This study analyzed the genetic etiology of nonsyndromic cleft lip and palate in Estonia. It found a high occurrence rate of cleft palate compared to cleft lip, with a ratio of 1:2:2. Environmental factors like stress, chemicals, and medications were identified in 22-36% of cases. The study genotyped SNPs in candidate genes and found associations between cleft lip with/without palate and genes like MSX1, MTHFR, and PVRL2 in Estonians. In Baltics, genes like FGF1, FOXE1, WNT9B, TIMP2, and PVRL2 showed associations. Genes like IRF6
Farnesoid x receptor (fxr) and intestinal mucosa - Stefano FiorucciAttività scientifica
Bile acids activated receptors regulate the integrity of gastrointestinal mucosafocus on FXR.
Stefano Fiorucci,
MD Department of Surgical and Biomedical Sciences
University of Perugia
For The Japanese Society of Gastroenterology (JSGE) COI Disclosure
NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in genes that encode receptor subunits are associated with several intractable neurodevelopmental disorders, including developmental and epileptic encephalopathy (DEE). To extend understanding of these intractable childhood diseases, we have begun to model these variants in laboratory mice.
Models studied so far are a constitutive knockin for GRIN2A variant p.Ser644Gly (S644G) based on one case, and a GRIN2D variant, p.Val667Ile (V667I), noted in at least three unrelated cases. Homozygous and heterozygous Grin2a S644G mice exhibit altered hippocampal morphology at 2 weeks, and homozygotes exhibit lethal tonic-clonic seizures in week 3. Heterozygotes have a normal lifespan without spontaneous seizures, but display a variety of distinct features including
resistance to electrically induced limbic seizures, as well as hyperactivity and repetitive and reduced anxiety behaviors. Multielectrode recordings of mutant neuronal networks reveal hyperexcitability and altered bursting and synchronicity of both mutant genotypes. When expressed in heterologous cells, mutant receptors exhibit enhanced NMDAR agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. Consistent with this, NMDAR-mediated synaptic currents in hippocampal slices from mutant mice show a prolonged deactivation time course. Standard antiepileptic drug monotherapy was ineffective in the patient, but combined treatment of NMDAR antagonists with antiepileptic drugs substantially reduced the seizure burden albeit without appreciable developmental improvement. Chronic treatment of homozygous mutant mouse pups with NMDAR antagonists delayed the onset of lethal seizures but did not prevent them.
Grin2d V667I knockin mice are at an earlier stage of study. In contrast to Grin2a S644G, V667I heterozygous mice are severely impaired and suffer from lethal tonic-clonic seizures with an onset from about 18 days to 3 months. The impairment precludes natural mating such that the line needs to be propagated by ovary transplantation. Young heterozygotes adults in video-EEG also exhibit very frequent interictal epileptiform spiking and spike-wave discharge activity, resembling absence seizures. Preliminary histology shows significant pyknotic nuclei appearing to evidence
cell death in the cerebral cortex. Pup developmental milestones, while not evidencing significant developmental delay, show unusual features including excessive maternal separation induced pup vocalization. Further studies are ongoing. Together these efforts illustrate the power of modelling severe neurodevelopmental seizure disorders using multiple experimental modalities and suggest their utility in identifying and evaluating new therapies.
Computational models for the analysis of gene expression regulation and its a...amathelier
Anthony Mathelier has recently been appointed as a new group leader in Computational Biology at the NCMM in Oslo, focusing on computational methods to study gene regulation. He will present one of his recent studies that coupled experimental data and targeted computational analysis with TF binding profiles to interpret cis-regulatory somatic mutations of 84 matched tumour-normal whole genomes from B-cell lymphomas. Transcription factor binding sites (TFBSs) representing the core of gene cis-regulation, he will finally introduce new models to improve the prediction of TFBSs from ChIP-seq data.
Farnesoid x receptor (fxr) and intestinal mucosa - Stefano FiorucciAttività scientifica
Bile acids activated receptors regulate the integrity of gastrointestinal mucosafocus on FXR.
Stefano Fiorucci,
MD Department of Surgical and Biomedical Sciences
University of Perugia
For The Japanese Society of Gastroenterology (JSGE) COI Disclosure
NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in genes that encode receptor subunits are associated with several intractable neurodevelopmental disorders, including developmental and epileptic encephalopathy (DEE). To extend understanding of these intractable childhood diseases, we have begun to model these variants in laboratory mice.
Models studied so far are a constitutive knockin for GRIN2A variant p.Ser644Gly (S644G) based on one case, and a GRIN2D variant, p.Val667Ile (V667I), noted in at least three unrelated cases. Homozygous and heterozygous Grin2a S644G mice exhibit altered hippocampal morphology at 2 weeks, and homozygotes exhibit lethal tonic-clonic seizures in week 3. Heterozygotes have a normal lifespan without spontaneous seizures, but display a variety of distinct features including
resistance to electrically induced limbic seizures, as well as hyperactivity and repetitive and reduced anxiety behaviors. Multielectrode recordings of mutant neuronal networks reveal hyperexcitability and altered bursting and synchronicity of both mutant genotypes. When expressed in heterologous cells, mutant receptors exhibit enhanced NMDAR agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. Consistent with this, NMDAR-mediated synaptic currents in hippocampal slices from mutant mice show a prolonged deactivation time course. Standard antiepileptic drug monotherapy was ineffective in the patient, but combined treatment of NMDAR antagonists with antiepileptic drugs substantially reduced the seizure burden albeit without appreciable developmental improvement. Chronic treatment of homozygous mutant mouse pups with NMDAR antagonists delayed the onset of lethal seizures but did not prevent them.
Grin2d V667I knockin mice are at an earlier stage of study. In contrast to Grin2a S644G, V667I heterozygous mice are severely impaired and suffer from lethal tonic-clonic seizures with an onset from about 18 days to 3 months. The impairment precludes natural mating such that the line needs to be propagated by ovary transplantation. Young heterozygotes adults in video-EEG also exhibit very frequent interictal epileptiform spiking and spike-wave discharge activity, resembling absence seizures. Preliminary histology shows significant pyknotic nuclei appearing to evidence
cell death in the cerebral cortex. Pup developmental milestones, while not evidencing significant developmental delay, show unusual features including excessive maternal separation induced pup vocalization. Further studies are ongoing. Together these efforts illustrate the power of modelling severe neurodevelopmental seizure disorders using multiple experimental modalities and suggest their utility in identifying and evaluating new therapies.
Computational models for the analysis of gene expression regulation and its a...amathelier
Anthony Mathelier has recently been appointed as a new group leader in Computational Biology at the NCMM in Oslo, focusing on computational methods to study gene regulation. He will present one of his recent studies that coupled experimental data and targeted computational analysis with TF binding profiles to interpret cis-regulatory somatic mutations of 84 matched tumour-normal whole genomes from B-cell lymphomas. Transcription factor binding sites (TFBSs) representing the core of gene cis-regulation, he will finally introduce new models to improve the prediction of TFBSs from ChIP-seq data.
Dr. José Baselga - Simposio Internacional 'Terapias oncológicas avanzadas'Fundación Ramón Areces
Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
Insilico analysis of pkd genes in polycystic kidney disease patientsVeeramuthumariPandia1
The power point tells about the gene polymorphism alters the protein structure. Alteration in protein structure leads to malfunction of gene causes disease. PKD gnes-Polycystin 1 and 2 protein - Polycystic kidney disease.
George D. Demetri, MD, Prof. Jean-Yves Blay, MD, and Steven DuBois, MD, MS, prepared useful practice aids pertaining to advanced sarcoma for this CME activity titled "The Promise of New Concepts and Innovative Therapy in Advanced Sarcoma: From Established Targets to TRK Inhibition and Beyond." For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2L3jwcf. CME credit will be available until December 26, 2019.
Dr. José Baselga - Simposio Internacional 'Terapias oncológicas avanzadas'Fundación Ramón Areces
Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
Insilico analysis of pkd genes in polycystic kidney disease patientsVeeramuthumariPandia1
The power point tells about the gene polymorphism alters the protein structure. Alteration in protein structure leads to malfunction of gene causes disease. PKD gnes-Polycystin 1 and 2 protein - Polycystic kidney disease.
George D. Demetri, MD, Prof. Jean-Yves Blay, MD, and Steven DuBois, MD, MS, prepared useful practice aids pertaining to advanced sarcoma for this CME activity titled "The Promise of New Concepts and Innovative Therapy in Advanced Sarcoma: From Established Targets to TRK Inhibition and Beyond." For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2L3jwcf. CME credit will be available until December 26, 2019.
This is a presentation by Dada Robert in a Your Skill Boost masterclass organised by the Excellence Foundation for South Sudan (EFSS) on Saturday, the 25th and Sunday, the 26th of May 2024.
He discussed the concept of quality improvement, emphasizing its applicability to various aspects of life, including personal, project, and program improvements. He defined quality as doing the right thing at the right time in the right way to achieve the best possible results and discussed the concept of the "gap" between what we know and what we do, and how this gap represents the areas we need to improve. He explained the scientific approach to quality improvement, which involves systematic performance analysis, testing and learning, and implementing change ideas. He also highlighted the importance of client focus and a team approach to quality improvement.
Ethnobotany and Ethnopharmacology:
Ethnobotany in herbal drug evaluation,
Impact of Ethnobotany in traditional medicine,
New development in herbals,
Bio-prospecting tools for drug discovery,
Role of Ethnopharmacology in drug evaluation,
Reverse Pharmacology.
How to Create Map Views in the Odoo 17 ERPCeline George
The map views are useful for providing a geographical representation of data. They allow users to visualize and analyze the data in a more intuitive manner.
Palestine last event orientationfvgnh .pptxRaedMohamed3
An EFL lesson about the current events in Palestine. It is intended to be for intermediate students who wish to increase their listening skills through a short lesson in power point.
Students, digital devices and success - Andreas Schleicher - 27 May 2024..pptxEduSkills OECD
Andreas Schleicher presents at the OECD webinar ‘Digital devices in schools: detrimental distraction or secret to success?’ on 27 May 2024. The presentation was based on findings from PISA 2022 results and the webinar helped launch the PISA in Focus ‘Managing screen time: How to protect and equip students against distraction’ https://www.oecd-ilibrary.org/education/managing-screen-time_7c225af4-en and the OECD Education Policy Perspective ‘Students, digital devices and success’ can be found here - https://oe.cd/il/5yV
We all have good and bad thoughts from time to time and situation to situation. We are bombarded daily with spiraling thoughts(both negative and positive) creating all-consuming feel , making us difficult to manage with associated suffering. Good thoughts are like our Mob Signal (Positive thought) amidst noise(negative thought) in the atmosphere. Negative thoughts like noise outweigh positive thoughts. These thoughts often create unwanted confusion, trouble, stress and frustration in our mind as well as chaos in our physical world. Negative thoughts are also known as “distorted thinking”.
2024.06.01 Introducing a competency framework for languag learning materials ...Sandy Millin
http://sandymillin.wordpress.com/iateflwebinar2024
Published classroom materials form the basis of syllabuses, drive teacher professional development, and have a potentially huge influence on learners, teachers and education systems. All teachers also create their own materials, whether a few sentences on a blackboard, a highly-structured fully-realised online course, or anything in between. Despite this, the knowledge and skills needed to create effective language learning materials are rarely part of teacher training, and are mostly learnt by trial and error.
Knowledge and skills frameworks, generally called competency frameworks, for ELT teachers, trainers and managers have existed for a few years now. However, until I created one for my MA dissertation, there wasn’t one drawing together what we need to know and do to be able to effectively produce language learning materials.
This webinar will introduce you to my framework, highlighting the key competencies I identified from my research. It will also show how anybody involved in language teaching (any language, not just English!), teacher training, managing schools or developing language learning materials can benefit from using the framework.
3. Definitions
• Cleft lip with or without cleft palate
(CL/P):
ICBDMS, International Clearinghouse for Birth Defect Monitoring Systems
4. Definitions
• Cleft palate without cleft lip (CP):
ICBDMS, International Clearinghouse for Birth Defect Monitoring Systems
5. • 660 children/ per day
• 1 child per 2 minutes
• 235,000 children per year
• an additional 3,200 cleft children per year
6. Prevalence
•Oral clefts (OC) 1:700 live births.
•CL/P 9.92 per 10,000
•CL 3.28 per 10,000
•CLP 6.64 per 10,000
•CP 6,2 per 10,000
•CL:CLP:CP for Caucasians 1:2:1
International Perinatal Database of Typical Orofacial Clefts 2011
11. Gene discovery in
nonsyndromic clefts
• The Online Mendelian Inheritance in
Man catalog (OMIM) - 720 syndromes
• 75% CL/P and 50% CP are nonsyndromic
• Multifactorial etiology
• environmental
• genetic factors
12. Genetic approaches
• Linkage analysis
• Association studies
• Identification of chromosomal anomalies
or microdeletions in cases
• Direct sequencing of DNA samples
13. Candidate genes for oral clefts
Gene Evidence References
Confirmed
Zucchero et al., 2004; Blanton et al., 2005; Ghassibe
IRF6 GWA, LD, L, M et al., 2005; Scapoli et al., 2005; Srichomthong et al.,
2005; Rahimov et al., 2008;
8q24 locus GWA, LD Marazita et al., 2009; Birnbaum et al., 2009.
VAX1 GWA, LD Beaty et al., 2010; Mangold et al., 2010.
14. Gene Evidence References
Likely
ABCA4 (locus only) GWA Beaty et al., 2010.
Van der Boogaard et al., 2000; Maestri et al., 1997; Mitchell et
MSX1 LD, M al., 2001; Romitti et al., 1999; Jezewski, 2003; Lidral et al.,
1998; Vieira et al., 2003; Suzuki et al., 2004.
FOXE1 L, LD, M Vieira et al., 2005b; Venza et al., 2006; Moreno et al., 2009a.
FGFR2 M Riley et al., 2007; Riley and Murray, 2007; Osoegawa, 2008.
BMP4 M Lin et al., 2008; Suzuki et al., 2009; Jianyan et al., 2010.
17q22 locus LD Beaty et al., 2010; Mangold et al., 2010.
MAFB GWA Beaty et al., 2010.
Birnbaum et al., 2009; Martinelli et al., 2007; Chiquet et al.,
MYH9 GWA 2009; Jia et al., 2010.
15. Gene Evidence References
Intensively studied
Martinelli et al., 2001; Blanton et al., 2000; Botto and Yang, 2000;
MTHFR LD Jugessur et al., 2003b; Jagomägi et al., 2010.
Marazita and Mooney, 2004; Mitchell, 1997; Hwang et al.,1995; Maestri
TGF-α LD et al.,1997; Miettinen et al., 1989; Suzuki et al., 2004; Carter et al., 2010.
Alkuraya et al., 2006; Shi et al., 2009; Mostowska et al., 2010; Carter et
SUMO1 M al., 2010.
PDGFC LD, M Ding et al., 2004; Choi et al., 2009; Jugessur et al., 2009.
FGF8 M Riley and Murray, 2007; Riley et al., 2007.
PVRL1 M, LD Avila et al., 2006; Sözen et al., 2001; Sözen et al., 2009.
Miettinen et al.,1999; Maestri et al.,1997; Hwang, 1992; Lidral et
TGF-β3 LD, M al.,1998; Suzuki et al., 2004; Beaty et al., 2002; Suazo et al., 2010.
CRISPLD2 LD Chiquet et al., 2007; Letra et al., 2010
GSTT1 LD Shi et al., 2007
17. Aims of the study
• To record the occurrence rate of OC, on the
basis of records of patients treated in the
Department of Oral and Maxillofacial Surgery
of the Tartu University Hospital, during the
period of 1910–2000.
18. Aims of the study
• To determine the rate of occurrence between
different cleft types on the basis of gender and
location.
19. Aims of the study
• To record the epidemiological factors which
may influence the development of OC, and to
evaluate their occurrence regularities.
20. Aims of the study
• To investigate the possible contribution of
recognized candidate genes in the
development of nonsyndromic OC in an
Estonian population and in the Baltic region
(Estonia, Latvia, Lithuania).
39. IRF6
• In Baltic sample we could not demonstrate
convincing evidence of an association between
CL/P and variants in IRF6
• CL/P candidate gene
• most accordant results
• VWS - Van der Woude syndrome
• Baltic CP sample IRF6 SNP
rs17389541/novel implication
40. Conclusion
• Overview of OC
• High occurrence rate of CP
• CL:CLP:CP 1:2:2
• Overview of possible enironmental factors
• Candidate genes
• MSX1, MTHFR, OFC3, IRF6, COL2A1,
COL11A2, WNT3, FGF1, TIMP2, WNT9B,
FOXE1
41. Concluding remarks
• Surveillance system and official statistics
• Multifactorial etiology
• Genetic factors and environmental factors are
ethnicity-specific, location-specific
• A specific protocol for cleft prevention has to be
worked out based on:
• genetic
• environmental
• lifestyle studies of each specific population
group
Editor's Notes
Dear (vice dean of research)( or dear dean of medical faculty), dear council members of medical faculty; dear opponent; dear colleagues and friends.
Cleft lip with or without cleft palate palate is: a congenital malformation characterized by partial or complete clefting of the upper lip, with or without clefting of the alveolar ridge or the hard palate. “ Cleft of the lip arises by non-fusion of various processes that build up the face. Clefts may be unilateral, predominantly on the left side, or bilateral
Cleft palate is: a congenital malformation characterized by a closure defect of the hard and/or soft palate behind the foramen incisivum without cleft lip. Includes sub-mucous cleft palate. The cleft originates in the non-fusion of the maxillar palatal processes during the tenth week of embryonic development.
660 children born every day with orofacial clefts Every two minutes, one child is born in the world with cleft 235,000 children with OCs born in a year The annual world population is growing by about 1.8 million; therefore, in the future an additional 3,200 cleft children are expected per year
Prevalence of Oral clefts is approximately 1 in every 700 live births; that is, with about the same frequency as Down syndrome, neural tube defects, polydactyly, and other so-called “common” congenital anomalies. There is a large geographical variation in the birth prevalence rate. Proportions for different cleft types for Caucasians are given by Fogh-Andersen.
CL/P prevalence in literature is 1:1000 or 9,92/10 000 in the word, so only some countries in Europe have so big CL/P prevalence. Mostly this is in Europe around 6-7 cases per 10 000. The highest reported prevalence rate for CP in the world is that of Finland 10-14 cases per 10 000. The prevalence for both OC main types, seems to depend largely on the same macro ethnicity, with maximum values among Mongols, lowest among Africans, and intermediate in Caucasians. For CL/P in Europe, higher prevalence rates are reported from northern than from southern countries
In American continent the case is different. Native Americans from south-America and Mexico have high incidence of oral clefts. This is more than 10 cases per 10 000 births. The highest reported prevalence rate in the world is that of Bolivia. Known data comes mainly from the city of La Paz, at 4000 meters above sea level, with a large proportion of its population being of Amerindian ethnic background. The role of both environmental factors, like chronic hypobaric hypoxia from altitude and Genetic factors like (Mongolic Amerindian ethnicity) their interactions are still unknown. Interestingly, a similarly high prevalence rate for CL/P seems to exist in the ethnic Mongolian population of Tibet at an almost equally high altitude.
National and official statistics about oral clefts in Estonia is nonexistent. Why there is no Estonian date available in world publications. Birth rate in Estonia was last year around 14 500 and we had 14 cleft cases. This makes 9,6 clefts per 10 000 newborns. CL/P mean value for the word is 9,92 but in Europe 6-7 cases per 10 000. Cleft ratio is different from Caucasians as we have more CP cases.
Nonsyndromic OC have multifactorial etiology, which involves both: environmental and genetic factors. Known specific exposures are: cigarette smoking; medications and drugs, alcohol; solvents and pesticide and in prevention vitamins and diet are important.
There are over 720 known syndromes featuring OC as cardinal symptoms. Most of orofacial clefts are belived to be nonsyndromic, with the rare syndromic cases. Evidence for genetic component has been obtained from studies of familial recurrence, which indicate that the relative risk for siblings is 30-40 times higher than average population risk. The lack of complete concordance in monozygotic twins illustrates the importance of environmental factors in the etiology of Cl/P.
To date, genetic approaches to non-syndromic CLP have included: Linkage analysis , using large, multiplex families or smaller but inbred families, or analysis of affected relative pairs; association studies, using case–parent trios or case–control samples; identification of chromosomal anomalies or microdeletions in cases; and direct sequencing of DnA samples from affected individuals. These methods can be applied to candidate genes or genome-wide strategies can be used. Each approach as its own advantages and disadvantages, some of which will depend on the underlying genetic architecture of the disease, as well as the realities of economics and technology. I briefly summarize successes using a range of those different approaches.
Recent successes in genome-wide linkage and association studies have identified novel loci that are significantly associated with CLP. Researchers are currently striving to identify the etiologic variants at these novel loci to understand the developmental disturbances leading to CLP. In this slide you can see the genes from Studies with the confirmed evidence, where at least two independent studies reaching conservative levels of significance.
Those are the genes that have likely the role in CLP. There are the genes where at least one study is with conservation/compelling data and other supportative studies is done.
Those are the genes that have intensively studied. There are a multiple studies but no consensus have found.
In our first study a total of 585 health files of patients with OCs had been preserver. There were more boys then girls. CP was almost as common as CLP.
Estonian study group for candidate genes included 153 patients : 100 patients with CL/P and 53 patients with CP. Estonian controls were selected from the Biobank of the Estonian Genome Center.
The Latvian subjects included 32 patients with CP and 108 patients with CL/P. The latvian control group consisted of 182 randomly selected individuals collected at the Latvian Biomedical research and study center The Lithuanian subjects included 19 patients with CP and 92 patients with CL/P. The Lithuanian control group consisted of 219 individuals selected from six ethnolinguistic group of Lithuania with an equal male-to female ratio.
18 candidate genes for study II and 40 candidate genes for study III and IV were selected on the basis of previously published findings : from association and linkage studies, from gene expression patterns during craniofacial development, from cleft phenotype in knockout or transgenic mouse models, from genes that underlie mendelian syndromic forms of clefting, and from studies of chromosomal rearrangements associated with orofacial cleft phenotypes in humans.
The selected genes are encoding for a variety of molecules implicated in craniofacial morphogenesis: transcription factors (IRF6, MSX1, TBX22), growth factors (FGF1, 2), polarizing signals (BMP2 and 4 or WNT genes), cell adhesion moleculs (PVRL1 and 2) and extracellular matrix moleculs (COL genes; MMP-s and TIMP2)
genomic DNA was extracted from peripheral blood lymphocytes. Genotyping in a Baltic sample was performed according to the principles of an arrayed primer extension-based genotyping method.
Descriptive statistics was performed using Statistical package for social sciences software. Statistical analyses were conducted using PLINK software which is a free, open-source whole genome association analysis toolset. LD measures were calculated and the haplotype blocks were defined using the confidence interval method, and haplotype frequencies were estimated with Haploview software. Power analysis was performed with Power Calculator for Two Stage Association Studies
Fogh-Andersen was the first to emphasize the proportions of occurrence of different cleft types in the Caucasians. The prevalence of CP varies significantly in Europe, not only between registers but also within countries. Our study find a high occurrence rate for CP, which is similar to the studies conducted in Finland and Sweden, but not so high as in Finland. The reason for this finding need further research. Different ethnic groups have different occurrence proportions for different clefts. From last year clefts, the same proportion was seen as I showed previously.
The most common cleft type was incomplete CP and the least frequent was BCL. The most common cleft type for boys was left side CLP and the most common for girls was CP. Left side of the face was affected 2,2 times more frequently then right side. No definite explanation for the difference in left and right side occurrences is given in literature. Johnston and Brown have suggested that blood vessels supplying the right side of the fetal head leave the aortic arch closer to the heart and may be better perfuse by blood than those on the left side. Men have CLP twice as often as female and CP is more common among women. There is no definite scientific explanation for the differences in clefts, between genders. One reason given is that the development of clefts occur at different stages of development in male and female fetuses in the critical stage, but there is no justification for this claim.
Many risk factors and mechanisms have been described in the literature for OC. Several studies have shown that the birth weight of children with clefts is similar to the birth weight of children without clefts, which was also confirmed by the present study. During the last 20 years, maternal and paternal ages have increased. Some malformations are clearly associated with older maternal age, but the effect of paternal old age is less certain. Increased maternal age is a risk factor for both chromosomal and non-chromosomal abnormalities.
There is little information regarding the temporal sequence between exposures and the outcome of the environmental risk factors and dose response relationship cannot be demonstrated. Not enough information is available to draw any conclusions about the role of these exposures and the risk of oral cleft formation. There is the list of different exposures, reported in patients case histories. As most of those patients were born during soviet time the contact of the mothers during or before pregnancy with toxic substantsis was marked We could not analyze that information because those groups were small compared with the all study. We only documented these findings.
Results from genome scans suggest that severe regions may contain genes predisposing to the development of NS clefts. We analyzed the role of 18 genes in the Estonian sample for a possible association with CL/P and 26 NPs in 9 genes showed nominal P-value less than 0.05. The most significant associations with CL/P were found for SNPs in MSX1, in methylentetrahydrofolate reductase and in poliovirus receptor-related 2 genes.
Concerning the Baltic study, the most significant associations were found for SNPs in the FGF1, FOXE1 and WNT9B genes. The strongest evidence of association was found for IIIII this SNP..... In the FGF1 gene. Additional evidence from haplotype analysis demonstrating the involvement of following gene variants in CL/P predisposition.
The strongest associations with nonsyndromic CP in Estonian study group was found for following genes....... Considering the small sample size of our patient group, which was 53 cases, we must emphasize that our study carries the risk of false-positive findings as a result of the large number of comparisons performed. Controversy we cannot exclude the possibility that a modest effect of polymorphisms or haplotypes in disease predisposition may become apparent in a large sample.
In Baltic sample, we genotyped 591 tag SNPs in 40 genes in 104 patients with CP. 35 SNPs in 17 genes showed nominal P value less than 0,05. IIIIIII The strongest evidence of association was found in IRF6 and in collagen type II alfa 1 genes. Additional evidence from haplotype analysis demostrated the possible involvement of those.... gene variants in predisposition to CP. We can assume that the described polymorphisms are not functionally significant variants that actually contribute to disease susceptibility, and our findings need confirmation by replication in other independent cohorts or by resequencing the selected candidate genes in patients to identify the causal variants.
IRF6 is one of the CL/P candidate genes with the most accordant results across studies. In Baltic sample we could not demonstrate convincing evidence of an association between CL/P and variants in IRF6 but., In the study from Baltic CP sample, the IRF6..showed evidence of association, which is a novel implication of IRF6 in nonsyndromic CP susceptibility IRF6 is essential for oral epithelial differentiation and plays a key role in the control of palatal adhesion and fusion.
With the study we documented the situation of Estonian OC, We found high occurrence of CP. We got the overview of possible environmental factors which may influence oral clefts in Estonia Our data provide additional confirmation for the role of MSX1 and MTHFR in the etiology of NS CL/P in Estonian sample. The results of this study provide further evidence that variations in FOXE1; TIMP2 and FGF and WNT signaling pathway genes are likely involved in the development of NS CL/P in North-Eastern European populations. Moreover, we have demonstrated that variations in cartilage collagen type II and 11 genes, IRF6 and FGF and Wnt signaling pathway genes are likely involved in the etiology of CP in Northeastern European populations.
Registration and classification of oral clefts is of paramount importance in providing a solid basis for epidemiologic, clinical and/or fundamental research. Official statistics of orla clefts in estonia does not exist. There is no doubt modern genetics have greatly influenced our professional and personal lives during the last decade. Uncovering genetic causes of many medical and dental pathologies is helping to narrow the diagnosis and select a treatment plan that would provide the best outcome. Importantly, having an understanding of multifactorial etiology helps direct our attention toward prevention. We now understand much better our own health problems. In some cases, we can modify our lifestyle and diet in order to prevent "environmental factors" from triggering the mutated genes inherited from our parents. One needs to understand genetic and environmental causes of nonsyndromic orofacial clefts in order to prevent them. With all this in mind,. It has been leading to a better understanding of etiology of nonsyndromic orofacial clefts. It has been learned that genetic factors and environmental factors are ethnicity-specific and, in many places throughout the world, location-specific. Thus, a specific protocol for cleft prevention has to be worked out based on genetic and environmental or lifestyle studies of each specific population group in order to be effective. This is our ultimate goal. And my work is just a small drop in big ocean and a first attempt to bring Estonian oral clefts into word map.