Nail Can Öztürk

DNA methylation program in developing hippocampus and its alteration by alcohol.

During hippocampal development, the Cornus Ammonis (CA) and the dentate gyrus (DG) undergo waves of neurogenesis and neuronal migration and maturation independently. This stage is widely known to be vulnerable to environmental stresses, but its underlying mechanism is unclear. Alcohol exposure has been shown to alter the expression of genes that regulate the fate, survival, migration and differentiation of pyramidal and granule cells. Undermining this process might compromise hippocampal development underlying the learning and memory deficits known in Fetal Alcohol Spectrum Disorders (FASD). We have previously demonstrated that DNA methylation was programmed along with neural tube development. Here, we demonstrated that DNA methylation program (DMP) proceeded along with hippocampal neuronal differentiation and maturation, and how this DMP was affected by fetal alcohol exposure. C57BL/6 mice were treated with 4% v/v ethanol through a liquid diet along with pair-fed and chow-fed controls from gestation day (E) 7 to E16. We found that a characteristic DMP, including 5-methylcytidine (5mC), 5-hydroxylmethylcytidine (5hmC) and their binding proteins, led the hippocampal neuronal differentiation and maturation spatiotemporally as indicated by their phenotypic marks in the CA and DG pre- and post-natally. Alcohol hindered the acquisition and progression of methylation marks, and altered the chromatin translocation of these marks in the nucleus, which was correlated with developmental retardation.

Epigenetic medicine and fetal alcohol spectrum disorders

Epigenetic medicine is still in its infancy. To date, only a handful of diseases have documented epigenetic correlates upstream of gene regulation including cancer, developmental syndromes and late-onset diseases. The finding that epigenetic markers are dynamic and heterogeneous at tissue and cellular levels, combined with recent identification of a new form of functionally distinct DNA methylation has opened a wider window for investigators to pry into the epigenetic world. It is anticipated that many diseases will be elucidated through this epigenetic inquiry. In this review, we discuss the normal course of DNA methylation during development, taking alcohol as a demonstrator of the epigenetic impact of environmental factors in disease etiology, particularly the growth retardation and neurodevelopmental deficits of fetal alcohol spectrum disorders.

Strain differences in developmental vulnerability to alcohol exposure via embryo culture in mice.

BACKGROUND Prenatal alcohol exposure can result in varying degrees of neurodevelopmental deficits, growth retardation, and facial dysmorphology. Variation in these adverse outcomes not only depends on the dose and pattern of alcohol exposure but also on less well understood interactions among environmental, genetic, and maternal factors. The current study tested the hypothesis that fetal genotype is an important determinant of ethanol teratogenesis by evaluating effects of ethanol exposure via embryo culture in 3 inbred strains of mice known to differ in the vulnerability of prenatal alcohol exposure in vivo. METHODS Three strains of mice, C57BL/6N (B6), DBA/2 (D2), and 129S6/SvEvTac (129S6) were assessed in a whole embryo culture beginning on embryonic day 8.25, with or without alcohol administration at 88 mM for 6 hours followed by 42 hours culture in ethanol-free media. RESULTS Contrasting strain differences in susceptibility were observed for the brain, the face, and other organ systems using the Maele-Fabry and Picard scoring system. The forebrain, midbrain, hindbrain, heart, optic vesicle, caudal neural tube, and hindlimbs of the B6 mice were severely delayed in growth, whereas compared to the respective controls, only the forebrain and optic vesicle were delayed in the D2 mice, and no effects were found in the 129S6 mice. A large number of cleaved (c)-caspase 3 positive (+) cells were found in regions of the brain, optic vesicles, cranial nerve nuclei V, VII, VIII, and IX as well as the craniofacial primordial; only a few were found in corresponding regions of the B6 controls. In contrast, only a small number of c-caspase 3 immunostaining cells were found in either the alcohol treated or the controls of the D2 embryos and in 129S6 embryos. The independent apoptotic markers TUNEL and Nile blue staining further confirmed the strain differences in apoptotic responses in both the neural tube and craniofacial primordia. CONCLUSIONS Under embryo culture conditions, in which alcohol exposure factors and fetal developmental staging were controlled, and maternal and intrauterine factors were eliminated, the degree of growth retardation and the extent and type of neurodevelopmental teratogenesis varied significantly across strains. Notably, the 129S6 strain was remarkably resistant to alcohol-induced growth deficits, confirming a previous in vivo study, and the D2 strain was also significantly less affected than the B6 strain. These findings demonstrate that fetal genotype is an important factor that can contribute to the variation in fetal alcohol spectrum disorder.

Anatomical variations of the foramen magnum, occipital condyle and jugular tubercle.

AIM The foramen magnum (FM) is a unique and complex anatomical region. The occipital condyle (OC) and jugular tubercle (JT) are the main bony structures which obscure the anterolaterally situated lesions of the FM.The aim of this study was to revisit the anatomy of the FM region and assess variations of the surrounding structures. MATERIAL AND METHODS Observations, on thirty dry skulls (dried specimens, 60 sides) and ten formalin-fixed cadaveric heads with perfused vessels, were carried out to define the microsurgical anatomy of the FM region. Morphometric analysis and variations of the FM, OC, JT and hypoglossal canal (HC) were noted. Radiological assessment (3D-computed tomography) of the OC, JT, HC were also conducted on dry skulls. RESULTS The short and long OC were demonstrated in 5% and 33% of the specimens, respectively. Flat formation of the JT was determined in 10% and tall JT was found in 23% of the specimens. The comparison of the anatomical measurements and the correspondent radiological mean values did not achieve statistical significance. CONCLUSION The OC and JT are the main bony prominences obstructing the anterolateral surface of the brainstem. Neurosurgeons should be familiar with variations of the structures surrounding the FM in order to perform the safest and widest exposure possible.

An unreported pattern of musculocutaneous and median nerve communication with multiple variations of biceps brachii: a case report

An unreported pattern of communication between musculocutaneous (Mcn) and median nerve (Mn) with multiple variations of biceps brachii (Bb) was observed during the dissection of a male cadaver. The first branch of the Mcn ended in coracobrachialis (Cb). The second was the main Mcn piercing the Cb and giving its motor branches to the muscles of the anterior compartment of the arm. It then continued as the lateral cutaneous nerve of the forearm. The largest third branch also pierced the Cb distal to the main Mcn and communicated with the Mn which was classically formed by relevant roots of the medial and lateral cords. Additionally, a third head of Bb was observed bilaterally. Slips from the pectoralis major were inserted on the tendon of the third head on both sides. The origin of the third head was the greater tubercle to the left and the joint capsule to the right. These extremely rare patterns of both variations which were seen concomitantly in the same subject do not exist in the literature. Lack of awareness of such variations with different patterns of communications between Mcn and Mn might complicate surgical repair of the nerves. Knowing different patterns of Bb variations also have clinical importance as they also may cause compression of neurovascular structures or confuse a surgeon during surgical procedures.

Fenestration of internal jugular vein and relation to spinal accessory nerve: Case report and review of the literature

Neck dissection surgery is routinely performed in the treatment of malignant disease of the upper aerodigestive tract, and it is important in the staging and treatment of cervical lymph node metastases in patients with head and neck malignancy. The internal jugular vein (IJV) and spinal accessory nerve (CNXI) provide clear landmarks intraoperatively, allowing precise and accurate surgery. Resecting or injuring these structures results in considerable morbidity. On this basis, a thorough understanding of the topographical anatomy of the CNXI and IJV is a basic prerequisite when performing neck dissection surgery (Bater et al., 2005). Venous fenestration is a rarely seen entity in the neck. Although its clinical significance is questionable, its importance in presurgical planning may be considerable. Fenestrations and complete divisions of the vasculature have been described in many of the craniocervical arteries, but venous fenestrations are rarely described (Towbin and Kanal, 2004). One study estimated that fenestration of the IJV occurs in as much as 0.4% of the population (Prades et al., 2002). During the neck dissection of a 58-year-old male cadaver, a unilateral fenestration of the IJV was encountered on the right side. CNXI passed through the fenestrated vein, pierced the carotid sheath, and then reached the sternocleidomastoid muscle (Fig. 1). There is confusion between the terms: duplication and fenestration in the literature, which are

An unusual case of a tortuous abdominal aorta with a common celiacomesenteric trunk: demonstrated by angiography

The abdominal aorta (AA) begins at the aortic hiatus of the diaphragm, in front of the lower border of the body of the last thoracic vertebra and descending in front of the vertebral column and ends on the body of the fourth lumbar vertebra, commonly a little to the left of the middle line by dividing into the two common iliac arteries. The celiac trunk (CeT) and superior mesenteric artery (SMA) are the two widest vessels arising from the ventral aorta. The celiac trunk divides into the left gastric, common hepatic and splenic arteries. SMA and the coeliac trunk can arise from the ventral aorta as a common origin.1 The unusual embryologic development of the ventral splanchnic arteries can lead to considerable variations.2 Many variational patterns of the CeT have been described. A review by Yi et al.3 summarized that only 87.7% of CeTs exhibited classic trifurcation. An incomplete CeT, namely bifurcation, accounted for 5.8–24.1%. Aside from these variations, the CeT itself may be absent and its branches can arise directly from the aorta. Moreover, in rare cases, the CeT and SMA may be fused into a common celiacomesenteric trunk (CMT), of which the incidence was mentioned as 0–11% (average, 1.5%).3 Many different types of catheter or intra‐aortic balloon pumping are commonly used either to diagnose vascular diseases or treat them via the AA. In abnormalities like a tortuous AA, use of catheters is advised with great caution; straight‐tipped catheters are discouraged.4-7

A rare combination of vascular variations of both kidneys.

Bilateral variations of renal vessels were encountered during the dissection of a 54-year-old male cadaver. There were triple renal arteries bilaterally, double renal veins on the right, and an unusual formation of renal vein on the left side. A bilateral occurrence of triple renal arteries has not been encountered in the literature, so does an incidence. Additional renal vessels have the potential to cause clinical complications such as hydronephrosis. Their existence has utmost importance in surgical and radiological interventions and radiological examinations.

Ectopic kidney with varied vasculature: demonstrated by CT angiography

An ectopic kidney was found incidentally in a 20-year-old male patient during the abdominopelvic CT angiography. It was situated on the right side at the abdominopelvic junction, partly in the abdomen at the level of the intervertebral disc between L3 and L4 superiorly and partly in the greater pelvis at the level of the promontorium and close to the inferior border of the sacroiliac joints. It was supplied by two arteries which were nearly in the same caliber, and each of which branched from the common iliac arteries both close to the aortic bifurcation. There were two renal veins. The larger one which was emerging from the lateral part of the ectopic kidney was draining into the inferior vena cava. The smaller one which was the only hilar vessel of the ectopic kidney was draining into the left common iliac vein. The orthotopic left kidney was also supplied by two arteries from the abdominal aorta. Ectopic kidneys pose a problem for any planned surgical intervention given their anomalous blood supply. Ectopic position and varied vasculature can predispose to iatrogenic trauma during interventional radiological and laparoscopic procedures, and emergency operations.

DNA Methylation program in normal and alcohol-induced thinning cortex

While cerebral underdevelopment is a hallmark of fetal alcohol spectrum disorders (FASD), the mechanism(s) guiding the broad cortical neurodevelopmental deficits are not clear. DNA methylation is known to regulate early development and tissue specification through gene regulation. Here, we examined DNA methylation in the onset of alcohol-induced cortical thinning in a mouse model of FASD. C57BL/6 (B6) mice were administered a 4% alcohol (v/v) liquid diet from embryonic (E) days 7-16, and their embryos were harvested at E17, along with isocaloric liquid diet and lab chow controls. Cortical neuroanatomy, neural phenotypes, and epigenetic markers of methylation were assessed using immunohistochemistry, Western blot, and methyl-DNA assays. We report that cortical thickness, neuroepithelial proliferation, and neuronal migration and maturity were found to be deterred by alcohol at E17. Simultaneously, DNA methylation, including 5-methylcytosine (5mC) and 5-hydroxcylmethylcytosine (5hmC), which progresses as an intrinsic program guiding normal embryonic cortical development, was severely affected by in utero alcohol exposure. The intricate relationship between cortical thinning and this DNA methylation program disruption is detailed and illustrated. DNA methylation, dynamic across the multiple cortical layers during the late embryonic stage, is highly disrupted by fetal alcohol exposure; this disruption occurs in tandem with characteristic developmental abnormalities, ranging from structural to molecular. Finally, our findings point to a significant question for future exploration: whether epigenetics guides neurodevelopment or whether developmental conditions dictate epigenetic dynamics in the context of alcohol-induced cortical teratogenesis.