Spina bifida is among the phenotypes of the larger condition known as neural tube defects (NTDs). It is the most common central nervous system malformation compatible with life and the second leading cause of birth defects after congenital heart defects. In this review paper, we define spina bifida and discuss the phenotypes seen in humans as described by both surgeons and embryologists in order to compare and ultimately contrast it to the leading animal model, the mouse. Our understanding of spina bifida is currently limited to the observations we make in mouse models, which reflect complete or targeted knockouts of genes, which perturb the whole gene(s) without taking into account the issue of haploinsufficiency, which is most prominent in the human spina bifida condition. We thus conclude that the need to study spina bifida in all its forms, both aperta and occulta, is more indicative of the spina bifida in surviving humans and that the measure of deterioration arising from caudal neural tube defects, more commonly known as spina bifida, must be determined by the level of the lesion both in mouse and in man.
Adhesion and fusion of epithelial sheets marks the completion of many morphogenetic events during embryogenesis. Neural tube closure involves an epithelial fusion sequence in which the apposing neural folds adhere initially via cellular protrusions, proceed to a more stable union, and subsequently undergo remodeling of the epithelial structures to yield a separate neural tube roof plate and overlying nonneural ectoderm. Cellular protrusions comprise lamellipodia and filopodia, and studies in several different systems emphasize the critical role of RhoGTPases in their regulation. How epithelia establish initial adhesion is poorly understood but, in neurulation, may involve interactions between EphA receptors and their ephrinA ligands. Epithelial remodeling is spatially and temporally correlated with apoptosis in the dorsal neural tube midline, but experimental inhibition of this cell death does not prevent fusion and remodeling. A variety of molecular signaling systems have been implicated in the late events of morphogenesis, but genetic redundancy, for example among the integrins and laminins, makes identification of the critical players challenging. An improved understanding of epithelial fusion can provide insights into normal developmental processes and may also indicate the mode of origin of clinically important birth defects.
Members of the Eph receptor tyrosine kinase have previously been implicated in cranial neural tube development. Failure of neural tube closure leads to the devastating conditions known as anencephaly and spina bifida. EphA2 and EphA4 are expressed at the tips of the closing spinal neural folds prior and during neural tube closure. We investigated the possible role of murine EphA2 and EphA4 during the last step of primary neural tube closure, which is adhesion and fusion. The individual mouse knockouts of EphA2 and EphA4 per se do not exhibit neural tube defects (NTDs). The embryos generated by the crossing of double heterozygotes Epha2tm1Jrui/+Epha4rb-2J/+ displayed NTDs with a wide degree of severity including close exencephaly and close spina bifida (spina bifida occulta). Interestingly, mutants displaying NTDs had skin covering the underlying lesion. The tissue sections revealed the elevated neural folds had not adhered and fused. The phenotypes seen in Epha2tm1Jrui/+Epha4rb-2J/+ double heterozygous embryos suggest both genes play a compensatory role with each other in the adhesion and fusion of the neural tube. In this study, there exists a >50% penetrance of NTDs in the mouse mutants, which genetically have a single allele each of EphA2 and EphA4 absent.
BackgroundThe aim of this study is to review the medical history of patients with spina bifida, encompassing both aperta and occulta types born between the years 2003 until 2016, spanning a 13-year time period. We assessed each patient and maternal parent information, details of the defects, and conditions associated with the primary defect. We also include information on patients’ ambulation and education level (where available).MethodsData from the Department of Patient Information University of Malaya Medical Centre (UMMC), Malaysia was captured from spina bifida patients (ICD10: Q05 spina bifida). Data involved patients referred to UMMC between 2003 and 2016 and/or born in UMMC within that particular time frame. We filtered and extracted the information according to the data of clinical examination, medical review, and social history provided in the medical records.ResultsA total of 86 patient records with spina bifida were analyzed. Spina bifida prevalence rate in this study ranged from 1.87 to 8.9 per 1,000 live births depending on weightage. We note that ethnicity was a factor whereby the highest numbers of spina bifida were from Malays (n = 36, 41.86%), followed by equal numbers of Chinese and Indians (n = 24, 27.91%). The highest number of diagnoses reported was myelomeningocele type-spina bifida (n = 39, 45.35%). The most common site of the spina bifida lesion was located at the lumbar region irrespective of aperta or occulta types (n = 23, 26.74%). Data on other associated phenotypes of spina bifida such as hydrocephalus and encephalocele was also captured at 37.21% (n = 32) and 1.16% (n = 1), respectively. In terms of mobility, 32.84% (n = 22/67) of patients between the ages 4 and 16 years old were found to be mobile. As many as 36.07% of patients ranging from 5 to 16 years of age (n = 22/61) received formal education ranging from preschool to secondary school.ConclusionThe prevalence of spina bifida in UMMC is as according to international statistics which is in the range of 0.5–10 per 1,000 live births. Majority of the reported cases were males, Malays, full term babies, and of the myelomeningocele phenotype located at the lumbar region.
BackgroundThe brown widow spider (Latrodectus geometricus Koch, 1841) has colonised many parts of the world from its continent of origin, Africa. By at least 1841, the species had successfully established populations in South America and has more recently expanded its range to the southern states of North America. This highly adaptable spider has been far more successful in finding its niche around the world than its famous cousins, the black widow, Latrodectus mactans, found in the south-eastern states of North America, and the red-back, Latrodectus hasselti, found mostly in Australia, New Zealand and Japan.MethodsWe performed an extensive web search of brown widow sightings and mapped the location of each sighting using ArcGIS. Specimens reputedly of the species L. geometricus were collected at three localities in Peninsular Malaysia. The spiders were identified and documented based on an examination of morphological characteristics and DNA barcoding.ResultsThe spiders found in Peninsular Malaysia were confirmed to be Latrodectus geometricus based on their morphological characteristics and DNA barcodes. We recorded 354 sightings of the brown widow in 58 countries, including Peninsular Malaysia.ConclusionReports from the Americas and the Far East suggest a global-wide invasion of the brown widow spider. Herein we report the arrival of the brown widow spider in Peninsular Malaysia and provide notes on the identification of the species and its recently expanded range.
The EphA4 receptor tyrosine kinase is involved in numerous cell-signalling activities during embryonic development. EphA4 has the ability to bind to both types of ephrin ligands, the ephrinAs and ephrinBs. The C57BL/6J-Epha4rb-2J/GrsrJ strain, denoted Epha4(rb-2J/rb-2J), is a spontaneous mouse mutant that arose at The Jackson Laboratory. These mutants exhibited a synchronous hind limb locomotion defect or "hopping gait" phenotype, which is also characteristic of EphA4 null mice. Genetic complementation experiments suggested that Epha4(rb-2J) corresponds to an allele of EphA4, but details of the genomic defect in this mouse mutant are currently unavailable. We found a single base-pair deletion in exon 9 resulting in a frame shift mutation that subsequently resulted in a premature stop codon. Analysis of the predicted structure of the truncated protein suggests that both the kinase and sterile α motif (SAM) domains are absent. Definitive determination of genotype is needed for experimental studies of mice carrying the Epha4(rb-2J) allele, and we have also developed a method to ease detection of the mutation through RFLP. Eph-ephrin family members are reportedly expressed as numerous isoforms. Hence, delineation of the specific mutation in EphA4 in this strain is important for further functional studies, such as protein-protein interactions, immunostaining and gene compensatory studies, investigating the mechanism underlying the effects of altered function of Eph family of receptor tyrosine kinases on phenotype.
BackgroundCoconut oil is commonly used as herbal medicine worldwide. There is limited information regarding its effects on the developing embryo and infant growth.MethodsWe investigated the effect of virgin coconut oil post-natally and until 6 weeks old in mice (age of maturity). Females were fed with either standard, virgin olive oil or virgin coconut oil diets 1 month prior to copulation, during gestation and continued until weaning of pups. Subsequently, groups of pups borne of the respective diets were continuously fed the same diet as its mother from weaning until 6 weeks old. Profiles of the standard and coconut oil diets were analysed by gas chromatography flame ionization detector (GCFID).ResultsAnalysis of the mean of the total weight gained/ loss over 6 weeks revealed that in the first 3 weeks, pups whose mothers were fed virgin coconut oil and virgin olive oil have a significantly lower body weight than that of standard diet pups. At 6 weeks of age, only virgin coconut oil fed pups exhibited significantly lower body weight. We report that virgin coconut oil modifies the fatty acid profiles of the standard diet by inducing high levels of medium chain fatty acids with low levels of essential fatty acids. Furthermore, pups borne by females fed with virgin coconut oil developed spiky fur.ConclusionOur study has demonstrated that virgin coconut oil could affect infant growth and appearance via maternal intake; we suggest the use of virgin coconut oil as herbal medicine to be treated with caution.
ObjectivesThe Neural Tube Defects Research Group of University of Malaya was approached to analyze a tablet named TELSE, which may have resulted in a baby born with central nervous system malformation at the University of Malaya Medical Centre. In this animal experimental study, we investigated the content of TELSE and exposure of its contents that resulted in failure of primary neurulation.ResultsLiquid Chromatography Tandem Mass spectrophotometry analysis of the TELSE tablet confirmed the presence of trimethoprim as the active compound. The TELSE tablet-treated females produced significant numbers of embryos with exencephaly (n = 8, 36.4%, *P < 0.0001), in all litters. The TELSE tablet-treated females subsequently given folic acid did not result in pregnancies despite there being evidence of possible resorption. Furthermore, after multiple rounds of mating which did not yield viable pregnancies, eventually, 2 embryos with exencephaly were harvested in a litter of 6 at 0.05% w/v pure trimethoprim once. The use of trimethoprim, a folic acid antagonist, peri-conceptionally increased the risk of exencephaly in the mouse.Electronic supplementary materialThe online version of this article (10.1186/s13104-018-3593-1) contains supplementary material, which is available to authorized users.
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