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Article: A New Methodology of Viewing Extra-Axial Fluid and Cortical Abnormalities in Children with Autism via Transcranial Ultrasonography.

Bradstreet, James Jeffrey / Pacini, Stefania / Ruggiero, Marco

2014 Volume 7, Page(s) 934

Abstract: Background: Autism spectrum disorders (ASDs) are developmental conditions of uncertain etiology which have now affected more than 1% of the school-age population of children in many developed nations. Transcranial ultrasonography (TUS) via the temporal ... ...

Abstract	Background: Autism spectrum disorders (ASDs) are developmental conditions of uncertain etiology which have now affected more than 1% of the school-age population of children in many developed nations. Transcranial ultrasonography (TUS) via the temporal bone appeared to be a potential window of investigation to determine the presence of both cortical abnormalities and increased extra-axial fluid (EAF). Methods: TUS was accomplished using a linear probe (10-5 MHz). Parents volunteered ASD subjects (N = 23; males 18, females 5) for evaluations (mean = 7.46 years ± 3.97 years), and 15 neurotypical siblings were also examined (mean = 7.15 years ± 4.49 years). Childhood Autism Rating Scale (CARS2(®)) scores were obtained and the ASD score mean was 48.08 + 6.79 (Severe). Results: Comparisons of the extra-axial spaces indicated increases in the ASD subjects. For EAF we scored based on the gyral summit distances between the arachnoid membrane and the cortical pia layer (subarachnoid space): (1) <0.05 cm, (2) 0.05-0.07 cm, (3) 0.08-0.10 cm, (4) >0.10 cm. All of the neurotypical siblings scored 1, whereas the ASD mean score was 3.41 ± 0.67. We also defined cortical dysplasia as the following: hypoechoic lesions within the substance of the cortex, or disturbed layering within the gray matter. For cortical dysplasia we scored: (1) none observed, (2) rare hypoechogenic lesions and/or mildly atypical cortical layering patterns, (3) more common, but separated areas of cortical hypoechogenic lesions, (4) very common or confluent areas of cortical hypoechogenicity. Again all of the neurotypical siblings scored 1, while the ASD subjects' mean score was 2.79 ± 0.93. Conclusion: TUS may be a useful screening technique for children at potential risk of ASDs which, if confirmed with repeated studies and high resolution MRI, provides rapid, non-invasive qualification of EAF, and cortical lesions.
Language	English
Publishing date	2014-01-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2425477-0
ISSN	1662-5161
ISSN	1662-5161
DOI	10.3389/fnhum.2013.00934
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Therapeutic role of hematopoietic stem cells in autism spectrum disorder-related inflammation.

Siniscalco, Dario / Bradstreet, James Jeffrey / Antonucci, Nicola

Frontiers in immunology

2013 Volume 4, Page(s) 140

Abstract: Autism and autism spectrum disorders (ASDs) are heterogeneous, severe neuro-developmental disorders with core symptoms of dysfunctions in social interactions and communication skills, restricted interests, repetitive - stereotypic verbal and non-verbal ... ...

Abstract	Autism and autism spectrum disorders (ASDs) are heterogeneous, severe neuro-developmental disorders with core symptoms of dysfunctions in social interactions and communication skills, restricted interests, repetitive - stereotypic verbal and non-verbal behaviors. Biomolecular evidence points to complex gene-environmental interactions in ASDs. Several biochemical processes are associated with ASDs: oxidative stress (including endoplasmic reticulum stress), decreased methylation capacity, limited production of glutathione; mitochondrial dysfunction, intestinal dysbiosis, increased toxic metal burden, and various immune abnormalities. The known immunological disorders include: T-lymphocyte populations and function, gene expression changes in monocytes, several autoimmune-related findings, high levels of N-acetylgalactosaminidase (which precludes macrophage activation), and primary immune deficiencies. These immunological observations may result in minicolumn structural changes in the brain, as well as, abnormal immune mediation of synaptic functions. Equally, these immune dysregulations serve as the rationale for immune-directed interventions such as hematopoietic stem cells (HSCs), which are pivotal in controlling chronic inflammation and in the restoration of immunological balance. These properties make them intriguing potential agents for ASD treatments. This prospective review will focus on the current state-of-the-art knowledge and challenges intrinsic in the application of HSCs for ASD-related immunological disorders.
Language	English
Publishing date	2013-06-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2013.00140
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Article ; Online: The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages.

Siniscalco, Dario / Bradstreet, James Jeffrey / Cirillo, Alessandra / Antonucci, Nicola

Journal of neuroinflammation

2014 Volume 11, Page(s) 78

Abstract: Background: Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly ... ...

Abstract	Background: Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls. Methods: To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods. Results: GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children. Conclusions: This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism.
MeSH term(s)	Amidohydrolases/genetics ; Amidohydrolases/metabolism ; Autistic Disorder/pathology ; Case-Control Studies ; Child ; Child, Preschool ; Endocannabinoids/genetics ; Endocannabinoids/metabolism ; Female ; Gene Expression Regulation/drug effects ; Humans ; Leukocytes, Mononuclear/metabolism ; Leukocytes, Mononuclear/pathology ; Macrophage-Activating Factors/pharmacology ; Macrophages/drug effects ; Male ; Phospholipase D/genetics ; Phospholipase D/metabolism ; RNA, Messenger/metabolism ; Receptor, Cannabinoid, CB2/genetics ; Receptor, Cannabinoid, CB2/metabolism ; Signal Transduction/drug effects ; Vitamin D-Binding Protein/pharmacology
Chemical Substances	Endocannabinoids ; Macrophage-Activating Factors ; RNA, Messenger ; Receptor, Cannabinoid, CB2 ; Vitamin D-Binding Protein ; vitamin D-binding protein-macrophage activating factor ; Phospholipase D (EC 3.1.4.4) ; NAPEPLD protein, human (EC 3.1.4.4.) ; Amidohydrolases (EC 3.5.-) ; fatty-acid amide hydrolase (EC 3.5.1.-)
Language	English
Publishing date	2014-04-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1742-2094
ISSN (online)	1742-2094
DOI	10.1186/1742-2094-11-78
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Article ; Online: Initial Observations of Elevated Alpha-N-Acetylgalactosaminidase Activity Associated with Autism and Observed Reductions from GC Protein—Macrophage Activating Factor Injections

James Jeffrey Bradstreet / Emar Vogelaar / Lynda Thyer

Autism Insights, Vol 2012, Iss 4, Pp 31-

2012 Volume 38

Keywords	Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Neurology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Language	English
Publishing date	2012-12-01T00:00:00Z
Publisher	Libertas Academica
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Epigenetic findings in autism: new perspectives for therapy.

Siniscalco, Dario / Cirillo, Alessandra / Bradstreet, James Jeffrey / Antonucci, Nicola

International journal of environmental research and public health

2013 Volume 10, Issue 9, Page(s) 4261–4273

Abstract: Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by dysfunctions in social interactions, communications, restricted interests, and repetitive stereotypic behaviors. Despite extensive genetic and ... ...

Abstract	Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by dysfunctions in social interactions, communications, restricted interests, and repetitive stereotypic behaviors. Despite extensive genetic and biological research, significant controversy surrounds our understanding of the specific mechanisms of their pathogenesis. However, accumulating evidence points to the involvement of epigenetic modifications as foundational in creating ASD pathophysiology. Epigenetic modifications or the alteration of DNA transcription via variations in DNA methylation and histone modifications but without alterations in the DNA sequence, affect gene regulation. These alterations in gene expression, obtained through DNA methylation and/or histone modifications, result from transcriptional regulatory influences of environmental factors, such as nutritional deficiencies, various toxicants, immunological effects, and pharmaceuticals. As such these effects are epigenetic regulators which determine the final biochemistry and physiology of the individual. In contrast to psychopharmacological interventions, bettering our understanding of how these gene-environmental interactions create autistic symptoms should facilitate the development of therapeutic targeting of gene expression for ASD biomedical care.
MeSH term(s)	Animals ; Child Development Disorders, Pervasive/genetics ; Child Development Disorders, Pervasive/therapy ; Environment ; Epigenesis, Genetic ; Histones/metabolism ; Humans
Chemical Substances	Histones
Language	English
Publishing date	2013-09-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2175195-X
ISSN	1660-4601 ; 1661-7827
ISSN (online)	1660-4601
ISSN	1661-7827
DOI	10.3390/ijerph10094261
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Perspectives on the use of stem cells for autism treatment.

Siniscalco, Dario / Bradstreet, James Jeffrey / Sych, Nataliia / Antonucci, Nicola

Stem cells international

2013 Volume 2013, Page(s) 262438

Abstract: Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders. ASDs are clinically defined by deficits in communication, social skills, and repetitive and/or restrictive interests and behaviours. With the prevalence rates for ASDs ... ...

Abstract	Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders. ASDs are clinically defined by deficits in communication, social skills, and repetitive and/or restrictive interests and behaviours. With the prevalence rates for ASDs rapidly increasing, the need for effective therapies for autism is a priority for biomedical research. Currently available medications do not target the core symptoms, can have markedly adverse side-effects, and are mainly palliative for negative behaviours. The development of molecular and regenerative interventions is progressing rapidly, and medicine holds great expectations for stem cell therapies. Cells could be designed to target the observed molecular mechanisms of ASDs, that is, abnormal neurotransmitter regulation, activated microglia, mitochondrial dysfunction, blood-brain barrier disruptions, and chronic intestinal inflammation. Presently, the paracrine, secretome, and immunomodulatory effects of stem cells would appear to be the likely mechanisms of application for ASD therapeutics. This review will focus on the potential use of the various types of stem cells: embryonic, induced pluripotential, fetal, and adult stem cells as targets for ASD therapeutics.
Language	English
Publishing date	2013-10-10
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2573856-2
ISSN	1687-9678 ; 1687-966X
ISSN (online)	1687-9678
ISSN	1687-966X
DOI	10.1155/2013/262438
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Article: Mesenchymal stem cells in treating autism: Novel insights.

Siniscalco, Dario / Bradstreet, James Jeffrey / Sych, Nataliia / Antonucci, Nicola

World journal of stem cells

2013 Volume 6, Issue 2, Page(s) 173–178

Abstract: Autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by dysfunctions in social interactions, abnormal to absent verbal communication, restricted interests, and repetitive stereotypic verbal and non-verbal behaviors, ... ...

Abstract	Autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by dysfunctions in social interactions, abnormal to absent verbal communication, restricted interests, and repetitive stereotypic verbal and non-verbal behaviors, influencing the ability to relate to and communicate. The core symptoms of ASDs concern the cognitive, emotional, and neurobehavioural domains. The prevalence of autism appears to be increasing at an alarming rate, yet there is a lack of effective and definitive pharmacological options. This has created an increased sense of urgency, and the need to identify novel therapies. Given the growing awareness of immune dysregulation in a significant portion of the autistic population, cell therapies have been proposed and applied to ASDs. In particular, mesenchymal stem cells (MSCs) possess the immunological properties which make them promising candidates in regenerative medicine. MSC therapy may be applicable to several diseases associated with inflammation and tissue damage, where subsequent regeneration and repair is necessary. MSCs could exert a positive effect in ASDs through the following mechanisms: stimulation of repair in the damaged tissue, e.g., inflammatory bowel disease; synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors; integrating into existing neural and synaptic network, and restoring plasticity. The paracrine mechanisms of MSCs show interesting potential in ASD treatment. Promising and impressive results have been reported from the few clinical studies published to date, although the exact mechanisms of action of MSCs in ASDs to restore functions are still largely unknown. The potential role of MSCs in mediating ASD recovery is discussed in light of the newest findings from recent clinical studies.
Language	English
Publishing date	2013-10-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2583482-4
ISSN	1948-0210
ISSN	1948-0210
DOI	10.4252/wjsc.v6.i2.173
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Article ; Online: Epigenetic Findings in Autism

James Jeffrey Bradstreet / Nicola Antonucci / Alessandra Cirillo / Dario Siniscalco

International Journal of Environmental Research and Public Health, Vol 10, Iss 9, Pp 4261-

New Perspectives for Therapy

2013 Volume 4273

Abstract	Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by dysfunctions in social interactions, communications, restricted interests, and repetitive stereotypic behaviors. Despite extensive genetic and biological research, significant controversy surrounds our understanding of the specific mechanisms of their pathogenesis. However, accumulating evidence points to the involvement of epigenetic modifications as foundational in creating ASD pathophysiology. Epigenetic modifications or the alteration of DNA transcription via variations in DNA methylation and histone modifications but without alterations in the DNA sequence, affect gene regulation. These alterations in gene expression, obtained through DNA methylation and/or histone modifications, result from transcriptional regulatory influences of environmental factors, such as nutritional deficiencies, various toxicants, immunological effects, and pharmaceuticals. As such these effects are epigenetic regulators which determine the final biochemistry and physiology of the individual. In contrast to psychopharmacological interventions, bettering our understanding of how these gene-environmental interactions create autistic symptoms should facilitate the development of therapeutic targeting of gene expression for ASD biomedical care.
Keywords	autism ; gene expression ; environmental factors ; Medicine ; R
Subject code	612
Language	English
Publishing date	2013-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Perspectives on the Use of Stem Cells for Autism Treatment

Dario Siniscalco / James Jeffrey Bradstreet / Nataliia Sych / Nicola Antonucci

Stem Cells International, Vol

2013 Volume 2013

Abstract	Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders. ASDs are clinically defined by deficits in communication, social skills, and repetitive and/or restrictive interests and behaviours. With the prevalence rates for ASDs rapidly increasing, the need for effective therapies for autism is a priority for biomedical research. Currently available medications do not target the core symptoms, can have markedly adverse side-effects, and are mainly palliative for negative behaviours. The development of molecular and regenerative interventions is progressing rapidly, and medicine holds great expectations for stem cell therapies. Cells could be designed to target the observed molecular mechanisms of ASDs, that is, abnormal neurotransmitter regulation, activated microglia, mitochondrial dysfunction, blood-brain barrier disruptions, and chronic intestinal inflammation. Presently, the paracrine, secretome, and immunomodulatory effects of stem cells would appear to be the likely mechanisms of application for ASD therapeutics. This review will focus on the potential use of the various types of stem cells: embryonic, induced pluripotential, fetal, and adult stem cells as targets for ASD therapeutics.
Keywords	Internal medicine ; RC31-1245
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Biomarker-guided interventions of clinically relevant conditions associated with autism spectrum disorders and attention deficit hyperactivity disorder.

Bradstreet, James Jeffrey / Smith, Scott / Baral, Matthew / Rossignol, Daniel A

Alternative medicine review : a journal of clinical therapeutic

2010 Volume 15, Issue 1, Page(s) 15–32

Abstract: Autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD) are common and complex neurodevelopmental conditions. Diagnostic criteria for these conditions have traditionally relied solely on behavioral criteria without ... ...

Abstract	Autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD) are common and complex neurodevelopmental conditions. Diagnostic criteria for these conditions have traditionally relied solely on behavioral criteria without consideration for potential biomedical underpinnings. Newer evidence, however, reveals that ASDs are associated with: oxidative stress; decreased methylation capacity; limited production of glutathione; mitochondrial dysfunction; intestinal dysbiosis; increased toxic metal burden; immune dysregulation, characterized by a unique inflammatory bowel disease and immune activation of neuroglial cells; and ongoing brain hypoperfusion. Many of these same problems are common features in children with ADHD. These medical conditions, whether co-morbidities or etiopathogenic, would be expected to have synergistically negative effects on the development, cognition, focus, and attention of affected children. It is likely these biological abnormalities contribute significantly to the behavioral symptoms intrinsic in these diagnoses. However, treatment for these underlying medical disorders is clinically justified, even if no clear immediate behavioral improvements are observed. This article reviews the medical literature and discusses the authors clinical experience using various biomarkers for measuring oxidative stress, methylation capacity and transsulfuration, immune function, gastrointestinal problems, and toxic metal burden. These biomarkers provide useful guides for selection, efficacy, and sufficiency of biomedical interventions. The use of these biomarkers is of great importance in young children with ADHD or individuals of any age with ASD, because typically they cannot adequately communicate regarding their symptoms.
MeSH term(s)	Attention Deficit Disorder with Hyperactivity/complications ; Attention Deficit Disorder with Hyperactivity/etiology ; Attention Deficit Disorder with Hyperactivity/metabolism ; Biomarkers/metabolism ; Child ; Child Development Disorders, Pervasive/complications ; Child Development Disorders, Pervasive/etiology ; Child Development Disorders, Pervasive/metabolism ; Child Development Disorders, Pervasive/prevention & control ; Environmental Pollutants/toxicity ; Female ; Humans ; Inflammation/complications ; Inflammation/metabolism ; Intestinal Diseases/complications ; Male ; Metals, Heavy/toxicity ; Mitochondrial Diseases/complications ; Oxidative Stress
Chemical Substances	Biomarkers ; Environmental Pollutants ; Metals, Heavy
Language	English
Publishing date	2010-04
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1465535-4
ISSN	1089-5159
ISSN	1089-5159
Database	MEDical Literature Analysis and Retrieval System OnLINE

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