Lecithin-cholesterol acyltransferase (LCAT) deficiency without mutations in the coding sequence: a case report and literature review.

Familial lecithin-cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease characterized by corneal opacities, normocytic anemia, dyslipidemia, and proteinuria progressing to chronic renal failure. In all FLD cases, a mutation has been found in the coding sequence of the LCAT gene. FLD is clinically distinguished from an acquired form of LCAT deficiency by the presence of corneal opacities. Here we describe a 36-year-old woman presenting with clinical, pathological, and laboratory data compatible with FLD. Her mother and elder sister had corneal opacities. However, genetic analysis revealed there were no mutations in the LCAT coding sequences and no alterations in LCAT mRNA expression. Furthermore, we were unable to find any underlying conditions that may lead to LCAT deficiency. The present case therefore demonstrates that LCAT deficiency may be caused by factors other than mutations in the coding sequence and we suggest that a translational or posttranslational mechanism may be involved.

Phosphorylation of neuronal nitric oxide synthase at Ser847 in the nucleus intermediolateralis after spinal cord injury in mice.

We previously demonstrated that Ca2+/calmodulin (CaM)-dependent protein kinase IIalpha (CaM-KIIalpha) can phosphorylate neuronal nitric oxide synthase (nNOS) at Ser847 and attenuate NOS activity in neuronal cells. In the present study we focused on chronological alteration in levels and cellular location of nNOS, phosphorylated (p)-Ser847-nNOS (NP847), CaM-KII and p-Thr286-CaM-KIIalpha following spinal cord injury (SCI) in mice. Western blot analysis showed nNOS to be significantly phosphorylated at Ser847 from 3 h after SCI, peaking at 24 h and gradually decreasing thereafter, and CaM-KII to be colocalized with nNOS after SCI. Immunohistochemical analysis revealed that SCI causes an increase in both NP847 and p-Thr286-CaM-KIIalpha in the nucleus intermediolateralis. These findings suggest that SCI induces p-Thr286-CaM-KIIalpha, which phosphorylates the nNOS at Ser847 in the nucleus intermediolateralis where NO is thought to play a role as a neurotransmitter in autonomic preganglionic neurons. Thus, the NP847 signaling pathway might be involved in the autonomic failure which occurs immediately after SCI.

A case of posterior fossa dural arteriovenous fistulas successfully treated with transarterial embolization.

SUMMARY: A 40-year-old man was transferred to our hospital due to sudden headache while swimming in the pool. CT revealed cerebellar haematoma within vermis associated with subarachnoid haemorrhage (SAH). Digital subtraction angiography (DSA) showed dural arteriovenous fistulas (DAVFs) with venous pouch on the surface of cerebellar vermis. Fistulas were on the meningeal surface near the sinus confluence. Draining veins formed venous pouch invaginating into cerebellar vermis. Transarterial embolization (TAE) was performed under the concept that main feeder should be embolized last to occlude the DAVFs completely. Post-embolization 3D-CT showed the cast of N-butyl-cyanoacrylate (NBCA) in the fistulas as well as in the drainer. The good order of occlusion made the embolization complete.

Balance of risk of therapeutic hypothermia.

The complications of therapeutic hypothermia sometimes undermine its clinical effects. In this study we investigated the efficacy and safety of therapeutic hypothermia based on analysis of 20 severe head injury cases from 6 institutions treated with therapeutic hypothermia in 1999. The twenty patients with severe head injury were enrolled prospectively based on the following indications; Glasgow Coma Scale of 7 or less on admission, age 60 or younger, and systric BP over 100 mmHg. A control group consisting of 21 patients with severe head injury met the same criteria but were treated without therapeutic hypothermia in other institutions. Clinical benefit were evaluated by a comparison of clinical result in the two groups defined according to the Glasgow Outcome Scale six months after injury. The hypothermia group was divided into two groups based on a target temperature [mild hypothermia group: 32-34 degrees C (n = 10); very mild hypothermia group: 35-36 degrees C (n = 10)]. The complication rate, clinical results and the duration of therapeutic hypothermia were analyzed between two groups. In the hypothermia group, 12 patients obtained a favorable outcome (Good Recovery or Moderate Disabled in GOS) and the mortality rate was 35%. In the control group, however only 5 patients had a favorable outcome and the mortality rate was 57%. Comparison between mild hypothermia and very mild hypothermia groups revealed no difference in clinical outcome. In the hypothermia group, severe pneumonia was seen in three patients, all in the mild hypothermia group with a hypothermic duration of over 120 hours. Mild hypothermia should be ended within 120 hours to avoid severe complication. When long-lasting therapeutic hypothermia of more than 120 hours is planned, very mild hypothermia is the treatment of choice.

Effect of early induction of hypothermia on severe head injury.

Although therapeutic hypothermia for patients with head injury has improved the outcome, the results in the most severe cases (GCS 3-6) have not been satisfactory so far. We induced hypothermia in head injury patients within 3 hours after the trauma, and compared the outcome of the treatment without hypothermia. Fourteen patients with GCS less than 6 were entered into this study (age range 13 to 58, mean 27.0 years). Seven of them were treated by hypothermia and 6 by the conventional method. The patients undergoing hypothermia were cooled to 34 degrees C within 3 hours after injury, kept at 32-34 degrees C for 48 hours, and then rewarmed. The outcome was evaluated at 6 months post-trauma, and the results were compared in the two groups. Therapeutic hypothermia dramatically suppressed brain swelling on CT in 3 of 7 patients. Four patients including these 3 showed a favorable outcome (good or moderate disability) and 3 died in the hypothermia group. In the conventional treatment group, only 1 patient was moderately disabled and 6 exhibited an unfavorable outcome (severely disabled, vegetative, or death). Early induction of hypothermia can improve the outcome in patients with severe head injury by reducing the severe brain swelling.

Adrenomedullin reduces ischemic brain injury after transient middle cerebral artery occlusion in rats.

BACKGROUND: The effect of adrenomedullin, a vasodilatory peptide on transient middle cerebral artery (MCA) occlusion was investigated in rats. METHODS: Transient MCA occlusion for 2 hours was made by using the intra-arterial suture method, followed by reperfusion. FINDINGS: An intravenous infusion of adrenomedullin (1 microg/kg/min) from one hour before ischemia to one hour after ischemia significantly reduced the infarct size and improved neurological deficits (p<0.05), without affecting systemic blood pressure or other physiological parameters. The infarct size was reduced with adrenomedullin by 25.4+/-12.7%, 31.3+/-5.8%, 31.6+/-6.1% respectively at the coronal level 6, 8 and 10 mm posterior from the frontal pole. Adrenomedullin also significantly inhibited the increase in myeloperoxidase (MPO) activity in the MCA area of the ischemic hemisphere after 22-hour reperfusion (control: 0.205+/-0.054 unit/g wet tissue, adrenomedullin group: 0.047+/-0.009 unit/g wet tissue, p<0.0001). INTERPRETATION: These data suggest that adrenomedullin reduces acute ischemic brain injury and one of is neuroprotective mechanisms may be derived from inhibition of the infiltration of neutrophils into the ischemic tissue.

Vasodilatory effect of basic fibroblast growth factor in isolated rat cerebral arterioles: mechanisms involving nitric oxide and membrane hyperpolarization.

Basic fibroblast growth factor (bFGF), a potent mitogen, acutely dilates cerebral blood vessels and may be effective in reducing cerebral infarction. However, the vasodilatory mechanism, which may involve nitric oxide (NO), is not completely understood. This study investigated whether membrane hyperpolarization is also involved in this mechanism. Membrane potential (MP) of smooth muscle cells and vessel diameter of isolated intracerebral arterioles were simultaneously measured following extraluminal application of bFGF in rats. The involvement of NO and adenosine triphosphate-sensitive potassium (KATP) channels in bFGF-induced vasodilation and membrane hyperpolarization was evaluated using specific inhibitors, NG-monomethyl-L-arginine (L-NMMA, 10(-4) M) and glibenclamide (GB, 10(-5) M), respectively. The resting MP was recorded at a mean value of -31.9 +/- 4.5 mV. bFGF (1 to 1000 ng/ml) produced significant vasodilation and hyperpolarization. Treatment with L-NMMA caused vasoconstriction and significantly attenuated bFGF-induced vasodilation without affecting membrane hyperpolarization. In the presence of GB, the membrane potential was significantly depolarized but the vessel diameter was only marginally reduced, so bFGF-induced membrane hyperpolarization was inhibited while arteriolar dilation was attenuated. These results suggest that bFGF-induced vasodilation is mediated by a mechanism involving both NO and membrane hyperpolarization, and that membrane hyperpolarization is caused by the activation of KATP channels.

Time course of expression of three nitric oxide synthase isoforms after transient middle cerebral artery occlusion in rats.

The involvement of nitric oxide synthase (NOS) in ischemia was evaluated by detecting the expression of neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS) by the immunohistochemical method in the rat model of middle cerebral artery (MCA) occlusion. Transient MCA occlusion (2 hours) was induced in 32 male Wistar rats by extracranial insertion of a 3-0 nylon thread through the internal carotid artery into the MCA. Animals were killed at 0, 6, 24, 72, and 168 hours after MCA occlusion (n = 6, 6, 8, 6, and 6, respectively). The brains were fixed with periodate-lysine-paraformaldehyde, frozen, and sectioned. Sections were stained with polyclonal antibody against nNOS, eNOS, and iNOS. Each section was evaluated by microscopic observation (x100). The number of nNOS-positive neurons was 41.6 +/- 5.8 (mean +/- SD) in the control hemisphere. nNOS was upregulated in the ischemic hemisphere (88.3 +/- 18.9), especially in the border zone at 6 hours after MCA occlusion. However, the number decreased to 36.4 +/- 3.6 and 26.3 +/- 7.3 in the ischemic hemisphere after 72 and 168 hours, respectively. eNOS immunoreactivity was present in the endothelium of major vessels at each time point. eNOS was not detected in the microvessels before ischemia, but faint staining was found in the endothelium at 6 hours after MCA occlusion. Immunostaining became more intense thereafter. Faint iNOS immunoreactivity was seen in the microvessels at 6 hours after MCA occlusion. Macrophages in the ischemic core and astrocytes in the border zone showed immunoreactivity to iNOS at 72 and 168 hours after MCA occlusion. Three types of NOS must be related to different stages of ischemic brain damage. nNOS may be neurotoxic in ischemia in the early phase, like iNOS in the late phase. On the other hand, eNOS seemed to be neuroprotective in all stages. These observations suggest the necessity for tailored therapeutic intervention against NOS isoforms at each stage in patients with ischemic stroke.

En bloc laminoplasty performed with threadwire saw.

OBJECTIVE: To introduce a method for a simple, nonexpansive laminoplasty that can be performed with a threadwire saw (T-saw) after en bloc laminotomy has been performed. The method can be applied along the entire spinal region, including the thoracic and lumbar spine. METHODS: An en bloc laminotomy of trapezoid shape at the cross section is performed bilaterally at the junctional area of the lamina and facet joint with a thin, flexible T-saw, while preserving the supraspinous, interspinous, and interlaminar ligaments. After the intradural procedure has been performed, the laminar flap is replaced in its original site and fixed with 1-0 nylon sutures, resulting in the complete reconstruction of the posterior supporting elements of the spinal column. RESULTS: En bloc laminoplasty was performed on 16 patients via a T-saw; most of the patients had intradural spinal tumors. The patients did not need their spinal canals to be enlarged after the intradural procedure had been performed. The follow-up period ranged from 2 to 40 months (mean +/- standard error, 22.6 +/- 3.4 mo). The laminoplasty was performed from the upper cervical to the sacral regions, although the most frequently operated level was the lower thoracic level. Two-level laminoplasty was performed in 12 patients, and three-level laminoplasty was performed in four. The laminoplasty was done safely and without any complications, except in one patient, who experienced thoracic root injury from a T-saw that was accidentally inserted anterior to the roots. No spinal column deformity or sinking of the replaced laminar flap was noted during the follow-up period; patients were assessed at follow-up via radiographs or computed tomographic scans. Computed tomographic scans obtained later indicated that bony fusion occurred at the cutting edges 1.0 to 4.0 months after surgery (mean, 1.90 +/- 0.34 mo). CONCLUSION: Simple en bloc laminoplasty performed with a T-saw is a useful, safe procedure that can be used to reconstruct the posterior spinal elements throughout the whole spinal region after the intradural procedure has been performed.

Recurrence of a neurenteric cyst with malignant transformation in the foramen magnum after total resection. Case report.

A 53-year-old man presented with recurrence of a neurenteric cyst with malignant transformation in the foramen magnum 3.5 years after total resection of the original tumor had been reported. For 2 years following the initial surgery, the patient had been in good condition, but then underwent ventriculoperitoneal shunt placement for intracranial hypertension. At the time there was no evidence of recurrence of the tumor on magnetic resonance (MR) images. One and one-half years later, he presented with headache and anorexia. A massive recurrent tumor was identified on MR images. The tumor was severely adhesive to the brainstem, cranial nerves, and vessels, allowing only partial resection. Histological examination of tumor specimens obtained during the first and second craniotomies indicated a malignant change from a typical neurenteric cyst with a one-layer epithelium in the first specimen to an adenocarcinoma with papillary proliferation in the second. The results of various immunohistochemical studies of the first specimen were typical of those of a neurenteric cyst. The second specimen displayed stronger staining of carbohydrate 19-9 and carcinoembryonic antigens than the initial specimen. The percentage of Ki-67 antigen (MIB-1)-positive cells increased from 0% in the first specimen to 6.7% in the second. To the authors' knowledge this is the first case in which malignant transformation has been demonstrated after total resection of a neurenteric cyst in the foramen magnum.

Percutaneous microcompression of the trigeminal ganglion for elderly patients with trigeminal neuralgia and patients with atypical trigeminal neuralgia.

Percutaneous microcompression of the trigeminal ganglion (PMTG) was performed in nine elderly patients (> 70 years) with trigeminal neuralgia and six patients with atypical neuralgia under short-acting anesthesia using propofol. Two patients had postherpetic neuralgia and two had postoperative neuralgia following removal of a posterior fossa neurinoma. Four patients had recurrent neuralgia following microvascular decompression (MVD). PMTG provided complete relief in 10 patients and the other five patients reported at least 50% improvement. No major complications occurred. PMTG is effective for typical trigeminal neuralgia in elderly patients, patients with atypical trigeminal neuralgia, and patients with recurrence after MVD.

Protein kinase inhibition by fasudil hydrochloride promotes neurological recovery after spinal cord injury in rats.

OBJECT: In Japan fasudil hydrochloride (HA1077), a protein kinase inhibitor, is widely administered to prevent vasospasm in patients after subarachnoid hemorrhage. The effects of fasudil on experimental spinal cord injury (SCI) were investigated and compared with those obtained using methylprednisolone. METHODS: Spinal cord contusion was induced in rats by applying an aneurysm clip extradurally to the spinal cord at T-3 for 1 minute. After injury three groups of rats were treated with intravenously administered saline (control), intraperitoneally administered fasudil (10 mg/kg), or intravenously administered methylprednisolone (four 30 mg/kg injections). Neurological recovery was evaluated periodically over 1 month by using a modified combined behavioral scale and histopathological examination. Leukocyte infiltration near the injury site was evaluated by measuring myeloperoxidase (MPO) activity at 24 hours. Spinal cord blood flow was measured at intervals up to 3 hours after injury by using laser Doppler flowmetry. In rats in the fasudil-treated group significant improvement in modified combined behavioral score was demonstrated at each time point, whereas in the methylprednisolone-treated rats no beneficial effects were shown. In the fasudil-treated group, reduction of traumatic spinal cord damage was evident histologically in the caudal portion of the injured areas, and tissue MPO activity in tissue samples was reduced. Spinal cord blood flow was not significantly different between fasudil-treated and control group rats. CONCLUSIONS: Fasudil hydrochloride showed promise of effectiveness in promoting neurological recovery after traumatic SCI. Possible mechanisms of this effect include protein kinase inhibition and decreased infiltration by neutrophils.

Clinical safety and performance of Sugita titanium aneurysm clips.

BACKGROUND: In spite of advantages for neuro-imaging, titanium aneurysm clips are not yet chosen for routine use for clipping of intracranial aneurysms, probably because their reliability has not been demonstrated in large numbers of cases. We assess reliability and safety of Sugita titanium aneurysm clips for routine clinical use in a large number of operated cases. METHOD: Intra-operative performance and safety of Sugita titanium aneurysm clips were evaluated in 347 patients in our institutions. Aneurysms in 261 patients had ruptured: 86 patients had unruptured aneurysms. RESULTS: A total of 441 clips of 52 different types were used. No early or delayed complications occurred in relation to the titianium clips, such as deformity or slippage of a clip. Patient outcome according to the Glasgow Outcome Scale was similar to that when conventional cobalt-based aneurysm clips were used. INTERPRETATION: Reliability and safety of Sugita aneurysm clips were demonstrated in a large number of patients. The clips are suitable for routine use in aneurysm surgery.

[Intramedullary spinal cord metastasis associated with hemorrhage: a case report].

A rare case of intramedullary spinal cord metastasis associated with hemorrhage was reported. A 74-year-old man had a subacute onset of paraparesis. He became almost paraplegic within a few days. MRI revealed an intramedullary spinal lesion in the epiconus at the Th 11 and Th 12 level, but spinal angiography did not show any abnormality. Since repeated MRI showed enlargement of the lesion, surgery was performed under the diagnosis of an intramedullary spinal cord tumor. Under general anesthesia, a midline myelotomy of about 3 cm was performed and a grayish, elastic and circumscribed tumor as well as a liquefied hematoma in the caudal part was observed. Both the tumor and the hematoma were removed almost totally. The patient's paraparesis improved slightly after surgery. The histological diagnosis was adenocarcinoma. The primary source was unknown, but multiple small metastatic tumors were found in the lung, liver and brain, etc. Hemorrhage from intramedullary spinal cord metastasis is extremely rare with only 6 reported cases in the recent literature. Rapid deterioration of symptoms caused by the hematoma may make the diagnosis more difficult. Indication of surgical treatment should be carefully determined because prognosis of intramedullary spinal cord metastasis is generally very poor.

Elevation of nitric oxide metabolites in the cerebrospinal fluid of patients with moyamoya disease.

BACKGROUND: To investigate whether nitric oxide (NO) contributes to formation of abnormal collateral circulation in patients with moyamoya disease. METHODS: Cerebrospinal fluid (CSF) samples were obtained from the subarachnoid space of the Sylvian fissure during combined bypass surgery for moyamoya disease and kept frozen until NO metabolites, nitrate and nitrite, were measured using a Griess method. RESULTS: Compared with control CSF obtained from 18 patients with hemifacial spasm, unruptured aneurysm, etc., concentrations of NO metabolites in 26 CSF samples of 18 patients with moyamoya disease were significantly higher (mean +/- SE; 17.6 +/- 1.2 vs. 10.5 +/- 1.0 microM, p < 0.01). In eight patients, the CSF samples from both the first and second operation could be obtained. NO metabolite concentrations (20.5 +/- 2.3 microM) in CSF obtained from the first surgery decreased to 15.7 +/- 1.8 microM (p < 0.01) in CSF obtained from the second, contralateral procedure. The cases of moyamoya disease with greater development of moyamoya vessels at angiographic stage 3 and 4 tended to show higher concentrations of NO metabolites than cases at earlier or later stages with a few moyamoya vessels. INTERPRETATION: Nitric oxide concentrations in CSF are chronically elevated in moyamoya disease, probably reflecting development of abnormal collateral circulation. i.e. moyamoya vessels. Vascular bypass surgery can reduce abnormal collateral circulation with reduced production of nitric oxide.

Role of nitric oxide in the control of cerebral microcirculation under physiological and pathological conditions.

Effect of nitric oxide (NO) on vasomotor tone of cerebral parenchymal arterioles was studied in rats. Then, the role of NO was clinically investigated in the pathogenesis of progressive cerebral vascular occlusive disease, moyamoya disease. In rat, the cerebral arterioles, about 30-60 microm in diameter, were dilated by L-arginine, a precursor of NO, at concentrations as low as 0.1 micromol with maximal dilation of 14% at 100 micromol. The arterioles were constricted by N(G)-monomethyl-L-arginine (L-NMMA), a NO synthesis inhibitor. Superoxide dismutase, which seems to protect NO from inactivation, increased sensitivity of L-arginine. Compared with control specimens of cerebral spinal fluid (CSF) obtained from 16 patients, concentrations NO metabolites in the CSF of 23 patients with moyamoya disease were significantly higher. NO metabolites concentrations obtained during initial surgery decreased during a second, contralateral procedure. NO plays an important role in the regulation of basal tone of cerebral parenchymal arterioles and contributes to the increase in collateral circulation in cerebral occlusive disease like moyamoya disease. Vascular bypass surgery can reduce NO metabolites together with abnormal collateral circulation.

Treatment of traumatic atlanto-occipital dislocation in chronic phase.

We report the case of 27-year-old woman who presented with mild neurological deficits with significant anterior dislocation of the atlanto-occipital junction in a chronic phase after initial conservative treatment in another hospital. The importance of early diagnosis and treatment for atlanto-occipital dislocation is emphasized. The dislocation could not be reduced sufficiently either by halo ring cervical traction or surgical procedure 5 months after the accident. Therefore, transoral odontoidectomy for decompression of the medulla, together with the posterior occipitocervical fusion with a titanium loop brace was performed. The patient's symptoms disappeared completely within a few months after the operation. Magnetic resonance imaging findings suggesting soft tissue damage is the key to an early diagnosis and subsequent stabilization of traumatic atlanto-occipital dislocation in the early phase. Transoral decompressive odontoidectomy combined with posterior fusion may be considered for the treatment of irreducible atlanto-occipital dislocation in a chronic phase.

Osteoplastic anterolateral vertebrotomy without fusion for multilevel cervical ossification of the posterior longitudinal ligament.

OBJECTIVE: To introduce a new method for osteoplastic anterolateral vertebrotomy without fusion to resect multilevel cervical ossification of the posterior longitudinal ligament. METHODS: A multilevel vertebral column graft containing portions of the intervertebral discs is cut with a microsurgical saw from the anterolateral part of the vertebra via a thin lateral gutter placed in advance. A sufficiently wide oblique operative field is provided for resection of the ossified ligament with this method, and only a narrow bony defect remains after simple replacement of the vertebral graft. Postoperatively, patients are allowed to walk, usually within 2 to 3 days, wearing simple cervical collars. RESULTS: Twelve patients underwent resection of the ossified ligaments in two to five vertebral bodies. Clinical results were satisfactory except in one patient, who died as a result of a pulmonary embolism that occurred 10 days after surgery. In all of the other patients, the vertebral column grafts were fused within a few months, and there were no graft-related problems. Postoperative lateral radiographs revealed that cervical alignment was preserved, with intervertebral mobility at the operated segment in flexion-extension views. CONCLUSION: The osteoplastic anterolateral vertebrotomy method provided a sufficiently wide operative field for satisfactory resection of multilevel cervical ossification of the posterior longitudinal ligament, simplifying graft replacement and postoperative patient care. The cervical alignment was preserved.

Intra-arterial infusion of fasudil hydrochloride for treating vasospasm following subarachnoid haemorrhage.

In this pilot study we treated cerebral vasospasm in patients with subarachnoid haemorrhage to assess intra-arterial fasudil hydrochloride. We analysed effects of intra-arterial infusion on angiographically evident cerebral vasospasm in 10 patients including 3 with symptoms of vasospasm. Over 10 to 30 min 15 to 60 mg was administered via the proximal internal carotid artery or vertebral artery following standard angiography, without superselective techniques. A total of 24 arterial territories (21 internal carotid, 3 vertebral) were treated. Angiographic improvement of vasospasm was demonstrated in 16 arterial territories (local dilation in 2, diffuse dilation in 14) in 9 patients. In 2 symptomatic patients, intra-arterial fasudil hydrochloride was associated with resolution of symptoms without sequelae. In the third symptomatic patient the benefit of fasudil hydrochloride was only temporary, and a large cerebral infarction occurred. All asymptomatic patients showed no progression of angiographic to symptomatic vasospasm after treatment with intra-arterial fasudil hydrochloride. No adverse effect was encountered.