Acetylcholine precursor, citicoline (cytidine 5'-diphosphocholine), reduces hypoglycaemia-induced neuronal death in rats.

Citicoline (cytidine 5'-diphosphocholine) is an important precursor for the synthesis of neuronal plasma membrane phospholipids, mainly phosphatidylcholine. The administration of citicoline serves as a choline donor for the synthesis of acetylcholine. Citicoline has been shown to reduce the neuronal injury in animal models with cerebral ischaemia and in clinical trials of stroke patients. Citicoline is currently being investigated in a multicentre clinical trial. However, citicoline has not yet been examined the context of hypoglycaemia-induced neuronal death. To clarify the therapeutic impact of citicoline in hypoglycaemia-induced neuronal death, we used a rat model with insulin-induced hypoglycaemia. Acute hypoglycaemia was induced by i.p. injection of regular insulin (10 U kg-1 ) after overnight fasting, after which iso-electricity was maintained for 30 minutes. Citicoline injections (500 mg/kg, i.p.) were started immediately after glucose reperfusion. We found that post-treatment of citicoline resulted in significantly reduced neuronal death, oxidative injury and microglial activation in the hippocampus compared to vehicle-treated control groups at 7 days after induced hypoglycaemia. Citicoline administration after hypoglycaemia decreased immunoglobulin leakage via blood-brain barrier disruption in the hippocampus compared to the vehicle group. Citicoline increased choline acetyltransferase expression for phosphatidylcholine synthesis after hypoglycaemia. Altogether, the present findings suggest that neuronal membrane stabilisation by citicoline administration can save neurones from the degeneration process after hypoglycaemia, as seen in several studies of ischaemia. Therefore, the results suggest that citicoline may have therapeutic potential to reduce hypoglycaemia-induced neuronal death.

Quantitative analysis of a spinal surgeon's learning curve for scoliosis surgery.

AIMS: The aim of this study was a quantitative analysis of a surgeon's learning curve for scoliosis surgery and the relationship between the surgeon's experience and post-operative outcomes, which has not been previously well described. PATIENTS AND METHODS: We have investigated the operating time as a function of the number of patients to determine a specific pattern; we analysed factors affecting the operating time and compared intra- and post-operative outcomes. We analysed 47 consecutive patients undergoing scoliosis surgery performed by a single, non-trained scoliosis surgeon. Operating time was recorded for each of the four parts of the procedures: dissection, placement of pedicle screws, reduction of the deformity and wound closure. RESULTS: The median operating time was 310 minutes (interquartile range 277.5 to 432.5). The pattern showed a continuous decreasing trend in operating time until the patient number reached 23 to 25, after which it stabilised with fewer patient-dependent changes. The operating time was more affected by the patient number (r =- 0.75) than the number of levels fused (r = 0.59). Blood loss (p = 0.016) and length of stay in hospital (p = 0.012) were significantly less after the operating time stabilised. Post-operative functional outcome scores and the rate of complications showed no significant differences. TAKE HOME MESSAGE: We describe a detailed learning curve for scoliosis surgery based on a single surgeon's practise, providing useful information for novice scoliosis surgeons and for those responsible for training in spinal surgery. Cite this article: Bone Joint J 2016;98-B:679-85.

Continuous distraction-induced delayed spinal cord injury on motor-evoked potentials and histological changes of spinal cord in a porcine model.

STUDY DESIGN: Experimental study. OBJECTIVES: This study evaluated distraction-induced delayed spinal cord injury in a porcine model. SETTING: Department of Orthopedics, Korea University Guro Hospital, Seoul, Korea. METHODS: Global osteotomy of three columns was performed on the thirteenth thoracic vertebrae with 13 pigs. The osteotomized vertebrae were distracted to 57-103% of segmental vertebral height (SVH) length, which was less than the distraction length that induces prompt SCI. The vertebral height was maintained until the loss of motor-evoked potential (MEP) signals with continuous distraction. The distraction distance and the time at which SCI occurred were measured, and distraction was then released to observe MEP recovery patterns. RESULTS: We found delayed SCI in 8 of the 12 pigs, with a mean 20.9 mm (range 19-25 mm) and 10.7 min (range 8-12 min) of continuous spinal distraction, which was equivalent to 74.3% (68-84%) of SVH and 3.63% (3.42-4.31%) of thoracolumbar spinal length. A continuous 74.3% SVH distraction over an average of 10.7 min caused a delayed SCI, which was indicated by mild histologic changes in the spinal cord. Recovery patterns from SCI after distraction release were compatible with the degree of histological change; however, these patterns differed from the previously investigated prompt type of SCI. CONCLUSION: Late onset injury due to continuous spinal distraction, which is comparable to iatrogenic SCI in spinal correction surgery, is important for understanding the impact of corrective surgery.

Internal herniation due to an omphalomesenteric duct cyst in a 69-year-old man.

Previous abdominal surgery is the most common cause of mechanical small bowel obstruction. However, in patients with no history of abdominal surgery, the diagnosis and treatment of mechanical small bowel obstruction is difficult. A persistent omphalomesenteric duct remnant is a rare finding that typically presents in the pediatric population and is extremely rare in patients aged > 60 years. In the present report, we describe the case of an omphalomesenteric duct cyst causing small bowel obstruction in a 69-year-old man with no history of a surgical procedure.

Change in body surface temperature as an ancillary measurement to motor evoked potentials.

STUDY DESIGN: Experimental study. OBJECTIVES: To study the role of surface temperature as an adjunct to motor evoked potentials (MEPs) in rabbit spinal cord injury (SCI) model. SETTING: Department of Orthopedics, Korea University Guro Hospital, Seoul, Korea. METHODS: Rabbits (n =18) were divided into Complete (n = 9) and Incomplete (n = 9) SCI groups. Complete SCI was defined as being non-responsive to a wake-up test with loss of MEPs after transection of spinal cord. Incomplete SCI was defined as being responsive to a wake-up test with significant attenuation (⩾ 80%) of MEPs after impaction on spinal cord. Surface temperature of upper and lower extremities, core temperature and MEPs signals were checked before, during and after SCI for 20 min. A wake-up test was conducted and spinal cord was histologicaly evaluated. RESULTS: Experimental conditions between the two groups were statistically similar (P > 0.005 for all values). After SCI, upper extremity temperatures did not change in either group (P > 0.005); however, the surface temperature of the lower extremities in the Complete SCI Group elevated to 1.7 ± 0.5°C in comparison to 0.5 ± 0.1°C in the Incomplete SCI Group (P < 0.001). The scores of wake-up test in the Incomplete SCI Group were significantly different from that of the Complete SCI Group (P < 0.001), while white and gray matter damage was variable on histology. CONCLUSIONS: Monitoring of changes of body surface temperature of the lower extremities can be potentially used to identify the completeness of SCI in a rabbit model.

Outcome and technical aspects of liver retransplantation: analysis of 25-year experience in a single major center.

BACKGROUND: The need for liver retransplantation (re-LT) has been increasing. Here we describe the outcome and technical aspects of re-LT during 25 years in a single major center. METHODS: We retrospectively reviewed patients who underwent LT from March 1988 to February 2013. Among 1,312 LTs during 25 years, 38 (2.9%) were re-LTs, including 28 adults (mean age 52.0 y) and 10 children (mean age 5.7 y). RESULTS: The most common indication was primary nonfunction in early re-LT and biliary complication in late re-LT. Preoperative major comorbidity was very common (81.6%). Among them, infection was the most frequent (52.6%). Living-donor re-LT constituted 21.1%. In operative technique, nonconventional methods were substantially performed, including high hilar dissection for hepatectomy (>50%), arterial anastomosis with the use of right gastroepiploic or jump graft (23.7%), and hepaticoenterostomy (60.5%). Several reanastomoses were needed in 10.5% for artery and 5.3% for duct. In adults and children, mean estimated blood losses were 9,541 mL and 977 mL, respectively. Mean operative times for adults and children were 508 and 432 minutes, respectively. In-hospital mortality was 35.7% in adults and 40.0% in children. The main cause of death was sepsis for both adults and children. Survival rates at 1 month and 1, 3, and 5 years were, respectively, 89.4%, 56.5%, 50.3%, and 50.3% in adults, and 70.0%, 60.0%, 60.0%, and 60.0% in children. CONCLUSIONS: Outcome of re-LT is poorer than primary LT regardless of the cause of graft failure. Therefore, more technical concerns need to be considered. We also need more efforts to control perioperative infections to improve survival after re-LT.

The "ABO cross-transplantation problem" in liver transplantation in Korea.

ABO blood group matching policy between donor and recipients is a chief element of organ allocation. However, O blood group donors may donate to all other blood group recipients, and ABO cross-transplantation has led to excessively long delays for blood group O. To investigate the consequence of this problem, we analyzed the recipients/donor rates according to ABO blood groups and cross-transplantation rates among them. Data about deceased donors and liver transplants performed in Korea from January 2008 to September 2012 were reviewed. The proportion of recipient to donor in the O blood group was lower compared to non-O groups (0.61). The percentage of O blood group transplantations in the Korean Network for Organ Sharing (KONOS) status 2B was lower than non-O groups (13.6%). In the status 1 and 2A groups, 44.4% of O blood group donors were allocated to non-O transplantations. Also, 30.7% O blood group donors were allocated to non-O transplantations in the status 2B groups. In conclusion, the ABO cross-transplantation in blood group O donors has led to lower transplantation rates of blood group O in status 1, 2A, and especially, the 2B group. Therefore, the KONOS allocation system should be re-evaluated to address this problem.

Small bowel ischemia after angiographic embolization for angiodysplasia of lower gastrointestinal tract: the case for conservative management.

However, transarterial embolization for angiodysplasia has become widely used, the possibility of complications such as bowel ischemia and infarction still exists. We experienced a 60-year-old woman of small bowel ischemia after angiographic embolization for the angiodysplasia of cecum treated with conservative management. We should consider the possibility of recovery via the rich intramural vascular networks of the lower GI tract before deciding to operate.

The protective effects of interleukin-18 and interferon-γ on neuronal damages in the rat hippocampus following status epilepticus.

To elucidate whether interleukin-18 (IL-18) or interferon-γ (IFN-γ) participates in neurodegeneartion, we investigated the changes in IL-18 and IFN-γ systems within the rat hippocampus following status epilepticus (SE). In non-SE induced animals, IL-18, IL-18 receptor α (IL-18Rα), IFN-γ and IFN-γ receptor α (IFN-γRα) immunoreactivity was not detected in the hippocampus. Following SE, IL-18 immunoreactivity was increased in CA1-3 pyramidal cells as well as dentate granule cells. IL-18 immunoreactivity was also up-regulated in astrocytes and microglia/macrophages. IL-18Rα immunoreactivity was detected in astrocytes and microglia/macrophages. IFN-γ immunoreactivity was detected only in astrocytes within all regions of the hippocampus. IFN-γRα immunoreactivity was increased in neurons as well as astrocytes. Intracerebroventricular infusions of recombinant rat IL-18 or IFN-γ alleviated SE-induced neuronal damages, while neutralization of IL-18, IFN-γ or their receptors aggravated them, as compared to saline-infused animals. These findings suggest that astroglial-mediated IFN-γ pathway in response to IL-18 induction may play an important role in alleviation of SE-induced neuronal damages.

The prevalence and radiological findings in 1347 elderly patients with scoliosis.

In order to determine the epidemiology of adult scoliosis in the elderly and to analyse the radiological parameters and symptoms related to adult scoliosis, we carried out a prospective cross-sectional radiological study on 1347 adult volunteers. There were 615 men and 732 women with a mean age of 73.3 years (60 to 94), and a mean Cobb angle of 7.55 degrees (sd 5.95). In our study, 478 subjects met the definition of scoliosis (Cobb angle > or = 10 degrees ) showing a prevalence of 35.5%. There was a significant difference in the epidemiological distribution and prevalence between the age and gender groups. The older adults showed a larger prevalence and more severe scoliosis, more prominent in women (p = 0.004). Women were more affected by adult scoliosis and showed more linear correlation with age (p < 0.001). Symptoms were more severe in those with scoliosis than in the normal group, but were similar between the mild, moderate and severe scoliosis groups (p = 0.224) and between men and women (p = 0.231). Adult scoliosis showed a significant relationship with lateral listhesis, vertebral rotation, lumbar hypolordosis, sagittal imbalance and a high level of the L4-5 disc (p < 0.0001, p < 0.0001, p = 0.002, p = 0.002, p < 0.0001 respectively). Lateral listhesis, lumbar hypolordosis and sagittal imbalance were related to symptoms (p < 0.0001, p = 0.001, p < 0.0001 respectively).

Grade 4 spondylolisthesis of the L5 vertebra associated with dural ectasia in neurofibromatosis.

Spondylolisthesis associated with neurofibromatosis is rare, and only 12 cases have been reported so far. However, only one report of grade 4 spondylolisthesis with neurofibromatosis has been reported in the literature. A 15-year-old boy with neurofibromatosis was admitted for back pain and neurological claudication. Radiograph showed grade 4 spondylolisthesis of the L5 vertebra with scalloping of the L4-L5 vertebrae. L4-L5 laminectomy, reduction, L3-S1 posterior instrumentation and fusion were performed. The reduction of the spondylisthesis was done entirely from the posterior approach using pedicle screws. Radiography at four months showed a broken S1 screw with a loss of reduction. The patient was re-operated on, to provide additional stability with pelvic fixation. He was pain-free with a good fusion at the two-year follow-up. Adequate posterior stabilisation with fusion gives good results in grade 4 spondylolisthesis associated with neurofibromatosis and dural ectasia.

Development of genu varum in achondroplasia: relation to fibular overgrowth.

Genu varum in the achondroplastic patient has a complex and multifactorial aetiology. There is little mention in the literature of the role of fibular overgrowth. Using the ratio of fibular to tibial length as a measurement of possible fibular overgrowth, we have related it to the development of genu varum. Full-length standing anteroposterior radiographs of 53 patients with achondroplasia were analysed. There were 30 skeletally-immature and 23 skeletally-mature patients. Regression analysis was performed in order to determine if there was a causal relationship between fibular overgrowth and the various indices of alignment of the lower limb. Analysis showed that the fibular to tibial length ratio had a significant correlation with the medial proximal tibial angle and the mechanical axial deviation in the skeletally-immature group. We conclude that there is a significant relationship between fibular overgrowth and the development of genu varum in the skeletally-immature achondroplastic patient.

MRI study of the lumbar spine in achondroplasia. A morphometric analysis for the evaluation of stenosis of the canal.

We carried out an MRI study of the lumbar spine in 15 patients with achondroplasia to evaluate the degree of stenosis of the canal. They were divided into asymptomatic and symptomatic groups. We measured the sagittal canal diameter, the sagittal cord diameter, the interpedicular distance at the mid-pedicle level and the cross-sectional area of the canal and spinal cord at mid-body and mid-disc levels. The MRI findings showed that in achondroplasia there was a significant difference between the groups in the cross-sectional area of the body canal at the upper lumbar levels. Patients with a narrower canal are more likely to develop symptoms of spinal stenosis than others.

Origin of lumbar spinal roots and their relationship to intervertebral discs: a cadaver and radiological study.

Previous studies on the anatomy of the lumbar spine have not clarified the precise relationship of the origin of the lumbar roots to their corresponding discs or their angulation to the dural sac. We studied 33 cadavers (25 formalin-preserved and eight fresh-frozen) and their radiographs to determine these details. All cadavers showed a gradual decrease in the angle of the nerve root from L1 to S1. The origin of the root was found to be below the corresponding disc for the L1 to L4 roots. In the formalin-preserved cadavers 8% of the L5 roots originated above, 64% below and 28% at the L4/L5 disc. In the fresh cadavers the values were 12.5%, 62.5% and 25%, respectively. For the S1 root 76% originated above and 24% at the L5-S1 disc in the formalin-preserved cadavers and 75% and 25%, respectively, in the fresh cadavers.A herniated disc usually compresses the root before division of the root sleeve. Thus, compression of the thecal sac before the origin of the root sleeve is common for L1 to L5 whereas compression at the root sleeve is common for S1. Our findings are of value in understanding the pathophysiology of prolapse of the disc and in preventing complications during surgery.

The TB structural genomics consortium: a resource for Mycobacterium tuberculosis biology.

The TB Structural Genomics Consortium is an organization devoted to encouraging, coordinating, and facilitating the determination and analysis of structures of proteins from Mycobacterium tuberculosis. The Consortium members hope to work together with other M. tuberculosis researchers to identify M. tuberculosis proteins for which structural information could provide important biological information, to analyze and interpret structures of M. tuberculosis proteins, and to work collaboratively to test ideas about M. tuberculosis protein function that are suggested by structure or related to structural information. This review describes the TB Structural Genomics Consortium and some of the proteins for which the Consortium is in the progress of determining three-dimensional structures.

Nitric oxide causes apparent release of zinc from presynaptic boutons.

One of us showed previously [Cuajungco and Lees (1998) Brain Res. 799, 188-129] that nitric oxide injected into the cerebrum in vivo causes zinc staining to appear in the somata of neurons and suggested that this staining of somata might be accompanied by a depletion (release) of zinc from axon terminals. In the present study, we confirm earlier results and report that there is a dramatic loss (apparent release) of histologically reactive zinc from the boutons of zinc-containing axons induced by infusion of nitric oxide into the brain in vivo. Rats were anesthetized with halothane and a cannula was inserted into the hippocampus. Either nitric oxide donor (spermineNONOate, 100 mM/2 microl) or control (spermine, 100 mM/2 l) was infused into the hippocampus or the cerebellar cortex. Two hours after infusion, N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) staining for zinc in the brains revealed that sperminenitric oxide, but not control (spermine only) produced up to 95% depletion of zinc staining from the zinc-containing boutons. TSQ-positive neurons were also conspicuous throughout injection sites, in both the cerebral cortex and in the cerebellar cortex, where the Purkinje neurons were especially vivid, despite the scarcity of zinc-containing axonal boutons. It is suggested that the TSQ-stainable zinc in somata might represent intracellular stores mobilized from within or permeating extracellular stores.

Rapid translocation of Zn(2+) from presynaptic terminals into postsynaptic hippocampal neurons after physiological stimulation.

Zn(2+) is found in glutamatergic nerve terminals throughout the mammalian forebrain and has diverse extracellular and intracellular actions. The anatomical location and possible synaptic signaling role for this cation have led to the hypothesis that Zn(2+) is released from presynaptic boutons, traverses the synaptic cleft, and enters postsynaptic neurons. However, these events have not been directly observed or characterized. Here we show, using microfluorescence imaging in rat hippocampal slices, that brief trains of electrical stimulation of mossy fibers caused immediate release of Zn(2+) from synaptic terminals into the extracellular microenvironment. Release was induced across a broad range of stimulus intensities and frequencies, including those likely to induce long-term potentiation. The amount of Zn(2+) release was dependent on stimulation frequency (1-200 Hz) and intensity. Release of Zn(2+) required sodium-dependent action potentials and was dependent on extracellular Ca(2+). Once released, Zn(2+) crosses the synaptic cleft and enters postsynaptic neurons, producing increases in intracellular Zn(2+) concentration. These results indicate that, like a neurotransmitter, Zn(2+) is stored in synaptic vesicles and is released into the synaptic cleft. However, unlike conventional transmitters, it also enters postsynaptic neurons, where it may have manifold physiological functions as an intracellular second messenger.

Crystallization and preliminary X-ray studies of Trp138Phe/Val185Thr xylose isomerases from Thermotoga neapolitana and Thermoanaerobacterium thermosulfurigenes.

Xylose isomerases from Thermotoga neapolitana (TNXI) and Thermoanaerobacterium thermosulfurigenes (TTXI) share 70.4% sequence identity and are thermostable. The double mutants Trp138Phe/Val185Thr of TNXI and TTXI have higher catalytic efficiencies than TNXI and TTXI, respectively. The Trp138Phe/Val185Thr TNXI and TTXI mutants were overexpressed in Escherichia coli strain BL21(DE3) and purified. Crystals of the two proteins were grown with polyethylene glycol 8000 as the major precipitant by the hanging-drop vapour-diffusion method. Crystals of the TNXI mutant were obtained in the absence of substrate, in complex with glucose and in complex with fructose. Crystals of the TTXI mutant were obtained complexed with glucose. Diffraction data were collected at 1.9, 2.1 and 2.1 A resolution for the fructose-TNXI mutant, glucose-TNXI mutant and substrate-unbound TNXI mutant, respectively. The diffraction data for the glucose-TTXI mutant were collected at 2.0 A resolution. The crystals belong to the orthorhombic space groups C222(1) (TNXI mutant) and P2(1)2(1)2(1) (TTXI mutant). The TNXI and TTXI mutant crystals contain two and four monomers in the asymmetric unit, respectively.

Replacement of a tracheal defect with autogenous mucosa lined tracheal prosthesis made from polypropylene mesh.

Reliable prosthetic or tissue grafts for the trachea have not, as yet, been developed for reconstruction of large, circumferential tracheal defects. Major limitations are anastomotic dehiscence and stenosis, attributed to the poor epithelialization and vascularization of the prosthetic graft. We have developed a new tracheal prosthesis that has a well vascularized and viable mucosa. The prosthesis consists of a Prolene mesh reinforced with polypropylene rings, and coated with gelatin. We lined the luminal surface of the prosthesis with transplanted autogenous oral mucosa, wrapped the prosthesis with greater omentum, and placed it in the peritoneal cavity for 2 weeks. Complete surgical resection and replacement of a segment (5 cm in length, 8 to 10 tracheal rings) of the thoracic trachea was then performed in nine adult mongrel dogs. The transplanted mucosa was well vascularized and maintained its normal histology in prereplacement analysis. Dogs with tracheal replacement regained their full activity and did not show any respiratory problems until sacrifice at 1, 2, and 6 months. After 6 months, the prostheses were completely incorporated by the host trachea in all dogs and confluent epithelialization was confirmed histologically from the upper to the lower anastomotic site of the prosthesis; furthermore, the transplanted mucosal cells had changed to ciliated columnar epithelium.

Crystal structure and functional analysis of the SurE protein identify a novel phosphatase family.

Homologs of the Escherichia coli surE gene are present in many eubacteria and archaea. Despite the evolutionary conservation, little information is available on the structure and function of their gene products. We have determined the crystal structure of the SurE protein from Thermotoga maritima. The structure reveals the dimeric arrangement of the subunits and an active site around a bound metal ion. We also demonstrate that the SurE protein exhibits a divalent metal ion-dependent phosphatase activity that is inhibited by vanadate or tungstate. In the vanadate- and tungstate-complexed structures, the inhibitors bind adjacent to the divalent metal ion. Our structural and functional analyses identify the SurE proteins as a novel family of metal ion-dependent phosphatases.