Diffusion with rearranging traps

A model for diffusion on a cubic lattice with a random distribution of traps is developed. The traps are redistributed at certain time intervals. Such models are useful for describing systems showing dynamic disorder, such as ion-conducting polymers. In the present model the traps are infinite, unlike an earlier version with finite traps, this model has a percolation threshold. For the infinite trap version a simple analytical calculation is possible and the results agree qualitatively with simulation.Comment: Latex, five figure

Phosphodiesterase-III Inhibitor Prevents Hemorrhagic Transformation Induced by Focal Cerebral Ischemia in Mice Treated with tPA

The purpose of the present study was to investigate whether cilostazol, a phosphodiesterase-III inhibitor and antiplatelet drug, would prevent tPA-associated hemorrhagic transformation. Mice subjected to 6-h middle cerebral artery occlusion were treated with delayed tPA alone at 6 h, with combined tPA plus cilostazol at 6 h, or with vehicle at 6 h. We used multiple imaging (electron microscopy, spectroscopy), histological and neurobehavioral measures to assess the effects of the treatment at 18 h and 7 days after the reperfusion. To further investigate the mechanism of cilostazol to beneficial effect, we also performed an in vitro study with tPA and a phosphodiesterase-III inhibitor in human brain microvascular endothelial cells, pericytes, and astrocytes. Combination therapy with tPA plus cilostazol prevented development of hemorrhagic transformation, reduced brain edema, prevented endothelial injury via reduction MMP-9 activity, and prevented the blood-brain barrier opening by inhibiting decreased claudin-5 expression. These changes significantly reduced the morbidity and mortality at 18 h and 7 days after the reperfusion. Also, the administration of both drugs prevented injury to brain human endothelial cells and human brain pericytes. The present study indicates that a phosphodiesterase-III inhibitor prevents the hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA

Haemoglobin level at birth is associated with short term outcomes and mortality in preterm infants

Background Blood volume and haemoglobin (Hb) levels are increased by delayed umbilical cord clamping, which has been reported to improve clinical outcomes of preterm infants. The objective was to determine whether Hb level at birth was associated with short term outcomes in preterm infants born at ≤32 weeks gestation. Methods Data were collected retrospectively from electronic records: Standardised Electronic Neonatal Database, Electronic Patient Record, Pathology (WinPath), and Blood Bank Electronic Database. The study was conducted in a tertiary perinatal centre with around 5,500 deliveries and a neonatal unit admission of 750 infants per year. All inborn preterm infants of 23 to 32 weeks gestational age (GA) admitted to the neonatal unit from January 2006 to September 2012 were included. The primary outcomes were intra-ventricular haemorrhage, necrotising entero-colitis, broncho-pulmonary dysplasia, retinopathy of prematurity, and death before discharge. The secondary outcomes were receiving blood transfusion and length of intensive care and neonatal unit days. The association between Hb level (g/dL) at birth and outcomes was analysed by multiple logistic regression adjusting for GA and birth weight (BWt). Results Overall, 920 infants were eligible; 28 were excluded because of missing data and 2 for lethal congenital malformation. The mean (SD) GA was 28.3 (2.7) weeks, BWt was 1,140 (414) g, and Hb level at birth was 15.8 (2.6) g/dL. Hb level at birth was significantly associated with all primary outcomes studied (P <0.001) in univariate analyses. Once GA and BWt were adjusted for, only death before discharge remained statistically significant; the OR of death for infants with Hb level at birth <12 g/dL compared with those with Hb level at birth of ≥18 g/dL was 4.1 (95% CI, 1.4–11.6). Hb level at birth was also significantly associated with blood transfusion received (P <0.01) but not with duration of intensive care or neonatal unit days. Conclusions Low Hb level at birth was significantly associated with mortality and receiving blood transfusion in preterm infants born at ≤32 weeks gestation. Further studies are needed to determine the association between Hb level at birth and long-term neurodevelopmental outcomes

uPA is upregulated by high dose celecoxib in women at increased risk of developing breast cancer

<p>Abstract</p> <p>Background</p> <p>While increased urokinase-type plasminogen activator (uPA) expression in breast cancer tissue is directly associated with poor prognosis, recent evidence suggests that uPA overexpression may suppress tumor growth and prolong survival. Celecoxib has been shown to have antiangiogenic and antiproliferative properties. We sought to determine if uPA, PA inhibitor (PAI)-1 and prostaglandin (PG)E₂expression in nipple aspirate fluid (NAF) and uPA and PGE₂expression in plasma were altered by celecoxib dose and concentration in women at increased breast cancer risk.</p> <p>Methods</p> <p>NAF and plasma samples were collected in women at increased breast cancer risk before and 2 weeks after taking celecoxib 200 or 400 mg twice daily (bid). uPA, PAI-1 and PGE₂were measured before and after intervention.</p> <p>Results</p> <p>Celecoxib concentrations trended higher in women taking 400 mg (median 1025.0 ng/mL) compared to 200 mg bid (median 227.3 ng/mL), and in post- (534.6 ng/mL) compared to premenopausal (227.3 ng/mL) women. In postmenopausal women treated with the higher (400 mg bid) celecoxib dose, uPA concentrations increased, while PAI-1 and PGE₂decreased. In women taking the higher dose, both PAI-1 (r = -.97, p = .0048) and PGE₂(r = -.69, p = .019) in NAF and uPA in plasma (r = .45, p = .023) were correlated with celecoxib concentrations.</p> <p>Conclusion</p> <p>Celecoxib concentrations after treatment correlate inversely with the change in PAI-1 and PGE₂in the breast and directly with the change in uPA in the circulation. uPA upregulation, in concert with PAI-1 and PGE₂downregulation, may have a cancer preventive effect.</p

Induction of Blood Brain Barrier Tight Junction Protein Alterations by CD8 T Cells

Disruption of the blood brain barrier (BBB) is a hallmark feature of immune-mediated neurological disorders as diverse as viral hemorrhagic fevers, cerebral malaria and acute hemorrhagic leukoencephalitis. Although current models hypothesize that immune cells promote vascular permeability in human disease, the role CD8 T cells play in BBB breakdown remains poorly defined. Our laboratory has developed a novel murine model of CD8 T cell mediated central nervous system (CNS) vascular permeability using a variation of the Theiler's virus model of multiple sclerosis. In previous studies, we observed that MHC class II−/− (CD4 T cell deficient), IFN-γR−/−, TNF-α−/−, TNFR1−/−, TNFR2−/−, and TNFR1/TNFR2 double knockout mice as well as those with inhibition of IL-1 and LTβ activity were susceptible to CNS vascular permeability. Therefore, the objective of this study was to determine the extent immune effector proteins utilized by CD8 T cells, perforin and FasL, contributed to CNS vascular permeability. Using techniques such as fluorescent activated cell sorting (FACS), T1 gadolinium-enhanced magnetic resonance imaging (MRI), FITC-albumin leakage assays, microvessel isolation, western blotting and immunofluorescent microscopy, we show that in vivo stimulation of CNS infiltrating antigen-specific CD8 T cells initiates astrocyte activation, alteration of BBB tight junction proteins and increased CNS vascular permeability in a non-apoptotic manner. Using the aforementioned techniques, we found that despite having similar expansion of CD8 T cells in the brain as wildtype and Fas Ligand deficient animals, perforin deficient mice were resistant to tight junction alterations and CNS vascular permeability. To our knowledge, this study is the first to demonstrate that CNS infiltrating antigen-specific CD8 T cells have the capacity to initiate BBB tight junction disruption through a non-apoptotic perforin dependent mechanism and our model is one of few that are useful for studies in this field. These novel findings are highly relevant to the development of therapies designed to control immune mediated CNS vascular permeability

Evidence of Compromised Blood-Spinal Cord Barrier in Early and Late Symptomatic SOD1 Mice Modeling ALS

Background: The blood-brain barrier (BBB), blood-spinal cord barrier (BSCB), and blood-cerebrospinal fluid barrier (BCSFB) control cerebral/spinal cord homeostasis by selective transport of molecules and cells from the systemic compartment. In the spinal cord and brain of both ALS patients and animal models, infiltration of T-cell lymphocytes, monocyte-derived macrophages and dendritic cells, and IgG deposits have been observed that may have a critical role in motor neuron damage. Additionally, increased levels of albumin and IgG have been found in the cerebrospinal fluid in ALS patients. These findings suggest altered barrier permeability in ALS. Recently, we showed disruption of the BBB and BSCB in areas of motor neuron degeneration in the brain and spinal cord in G93A SOD1 mice modeling ALS at both early and late stages of disease using electron microscopy. Examination of capillary ultrastructure revealed endothelial cell degeneration, which, along with astrocyte alteration, compromised the BBB and BSCB. However, the effect of these alterations upon barrier function in ALS is still unclear. The aim of this study was to determine the functional competence of the BSCB in G93A mice at different stages of disease. Methodology/Principal Findings: Evans Blue (EB) dye was intravenously injected into ALS mice at early or late stage disease. Vascular leakage and the condition of basement membranes, endothelial cells, and astrocytes were investigated in cervical and lumbar spinal cords using immunohistochemistry. Results showed EB leakage in spinal cord microvessels from all G93A mice, indicating dysfunction in endothelia and basement membranes and confirming our previous ultrastructural findings on BSCB disruption. Additionally, downregulation of Glut-1 and CD146 expressions in the endothelial cells of the BSCB were found which may relate to vascular leakage. Conclusions/Significance: Results suggest that the BSCB is compromised in areas of motor neuron degeneration in ALS mice at both early and late stages of the disease

Co-bedding as a Comfort measure For Twins undergoing painful procedures (CComForT Trial)

<p>Abstract</p> <p>Background</p> <p>Co-bedding, a developmental care strategy, is the practice of caring for diaper clad twins in one incubator (versus separating and caring for each infant in separate incubators), thus creating the opportunity for skin-to-skin contact and touch between the twins. In studies of mothers and their infants, maternal skin-to-skin contact has been shown to decrease procedural pain response according to both behavioral and physiological indicators in very preterm neonates. It is uncertain if this comfort is derived solely from maternal presence or from stabilization of regulatory processes from direct skin contact. The intent of this study is to compare the comfort effect of co-bedding (between twin infants who are co-bedding and those who are not) on infant pain response and physiologic stability during a tissue breaking procedure (heelstick).</p> <p>Methods/Design</p> <p>Medically stable preterm twin infants admitted to the Neonatal Intensive Care Unit will be randomly assigned to a co-bedding group or a standard care group. Pain response will be measured by physiological and videotaped facial reaction using the Premature Infant Pain Profile scale (PIPP). Recovery from the tissue breaking procedure will be determined by the length of time for heart rate and oxygen saturation to return to baseline. Sixty four sets of twins (n = 128) will be recruited into the study. Analysis and inference will be based on the intention-to-treat principle.</p> <p>Discussion</p> <p>If twin contact while co-bedding is determined to have a comforting effect for painful procedures, then changes in current neonatal care practices to include co-bedding may be an inexpensive, non invasive method to help maintain physiologic stability and decrease the long term psychological impact of procedural pain in this high risk population. Knowledge obtained from this study will also add to existing theoretical models with respect to the exact mechanism of comfort through touch.</p> <p>Trial registration</p> <p>NCT00917631</p

Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

Background: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions: As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.Frances Corrigan, Kimberley A. Mander, Anna V. Leonard and Robert Vin