Bardzo tanie apteki z dostawą w całej Polsce kupic cialis i ogromny wybór pigułek.
Hindawi Publishing CorporationJournal of Biomedicine and BiotechnologyVolume 2012, Article ID 480289, 6 pagesdoi:10.1155/2012/480289
Autism Spectrum Disorders: Is Mesenchymal Stem Cell
Personalized Therapy the Future?
Dario Siniscalco,1, 2 Anna Sapone,3, 4 Alessandra Cirillo,5 Catia Giordano,1
Sabatino Maione,1 and Nicola Antonucci6
1 Division of Pharmacology “L. Donatelli”, Department of Experimental Medicine, Second University of Naples,
Via S. Maria di Costantinopoli, 16-80138 Napoli, Italy
2 Centre for Autism, La Forza del Silenzio, Caserta, 80138 Naples, Italy3 Department of Internal and Experimental Medicine “Magrassi-Lanzara”, Second University of Naples, 80138 Naples, Italy4 Center for Celiac Research and Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore,
5 Division of Biotechnology and Molecular Biology “A. Cascino”, Department of Experimental Medicine, Second University of Naples,
6 Biomedical Centre for Autism Research and Treatment, 70122 Bari, Italy
Correspondence should be addressed to Dario Siniscalco, [email protected]
Received 11 July 2011; Accepted 29 September 2011
Copyright 2012 Dario Siniscalco et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.
Autism and autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders. They are enigmatic conditionsthat have their origins in the interaction of genes and environmental factors. ASDs are characterized by dysfunctions in socialinteraction and communication skills, in addition to repetitive and stereotypic verbal and nonverbal behaviours. Immunedysfunction has been conﬁrmed with autistic children. There are no deﬁned mechanisms of pathogenesis or curative therapypresently available. Indeed, ASDs are still untreatable. Available treatments for autism can be divided into behavioural, nutritional,and medical approaches, although no deﬁned standard approach exists. Nowadays, stem cell therapy represents the great promisefor the future of molecular medicine. Among the stem cell population, mesenchymal stem cells (MSCs) show probably bestpotential good results in medical research. Due to the particular immune and neural dysregulation observed in ASDs, mesenchymalstem cell transplantation could oﬀer a unique tool to provide better resolution for this disease.
1. Autism Spectrum Disorders
of ASDs is unknown, likely it results from a complex combi-nation of genetic, environmental, and immunological factors
Autism and autism spectrum disorders (ASDs) are heteroge-
[5, 6]. This heritable disorder derives from genetic variations
neous neurodevelopmental disorders . They are enigmatic
in multiple genes , making its treatment particularly
conditions that have their origins in the interaction of
diﬃcult. Environment (i.e., air pollution, organophosphates,
genes and environmental factors. ASDs are characterized by
and heavy metals) also contributes to the incidence of ASDs
dysfunctions in social interaction and communication skills,
in addition to repetitive and stereotypic verbal and nonverbal
Frequency of these disorders is increasing: 56% reported
behaviours [2, 3]. Several biochemical events are associ-
increase in paediatric prevalence between 1991 and 1997
ated with ASDs: oxidative stress; endoplasmic reticulum
 until present rates of about 60 cases per 10,000 chil-
stress; decreased methylation capacity; limited production
dren, according to Center for Disease Control [10, 11].
of glutathione; mitochondrial dysfunction; intestinal dysbio-
ASDs are increasingly being recognized as a public health
sis; increased toxic metal burden; immune dysregulation;
problem . Pathophysiology and deﬁned mechanisms of
immune activation of neuroglial cells . The exact aetiology
pathogenesis of autism remain still unclear. There are no
drugs eﬀective for treatment of core symptoms of ASDs
surface of dishes when maintained in standard culture
. Indeed, ASDs are still untreatable. Current available
conditions; (2) express cytospeciﬁc cell surface markers, that
treatments for autism can be divided into behavioural,
is, CD105, CD90, and CD73, to be negative for other cell
nutritional, and pharmacological options, in addition to
surface markers, that is, CD45, CD34, CD14, and CD11b;
individual and family psychotherapy and other nonphar-
(3) possess the capacity to diﬀerentiate into mesenchymal
macologic interventions . However, no deﬁned stan-
lineages, under appropriate in vitro
conditions . MSCs
dard approach exists . Pharmacological approaches are
can be isolated from diﬀerent tissues other than bone
direct towards neuropsychiatric disorders coassociated with
marrow: adipose tissue, liver, tendons, synovial membrane,
ASDs. Psycho-stimulants, alpha-2 agonists, beta blockers,
amniotic ﬂuid, placenta, umbilical cord, and teeth. MSCs
lithium, anticonvulsant mood stabilizers, atypical antipsy-
show a high expansion potential, genetic stability, stable
chotics, traditional antipsychotics, selective serotonin reup-
phenotype, high proliferation rate as adherent cells, and
take inhibitors, antidepressants, and antipsychotics, are
self-renew capacity and can be easily collected and shipped
drugs commonly prescribed [14–16]. Catatonia is treated
from the laboratory to the bedside and are compatible with
with lorazepam and bilateral electroconvulsive therapy .
diﬀerent delivery methods and formulations [38, 39]. In
Selective serotonin reuptake inhibitors are prescribed for the
addition, MSCs have two other extraordinary properties:
treatment of depression, anxiety, and obsessive-compulsive
they are able to migrate to sites of tissue injury, where they
are able to inhibit the release of proinﬂammatory cytokines
Other nonpsychotropic drugs which are supported by
and have strong immunosuppressive activity that renders
at least 1 or 2 prospective randomized controlled trials or
them a useful tool for successful autologous, as well as
1 systematic review include melatonin, acetylcholinesterase
heterologous, transplantations without requiring pharma-
inhibitors, naltrexone, carnitine, tetrahydrobiopterin, vita-
cological immunosuppression [40–43]. Besides, MSCs are
min C, hyperbaric oxygen treatment, immunomodulation
easily isolated from a small aspirate of bone marrow and
and anti-inﬂammatory treatments, oxytocin, and even music
expanded with high eﬃciency . Given that MSCs are
multipotent cells with a number of potential therapeutic
Alternative and complementary treatments, not suﬃ-
applications, and they represent a future powerful tool in
ciently supported by medical literature, include herbal reme-
regenerative medicine, including ASDs. Mesenchymal stem
dies, vitamin and mineral therapies, piracetam, elimina-
cells could be transplanted directly without genetic modiﬁ-
tion diets, chelation, cyproheptadine, famotidine, glutamate
cation or pretreatments. They simply eventually diﬀerentiate
antagonists, special dietary supplements, acupuncture, neu-
according to cues from the surrounding tissues and do
rofeedback, and sensory integration training [14, 19, 20]. On
not give uncontrollable growth or tumours. In clinical
the other hand, behavioural treatment could represent the
application, there is no problem with immune rejection
eﬀective intervention strategy for autism [21–23]. A plethora
because of their in vivo
immunosuppressive properties [45,
of behavioural strategies and social skill trainings have been
46]. In addition, MSCs can readily be isolated from the
used [24–26]. However, it has been demonstrated that no
patients requiring transplant or from their parents. There is
deﬁnitive behavioural intervention completely improves all
also no tumour formation on transplantation . No moral
symptoms for all ASD patients [27, 28].
objection or ethical controversies are involved .
Summarizing, all these therapies indicate that further
In principle, mesenchymal stem cells can act through
research is needed to better address treatment of several
several possible mechanisms, that is, stimulating the plastic
medical conditions experienced by ASD patients .
response in the host damaged tissue, secreting survival-promoting growth factors, restoring synaptic transmitterrelease by providing local reinnervations, integrating into
2. Mesenchymal Stem Cells
existing neural and synaptic network, and reestablishingfunctional aﬀerent and eﬀerent connections . Since
Nowadays, stem cell therapy represents the great promise
MSCs have the capability to produce a large array of
for the future of molecular medicine. The progression of
trophic and growth factors both in vivo
and in vitro.
several diseases can be slowed or even blocked by stem cell
constitutively secrete interleukins (IL)-6, IL-7, IL-8, IL-11,
IL-12, IL-14, IL-15, macrophage colony-stimulating factor,
Among the stem cell population, mesenchymal stem cells
Flt-3 ligand, and stem-cell factor ). A more reasonable
(MSCs) show probably best potential good results in medical
explanation for the functional beneﬁt derived from MSC
research [31–33]. These cells are nonhematopoietic stem cells
transplantation is their paracrine activity, by which these
having a multilineage potential, as they have the capacity of
cells are able to produce factors that activate endogenous
diﬀerentiating into both mesenchymal and nonmesenchymal
restorative mechanisms within injured tissues contributing
lineages. MSCs are a population of progenitor cells of meso-
to recovery of function lost as a result of lesions [49, 51].
dermal origin found principally in the bone marrow ofadults, giving rise to skeletal muscle cells, blood, fat, vascular,
3. Autism, Personalized Therapy through
and urogenital systems, and to connective tissues throughout
Mesenchymal Stem Cells
the body [34–36]. According to the International Societyof Cellular Therapy, MSCs are deﬁned by the following
MSCs have a strong long-lasting immunosuppressive capac-
minimal set of criteria: (1) grown in adherence to plastic
ity . This extraordinary property is mediated via soluble
Anti-inﬂammatory cytokines overproduction
(IL-10) and IL-1β
Figure 1: Paracrine and immunomodulatory eﬀects as possible mechanisms of action of mesenchymal stem cells (MSCs) in autism spectrumdisorder (ASD) treatment. In humans, ASDs are associated with immune alterations and pro-inﬂammatory cytokines (i.e., IL-1β
) over-production. These cytokines are able to trigger pro-inﬂammatory cellular events. Data from in vitro
models show that MSCs are able to aﬀectnot only T cells, but also other cells of the immune system (i.e., NK cells). Immunoregulatory properties of MSCs are through secretionof large amounts of several bioactive molecules (paracrine activity), that is, PGE-2, IL-10. These molecules cause the inhibition or theunresponsiveness of T-cell mediated responses.
factors. MSCs are able to inhibit the proliferation of CD8+
It has been demonstrated that in postmortem brains
and CD4+ T lymphocytes and natural killer (NK) cells,
from ASD patients there is evidence of abnormal functioning
to suppress the immunoglobulin production by plasma
and cerebellum alterations [61–63]. Indeed, ASD subjects
cells, to inhibit the maturation of dendritic cells (DCs)
show a decreased number of Purkinje cells in the cere-
and the proliferation of regulatory T cells . It has
bellum . These changes could reﬂect defective cortical
been demonstrated that MSCs are also able to inhibit T
organization in ASDs development. In addition, autism is
lymphocyte pro-inﬂammatory cytokine production in vitro
associated with dysregulation in the maturation and plas-
[54, 55], as well as in vivo
. Their ability to modulate
ticity of dendritic spine morphology . Restoring injured
the immune system opens a wide range of cell-mediated
brain functioning could be achieved by stem-cell-based cell
applications, not only for autoimmune diseases and graft-
replacement . Indeed, transplanted MSCs are able to
versus-host disease. Due to the particular immune system
promote synaptic plasticity and functional recovery and
dysregulation observed in ASDs [57, 58], mesenchymal stem
rescue cerebellar Purkinje cells [67, 68]. Challenging newest
cell transplantation could oﬀer a unique tool to provide
study from Deng et al. suggests that granulocyte colony-
better resolution for this disease. Indeed, in ASDs patho-
stimulating factor (G-CSF) is able to mobilize MSCs into
genesis, innate and adaptive immunity changes have been
peripheral blood. These mobilized MSCs are incorporated
reported . ASD patients show an imbalance in CD3+,
and integrate into damaged brain in craniocerebral injured
CD4+, and CD8+ T cells, as well as in NK cells. In addition,
mice, ameliorating the eﬀect of trauma . It is noteworthy
peripheral blood mononuclear cells (PBMCs) extracted from
that MSC ability to migrate to the sites of injury and
ASD patients are able to overproduce IL-1β
participate in the repair process is a key issue in tissue repair
long-term immune alterations . MSC-mediated immune
. Also by this way, MSC therapy could restore the altered
suppressive activity could restore this immune imbalance
brain organization seen in autistic subjects (Table 1).
(Figure 1). Indeed, MSC immunoregulatory eﬀects strongly
A key dilemma in stem-cell-based therapy for autism
inhibit T-cell recognition and expansion by inhibiting TNF-α
treatment is whether endogenous or exogenous MSC admin-
production and increasing IL-10 levels .
istration is the best way of stem cell delivery. Endogenous
Table 1: Potential ameliorative eﬀects mediated by MSCs in ASD
 K. Williams, D. M. Wheeler, N. Silove, and P. Hazell, “Selective
serotonin reuptake inhibitors (SSRIs) for autism spectrumdisorders (ASD),” Cochrane Database of Systematic Reviews
ASD-induced changes in human Potential MSC ameliorative roles
 R. Toro, M. Konyukh, R. Delorme et al., “Key role for
gene dosage and synaptic homeostasis in autism spectrum
disorders,” Trends in Genetics
, vol. 26, no. 8, pp. 363–372, 2010.
 J. J. Bradstreet, S. Smith, M. Baral, and D. A. Rossignol,
“Biomarker-guided interventions of clinically relevant condi-
tions associated with autism spectrum disorders and attentiondeﬁcit hyperactivity disorder,” Alternative Medicine Review
 A. M. Persico and T. Bourgeron, “Searching for ways out of
the autism maze: genetic, epigenetic and environmental clues,”Trends in Neurosciences
, vol. 29, no. 7, pp. 349–358, 2006.
 R. Toro, M. Konyukh, R. Delorme et al., “Key role for
strategy could be limited by the availability of MSCs.
gene dosage and synaptic homeostasis in autism spectrum
Exogenous MSCs could show low rate of engraftment to
disorders,” Trends in Genetics
, vol. 26, no. 8, pp. 363–372, 2010.
provide cellular replacement. It is unclear if diﬀerentiated
 P. El-Fishawy and M. W. State, “The genetics of autism: key
cells are able to develop functional interconnections with
issues, recent ﬁndings, and clinical implications,” Psychiatric
the intrinsic cells of the recipient host . Controversy,
Clinics of North America
, vol. 33, no. 1, pp. 83–105, 2010.
few exogenous MSCs are able to exert paracrine activity.
 M. R. Herbert, “Contributions of the environment and
environmentally vulnerable physiology to autism spectrum
Indeed, exogenously applied MSCs have been shown to
disorders,” Current Opinion in Neurology
, vol. 23, no. 2, pp.
home to injured tissues and repair them by producing
chemokines, or by cell or nuclear fusion with host cells .
 R. Muhle, S. V. Trentacoste, and I. Rapin, “The genetics of
On the other hand, exogenous culture-expanded MSCs could
, vol. 113, no. 5, pp. e472–e486, 2004.
address endogenous MSCs in order to activate them and
 S. E. Levy, D. S. Mandell, and R. T. Schultz, “Autism,” The
guide intrinsic repair . In addition, exogenous delivery
, vol. 374, no. 9701, pp. 1627–1638, 2009.
bypasses surgical intervention on the autistic child.
 CDC, “Surveillance summaries,” Morbidity and Mortality
Cellular therapy could represent a new frontier in the
, vol. 56, pp. 1–28, 2007.
treatment of several diseases. Despite the fact that MSCs
 P. A. Main, M. T. Angley, P. Thomas, C. E. O’Doherty, and
have been enrolled in several clinical trials, long-term safety
M. Fenech, “Folate and methionine metabolism in autism: a
of MSC-based therapies is not yet well established; this fact
systematic review,” American Journal of Clinical Nutrition
could be one major limitation to clinical translation .
 A. M. Reiersen and R. D. Todd, “Co-occurrence of ADHD and
At the present, there are no preclinical studies on the use
autism spectrum disorders: phenomenology and treatment,”
of MSCs in ASD models. There is just one clinical trial
Expert Review of Neurotherapeutics
, vol. 8, no. 4, pp. 657–669,
(NCT01343511 http://www.clinicaltrial.gov/) concerning the
safety and eﬃcacy of human umbilical cord mesenchymal
 J. T. McCracken, “Safety issues with drug therapies for autism
stem cells (hUC-MSCs) and human cord blood mononuclear
spectrum disorders,” Journal of Clinical Psychiatry
, vol. 66,
cells (hCB-MNCs) transplantation in patients with autism by
Shenzhen Beike Bio-Technology Co., China. Results are not
 M. Tandon and J. R. Pruett Jr., “An overview of the use
of antidepressants in children and adolescents,” Missouri
However, personalized stem cell therapy will be the most
, vol. 105, no. 1, pp. 79–85, 2008.
eﬀective treatment for a speciﬁc autistic child, opening a new
 R. M. Nevels, E. E. Dehon, K. Alexander, and S. T. Gontkovsky,
era in autism management in the next future.
“Psychopharmacology of aggression in children and ado-lescents with primary neuropsychiatric disorders: a reviewof current and potentially promising treatment options,”
Experimental and Clinical Psychopharmacology
, vol. 18, no. 2,pp. 184–201, 2010.
The authors gratefully thank Mr. Enzo Abate, Ms. Giovanna
 D. M. Dhossche, A. Shah, and L. Wing, “Blueprints for the
Gallone, and the nonproﬁt organizations “La Forza del Silen-
assessment, treatment, and future study of catatonia in autism
zio” and “Cancellautismo,” Italy for their useful assistance.
spectrum disorders,” International Review of Neurobiology
The authors thank the Autism Research Institute, USA (ARI
grant “Research that makes a diﬀerence” 2010) for ﬁnancial
 D. A. Rossignol, “Novel and emerging treatments for autism
spectrum disorders: a systematic review,” Annals of ClinicalPsychiatry
, vol. 21, no. 4, pp. 213–236, 2009.
 H. G. S¸enel, “Parents’ views and experiences about com-
plementary and alternative medicine treatments for theirchildren with autistic spectrum disorder,” Journal of Autism
 A. Fasano, “Intestine, leaky gut, autism and probiotics,” in
and Developmental Disorders
, vol. 40, no. 4, pp. 494–503, 2010.
Cutting Edge Therapies
, N. J. Lyndhurst, Ed., pp. 192–198,
 V. C. Wong and J. G. Sun, “Randomized controlled trial of
acupuncture versus sham acupuncture in autism spectrum
disorder,” Journal of Alternative and Complementary Medicine
clinical trials with mesenchymal stem cells,” Journal of Cellular
vol. 16, no. 5, pp. 545–553, 2010.
, vol. 211, no. 1, pp. 27–35, 2007.
 P. A. Filipek, R. Steinberg-Epstein, and T. M. Book, “Interven-
 K. L. Pricola, N. Z. Kuhn, H. Haleem-Smith, Y. Song, and
tion for autistic spectrum disorders,” NeuroRx
, vol. 3, no. 2,
R. S. Tuan, “Interleukin-6 maintains bone marrow-derived
mesenchymal stem cell stemness by an ERK1/2-dependent
 L. A. Vismara and S. J. Rogers, “Behavioral treatments in
mechanism,” Journal of Cellular Biochemistry
, vol. 108, no. 3,
autism spectrum disorder: what do we know?” Annual Review
of Clinical Psychology
, vol. 6, pp. 447–468, 2010.
 K. Le Blanc and M. F. Pittenger, “Mesenchymal stem cells:
 C. Kasari and K. Lawton, “New directions in behavioral
progress toward promise,” Cytotherapy
, vol. 7, no. 1, pp. 36–
treatment of autism spectrum disorders,” Current Opinion in
, vol. 23, no. 2, pp. 137–143, 2010.
 K. J. Beggs, A. Lyubimov, J. N. Borneman et al., “Immunologic
 L. C. Murdock and J. Q. Hobbs, “Picture me playing:
consequences of multiple, high-dose administration of allo-
increasing pretend play dialogue of children with autism
geneic mesenchymal stem cells to baboons,” Cell Transplanta-
spectrum disorders,” Journal of Autism and Developmental
, vol. 15, no. 8-9, pp. 711–721, 2006.
, vol. 41, pp. 870–878, 2011.
 A. Uccelli, L. Moretta, and V. Pistoia, “Mesenchymal stem cells
 F. Frankel and C. Whitham, “Parent-assisted group treatment
in health and disease,” Nature Reviews Immunology
, vol. 8, no.
for friendship problems of children with autism spectrum
disorders,” Brain Research
, vol. 1380, pp. 240–245, 2011.
 C. E. P. Aronin and R. S. Tuan, “Therapeutic potential of
 M. Valenti, R. Cerbo, F. Masedu, M. De Caris, and G.
the immunomodulatory activities of adult mesenchymal stem
Sorge, “Intensive intervention for children and adolescents
cells,” Birth Defects Research Part C Embryo Today
, vol. 90, no.
with autism in a community setting in Italy: a single-
group longitudinal study,” Child and Adolescent Psychiatry and
 D. Siniscalco, “Transplantation of human mesenchymal stem
, vol. 4, article no. 23, 2010.
cells in the study of neuropathic pain,” Methods in Molecular
 M. B. Ospina, J. K. Seida, B. Clark et al., “Behavioural and
, vol. 617, pp. 337–345, 2010.
developmental interventions for autism spectrum disorder: a
 P. A. Sotiropoulou and M. Papamichail, “Immune properties
clinical systematic review,” PLoS One
, vol. 3, no. 11, Article ID
of mesenchymal stem cells,” Methods in Molecular Biology
 A. C. Stahmer, L. Schreibman, and A. B. Cunningham,
 R. E. Newman, D. Yoo, M. A. LeRoux, and A. Danilkovitch-
“Toward a technology of treatment individualization for
Miagkova, “Treatment of inﬂammatory diseases with mes-
young children with autism spectrum disorders,” Brain
enchymal stem cells,” Inﬂammation and Allergy
, vol. 8, no. 2,
, vol. 1380, pp. 229–239, 2011.
 D. Coury, “Medical treatment of autism spectrum disorders,”
 T. Meyerrose, S. Olson, S. Pontow et al., “Mesenchymal stem
Current Opinion in Neurology
, vol. 23, no. 2, pp. 131–136,
cells for the sustained in vivo delivery of bioactive factors,”
Advanced Drug Delivery Reviews
, vol. 62, no. 12, pp. 1167–
 D. Siniscalco, N. Sullo, S. Maione, F. Rossi, and B. D’Agostino,
“Stem cell therapy: the great promise in lung disease,”
 K. Ksiazek, “A comprehensive review on mesenchymal stem
Therapeutic Advances in Respiratory Disease
, vol. 2, no. 3, pp.
cell growth and senescence,” Rejuvenation Research
, vol. 12, no.
 G. Brooke, M. Cook, C. Blair et al., “Therapeutic applications
of mesenchymal stromal cells,” Seminars in Cell and Develop-
 D. Siniscalco, C. Giordano, U. Galderisi et al., “Intra-brain
, vol. 18, no. 6, pp. 846–858, 2007.
microinjection of human mesenchymal stem cells decreases
 A. Arthur, A. Zannettino, and S. Gronthos, “The therapeutic
allodynia in neuropathic mice,” Cellular and Molecular Life
applications of multipotential mesenchymal/stromal stem
, vol. 67, no. 4, pp. 655–669, 2010.
cells in skeletal tissue repair,” Journal of Cellular Physiology
 M. K. Majumdar, M. A. Thiede, J. D. Mosca, M. Moorman,
and S. L. Gerson, “Phenotypic and functional comparison of
 P. C. Chagastelles, N. B. Nardi, and M. Camassola, “Biology
cultures of marrow-derived mesenchymal stem cells (MSCs)
and applications of mesenchymal stem cells,” Science Progress
and stromal cells,” Journal of Cellular Physiology
, vol. 176, no.
vol. 93, no. 2, pp. 113–127, 2010.
 B. Short, N. Brouard, T. Occhiodoro-Scott, A. Ramakrishnan,
 L. da Silva Meirelles, A. M. Fontes, D. T. Covas, and A. I.
and P. J. Simmons, “Mesenchymal stem cells,” Archives of
Caplan, “Mechanisms involved in the therapeutic properties
, vol. 34, no. 6, pp. 565–571, 2003.
of mesenchymal stem cells,” Cytokine and Growth Factor
 N. Beyer Nardi and L. da Silva Meirelles, “Mesenchymal
, vol. 20, no. 5-6, pp. 419–427, 2009.
stem cells: isolation, in vitro expansion and characterization,”
 M. Giuliani, M. Fleury, A. Vernochet et al., “Long-lasting
Handbook of Experimental Pharmacology
, no. 174, pp. 249–
inhibitory eﬀects of fetal liver mesenchymal stem cells on T-
lymphocyte proliferation,” PLoS One
, vol. 6, no. 5, Article ID
 S. Sethe, A. Scutt, and A. Stolzing, “Aging of mesenchymal
stem cells,” Ageing Research Reviews
, vol. 5, no. 1, pp. 91–116,
 M. J. Hoogduijn, F. Popp, R. Verbeek et al., “The immuno-
modulatory properties of mesenchymal stem cells and their
 M. Dominici, K. Le Blanc, I. Mueller et al., “Minimal criteria
use for immunotherapy,” International Immunopharmacology
for deﬁning multipotent mesenchymal stromal cells. The
vol. 10, no. 12, pp. 1496–1500, 2010.
International Society for Cellular Therapy position state-
 M. D. Nicola, C. Carlo-Stella, M. Magni et al., “Human bone
, vol. 8, no. 4, pp. 315–317, 2006.
marrow stromal cells suppress T-lymphocyte proliferation
 A. Giordano, U. Galderisi, and I. R. Marino, “From the
induced by cellular or nonspeciﬁc mitogenic stimuli,” Blood
laboratory bench to the patient’s bedside: an update on
vol. 99, no. 10, pp. 3838–3843, 2002.
 S. Beyth, Z. Borovsky, D. Mevorach et al., “Human mesenchy-
 L. Li and J. Jiang, “Regulatory factors of mesenchymal stem cell
mal stem cells alter antigen-presenting cell maturation and
migration into injured tissues and their signal transduction
induce T-cell unresponsiveness,” Blood
, vol. 105, no. 5, pp.
mechanisms,” Frontier Medical
, vol. 5, pp. 33–39, 2011.
 D. J. Prockop, C. A. Gregory, and J. L. Spees, “One strategy
 F. Dazzi and F. M. Marelli-Berg, “Mesenchymal stem cells
for cell and gene therapy: harnessing the power of adult stem
for graft-versus-host disease: close encounters with T cells,”
cells to repair tissues,” Proceedings of the National Academy of
European Journal of Immunology
, vol. 38, no. 6, pp. 1479–1482,
Sciences of the United States of America
, vol. 100, no. 1, pp.
 P. Ashwood, B. A. Corbett, A. Kantor, H. Schulman, J.
 A. Augello, T. B. Kurth, and C. De Bari, “Mesenchymal stem
Van de Water, and D. G. Amaral, “In search of cellular
cells: a perspective from in vitro cultures to in vivo migration
immunophenotypes in the blood of children with autism,”
and niches,” European Cells and Materials
, vol. 20, pp. 121–
, vol. 6, no. 5, Article ID e19299, 2011.
 K. Suzuki, H. Matsuzaki, K. Iwata et al., “Plasma cytokine
 E. N. Momin, A. Mohyeldin, H. A. Zaidi, G. Vela,
proﬁles in subjects with high-functioning autism spectrum
nones-Hinojosa, “Mesenchymal stem cells: new
disorders,” PLoS One
, vol. 6, no. 5, Article ID e20470, 2011.
approaches for the treatment of neurological diseases,” Cur-
 S. Gupta, D. Samra, and S. Agrawal, “Adaptive and innate
rent Stem Cell Research and Therapy
, vol. 5, no. 4, pp. 326–344,
immune responses in autism: rationale for therapeutic use of
intravenous immunoglobulin,” Journal of Clinical Immunol-ogy
, vol. 30, supplement 1, pp. S90–S96, 2010.
 A. M. Enstrom, C. E. Onore, J. A. Van de Water, and P.
Ashwood, “Diﬀerential monocyte responses to TLR ligandsin children with autism spectrum disorders,” Brain, Behavior,and Immunity
, vol. 24, no. 1, pp. 64–71, 2010.
 A. L. Oblak, D. L. Rosene, T. L. Kemper, M. L. Bauman, and G.
J. Blatt, “Altered posterior cingulate cortical cyctoarchitecture,but normal density of neurons and interneurons in theposterior cingulate cortex and fusiform gyrus in autism,”Autism Research
, vol. 4, pp. 200–211, 2011.
 E. R. Whitney, T. L. Kemper, D. L. Rosene, M. L. Bauman,
and G. J. Blatt, “Density of cerebellar basket and stellate cellsin autism: evidence for a late developmental loss of Purkinjecells,” Journal of Neuroscience Research
, vol. 87, no. 10, pp.
 E. Courchesne, C. M. Karns, H. R. Davis et al., “Unusual brain
growth patterns in early life in patients with autistic disorder:an MRI study,” Neurology
, vol. 57, no. 2, pp. 245–254, 2001.
 M. L. Bauman and T. L. Kemper, “Neuroanatomic observa-
tions of the brain in autism: a review and future directions,”International Journal of Developmental Neuroscience
, vol. 23,no. 2-3, pp. 183–187, 2005.
 D. A. Fortin, T. Srivastava, and T. R. Soderling, “Structural
modulation of dendritic spines during synaptic plasticity,”Neuroscientist
. In press.
 A. T. Sørensen, N. Rogelius, C. Lundberg, and M. Kokaia,
“Activity-dependent long-term plasticity of aﬀerent synapseson grafted stem/progenitor cell-derived neurons,” Experimen-tal Neurology
, vol. 229, no. 2, pp. 274–281, 2011.
 R. C. Rodrigues Hell, M. M. Silva Costa, A. M. Goes, and A. L.
Oliveira, “Local injection of BDNF producing mesenchymalstem cells increases neuronal survival and synaptic stabilityfollowing ventral root avulsion,” Neurobiology of Disease
33, no. 2, pp. 290–300, 2009.
 Y. K. Chang, M. H. Chen, Y. H. Chiang et al., “Mesenchymal
stem cell transplantation ameliorates motor function deterio-ration of spinocerebellar ataxia by rescuing cerebellar Purkinjecells,” Journal of Biomedical Science
, vol. 18, article 54, no. 1,2011.
 J. Deng, Z. M. Zou, T. L. Zhou et al., “Bone marrow
mesenchymal stem cells can be mobilized into peripheralblood by G-CSF in vivo and integrate into traumaticallyinjured cerebral tissue,” Neurological Sciences
, vol. 32, no. 4,pp. 641–651, 2011.
UK Jewish Gay and Lesbian Group | Welcome to the World Congress of Gay Lesbian Bisexual and Transgender Jewish OrganizationsΣάββατο, 19 Ιουλίου 2008 06:34:06 Europe/Athens UK Jewish Gay and Lesbian Group Introduction The Jewish Gay and Lesbian Group, JGLG, was founded in 1972 when a small advert in "Gay News" attractedthe astonishing total of 190
Phone: (760) 745-8115 Fax: (760) 745-7814 www.aahc.us SPECIAL PROBLEMS OF PET RABBITS General Information Rabbits have several unique problems; understanding these problems will allow you to better care for your pet and minimize future health care problems. Diarrhea / Mucoid Enteropathy Diarrhea is often seen in rabbits. While it can be due to coccidia (a one-cell protozoan) or