The roles of p53 and p21 in normal development and hyperthermia‐induced malformations

BACKGROUND : Hyperthermia (HS) is a well‐studied teratogen that induces serious malformations, including neural tube defects. Our previous studies have shown that HS induces apoptosis by activating the mitochondrial apoptotic pathway. Prior to activation of the mitochondrial apoptotic pathway, HS also activates p53 and its target genes. In the present study, we determine whether p53 and/or p21 play a role as teratogen suppressors or inducers of HS‐induced malformations. METHODS : Pregnant mice carrying all three p53 or p21 genotype embryos were exposed to HS on day 8.5. Subsequently, fetuses were collected on day 15.5, and genotyped. In addition to genotype, we also determined the number of resorptions and dead fetuses as well as the number and types of external malformations. RESULTS : In the absence of HS exposure, fetuses exhibiting exencephaly and spina bifida were observed in approximately 11% of p53 ?/? fetuses, whereas no malformations were observed among p21 ?/? fetuses. Exposure to HS resulted in an increase in exencephaly and polydactyly in fetuses of all three p53 genotypes. However, the incidence of these malformations was statistically significantly higher in p53 ?/? compared to p53 +/? and p53 +/+ fetuses. Exencephaly was the only malformation observed in p21 fetuses exposed to HS, with an approximately 2‐fold increase among p21 +/? and a 3‐fold increase among p21 ?/? compared to p21 +/+ fetuses. CONCLUSIONS : Our study confirms that p53 plays a role in normal development and has shown, for the first time that p53 and p21 function to suppress HS‐induced malformations. Birth Defects Res (Part B) 86:40‐47, 2009. © 2009 Wiley‐Liss, Inc.     

A review on data mining and continuous optimization applications in computational biology and medicine

An emerging research area in computational biology and biotechnology is devoted to mathematical modeling and prediction of gene‐expression patterns; it nowadays requests mathematics to deeply understand its foundations. This article surveys data mining and machine learning methods for an analysis of complex systems in computational biology. It mathematically deepens recent advances in modeling and prediction by rigorously introducing the environment and aspects of errors and uncertainty into the genetic context within the framework of matrix and interval arithmetics. Given the data from DNA microarray experiments and environmental measurements, we extract nonlinear ordinary differential equations which contain parameters that are to be determined. This is done by a generalized Chebychev approximation and generalized semi‐infinite optimization. Then, time‐discretized dynamical systems are studied. By a combinatorial algorithm which constructs and follows polyhedra sequences, the region of parametric stability is detected. In addition, we analyze the topological landscape of gene‐environment networks in terms of structural stability. As a second strategy, we will review recent model selection and kernel learning methods for binary classification which can be used to classify microarray data for cancerous cells or for discrimination of other kind of diseases. This review is practically motivated and theoretically elaborated; it is devoted to a contribution to better health care, progress in medicine, a better education, and more healthy living conditions. Birth Defects Research (Part C) 87:165–181, 2009. © 2009 Wiley‐Liss, Inc.     

Cell fate determination during tooth development and regeneration

Teeth arise from sequential and reciprocal interactions between the oral epithelium and the underlying cranial neural crest‐derived mesenchyme. Their formation involves a precisely orchestrated series of molecular and morphogenetic events, and gives us the opportunity to discover and understand the nature of the signals that direct cell fates and patterning. For that reason, it is important to elucidate how signaling factors work together in a defined number of cells to generate the diverse and precise patterned structures of the mature functional teeth. Over the last decade, substantial research efforts have been directed toward elucidating the molecular mechanisms that control cell fate decisions during tooth development. These efforts have contributed toward the increased knowledge on dental stem cells, and observation of themolecular similarities that exist between tooth development andregeneration. Birth Defects Research (Part C) 87:199–211, 2009. © 2009 Wiley‐Liss, Inc.     

Application of autologous periosteal cells for the regeneration of class III furcation defects in Beagle dogs

The aim of this study was to evaluate the healing of class III furcation defects following transplantation of autogenous periosteal cells combined with β-tricalcium phosphate (β-TCP). Periosteal cells obtained from Beagle dogs’ periosteum explant cultures, were inoculated onto the surface of β-TCP. Class III furcation defects were created in the mandibular premolars. Three experimental groups were used to test the defects’ healing: group A, β-TCP seeded with periosteal cells were transplanted into the defects; group B, β-TCP alone was used for defect filling; and group C, the defect was without filling materials. Twelve weeks post surgery, the tissue samples were collected for histology, immunohistology and X-ray examination. It was found that both the length of newly formed periodontal ligament and the area of newly formed alveolar bone in group A, were significantly increased compared with both group B and C. Furthermore, both the proportion of newly formed periodontal ligament and newly formed alveolar bone in group A were much higher than those of group B and C. The quantity of cementum and its percentage in the defects (group A) were also significantly higher than those of group C. These results indicate that autogenous periosteal cells combined with β-TCP application can improve periodontal tissue regeneration in class III furcation defects.     

Left ventricular dysfunction due to right ventricular stimulation: is biventricular upgrade really necessary?

Left ventricular (LV) dysfunction can occur due to chronic right ventricular apical pacing. Upgrading of the pacemaker to biventricular pacing is an option to reverse LV dysfunction but reprogramming of the atrioventricular (AV) timing can also be favourable. In this case report we describe the effect of AV-time reprogramming in a patient with LV function deterioration that emerged two years after implantation of a dual chamber system for sick sinus syndrome. Echocardiographc studies demonstrated a tremendous improvement in LV function during two years follow-up whereas the percentage of right ventricular pacing diminished dramatically. Careful analysis of the cause of LV deterioration can avoid unnecessary upgrading to biventricular pacing. (Neth Heart J 2010;18:604–5.)     

A new perspective on neural tube defects: Folic acid and microRNA misexpression

Neural tube defects (NTDs) are the second most common birth defects in the United States. It is well known that folic acid supplementation decreases about 70% of all NTDs, although the mechanism by which this occurs is still relatively unknown. The current theory is that folic acid deficiency ultimately leads to depletion of the methyl pool, leaving critical genes unmethylated, and, in turn, their improper expression leads to failure of normal neural tube development. Recently, new studies in human cell lines have shown that folic acid deficiency and DNA hypomethylation can lead to misexpression of microRNAs (miRNAs). Misexpression of critical miRNAs during neural development may lead to a subtle effect on neural gene regulation, causing the sometimes mild to severely debilitating range of phenotypes exhibited in NTDs. This review seeks to cohesively integrate current information regarding folic acid deficiency, methylation cycles, neural development, and miRNAs to propose a potential model of NTD formation. In addition, we have examined the relevant gene pathways and miRNAs that are predicted to affect them, and based on our investigation, we have devised a basic template of experiments for exploring the idea that miRNA misregulation may be linked to folic acid deficiency and NTDs. genesis 48:282–294, 2010. © 2010 Wiley‐Liss, Inc.     

Maternal obesity and morbid obesity: The risk for birth defects in the offspring

BACKGROUND : The objective of this study was to assess, in a large data set from Swedish Medical Health Registries, whether maternal obesity and maternal morbid obesity were associated with an increased risk for various structural birth defects. METHODS : The study population consisted of 1,049,582 infants born in Sweden from January 1, 1995, through December 31, 2007, with known maternal weight and height data. Women were grouped in six categories of body mass index (BMI) according to World Health Organization classification. Infants with congenital birth defects were identified from three sources: the Swedish Medical Birth Registry, the Register of Birth Defects, and the National Patient Register. Maternal age, parity, smoking, and year of birth were thought to be potential confounders and were included as covariates in the adjusted odds ratio analyses. RESULTS : Ten percent of the study population was obese. Morbid obesity (BMI ≥ 40) occurred in 0.7%. The prevalence of congenital malformations was 4.7%, and the prevalence of relatively severe malformations was 3.2%. Maternal prepregnancy morbid obesity was associated with neural tube defects OR 4.08 (95% CI 1.87–7.75), cardiac defects OR 1.49 (95% CI 1.24–1.80), and orofacial clefts OR 1.90 (95% CI 1.27–2.86). Maternal obesity (BMI ≥ 30) significantly increased the risk of hydrocephaly, anal atresia, hypospadias, cystic kidney, pes equinovarus, omphalocele, and diaphragmatic hernia. CONCLUSION : The risk for a morbidly obese pregnant woman to have an infant with a congenital birth defect is small, but for society the association is important in the light of the ongoing obesity epidemic. Birth Defects Research (Part A), 2010. © 2009 Wiley‐Liss, Inc.     

A case–control study of the effects of pregnancy planning on neural tube defects and its primary preventive measures

BACKGROUND: Measures for prevention of neural tube defects (NTDs) have been recommended for many years in China, but the compliance with these measures is unsatisfactory. This study aims to compare the effect differences between planned pregnancy and unplanned pregnancy in the compliance with these measures and analyze the interactions between pregnancy planning and these measures for NTD prevention. METHODS: A 1:1 matched case‐control study was conducted. We randomly selected 349 women who delivered or gestated babies/fetuses with NTDs in the last two years in two provinces and matched them with 349 women who delivered babies without obvious birth defects as controls. RESULTS: In the case group, 99 women reported that they had planned their pregnancies, accounting for 28.4%, and the proportion who received preconception examinations and took folic acid prior to conception was 13.8 and 8.6%, respectively. According to the multivariate analysis, health education (odds ratio [OR], 0.350), preconception examinations (OR, 0.497) and folic acid consumption prior to conception (OR, 0.257) all had preventative effects on NTDs (for all, p < 0.05). In both groups, the proportions of women who received preconception examinations and reported folic acid intake were much higher for those who reported planning their pregnancies compared to women with an unplanned pregnancy (for all, p < 0.01); and for NTD prevention, synergistic interactions existed between pregnancy planning and the other preventive measures. CONCLUSION: Folic acid consumption prior to conception, preconception examinations, and health education have preventive effects on NTDs. Pregnancy planning can significantly promote compliance with these preventive behaviors. In addition, there are synergistic interactions between pregnancy planning and these measures. Birth Defects Research (Part A), 2010. © 2010 Wiley‐Liss, Inc.     

Bimodal septal and cortical triggering and complex propagation patterns of spontaneous waves of activity in the developing mouse cerebral cortex

Spontaneous waves of activity that propagate across large structures during specific developmental stages play central roles in CNS development. To understand the genesis and functions of these waves, it is critical to understand the spatial and temporal patterns of their propagation. We recently reported that spontaneous waves in the neonatal cerebral cortex originate from a ventrolateral pacemaker region. We have now analyzed a large number of spontaneous waves using calcium imaging over the entire area of coronal slices from E18‐P1 mouse brains. In all waves, the first cortical region active is this ventrolateral pacemaker. In half of the waves, however, the cortical pacemaker activity is itself triggered by preceding activity in the septal nuclei. Most waves are restricted to the septum and/or ventral cortex, with only some invading the dorsal cortex or the contralateral hemisphere. Waves fail to propagate at very stereotyped locations at the boundary between ventral and dorsal cortex and at the dorsal midline. Waves that cross these boundaries pause at these same locations. Waves at these stages are blocked by both picrotoxin and CNQX, indicating that both GABA_A and AMPA receptors are involved in spontaneous activity. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 679–692, 2010     

Effect of transforming growth factor-beta 1 (TGF-ß1) released from a scaffold on chondrogenesis in an osteochondral defect model in the rabbit

Articular cartilage repair might be stimulated by the controlled delivery of therapeutic factors. We tested the hypotheses whether TGF-ß1 can be released from a polymeric scaffold over a prolonged period of time in vitro and whether its transplantation modulates cartilage repair in vivo. Unloaded control or TGF-ß1 poly(ether-ester) copolymeric scaffolds were applied to osteochondral defects in the knee joints of rabbits. In vitro, a cumulative dose of 9 ng TGF-ß1 was released over 4 weeks. In vivo, there were no adverse effects on the synovial membrane. Defects treated with TGF-ß1 scaffolds showed no significant difference in individual parameters of chondrogenesis and in the average cartilage repair score after 3 weeks. There was a trend towards a smaller area (42.5 %) of the repair tissue that stained positive for safranin O in defects receiving TGF-ß1 scaffolds. The data indicate that TGF-ß1 is released from emulsion-coated scaffolds over a prolonged period of time in vitro and that application of these scaffolds does not significantly modulate cartilage repair after 3 weeks in vivo. Future studies need to address the importance of TGF-ß1 dose and release rate to modulate chondrogenesis.