A developmental increase in allostatic load from ages 3 to 11 years is associated with increased schizotypal personality at age 23 years

Although allostatic load has been investigated in mood and anxiety disorders, no prior study has investigated developmental change in allostatic load as a precursor to schizotypal personality. This study employed a multilevel developmental framework to examine whether the development of increased allostatic load, as indicated by impaired sympathetic nervous system habituation from ages 3 to 11 years, predisposes to schizotypal personality at age 23 years. Electrodermal activity to six aversive tones was recorded in 995 subjects at age 3 years and again at 11 years. Habituation slopes at both ages were used to create groups who showed a developmental increase in habituation (decreased allostatic load), and those who showed a developmental decrease in habituation (increased allostatic load). Children who showed a developmental increase in allostatic load from ages 3 to 11 years had higher levels of schizotypal personality at 23 years. A breakdown of total schizotypy scores demonstrated specificity of findings to cognitive-perceptual features of schizotypy. Findings are the first to document a developmental abnormality in allostasis in relation to adult schizotypal personality. The relative failure to develop normal habituation to repeated stressors throughout childhood is hypothesized to result in an accumulation of allostatic load and consequently increased positive symptom schizotypy in adulthood.     

The effect of acute treadmill walking on cognitive control and academic achievement in preadolescent children

The effect of an acute bout of moderate treadmill walking on behavioral and neuroelectric indexes of the cognitive control of attention and applied aspects of cognition involved in school-based academic performance were assessed. A within-subjects design included 20 preadolescent participants (age=9.5±0.5 years; eight female) to assess exercise-induced changes in performance during a modified flanker task and the Wide Range Achievement Test 3. The resting session consisted of cognitive testing followed by a cardiorespiratory fitness assessment to determine aerobic fitness. The exercise session consisted of 20 min of walking on a motor-driven treadmill at 60% of estimated maximum heart rate followed by cognitive testing once heart rate returned to within 10% of pre-exercise levels. Results indicated an improvement in response accuracy, larger P3 amplitude, and better performance on the academic achievement test following aerobic exercise relative to the resting session. Collectively, these findings indicate that single, acute bouts of moderately-intense aerobic exercise (i.e. walking) may improve the cognitive control of attention in preadolescent children, and further support the use of moderate acute exercise as a contributing factor for increasing attention and academic performance. These data suggest that single bouts of exercise affect specific underlying processes that support cognitive health and may be necessary for effective functioning across the lifespan.     

New bedding site examination-based method to analyse deer ked (Lipoptena cervi) infection in cervids

Invasion of the deer ked (Lipoptena cervi), an ectoparasitic fly commonly found in cervids, has been rapid in Finland during the last four decades. As the distribution area of this species has expanded from the south towards the northern latitudes, the associated problems have become more evident. Various animals such as horses, cattle and especially reindeer have been reported to host this parasite. Moreover, in certain areas, the deer ked causes major inconveniences for humans potentially limiting recreational activities in forests. We wanted to study if deer ked parasitism and intensity of the infection in winter time could be detected by using visual examination of the snow on cervid bedding sites and by analysing biotic samples found from the bedding sites. Our results demonstrate that chronic deer ked infection causes reddish-brown snow discolouration (host tissue fluid and deer ked faeces) on the bedding sites to the extent that parasitism can be diagnosed. Hence, we suggest that deer ked infection prevalence and range expansion could be rapidly monitored using our new practical and reliable method. In the future, bedding site analyses will likely be useful in predicting and potentially preventing the negative effects of this ecologically and socio-economically important parasite.     

Up-Regulation of Soluble Axl and Mer Receptor Tyrosine Kinases Negatively Correlates with Gas6 in Established Multiple Sclerosis Lesions

Multiple sclerosis is a disease that is characterized by inflammation, demyelination, and axonal damage; it ultimately forms gliotic scars and lesions that severely compromise the function of the central nervous system. Evidence has shown previously that altered growth factor receptor signaling contributes to lesion formation, impedes recovery, and plays a role in disease progression. Growth arrest-specific protein 6 (Gas6), the ligand for the TAM receptor tyrosine kinase family, consisting of Tyro3, Axl, and Mer, is important for cell growth, survival, and clearance of debris. In this study, we show that levels of membrane-bound Mer (205 kd), soluble Mer (∼150 kd), and soluble Axl (80 kd) were all significantly elevated in homogenates from established multiple sclerosis lesions comprised of both chronic active and chronic silent lesions. Whereas in normal tissue Gas6 positively correlated with soluble Axl and Mer, there was a negative correlation between Gas6 and soluble Axl and Mer in established multiple sclerosis lesions. In addition, increased levels of soluble Axl and Mer were associated with increased levels of mature ADAM17, mature ADAM10, and Furin, proteins that are associated with Axl and Mer solubilization. Soluble Axl and Mer are both known to act as decoy receptors and block Gas6 binding to membrane-bound receptors. These data suggest that in multiple sclerosis lesions, dysregulation of protective Gas6 receptor signaling may prolong lesion activity.Multiple sclerosis (MS) is a debilitating white matter disease of the central nervous system (CNS). Although much of the evidence from animal models and MS suggests it to be an autoimmune disorder mediated by TH-1 type T cells,¹ other possible causes include genetic and environmental factors, antibody-dependent cytotoxicity, and bacterial and viral infections that may mediate altered protein expression resulting in inflammation, axonal and oligodendrocyte damage, demyelination and CNS scarring.² Growth and survival factors that protect against axonal and oligodendrocyte damage or loss, and dampen the inflammatory response are actively being pursued for MS therapy.^2,3,4,5,6 One growth factor associated with oligodendrocyte maturation, survival and dampening the immune response is growth-arrest specific protein 6 (Gas6). Gas6 is a secreted protein that is widely expressed in the central and peripheral nervous systems by endothelial cells and neurons, and is involved in numerous physiological and pathological functions including cell growth, survival and apoptosis.^{7,8,9,10,11,12} Gas6 binds and activates the TAM family of receptor tyrosine kinases consisting of Tyro3 (Rse/Dtk/Sky), Axl (Ufo), and Mer (Eyk).^{8,11,13,14,15} Many cell types express all three receptors and receptor activation can result from homophilic and heterophilic interactions.^16,17 Axl contains the major and minor Gas6 binding groove. Only the minor groove is conserved in Tyro3 and Mer and as a result, response to Gas6 is mediated in a concentration-dependent manner; Gas6 binding affinity is Axl>Tyro3>Mer.¹⁸We previously reported mRNA expression of Axl, Tyro3, and Mer receptors on human fetal oligodendrocytes and the ability of Gas6 to promote oligodendrocyte survival in vitro by activating Axl, resulting in Axl directly and indirectly recruiting phosphatidylinositol 3 kinase and activating the Akt pathway.^19,20 Moreover, we have shown that Gas6/Axl signaling through the Akt pathway can protect oligodendrocytes from tumor necrosis factor α (TNFα)-induced apoptosis.²¹ Down-regulation or deletion of Axl, even in the presence of Gas6, results in loss of protection against TNFα.²²During the relapse phase of relapsing-remitting MS, serum TNFα levels and TNFα mRNA are elevated.^23,24 TNFα is one of the major cytokines expressed in MS lesions.²⁵ TNFα is cleaved to its mature, soluble, secretable form by the matrix metalloproteinase (MMP) TNFα converting enzyme, also known as ADAM17.^26,27,28 MMPs, including ADAM17 and ADAM10 are involved in normal processes such as wound repair and tissue remodeling and are associated with disease states, including MS.^{29,30,31,32,33,34,35,36} Expression of ADAM17 is observed in acute and chronic active MS lesions, primarily in perivascular cuffs and cells morphologically resembling lymphocytes.³⁷ ADAM17 up-regulation in cerebrospinal fluid of MS patients is associated with inflammation and increased soluble TNFα.^37,38 ADAM10 is constitutively expressed on astrocytes in normal appearing white matter and on astrocytes and perivascular macrophages in MS lesions.^38,39,40,41 ADAM10 cleaves Axl, and ADAM17 cleaves Axl and Mer. Cleaved forms of receptors can result in internalization of the receptor and transport off the membrane for recycling. Cleavage can also result in shortened, soluble forms that act as a decoy to regulate the level of a growth factor at the membrane.^41,42Soluble forms of Axl and Mer can reduce the number of viable receptors for Gas6 binding and act as a decoy by sequestering Gas6 extracellularly; potentially a normal mechanism of receptor activation regulation.^40,41 During inflammation, soluble Mer has been reported to inhibit macrophage clearance of apoptotic cells.^41,43 Also, soluble Axl blocked the protective effect of membrane-bound Axl by inhibiting Gas6 induced tyrosine phosphorylation of Axl.⁴⁴ The binding of Gas6 to TAM receptors acts as an inhibitor of inflammation by inhibiting Toll-like receptor and cytokine receptor cascades.⁴⁴ Up-regulation of Axl and its subsequent interaction with interferon α and β receptors results in the expression of cytokine and Toll-like receptor inhibitors.^44,45 Thus, loss of Gas6 signaling, along with dysregulation of the balance between Gas6, Axl and Mer by increased extracellular levels of soluble Axl and Mer, might detrimentally impact the nervous system, especially in established (chronic active and chronic silent) lesions associated with MS. Chronic active MS lesions are characterized by ongoing demyelination, astrogliosis, macrophage and lymphocyte infiltration, astroglial hypertrophy, and oligodendrocyte hyperplasia.⁴⁶ Chronic silent MS lesions are characterized by the absence of actively infiltrating and inflammatory cells, oligodendrocyte loss and no evidence of ongoing demyelination.^46,47,48In this study, we investigated in chronic active and chronic silent MS lesions whether increased expression of soluble Axl and Mer was associated with increased expression of the MMPs ADAM17 and ADAM10, similar to previous studies that showed an association between increased ADAM17 and ADAM10 with TNFα in the CNS of MS patients.^37,38 We also investigated whether in lesions increased soluble Axl and Mer was associated with decreased Gas6, resulting in loss of the beneficial effects from activating membrane-bound Axl and Mer receptors.     

Caveolin-1 Expression Determines the Route of Neutrophil Extravasation through Skin Microvasculature

Interleukin-8 plays a key role in the acute inflammatory response by mediating recruitment of neutrophils through vessel walls into affected tissues. During this process, molecular signals guide circulating blood neutrophils to target specific vessels for extravasation and to migrate through such vessels via particular routes. Our results show that levels of endothelial caveolin-1, the protein responsible for the induction of the membrane domains known as caveolae, are critical to each of these processes. We demonstrate that, in response to the intradermal injection of interleukin-8, neutrophils are preferentially recruited to a unique subset of venules that express high levels of intercellular adhesion molecule-1 and low levels of caveolin-1. Our results show that neutrophils traverse human dermal microvascular endothelial cells using one of two pathways: a transcellular route directly through the cell or a paracellular route through cellular junctions. Caveolin-1 expression appears to favor the transcellular path while down-regulation of caveolin-1 promotes the paracellular route.Wounding of the epithelium and entry of a foreign body elicit a series of responses from the innate immune system. One of the main hallmarks of acute inflammation is neutrophil infiltration at the affected site.^1,2 In response to injury or infection, resident phagocytic cells become activated and release inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-8. TNF-α activates the vascular endothelium causing vasodilation and cellular infiltration.³ IL-8 functions as a critical chemotactic factor attracting neutrophils from the blood to the affected area.^1,4It is currently thought that leukocyte recruitment and migration through the vasculature is an active process not only for migrating blood cells but also for endothelial cells lining the vessels. Initially, inflammatory cytokines or bacterial endotoxins induce expression of P- and E-selectin on the surface of microvascular endothelial cells.^5,6 These molecules recognize carbohydrate counterligands on the surface of circulating leukocytes and mediate the tethering and rolling of these cells along vessel walls.^5,6,7 Firm adhesion is then initiated through the upregulation of endothelial adhesion molecules such as intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1, which bind to integrins expressed on the leukocyte surface.^5,7,8 Finally, the leukocyte is induced to migrate through the vessel in a process known as diapedesis.^5,6,7Among the many proteins implicated in the process of diapedesis, the adhesion molecule ICAM-1, which is up-regulated on activated endothelium, and caveolin-1, which is expressed on most terminally differentiated cell types but is largely undetectable in white blood cells, have been most closely associated with the route of transendothelial migration in in vitro systems.^7,9,10 A recent study by Millan et al clearly demonstrates that ICAM-1 and caveolin-1 are involved in directing the path of T lymphoblast migration through human umbilical vein endothelial cells (HUVECs).⁷Although both caveolin-1 and ICAM-1 have been associated with leukocyte transendothelial migration in vitro, the distribution of these proteins in vessels used by migrating leukocytes in vivo remain unclear. While all endothelial cells (ECs) share common features, the vascular tree is known to be extremely heterogeneous. As a result, the precise molecular profile of selectins and adhesion molecules defining vessels targeted for extravasation by circulating leukocytes is unknown. Furthermore, since the phenotype of vessel ECs is determined in large part by their unique in vivo microenvironment, site specific and regional differences in the expression of molecules contributing to the regulation of leukocyte transmigration have yet to be thoroughly characterized.^11,12 In this study, we have examined the in vivo molecular profile of vessels targeted by circulating neutrophils in response to IL-8 in the skin and have determined the effect of the expression of these factors on the route of neutrophil transmigration in vitro.     

Stem cells ameliorate EAE via an indoleamine 2,3-dioxygenase (IDO) mechanism

Syngeneic, pluripotent Lin(-)Sca1(+) bone marrow stem cells (SC), transferred to mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis, enhanced recovery, prevented relapses and promoted myelin repair. SC-treated mice showed elevated interferon-gamma production and induction of indoleamine 2,3-dioxygenase (IDO) in CD11c(+) dendritic cells (DC). IDO induction was specific since in the presence of IDO-producing CD11c(+) DC, PLP stimulated T cell proliferation was inhibited and the IDO-inhibitor, 1-MT, abrogated the SC effect. Relapse prevention during chronic disease correlated with decreased responsiveness to PLP(178-191) and MBP(85-99). Thus, pluripotent SC induce IDO in DC leading to inhibition of antigen reactivity and spreading in EAE.     

Serial adoptive transfer of murine experimental allergic encephalomyelitis: successful transfer is dependent on active disease in the donor

In an attempt to understand the mechanisms underlying disease progression in adoptively transferred experimental allergic encephalomyelitis (EAE), and perhaps multiple sclerosis (MS), this study has examined the transfer of EAE serially from primary to secondary and tertiary recipients using myelin basic protein (MBP)-responsive lymphocytes. It was found that EAE could be serially transferred only when there was acute or relapsing disease activity in the donor animal. Cells from donors with quiescent disease did not transfer EAE. Autoradiographic attempts to locate primary adoptively transferred cells in the central nervous system of secondary and tertiary recipients were uniformly unsuccessful. These findings implicate the requirement of effector cell activation in the donor and the recruitment of augmenting autoimmune cells in lesion formation.