Rapid Spontaneous Resolution of Acute Subdural Hematoma in a Patient with Liver Cirrhosis / 대한신경손상학회지

Acute subdural hematoma (ASDH) constitutes one of the most critical emergencies in neurosurgery and rapid spontaneous resolution of ASDH is an infrequent phenomenon. Several mechanisms have been attributed to explain this phenomenon including redistribution of subdural blood, dilution by cerebral spinal fluid and brain atrophy. Rapid resolution of ASDH related to coagulopathy is a rare phenomenon; to our knowledge, only one case has been reported. We report on a patient who showed rapid resolution of ASDH with coagulopathy and also discuss such a rare case with speculation of the coagulopathy as a factor to promote this phenomenon.

Endovascular Treatment of the Distal Internal Carotid Artery Large Aneurysm

OBJECTIVE: According to the development of endovascular technique and devices, larger aneurysms on the distal internal carotid artery (ICA) can be treated using a less invasive method. The authors report on clinical and angiographic outcomes of these aneurysms treated using an endovascular technique. MATERIALS AND METHODS: Data on 21 patients with large aneurysms at distal ICA treated by endovascular method between January 2005 and December 2012 were included in this retrospective analysis. RESULTS: Clinical outcome of patients showed strong correlation with the initial neurologic status (p < 0.05). Aneurysm morphology showed saccular, fusiform, and wide-neck in 12, six and three patients. Six patients underwent stent assisted coiling and the other 15 patients underwent simple coiling. Aneurysm occlusion was performed immediately after embolization with near-complete (Raymond class 1-2) in 20 patients (95.2%) and incomplete (Raymond class 3) in one patient (4.8%). Delayed thrombotic occlusion occurred in two patients and their clinical result was fatal. Another five patients died in the hospital, from massive brain edema and/or increased intracranial pressure due to initial subarachnoid hemorrhage. Overall mortality was 30% (seven out of 21). Fatal complication related to the endovascular procedure occurred in two patients with thrombosis at middle cerebral artery (one with stent, the other without it). CONCLUSION: Recent developed endovascular device and technique is safe enough and a less invasive method for distal large or giant aneurysms. Based on our analysis of the study, we suspect that coil embolization of large distal ICA aneurysms (with or without stenting) is effective and safe.

Thirteen-year Experience of 44 Patients with Adult Hemorrhagic Moyamoya Disease from a Single Institution: Clinical Analysis by Management Modality

Our objective was a retrospective assessment of the management modalities that provided the most beneficial treatment in hemorrhagic moyamoya disease during the last 13 years at our institution. The clinical results of 44 patients with hemorrhagic moyamoya disease were investigated, comparing revascularization surgery (direct, indirect, and combined bypass) or conservative treatment. Angiographic features, rebleeding, and clinical outcome were investigated. Six of the 35 patients (17.1%) with revascularization surgery experienced rebleeding, as did 4 of 9 patients (44.4%) with conservative treatment. However, patients who underwent bypass surgery had a lower chance of rebleeding. No significant difference in chance of rebleeding was observed between bypass surgery and non surgery groups (p > 0.05). Cerebral angiography performed after bypass surgery showed that for achieving good postoperative revascularization, direct and combined bypass methods were much more effective (p < 0.05). While the risk of rebleeding in the revascularization group was generally lower than in the conservative treatment group, there was no statistically significant difference between treatment modalities and conservative treatment. Although statistical significance was not attained, direct and combined bypass may reduce the risk of hemorrhage more effectively than indirect bypass.

Thirteen-year Experience of 44 Patients with Adult Hemorrhagic Moyamoya Disease from a Single Institution: Clinical Analysis by Management Modality

Our objective was a retrospective assessment of the management modalities that provided the most beneficial treatment in hemorrhagic moyamoya disease during the last 13 years at our institution. The clinical results of 44 patients with hemorrhagic moyamoya disease were investigated, comparing revascularization surgery (direct, indirect, and combined bypass) or conservative treatment. Angiographic features, rebleeding, and clinical outcome were investigated. Six of the 35 patients (17.1%) with revascularization surgery experienced rebleeding, as did 4 of 9 patients (44.4%) with conservative treatment. However, patients who underwent bypass surgery had a lower chance of rebleeding. No significant difference in chance of rebleeding was observed between bypass surgery and non surgery groups (p > 0.05). Cerebral angiography performed after bypass surgery showed that for achieving good postoperative revascularization, direct and combined bypass methods were much more effective (p < 0.05). While the risk of rebleeding in the revascularization group was generally lower than in the conservative treatment group, there was no statistically significant difference between treatment modalities and conservative treatment. Although statistical significance was not attained, direct and combined bypass may reduce the risk of hemorrhage more effectively than indirect bypass.

Hybrid Surgery of Multilevel Cervical Degenerative Disc Disease : Review of Literature and Clinical Results

OBJECTIVE: In the present study, we evaluated the effect, safety and radiological outcomes of cervical hybrid surgery (cervical disc prosthesis replacement at one level, and interbody fusion at the other level) on the multilevel cervical degenerative disc disease (DDD). METHODS: Fifty-one patients (mean age 46.7 years) with symptomatic multilevel cervical spondylosis were treated using hybrid surgery (HS). Clinical [neck disability index (NDI) and Visual Analogue Scale (VAS) score] and radiologic outcomes [range of motion (ROM) for cervical spine, adjacent segment and arthroplasty level] were evaluated at routine postoperative intervals of 1, 6, 12, 24 months. Review of other similar studies that examined the HS in multilevel cervical DDD was performed. RESULTS: Out of 51 patients, 41 patients received 2 level hybrid surgery and 10 patients received 3 level hybrid surgery. The NDI and VAS score were significantly decreased during the follow up periods (p<0.05). The cervical ROM was recovered at 6 and 12 month postoperatively and the mean ROM of inferior adjacent segment was significantly larger than that of superior adjacent segments after surgery. The ROM of the arthoplasty level was preserved well during the follow up periods. No surgical and device related complications were observed. CONCLUSION: Hybrid surgery is a safe and effective alternative to fusion for the management of multilevel cervical spondylosis.

Surgical Treatment of Craniovertebral Junction Instability : Clinical Outcomes and Effectiveness in Personal Experience

OBJECTIVE: Craniovertebral junction (CVJ) consists of the occipital bone that surrounds the foramen magnum, the atlas and the axis vertebrae. The mortality and morbidity is high for irreducible CVJ lesion with cervico-medullary compression. In a clinical retrospective study, the authors reviewed clinical and radiographic results of occipitocervical fusion using a various methods in 32 patients with CVJ instability. METHODS: Thirty-two CVJ lesions (18 male and 14 female) were treated in our department for 12 years. Instability resulted from trauma (14 cases), rheumatoid arthritis (8 cases), assimilation of atlas (4 cases), tumor (2 cases), basilar invagination (2 cases) and miscellaneous (2 cases). Thirty-two patients were internally fixed with 7 anterior and posterior decompression with occipitocervical fusion, 15 posterior decompression and occipitocervical fusion with wire-rod, 5 C1-2 transarticular screw fixation, and 5 C1 lateral mass-C2 transpedicular screw. Outcome (mean follow-up period, 38 months) was based on clinical and radiographic review. The clinical outcome was assessed by Japanese Orthopedic Association (JOA) score. RESULTS: Nine neurologically intact patients remained same after surgery. Among 23 patients with cervical myelopathy, clinical improvement was noted in 18 cases (78.3%). One patient died 2 months after the surgery because of pneumonia and sepsis. Fusion was achieved in 27 patients (93%) at last follow-up. No patient developed evidence of new, recurrent, or progressive instability. CONCLUSION: The authors conclude that early occipitocervical fusion to be recommended in case of reducible CVJ lesion and the appropriate decompression and occipitocervical fusion are recommended in case of irreducible craniovertebral junction lesion.

Bilateral Multiple Intracerebral Hemorrhagic Infarction after Cranioplasty in a Patient with Cerebral Infarction: Case Report / 대한뇌혈관외과학회지

Bilateral multiple intracranial hemorrhagic infarction after cranioplasty is an extremely rare complication. We present a case of a bilateral multiple intracranial hemorrhagic infarction following cranioplasty with an autologous bone graft. A 63-year-old woman had a previous decompressive craniectomy after a right middle cerebral artery infarction. The possible pathogenesis of the complication is discussed.

Risk Factors and Surgical Treatment for Symptomatic Adjacent Segment Degeneration after Lumbar Spine Fusion

OBJECTIVE: The present study analyzed the risk factors, prevalence and clinical results following revision surgery for adjacent segment degeneration (ASD) in patients who had undergone lumbar fusion. METHODS: Over an 8-year period, we performed posterior lumbar fusion in 81 patients. Patients were followed a minimum of 2 years (mean 5.5 years). During that time, 9 patients required revision surgery due to ASD development. Four patients underwent autogenous posterolateral arthrodesis and extended transpedicle screw fixation, 4 patients underwent decompressive laminectomy and interspinous device implantation, and 1 patient underwent simple decompression. RESULTS: Of the 9 of patients with clinical ASD, 33.3% (3 of 9) of patients did not have radiographic ASD on plain radiographs. Following revision surgery, the clinical results were excellent or good in 8 patients (88.9%). Age > 50 years at primary surgery was a significant risk factor for ASD development, while number of fusion levels, initial diagnosis and type of fusion were not. CONCLUSION: The incidence of ASD development after lumbar surgery was 11.1% (9 of 81) in this study. Age greater than 50 was the statistically significant risk factor for ASD development. Similar successful clinical outcomes were observed after extended fusion with wide decompression or after interspinous device implantation. Given the latter procedure is less invasive, the findings suggest it may be considered a treatment alternative in selected cases but it needs further study.

ICP Trend in Massive ICH Patients After Decompressive Craniectomy / 대한뇌혈관외과학회지

OBJECTIVE: Massive intracerebral hemorrhage (ICH) is devastating neurosurgical disease. Decompression surgery has been performed to manage the uncontrolled increased intracranial pressure and good clinical result has been reported. Authors analyze the ICP trend after the decompression surgery and report the clinical usefulness. METHODS: Thirty patients data with massive ICH were analyzed retrospectively. Surgical indication was constantly followed in these patient ; Glasgowcoma scale score less than 8, midline shift more than 6 mm on brain CT. In all patients ventricular puncture was done before the decompression and monitored the ventricular pressure changes during and after the surgery. RESULTS: In massive ICH patients, the ICP was maintained in physiological range if the hematoma was removed more than 80%. And when we tried additional therapies like hypothermia or coma therapies in another group, the ICP was elevated at the time of the additional therapy. CONCLUSION: From this study, if the ICH removed more than 80% and The ICP was not exceed 20 mmHg during the first post-operation day, the ICP hardly exceed 20 mmHg after than. Authors thought that decompression surgery is not an essential treatment for the massive ICH patient if their hematoma removed enough.

Evaluation of Surgery for Aneurysms that arise from a Non-Branching Site of the Intracranial Internal Carotid Artery (ICA) / 대한뇌혈관외과학회지

OBJECT: Surgery for aneurysms at non-branching sites of an internal carotid artery (ICA) is considered based on the size, shape, direction and site of the aneurysm. In this study, we analyzed characteristics of aneurysms that have arisen from non-branching sites of an ICA from the viewpoint of surgery. METHODS: From 2003 to 2007, 346 intracranial aneurysms were treated at our institute. 19 (5.5%) aneurysms were non-branching site aneurysms of an ICA. Surgery for these aneurysms was retrospectively analyzed in view of the treatment strategy according to the site, size, and configuration of the aneurysms in videos obtained during surgery. RESULTS: There were 13 cases of a ruptured aneurysm (68.4%) and six cases of an unruptured aneurysm (31.6%). There were ten cases of a saccular type of aneurysm (52.6%) and nine cases of a blood blister-like aneurysm (47.4%). There were seven aneurysms that arose from the dorsal wall of an ICA (36.8%), six aneurysms that arose from the ventral wall (31.6%), four aneurysms that arose from the lateral wall (21.1%) two aneurysms that arose from the medial wall (10.5%). Three patients with unruptured blood blister-like aneurysms underwent simple wrapping and wrapping with the use of clip. Three unruptured saccular aneurysms could be clipped perpendicular to an ICA or at a slant to an ICA. Three out of six (50%) ruptured blood blister-like aneurysms were ruptured during surgery. These aneurysms were clipped with the partial wall of an ICA, resulting in ICA stenosis. We treated 15 (84%) of 19 cases by only clipping, one case (5.2%) was treated by clipping with bypass surgery and three cases (15%) were treated by wrapping. CONCLUSION: Ruptured aneurysms of nonbranching sites of an ICA such as blister-like or dorsal saccular aneurysms have a high risk of rupture and can be difficult to clip. If clipping of the aneurysms is possible, preoperative balloon test occlusion should be performed to avoid ICA stenosis after clipping of the aneurysm neck with the arterial wall. Clipping after bypass or trapping can vary the treatment strategy and improve patient outcome. For small-unruptured aneurysms from nonbranching sties of an ICA, wrapping with the use of clip may be a useful method for treatment regardless of the clipping direction.

Effect of Single Growth Factor and Growth Factor Combinations on Differentiation of Neural Stem Cells

OBJECTIVE: The effects on neural proliferation and differentiation of neural stem cells (NSC) of basic fibroblast growth factor-2 (bFGF), insulin growth factor-I (IGF-I), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) were assessed. Also, following combinations of various factors were investigated : bFGF+IGF-I, bFGF+BDNF, bFGF+NGF, IGF-I+BDNF, IGF-I+NGF, and BDNF+NGF. METHODS: Isolated NSC of Fisher 344 rats were cultured with individual growth factors, combinations of factors, and no growth factor (control) for 14 days. A proportion of neurons was analyzed using beta-tubulin III and NeuN as neural markers. RESULTS: Neural differentiations in the presence of individual growth factors for beta-tubulin III-positive cells were : BDNF, 35.3%; IGF-I, 30.9%; bFGF, 18.1%; and NGF, 15.1%, and for NeuN-positive cells was : BDNF, 34.3%; bFGF, 32.2%; IGF-1, 26.6%; and NGF, 24.9%. However, neural differentiations in the absence of growth factor was only 2.6% for beta-tubulin III and 3.1% for NeuN. For beta-tubulin III-positive cells, neural differentiations were evident for the growth factor combinations as follows : bFGF+IGF-I, 73.1%; bFGF+NGF, 65.4%; bFGF+BDNF, 58.7%; BDNF+IGF-I, 52.2%; NGF+IGF-I, 40.6%; and BDNF+NGF, 40.0%. For NeuN-positive cells : bFGF+IGF-I, 81.9%; bFGF+NGF, 63.5%; bFGF+BDNF, 62.8%; NGF+IGF-I, 62.3%; BDNF+NGF, 56.3%; and BDNF+IGF-I, 46.0%. Significant differences in neural differentiation were evident for single growth factor and combination of growth factors respectively (p<0.05). CONCLUSION: Combinations of growth factors have an additive effect on neural differentiation. The most prominent neural differentiation results from growth factor combinations involving bFGF and IGF-I. These findings suggest that the combination of a mitogenic action of bFGF and postmitotic differentiation action of IGF-I synergistically affects neural proliferation and NSC differentiation.

Rupture of Middle Cerebral Artery Aneurysm in a 22-month-old Infant : Case Report / 대한뇌혈관외과학회지

A 22-month-old male infant visited at our hospital with stuporous mentality. Brain CT angiography revealed right M1 aneurysm with subarachnoid hemorrhage and intraventricular hemorrhage. After one month from ictus, aneurysmectomy and neck clipping was done. We report here on an extremely rare case of ruptured intracranial aneurysm under the age of 5 years.

Increase of Angiogenesis and Neurogenesis, and Neurobehavioral Recovery by Transplanted Mesenchymal Stem Cells in the Ischemic Rat Brain / 대한뇌혈관외과학회지

OBJECT: In this study, murine mesechymal stem cells (MSC) was grafted to cerebral ischemia rats, the differentiation of the transplanted MSC was assessed, and at that time, the association of the level of the recovery of neurological function. METHODS: As experimental animals, the transient middle cerebral artery occlusion (MCAo) rat model was used, and MSC collected from the bone marrow of C57/Bl6 mice were cultured, 5microliter(105 microliter) cells marked with the fluorescent substance 3.3'-dilinoleyloxacarbocyanine(DIO) were transplanted into the ischemic cortex. Angiogenesis and neurogenesis were examined and the neurobehavioral evaluation were done. To assess the differentiation level of MSC, and it was evaluated as the percentage of the mean area of stained cells within each region of interest (ROI). RESULTS: In the MCA transplanted group, Neurobehavioral score was improved to twelve points one hour, one day, and three days after transplant, and seven days and fourteen days after transplant, to eleven points and nine points, respectively. The result of immunohistochemical staining showed that the angiogenesis on the day seven was 3.15% and on the day fourteen was 4.26%, the neurogenesis on the day seven was 2.29% and on the day fourteen was 3.82%. CONCLUSION: On the day seven and fourteen after MCS transplantation, the phenomenon of the actively ongoing angiogenesis and neurogenesis was detected, and it was found that at that time, the recovery of neurological function occurred. However, the level of differentiation from MSC was small, and thus it was not statistically significant.

Intracranial Atherosclerotic Disease; Current Options for Surgical or Medical Treatment

Recently, intracranial atherosclerosis has become a major cause of ischemic stroke, appearing more frequently in Koreans than Caucasians. Symptomatic or asymptomatic intracranial atherosclerosis is a disease that could recur readily even during the treatment with anti-platelet agents. When the symptoms develop, ischemic stroke can not be recovered readily. Therefore, aggressive treatments such as endovascular therapy and bypass surgery are required in addition to medical treatment for the intracranial artery stenosis. Recent intracranial stenting and drug eluting stenting have shown as very advanced effective therapeutic modalities. Nevertheless, until now, a randomized controlled study has not been conducted. Regarding bypass surgery, since the failed EC-IC bypass surgery study performed 20 years ago, extensive studies on its efficacy has not been conducted yet, and thus it has to be performed strictly only in hemodynamically compromised patients. Unless breakthrough drugs that suppress the progression of intracranial atherosclerosis and the formation of thrombi, and facilitate the regression of the arterial stenosis, the treatment concept of the recovery of the blood flow of stenotic arterial territory by mechanical recanalization or bypass surgery would be remained for the prevention as well as treatment of ischemic stroke caused by intracranial atherosclerosis.

Parenchymal Neurocutaneous Melanosis in Association with Intraventricular Dermoid and Dandy-Walker Variant: A Case Report

Neurocutaneous melanosis (NCM) is a rare congenital disease that is characterized by the presence of large or multiple congenital melanocytic nevi and melanotic lesions of the central nervous system. We report here on the CT and MR imaging findings of an unusual case of NCM that was associated with intraventricular dermoid and Dandy-Walker malformation.

Recurrent chondroblastoma on the right temporal area : a case report

Management Options and Prognosis of Carotid Artery Occlusive Disease / 대한뇌혈관외과학회지

OBJECT: The effective management of carotid occlusive disease still remains a challenge to neurosurgeons. The authors analyzed the series of management of carotid occlusive disease in order to determine whether our management strategy affected patient's clinical outcomes. Methods of identifying patients who stand to benefit from this therapy need to be established. METHOD: Clinical findings, management, complications and outcome in 52 patients with high grade carotid stenosis of at least 70% and occlusion were investigated. The patients were treated by percutaneous transluminal angioplasty (PTA) and/or stent (PTAS), Extracranial-Intracranial (EC-IC) bypass surgery, carotid endarterectomy (CEA) according to the neurologic status, medical condition, severerity of stenosis, collateral blood flow. RESULTS: The causes of carotid stenosis were 40 atherosclerosis arteries, 9 spontaneous dissections and 2 traumas, 1 fibomuscular dysplasia (FMD) of 52 patients. 9 patients were treated by PTA alone, and 28 patients by PTAS, 9 patients by EC-IC bypass surgery, 3 patients by PTAS followed by EC-IC bypass surgery, 3 patients by CEA. For the outcome according to management, 26 patients (100% of all bypass surgery only and CEA, 35% of all PTA and PTAS) recovered excellently, 14 patients (35% of all PTA and PTAS) had a good outcome. 2 patients died. CONCLUSION: The results of this study suggest that PTAS should be a useful and effective treatment method for some patients with the severe atherosclerotic stenosis or carotid artery dissection. However, the surgical management must be considered for the high risk, high grade carotid stenosis patients with collateral blood flow, and with or without mild or moderate deficits.

The Cell Survival and Differentiation after Transplantation, Which Harvest from Adult Rat Brain by High-speed Centrifugation Method

OBJECTIVE: Many recent reports have shown that the mature mammalian brain harbors multipotent stem cells, rendering the brain capable of generating new neurons and glia throughout life. Harvested stem cells from an adult rat are transplanted in order to evaluate the cell survival and differentiation. METHODS: Using a percoll gradient with a high speed centrifugation method, we isolate neural stem/progenitor cells were isolated from the subventricular zone(SVZ) of a syngeneic adult Fisher 344 rats brain. For 14days expansion, the cultured cells comprised of a heterogeneous population with the majority of cells expressing nestin and/or GFAP. After expanding the SVZ cells in the presence of basic fibroblast growth factor-2, and transplanting then into the hippocampus of normal rats, the survival and differentiation of those cells were examined. For transplantation, the cultured cells were labeled with BrdU two days prior to use. In order to test their survival, the cells were transplanted into the dorsal hippocampus of normal adult Fisher 344 rats. RESULTS: The preliminary data showed that at 7days after transplantation, BrdU+ transplanted cells were observed around the injection deposition sites. Immuno-fluorescent microscopy revealed that the cells co-expressed BrdU+ and neuronal marker beta-tubulin III. CONCLUSION: The data demonstrate that the in vitro expanded SVZ cells can survive in a heterotypic environment and develop a neuronal phenotype in the neurogenic region. However more research will be needed to examine the longer survival time points and quantifying the differentiation in the transplanted cells in an injured brain environment.

Hypothermia Effect on Apoptotic Neuronal Death in Traumatic Brain Injury Model

OBJECTIVE: Many researchers believe that the hypothermia shows neuroprotective effect on brain injury. To understand the molecular mechanism of the hypothermic treatment, this study investigated its effects on the expression of cell death or survival related proteins such as p53, Bcl-2 and Bax in the rat traumatic brain injury(TBI) model. METHODS: Twenty rats (Spraque Dawley, 200~250g) were subjected to the brain injury of moderate severity (2.4~2.6atm) using the fluid percussion injury device and five rats were received only same surgery as controls. During 30minutes after the brain injury, the hypothermia group was maintained the body temperature around 34 degrees C while the control group were maintained that of 36 degrees C. Five rats in each group were sacrificed 12h or 24h after brain injury and their brain sections was analyzed for physical damages by H-E stains and the extent of apoptosis by TUNEL assay and immunohistochemical stains. The tissue damage after TBI was mainly observed in the ipsilateral cortex and partly in the hippocampus. RESULTS: Apoptosis was observed by TUNEL assay and the Bax protein was detected in both sample which harvested 12h and 24h after TBI. In the hypothermia treatment group, tissue damage and apoptosis were reduced in HE stains and TUNEL assay. In hypothermia treatment group rat shows more expression of the Bcl-2 protein and shows less expression of the Bax protein, at both 12h and 24h after TBI. CONCLUSION: These results show that the hypothermia treatment is an effective treatment after TBI, by reducing the apoptotic process. Therefore, it could be suggested that hypothermia has a high therapeutic value for treating tissue damages after TBI.

Increase of Synapsin I, Phosphosynapsin (ser-9), and GAP-43 in the Rat Hippocampus after Middle Cerebral Artery Occlusion

The loss of neurons and synaptic contacts following cerebral ischemia may lead to a synaptic plastic modification, which may contribute to the functional recovery after a brain lesion. Using synapsin I and GAP-43 as markers, we investigated the neuronal cell death and the synaptic plastic modification in the rat hippocampus of a middle cerebral artery occlusion (MCAO) model. Cresyl violet staining revealed that neuronal cell damage occurred after 2 h of MCAO, which progressed during reperfusion for 2 weeks. The immunoreactivity of synapsin I and GAP-43 was increased in the stratum lucidum in the CA3 subfield as well as in the inner and outer molecular layers of dentate gyrus in the hippocampus at reperfusion for 2 weeks. The immunoreactivity of phosphosynapsin was increased in the stratum lucidum in the CA3 subfield during reperfusion for 1 week. Our data suggest that the increase in the synapsin I and GAP-43 immunoreactivity probably mediates either the functional adaptation of the neurons through reactive synaptogenesis from the pre-existing presynaptic nerve terminals or the structural remodeling of their axonal connections in the areas with ischemic loss of target cells. Furthermore, phosphosynapsin may play some role in the synaptic plastic adaptations before or during reactive synaptogenesis after the MCAO.