Biomarkers-Directed Strategies to Treat Autism

Autism is a neurodevelopmental disorder characterized by social, communication, and behavioral symptoms. Recent research has attempted to identify the potential mechanisms that may contribute to the pathogenesis of autism. Biomarkers as noninvasive quantitative biological measures with accurate indication of a specific mechanism can lead to a better understanding of the pathogenesis required to design the most effective treatments of autism. There is also great hope that the discovery of valid and predictive biomarkers for this disorder will help earlier and more targeted methods for diagnosis and intervention. In this chapter, we discuss some of the current theorized mechanisms contributing to autism, including inflammation, oxidative stress, impaired detoxification, glutamate excitotoxicity, gut-microbiota-brain axis, impaired fatty acid profiling, and serotonin (5-HT)/oxytocin (OT) abnormalities as target to treat autism. Moreover, based on our understanding of the role of these mechanisms, selected treatment strategies are suggested. These strategies include nutraceuticals, probiotics/prebiotics and ω-3 supplementation, targeting glutamate transporters or selective 5-HT reuptake inhibitors, and intranasal OT treatment. Of course, the joint efforts of scientists, caregivers, and other stakeholders must combine to identify valid, clinically useful autism biomarkers that may lead to efficient treatment strategy and/or combined strategies

Ocean circulation in the Toarcian (Early Jurassic), a key control on deoxygenation and carbon burial on the European Shelf

The Toarcian Oceanic Anoxic Event (T-OAE, ∼183 My) was a long-lasting episode of ocean deoxygenation during the Early Jurassic. The event is related to a period of global warming and characterized by major perturbations to the hydrological and carbon cycles with high rates of organic matter burial in shelf seas. Ocean circulation during the Toarcian and its influence on marine biogeochemical cycles are still not fully understood. Here,we assess the spatial extent of anoxia in the NW Tethys Ocean during the T-OAE, the relationship with ocean circulation and the impact on organic carbon burial, using new and existing sedimentary records from the European Epicontinental Shelf (EES) in combination with general circulation model results. We demonstrate that bottom waters on the southwestern part of the shelf were mainly oxic during the T-OAE, while those in the northeastern basins were mostly anoxic or even sulfidic. Results for two ocean-atmosphere models (FOAM and MITgcm) suggest the presence of a strong clockwise gyre over the EES, which brought oxygenated equatorial waters from the Tethys Ocean to the southern shelf. The northward limb of the gyre was significantly weakened due to the rough bathymetry of the northern shelf, making this relative small region highly sensitive to local ocean stratification. These sluggish ocean dynamics promoted bottom water anoxia and enhanced burial of organic carbon in the northeastern basins, which accounted for 3–5% of the total carbon extracted from the ocean-atmosphere system as recorded by the positive carbon isotope shift

Laser Vaporization of Mouth Lesions, an Overview

Lasers are utilized in dentistry as a therapeutic tool or as an auxiliary tool. The major purpose of employing lasers in dentistry is to overcome the difficulties that are currently observed in traditional dental treatment treatments. The laser is used in hard tissue applications such as caries prevention, bleaching, restorative removal and curing, cavity preparation, dentinal hypersensitivity, growth modulation, and diagnostics, whereas soft tissue applications include wound healing, removal of hyperplastic tissue to uncover impacted or partially erupted teeth, photodynamic therapy for malignancies, and photo-stimulation of herpetic lesions. Lasers' capacity to perform minimally invasive operations with minimum patient discomfort has proven effective in the patient delivery system in dentistry practice. The availability of lasers with various wavelengths has produced a surgical panacea, and laser technology has replaced traditional surgical techniques in many oral surgical operations

Population response during an Oceanic Anoxic Event: The case of Posidonotis (Bivalvia) from the Lower Jurassic of the Neuquén Basin, Argentina

Benthonic marine species show a wide range of biological reactions to seawater chemical changes through time, from subtle adjustments to extinction. The Early Toarcian Oceanic Anoxic Event (T-OAE) was recently recognized in the Neuquén Basin, Argentina, confirming its global scope. The event was identified chemostratigraphically on the basis of a relative increase in marine organic carbon and a characteristic negative carbonisotope excursion (δ13Corg) in bulk rock and fossil wood in the upper Pliensbachian-lower Toarcian interval in the Arroyo Lapa section (Neuquén). Simultaneously with collection of lithological samples, a high-resolution biostratigraphical survey was carried out, and the scarce benthonic fauna was collected in order to check the biotic response to changing marine geochemical conditions. We present here an analysis of size and abundance data from the T-OAE interval in the Neuquén Basin for the dominant bivalve species, the paper-clam Posidonotis cancellata (Leanza), and relate these data to geochemical proxies (%TOC and δ13Corg) obtained at the same locality. The abundance of P. cancellata increased when the rest of the benthos diminished, reaching a maximum at the onset level of the T-OAE, and then decreasing. Size-frequency distributions show a noteworthy lack of juvenile shells. Shell size shows a positive correlation with %TOC in the whole section, though over the T-OAE interval proper, it decreases below the level where the maximum %TOC value is attained and increases above it. Posidonotis cancellata shows features of opportunistic species, such as high tolerance to hypoxia, strong dominance in impoverished environments and a strong dependence on primary productivity, but at the same time had a reproductive strategy more similar to equilibrium species, with relatively low juvenile mortality rates. Several anatomical features suggest adaptation to permanently dysaerobic environments. The species disappeared just before the minimum negative carbon-isotope value was reached; and by the same time the genus became extinct worldwide

Evolution of the Toarcian (Early Jurassic) carbon-cycle and global climatic controls on local sedimentary processes (Cardigan Bay Basin, UK)

The late Early Jurassic Toarcian Stage represents the warmest interval of the Jurassic Period, with an abrupt rise in global temperatures of up to ∼7 °C in mid-latitudes at the onset of the early Toarcian Oceanic Anoxic Event (T-OAE; ∼183 Ma). The T-OAE, which has been extensively studied in marine and continental successions from both hemispheres, was marked by the widespread expansion of anoxic and euxinic waters, geographically extensive deposition of organic-rich black shales, and climatic and environmental perturbations. Climatic and environmental processes following the T-OAE are, however, poorly known, largely due to a lack of study of stratigraphically well-constrained and complete sedimentary archives. Here, we present integrated geochemical and physical proxy data (high-resolution carbon-isotope data (δ13C), bulk and molecular organic geochemistry, inorganic petrology, mineral characterisation, and major- and trace-element concentrations) from the biostratigraphically complete and expanded entire Toarcian succession in the Llanbedr (Mochras Farm) Borehole, Cardigan Bay Basin, Wales, UK. With these data, we (1) construct the first high-resolution biostratigraphically calibrated chemostratigraphic reference record for nearly the complete Toarcian Stage, (2) establish palaeoceanographic and depositional conditions in the Cardigan Bay Basin, (3) show that the T-OAE in the hemipelagic Cardigan Bay Basin was marked by the occurrence of gravity-flow deposits that were likely linked to globally enhanced sediment fluxes to continental margins and deeper marine (shelf) basins, and (4) explore how early Toarcian (tenuicostatum and serpentinum zones) siderite formation in the Cardigan Bay Basin may have been linked to low global oceanic sulphate concentrations and elevated supply of iron (Fe) from the hinterland, in response to climatically induced changes in hydrological cycling, global weathering rates and large-scale sulphide and evaporite deposition

Carbonate-platform response to the Toarcian Oceanic Anoxic Event in the southern hemisphere : Implications for climatic change and biotic platform demise

We are grateful to Zhifei Liu for TOC and analyses at the Tongji University. We thank also Wei An, Bo Zhou and Shiyi Li for their assistance in the field, and Zhicheng Huang, Yiwei Xu and Weiwei Xue for their help in the laboratory, and Chao Chang, Tianchen He and Bolin Zhang for their helpful discussion. Hugh Jenkyns commented on a draft of the manuscript. We would also like to thank Editor Derek Vance, Christopher Pearce and two anonymous reviewers whose comments greatly improved the manuscript. This study was financially supported by the National Natural Science Funds for Distinguished Young Scholar in China (41525007) and the Chinese MOST 973 Project (2012CB822001). DBK acknowledges support of NERC Fellowship NE/I02089X/1. This is a contribution to the IGCP 655.Peer reviewedPostprin

Oceanic response to Pliensbachian and Toarcian magmatic events: Implications from an organic-rich basinal succession in the NW Tethys

The Bächental bituminous marls (Bächentaler Bitumenmergel) belonging to the Sachrang Member of the Lower Jurassic Middle Allgäu Formation were investigated using a multidisciplinary approach to determine environmental controls on the formation of organic-rich deposits in a semi-restricted basin of the NW Tethys during the Early Jurassic. The marls are subdivided into three units on the basis of mineralogical composition, source-rock parameters, redox conditions, salinity variations, and diagenetic processes. Redox proxies (e.g., pristane/phytane ratio; aryl isoprenoids; bioturbation; ternary plot of iron, total organic carbon, and sulphur) indicate varying suboxic to euxinic conditions during deposition of the Bächental section. Redox variations were mainly controlled by sea-level fluctuations with the tectonically complex bathymetry of the Bächental basin determining watermass exchange with the Tethys Ocean. Accordingly, strongest anoxia and highest total organic carbon content (up to 13%) occur in the middle part of the profile (upper tenuicostatum and lower falciferum zones), coincident with an increase in surface-water productivity during a period of relative sea-level lowstand that induced salinity stratification in a stagnant basin setting. This level corresponds to the time interval of the lower Toarcian oceanic anoxic event (T-OAE). However, the absence of the widely observed lower Toarcian negative carbon isotope excursion in the study section questions its unrestricted use as a global chemostratigraphic marker. Stratigraphic correlation of the thermally immature Bächental bituminous marls with the Posidonia Shale of SW Germany on the basis of C27/C29 sterane ratio profiles and ammonite data suggests that deposition of organic matter-rich sediments in isolated basins in the Alpine realm commenced earlier (late Pliensbachian margaritatus Zone) than in regionally proximal epicontinental seas (early Toarcian tenuicostatum Zone). The late Pliensbachian onset of reducing conditions in the Bächental basin coincided with an influx of volcaniclastic detritus that was possibly connected to complex rifting processes of the Alpine Tethys and with a globally observed eruption-induced extinction event. The level of maximum organic matter accumulation in the Bächental basin corresponds to the main eruptive phase of the Karoo-Ferrar large igneous province (LIP), confirming its massive impact on global climate and oceanic conditions during the Early Jurassic. The Bächental marl succession is thus a record of the complex interaction of global (i.e., LIP) and local (e.g., redox and salinity variations, basin morphology) factors that caused reducing conditions and organic matter enrichment in the Bächental basin. These developments resulted in highly inhomogeneous environmental conditions in semi-restricted basins of the NW Tethyan domain during late Pliensbachian and early Toarcian time

Inflammogenesis of Secondary Spinal Cord Injury

Spinal cord injury (SCI) and spinal infarction lead to neurological complications and eventually to paraplegia or quadriplegia. These extremely debilitating conditions are major contributors to morbidity. Our understanding of SCI has certainly increased during the last decade, but remains far from clear. SCI consists of two defined phases: the initial impact causes primary injury, which is followed by a prolonged secondary injury consisting of evolving sub-phases that may last for years. The underlying pathophysiological mechanisms driving this condition are complex. Derangement of the vasculature is a notable feature of the pathology of SCI. In particular, an important component of SCI is the ischemia-reperfusion injury (IRI) that leads to endothelial dysfunction and changes in vascular permeability. Indeed, together with endothelial cell damage and failure in homeostasis, ischemia reperfusion injury triggers full-blown inflammatory cascades arising from activation of residential innate immune cells (microglia and astrocytes) and infiltrating leukocytes (neutrophils and macrophages). These inflammatory cells release neurotoxins (proinflammatory cytokines and chemokines, free radicals, excitotoxic amino acids, nitric oxide (NO)), all of which partake in axonal and neuronal deficit. Therefore, our review considers the recent advances in SCI mechanisms, whereby it becomes clear that SCI is a heterogeneous condition. Hence, this leads towards evidence of a restorative approach based on monotherapy with multiple targets or combinatorial treatment. Moreover, from evaluation of the existing literature, it appears that there is an urgent requirement for multi-centered, randomized trials for a large patient population. These clinical studies would offer an opportunity in stratifying SCI patients at high risk and selecting appropriate, optimal therapeutic regimens for personalized medicine.Grant #NPRP 4-571-3-171 from the Qatar National Research Fund(a member of Qatar Foundation)

Eruptive history of the Karoo lava flows and their impact on early Jurassic environmental change:

This paper reports new paleomagnetic and geochronologic data from a ~1500 m thick composite section belonging to the Drakensberg group, the thickest remnant of the Karoo lavas in Northern Lesotho. Flow‐by‐flow analysis of paleomagnetic directions reveals 21 magnetic directional groups, corresponding to single eruptive events, and 16 individual lava flows. The new age determinations of lava flows range from 180.1 ± 1.4 to 182.8 ± 2.6 Ma. These data, combined with previous results, allow us to propose that the main part of the Drakensberg group and the Karoo intrusive complex dated around 181–183 Ma may have been erupted over a period as short as 250 kyr and may have coincided with the two main phases of extinction in the Early Toarcian. This scenario agrees well with the discontinuous rhythm of environmental and biotic perturbations in the Late Pliensbachian‐Toarcian interval

Mechanisms that increase vascular reactivity following spinal cord injury

© 2013 Dr. Hussain Saad Al DeraPeople with spinal cord injury (SCI) can experience episodes of dangerously high blood pressure, termed autonomic dysreflexia, in response to a range of sensory stimuli. While SCI severs bulbospinal inputs to sympathetic preganglionic neurons, the spinal reflex pathways below the lesion remain intact and are unopposed by inhibitory inputs from the brainstem. As a result, somatosympathetic reflexes can produce pronounced constriction of arterial vessels. Studies in man indicate that SCI not only modifies spinal reflexes but also increases neurovascular transmission in arterial vessels. The objective of this thesis was to gain insight into the mechanisms underlying the augmentation of neurovascular transmission that occurs following SCI. In Chapter 2, I investigated the mechanisms that underlie SCI-induced enhancement of neurovascular transmission in the rat tail artery. Isometric contractions of arterial segments from T11 spinal cord-transected and sham-operated rats were compared 6 weeks postoperatively. SCI more than doubled the amplitudes of contractions evoked by nerve stimulation. In arteries from SCI rats, but not those from sham-operated rats, the L-type Ca2+ channel blocker nifedipine reduced nerve-evoked contractions. Furthermore, while the sensitivity to the agonists phenylephrine (α1-adrenoceptor selective) and clonidine (α2-adrenoceptor selective) was unaffected by SCI, nifedipine had a greater inhibitory effect on contractions to both agents in arteries from SCI rats. In arteries from unoperated rats, the L-type Ca2+ channel agonist Bay K8644 mimicked the effects of SCI. These findings demonstrate that the SCI-induced enhancement of neurovascular transmission in rat tail artery can largely be accounted for by an increased contribution of L-type Ca2+ channels to activation of the vascular muscle. In Chapter 3, the mechanisms underlying the enhancement of neurovascular transmission produced SCI and Bay K8644 were further investigated in rat tail artery. In situ electrochemical detection of noradrenaline and electrophysiological monitoring of purinergic transmission were used to assess if Bay K8644 changed neurotransmitter release. In addition, isometric contractions of arterial segments were used to assess if SCI and Bay K8644 similarly changed the contribution of α1-adrenoceptors to nerve-evoked contractions and if interfering with sarcoplamic reticulum (SR) Ca2+ uptake modified the contribution of L-type Ca2+ channels to activation of tail arteries. Bay K8644 did not change noradrenaline-induced oxidation currents or purinergic excitatory junction potentials. Both SCI and Bay K8644 reduced blockade of nerve-evoked contractions by BMY7378 (α1D-adenoceptor antagonist), but did not change that by RS100329 (α1A-adrenoceptor antagonist). Disruption of the SR Ca2+ stores with ryanodine increased both nerve-evoked contractions and blockade of these responses by nifedipine. The findings demonstrate that SCI and Bay K8644 increase the α1A-adrenoceptor-mediated component of nerve-evoked contractions. The findings also suggest that Ca2+ entering smooth muscle via L-type channels is rapidly sequestered by the SR limiting its access to the contractile mechanism. Studies in individuals with SCI suggest the vasculature is hyperreactive to angiotensin II (Ang II). In Chapter 4, the effects of SCI on the reactivity of rat tail and mesenteric arteries to Ang II were investigated. SCI increased contractions of both vessels evoked by Ang II. In tail arteries, the facilitatory effect of Ang II on neurovascular transmission was greatly increased. In contrast, SCI did not change the facilitatory action of Ang II on neurovascular transmission in mesenteric arteries. These findings provide the first direct evidence that SCI increases the reactivity of arterial vessels to Ang II. In addition, in tail artery, the findings indicate that Ang II may contribute to amplifying spinal reflex activation of this vessel