonic subsidence. Minor deep-water depocentres, controlled by halokinesis, accumulated mud turbidites during extreme low-stands of sea-level

QUATERNARY SEDIMENTARY HISTORY OF ADANA, CILICIA AND ISKENDERUN BASINS - NORTHEAST MEDITERRANEAN-SEA

Detailed single-channel airgun and 3.5 kHz profiles from the northeastern Mediterranean Sea show that the continental shelf is formed by superimposed deltaic successions (depositional sequences), separated by major erosional unconformities. Each depositional sequence is composed of a sigmoid prograding package overlain by an oblique prograding package, representing respectively delta progradation during high and low sea levels of interglacial and subsequent glacial stages. During the glacio-eustatic lowstands of sea level, deltas prograded seaward. The present-day shelf break denotes the topset to foreset transition at maximum progradation during the last glacial period. During post-glacial transgressions, the deltas initially lost their dynamic equilibrium with the environment and rapidly retreated landward. leading to the deposition of a thin veneer of sediments originating from reworking of formerly coastal sediments. At the highstand position the deltas were re-established in the ancestral Adana Bay and foreset progradation started. Chronology suggests that the Cilicia and Iskenderun Basins are subsiding at rates of 0.38 m 1000 yr-1 and 0.33 m 1000 yr-1. respectively. Seismic reflection profiling shows that delta architecture in the Adana. Cilicia and Iskenderun Basins is mainly controlled by glacio-eustatic sea-level fluctuations and continuous basin subsidence