Plenary Session Saturday April 6, 2013
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Інститут молекулярної біології і генетики НАН України
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irk-123456789-1537082019-06-15T01:29:32Z Plenary Session Saturday April 6, 2013 Abstracts 2013 Article Plenary Session Saturday April 6, 2013 / Вiopolymers and Cell. — 2013. — Т. 29, №. 2, доп. — С. 30-37. — англ. 0233-7657 http://dspace.nbuv.gov.ua/handle/123456789/153708 en Вiopolymers and Cell Інститут молекулярної біології і генетики НАН України |
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Plenary Session Saturday April 6, 2013 / Вiopolymers and Cell. — 2013. — Т. 29, №. 2, доп. — С. 30-37. — англ. |
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Вiopolymers and Cell |
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30
Abstracts
Plenary Session
Saturday April 6, 2013
31
The importance of newborn screening in defining the natural
history of congenital cytomegalovirus infection
Dreher AM, Fowler KB, Boppana SB, Ross SA, Britt WJ
Dept. of Pediatrics, Univ Alabama School of Medicine, Childrens Hospital,
Birmingham, Ala. 35223
Background: Congenital human cytomegalovirus (cCMV) infection represents the most
common intrauterine viral infection in humans. The prevalence of cCMV ranges from
0.5–2 % in live births. cCMV represents a significant cause of long term neurological
disease with approximately 5 % of infected infants developing cognitive and/or motor
impairment and 11–15 % suffering hearing loss.
Methods: Early screening programs used virus isolation and immunological detection
assays. Dried blood spots obtained for newborn metabolic screening have also been used
in screening programs. More recently, we reported screening for cCMV using saliva and
PCR based detection of CMV. Because the commitment of resources for the care of
children with cCMV will depend on the prevalence and the outcome of infected infants,
simplified screening programs represent an important advance. Estimates based on the
identification of cCMV infected infants using clinical criteria are subject to enrollment
biases. To determine the importance of such bias in natural history studies of cCMV, we
reviewed the records of a large cohort of infants identified and followed at UAB from the
1970s through 2000. Infants enrolled in this clinic included screened newborns born at a
University hospital and a second group referred from outside health care facilities
secondary to clinical findings consistent with cCMV.
Discussion: In earlier reports as well as recent meta-analyses, it has been suggested that
infants with clinically apparent cCMV (symptomatic infections) had a significant risk for
neurological sequelae. Our findings revealed that the severity of symptoms and long-term
neurological sequelae were significantly increased in the referred population as compared
to the screened population.
Conclusion: Combining these populations lead to a bias in the results from these earlier
studies and more importantly, lead investigators to conclude that the risk for long term
neurological sequelae following cCMV could be assigned based on the presence of
symptomatic infection. In contrast, our results indicate that cCMV infections in the
newborn infant represent a spectrum of disease phenotypes and that risks of long-term
neurological sequelae also varies with the nature of clinical abnormalities at birth.
Key words: newborn infant, human cytomegalovirus, congenital, neurological sequelae
32
Life course perspective of the origin of cardiovascular disease in
women
Calvin J. Hobel, MD¹´²
¹Cedars-Sinai Medical Center, Burns-Allen Research Institute, Department of Obstetrics, Gynecology
& Pediatrics, Division of Maternal Fetal Medicine, Los Angeles, California 8635 West 3rd Street, Suite
160 W, Los Angeles California 90048, USA
²David Geffen School of Medicine at UCLA, Los Angeles, California, USA
Background: Cardiovascular disease (CVD) is the leading cause of death in developed
countries and slightly less in developing countries. The progression of risk factors from
fetal life and childhood and CVD risk factors during pregnancy are now providing
epidemiologists & clinicians opportunities for identification and prevention of early CVD
in women soon after pregnancy. Large cohort studies have clearly shown that women
who develop hypertension, dysglycemia during pregnancy or who deliver low birth
weight or preterm infants are at significant risk of developing CVD earlier than women
who have a normal pregnancy.
Objectives: For the past 20 years our research team has been doing routine uterine artery
vascular resistance assessment during pregnancy to identify those at risk for poor fetal
growth. In 2009 (Placenta) we published results on 523 subjects beginning at 19–21 wks,
repeated at 29–31wks and at 34–36wks. 63 women delivered PT (32 spontaneous & 21
indicated.). We observed significantly elevated uterine artery (UtA) vascular resistance
(VR) at each time point compared to those delivering at term. On the fetal side of the
placenta at 19–21 wks there was no difference in fetal umbilical artery (UmA) VR
between those delivering PT vs. term; however, at 28–31wks and at 34–36wks those
infants delivering PT had significantly elevated UmAVR. We now interpret this finding
as the first observation of “fetal programming” where the fetuses destined to deliver PT
recognized the reduced UtA perfusion and developed increase UmAVR that persisted
until delivery.
Conclusions: Based upon the literature prior to 2001 Thorp JM (Curr Probl Obstet
Gynecol Fertil) proposed a unifying hypothesis of placental vascular compromise for
PTB. Our research team considers UtAVR in women destined to deliver PT is evidence
of early maternal cardiovascular disease which is consistent with epidemiological
evidence for why women with PTD, Preeclampsia/Hypertension, Obesity & Dysglycemia
are at risk for early cardiovascular disease.
33
Posttranslational titin isoform modifications in perinatal diastolic
dysfunction
Zoltan Papp, M.D., Ph.D., D.Sc.,
Institute of Cardiology, Division of Clinical Physiology,
University of Debrecen, Medical and Health Science Center
In newborns, the background of diastolic dysfunction (leading potentially to heart failure
with preserved ejection fraction, HFPEF) is unknown. Earlier, we have pointed out the
significance of cardiomyocyte passive force increase (Fpassive=tension determined in
Ca2+-free solution) in the pathogenesis of adult HFPEF. One of the most important
determinants of Fpassive is the giant sarcomeric protein, titin. We hypothesize, that
physiological and pathological adaptation processes to the extrauterine life involves
posttranslational modifications (phosphorylation and oxidation) of differentially
expressed titin isoforms, and that these changes together coordinate Fpassive of
newborns. Therefore, we will follow the titin isoform dependence of Fpassive in
permeabilized cardiomyocytes during the perinatal period in control and in transgenic
mice overexpressing the phosphodiesterase 5 isoform. In addition, in model experiments
on cardiomyocytes of mice, healthy rats at different stages of postnatal development and
of adult humans we will test how in vitro protein kinase A (PKA), or protein kinase G
(PKG) exposures, alone or in combination with oxidative insults (i.e. SH-group
oxidation, carbonylation) affect Fpassive. In a parallel clinical study, diastolic ventricular
function and oxidative plasma/urine markers will be followed to reveal their hypothetical
relationship during the postnatal period in term and preterm human newborns.
Altogether, our investigations will clarify the pathomechanism of perinatal diastolic
dysfunction due to inappropriate cardiovascular adaptation to the extrauterine life and
promote the development of new approaches for its pharmacological management.
34
Risk factors for ischemic heart disease in the Croatia, Czech
Republic, Hungary and Romania.
Jan Piťha1,2, Jaroslav A. Hubacek1,2 , Jitka Rynekrova 1,2, Maria Dorobantu2,
Rodica Niculescu 2, Maria Heffer 2, Attila Borbely2, Věra Adámková 1,
Věra Lánská 1, Sandor Vari2
1Institute of Clinical and Experimental Medicine, Center for Experimental Medicine,
Videnska 1958/9, 140 21, Prague, Czech Republic;
2 Regional Cooperation for Health, Science and Technology (RECOOP HST) Association
BACKGROUND: Despite of the strong prognostic value of all traditional cardiovascular
risk factors for ischemic heart disease (IHD), differences exist in the incidence of clinical
events between patients at apparently similar risk. One of the reasons could be different
genetic background of particular person. Interpretation of genetic factors associated with
IHD is complicated by different prevalence of risk factors in controls. In our previous
studies we observed association between connexin37 gene polymorphism and IHD,
limited only to non-smoking women. In this presentation we focused on complex and
gender oriented statistical analyses of differences in main cardiovascular risk factors
between patients with IHD from four European countries.
METHODS: Population consisted of 1,735 men and 661 women with IHD. Gender,
smoking status, presence of hypertension, diabetes mellitus, and polymorphism of
connexin 37 gene were analyzed. The control population consisted of 1,191 men and
1,368 women from the post-MONIKA study. For statistical analyses chi2 square test was
used.
RESULTS: In the whole group, all risk factors were more prevalent in patients than in
controls: smoking-67.7 vs. 46.7 %, p < 0.0001; diabetes mellitus-20.6 vs. 13.9 %,
p< 0.0001; hypertension-61.8 vs. 37.7 %, p < 0.0001. No difference was found for
connexin37 genotypes between patients and controls (CC/CT/TT): 10.4/43.0/46.5 vs.
9.6/44.0/46.4 5 %, p = 0.6102. Regarding diabetes mellitus, difference between patients
and controls was found in women: 25.7 vs. 11.7 %, p < 0.0001; but not for men 18.8 vs.
16.5 %, p = 0.1241. No differences were found between men and women in other risk
factors under study.
CONCLUSION: In the complex statistical evaluation, the only gender-related difference
in association between traditional cardiovascular factors and IHD was found in the case
of diabetes mellitus, which was associated with IHD only in women. No association was
found between polymorphism of the gene for connexin37 and ischemic heart disease
using complex statistical analyses. According to our previous results, also stratification of
patients according to prevalence of cardiovascular risk factors could reveal gene traits
associated with ischemic heart disease in particular populations.
Key words: cardiovascular risk factors- ischemic heart disease – gender differences -
connexin 37 gene polymorphism
35
Vascular responses to various physiological conditions
I. Drenjancevic
Faculty of Medicine University Josip Juraj Strossmayer Osijek, J. Huttlera 4, Osijek, Croatia;
ines.drenjancevic@mefos.hr
The endothelium plays an important role in maintaining vascular homeostasis in various
physiological conditions. Several endothelium-derived factors were shown to mediate
vascular responses, among which the metabolites of arachidonic acid (AA) have very
important role. AA could be metabolized via three pathways:
via cyclooxygenases (COX) to prostaglandins and thromboxanes,
via lypooxygenase to leukotrienes and
via P450 (CYP) pathway to epoxyeicosatrienoic acids (EETs) and 20-
hydroxyeicosatetraenoic acid (20-HETE). Each of them has particular effect on vascular
tone and subsequently tissue perfusion. Our recent studies demonstrated the role for CYP
metabolite in vascular responses to vasodilator stimuli, such as acetylcholine and reduced
pO2 in hyperbaric oxygenation conditions.
36
1001 Complement tales: carbon nanotubes, poly(ethylene glycol)s
and the just so forty complement proteins
S M Moghimi
Centre for Pharmaceutical Nanotechnology and Nanotoxicology (Faculty of Health and Medical
Sciences), and NanoScience Centre (Faculty of Science), University of Copenhagen, DK-2100
Copenhagen, Denmark
‘Verily the works and words of our ancestors have become signs and examples to
people of our modern age so that they may view what happened to other folk and take
heed; so that they may peruse the annals of ancient peoples and read about everything
they have experienced and thereby be guided and restrained.’ [Prologue: Arabian
Nights: A Selection; Translated by Sir Richard F. Burton, Penguin]
Not so long ago and still carbon nanotubes (CNTs) are in contention for site-specific drug
and nucleic acid delivery, photodynamic therapy, and photoacoustic molecular imaging,
particularly in experimental oncology [1]. Pristine carbon nanotubes are insoluble in
nearly all aqueous solvents and biological fluids. Accordingly, there have been many
measures in terms of surface treatment and functionalization strategies to render
nanotubes readily dispersible [1–3]. PEGylation is a widely used surface modification
approach, which not only renders pristine CNTs dispersible in aqueous solvents, but also
improves their circulation profiles in the vasculature [1, 3–6]. PEGylation, however, may
trigger the complement system, which is an integral part of innate immunity, where its
inadvertent activation can induce clinically significant anaphylaxis [2, 3, 7–9]. In this
presentation, I shall demonstrate that covalent functionalization of CNTs with
poly(ethylene glycol)s, regardless of PEG molecular mass and surface density, fails to
protect against complement activation [6]. On the other hand, surface adsorbed
methoxypoly(ethylene glycol)-based amphiphiles, which also confer solubility and
prolonged circulation profile to CNTs, can modulate activation of human complement
system differently, depending on the amphiphile structure. While immobilized linear
poly(ethylene glycol) amphiphiles fully trigger complement through both L-ficolin and
mannose-binding lectin sensing, high molecular weight amphiphiles with branched
poly(ethylene glycol) architecture neither initiate anaphylatoxin generation nor induce
triggering of the effector arm of the complement system, despite activating calcium-
sensitive pathways of the complement system [5]. Finally, increased PEG loading,
through adsorption of methoxypoly(ethylene glycol) amphiphiles on covalently PEG-
functionalized CNTs, generate fewer complement activation products; however,
complement activation is not completely eliminated [6]. These observations address two
critical issues: (a) the difficulty in making CNTs more compatible with innate immunity
through PEG functionalization and adsorption, and (b) offering a critical step towards
nanomaterial surface modification with branched methoxyPEG co-polymers with
appropriately distanced PEG chains for improved protein exclusion that can significantly
improve innate immunocompatibility. However, with the latter case problems still
37
persist; the high molecular weight of the copolymer limits its eventual excretion through
kidneys, where the cutoff for glomerular filtration is 60 kDa.
‘And yet, oh king, this tale is no more wondrous than the remarkable story of the
blood-traveller.’ To be continued.
Financial support by the Danish Agency for Science, Technology and Innovation (Det Strategiske
Forskningsråd), reference 09-065746 is gratefully acknowledged.
References
1. Andersen, A. J., Wibroe, P. P. and Moghimi, S. M. (2012) Perspectives on carbon
nanotube-mediated adverse immune effects. Adv. Drug Deliv. Rev. 64: 1700–
1705.
2. Moghimi, S. M. and Hunter, A. C. (2010) Complement monitoring of carbon
nanotubes. Nature Nanotechnol. 5: 382–382.
3. Moghimi, S. M., Andersen, A. J., Hashemi, S. H., Lettiero, B., Ahmadvand, D.,
Hunter, A. C., Andresen, T. L., Hamad, I. and Szebeni, J. (2010) Complement
activation cascade triggered by PEG-PL engineered nanomedicines and carbon
nanotubes: the challenges ahead. J. Control. Rel. 146: 175–181.
4. Moghimi, S. M., T. L. Andresen and Hunter, A. C. (2012) Factors controlling
nanoparticle pharmacokinetics: an integrated analysis and perspective. Annu. Rev.
Pharmacol. Toxicol. 52: 481–503.
5. Andersen, A. J., Robinson, J. T., Dai, H., Hunter, A. C., Andresen, T. L. and
Moghimi, S. M. (2013) Single-walled carbon nanotubes surface control of
complement sensing and activation. ACS Nano 7: 1108–1119.
6. Andersen, A. J., Windschiegl, B., Ilbasmis-Tamer, S., Degim, I. T., Hunter, A. C.,
Andresen, T. L. and Moghimi, S. M. (2013) Complement activation by PEG-
functionalized MWCNTs is independent of PEG molecular mass and surface
density. Nanomedicine: Nanotechnol. Biol. Med. (in press).
7. Hamad, I., Al- Hanbali, O., Hunter, A. C., Rutt, K. J., Andresen, T. L. and
Moghimi, S. M. (2010) Distinct polymer architecture mediates switching of
complement activation pathways at nanosphere-serum interface: implications for
stealth nanoparticles engineering. ACS Nano 4: 6629–6638.
8. Moghimi, S. M., Wibroe, P. P., Helvig, S., Farhangrazi, Z. S. and Hunter, A. C.
(2012) Genomic perspectives in inter-individual adverse responses following
nanomedicine administration: the way forward. Adv. Drug Deliv. Rev. 64: 1385–
1393.
9. Moghimi, S. M. and Farhangrazi, Z. S. (2013) Nanomedicine and the complement
paradigm. Nanomedicine: Nanotechnol. Biol. Med. (in press).
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