Serum retinol levels are associated with brain volume loss in patients with multiple sclerosis.

BACKGROUND: Although predicting future brain volume loss (BVL) in patients with multiple sclerosis (MS) is important, studies have shown only a few biomarkers that can predict BVL. OBJECTIVES: The aim of this study is to elucidate the association between longitudinal BVL and serum biomarker candidates. METHODS: This single-center, retrospective, observational study intended to cover MS patients during January 2008 to March 2016. Patients who underwent brain MRI two times at intervals of >24 months and had a blood test to measure biomarker candidates at the time or within three months of the MRI scan were included. Evaluation of brain volume was performed by using SIENAX and SIENA in the FMRIB software library. RESULTS: Twenty-three patients with MS were included in this study. We found that serum retinol binding protein (RBP) levels were significantly correlated with percentage brain volume change (PBVC) (p = 0.0079). Furthermore, best subset selection of multiple linear regression models identified baseline normalized brain volume and serum RBP as the best predictors of PBVC. CONCLUSIONS: Our study shows that lower serum retinol levels are associated with greater longitudinal BVL and that serum RBP and can be a predictor of BVL.

Spinal cord ring enhancement in patients with neuromyelitis optica.

OBJECTIVES: Clinical and pathological significance of gadolinium (Gd)-enhancing pattern on magnetic resonance imaging (MRI), including ring enhancement (RE), is well documented in multiple sclerosis but not in neuromyelitis optica (NMO), especially in the spinal cord. The purpose of this study is to examine the prevalence of spinal cord RE in NMO and to determine the association between clinical characteristics and spinal cord RE. MATERIALS AND METHODS: We retrospectively examined Gd-enhanced spinal cord MRI scans, during the acute phase, in patients with anti-aquaporin 4-positive NMO, including NMO spectrum disorder. We then analysed their clinical features and MRI imaging characteristics of spinal cord lesions. RESULTS: Of the 30 patients with NMO, we enrolled 12 patients with 16 Gd-enhanced spinal cord MRI scans in this study. Five scans revealed RE (31.2%). Male ratio, as well as myelin basic protein (MBP) levels, in the cerebrospinal fluid (CSF) of patients with RE was significantly higher than those of patients without RE (P = 0.018, P = 0.026, respectively). CONCLUSIONS: Spinal cord RE is common in patients with NMO. Higher MBP levels in the CSF of patients with RE can be associated with a higher degree of myelin damage.

Acute multiple brain infarction in large-artery atherosclerosis is associated with hyperhomocyst(e)inemia.

OBJECTIVES: Although hyperhomocyst(e)inemia had been proven to be a potent risk factor for ischemic stroke, it is still controversial which subtype of stroke is associated with hyperhomocyst(e)inemia. The aim of this study was to clarify the association between plasma homocyst(e)ine (Hcy) levels and stroke subtypes according to TOAST classifications based on MRI findings. METHODS: We prospectively recruited 124 consecutive first-ever ischemic stroke patients hospitalized in Toride Kyodo General Hospital. Each patient underwent brain MRI including diffusion-weighted imaging (DWI) and was evaluated for total plasma Hcy levels in addition to routine laboratory tests. RESULTS: Of the 93 patients enrolled in this study, 19 were subtyped with large-artery atherosclerosis with acute multiple brain infarction [LA-AMBI(+)], 13 with LA-AMBI(-). Patients with LA-AMBI(+) showed significantly higher plasma Hcy levels than those with LA-AMBI(-). Moreover, for LA-AMBI, the plasma Hcy level was associated with an OR of 1.3 (95% CI 1.06-1.71, P=0.017) per 1 mumol increase in concentration, and 1.4 (95% CI 1.04-1.77, P=0.025) after adjustment for age, sex and serum cholesterol levels. CONCLUSION: In the subset of patients with LA strokes, those with high Hcy levels are more likely to have AMBI than those without elevated Hcy levels possibly due to plaque instability.

Three-dimensional rotation venography using the digital subtraction angiography unit with a flat-panel detector: usefulness for the transtemporal/transtentorial approaches.

We obtained the venograms using the two-dimensional digital subtraction angiography (2D DSA) images and three dimensional rotation venography (3D RV) images and investigated the potential usefulness of the 3D RV compared with venograms of 2D DSA using the newly developed three-dimensional rotation angiography unit with a flat-panel detector (FPD). This study included 26 sides (11 left, 15 right) in 20 cases (4 males and 16 females) who underwent radiographic examination for management of intracranial tumors and vascular diseases between May 2003 and December 2003. Each patient underwent diagnostic angiography performed on a DSA unit with a FPD. In all patients, the 2D DSA images, including anteroposterior view and lateral view of the carotid artery, were obtained in two stereoscopic views. The 3D RV was used to produce volume-rendered images. Two neuroradiologists investigated the venous configuration of 3D RV compared with that of 2D DSA about the relationship of the venous drainage system on the temporal lobe according to Guppy et al.'s classification. Twenty-four sides of the 26 sides enabled the precious visualization on 3D RV images. In investigation of 2D DSA, 9 sides (37.5%) were classified into type A, 13 (54.2%) into type B, two (8.3%) into type C, and no sides into types D, E, and F. In investigation of 3D RV images, 10 sides (41.7%) were classified into type A, 9 (37.5%) into type B, 1 (4.2%) into type C, 2 (8.3%) into type E, and 2 (8.3%) into type F. Seven of 24 sides demonstrated discrepancy in results between 2D DSA and 3D RV. The 3D RV could be performed by setting the adequate delay in between the injection of the contrast material and starting time of third rotation to acquire the opacified images. In Guppy et al.'s classification, the 3D RV images could demonstrate the precious venous drainage including the venous lakes with use of multiple views and variable reconstruction compared with 2D DSA. Our DSA system with FPD could provide good 3D RV images. These images are very useful for the skull-base surgery because we can understand the three-dimensional vascular anatomy preoperatively.

[MR hydrography of the abdomen: technical consideration of data acquisition and future prospects for clinical applications].

Recent advances in MR hydrography have enabled various clinical applications in the areas of abdominal and pelvic disorders, for example, MR cholangiopancreatography (MRCP), MR urography(MRU), and MR hydrography of the fetus. Although the two-dimensional(2D) single-slice method provides excellent information as to the global relationship between lesions and various anatomical structures, small lesions or detailed anatomical characteristics may not be visualized owing to the partial volume effect. Source images of the 2D multislice method are most suitable for the detection of small lesions and detailed evaluation of anatomical structures as "tomographic imaging", while the three-dimensional(3D) method is useful in obtaining data sets for 3D imaging. MR hydrography is a promising method for the noninvasive evaluation of various abdominal disorders, and it has the potential to play new roles in various anatomical regions. However, knowledge of the proper indications is essential for successful clinical application.

Treatment of restenosis after percutaneous transluminal angioplasty for internal carotid artery stenosis.

The efficacy of repeated percutaneous transluminal angioplasty (PTA) and carotid endarterectomy (CEA) was examined in patients with restenosis after PTA for carotid stenosis. After percutaneous transluminal angioplasty (PTA) for 63 cases of internal carotid stenoses 13 cases of restenosis appeared. They were treated by PTA or carotid endarterectomy. The treatment was chosen by the patient after explanation of each treatment. We initially treated seven patients by repeat PTA and six by carotid endarterectomy. The degree of stenosis improved from 82% to 30% on average after repeated PTA. However, one patient in the PTA group had restenosis, and carotid endarterectomy was then performed. The other cases also had restenosis and were treated by PTA. The six cases treated by carotid endarterectomy were successfully treated without difficulty. The success rate of PTA was 5/7 (71%) in the restenosis cases. Patients with a greater residual stenosis after initial PTA had significantly more frequent restenosis. Repeat PTA and CEA both appeared effective treatment for restenosis after initial PTA, although PTA had a restenosis rate similar to that of initial PTA.

Promotion of survival and regeneration of nigral dopamine neurons in a rat model of Parkinson's disease after implantation of embryonal carcinoma-derived neurons genetically engineered to produce glial cell line-derived neurotrophic factor.

OBJECT: The P19 embryonal carcinoma-derived cell line consists of undifferentiated multipotential cells, which irreversibly differentiate into mature neurons after exposure to retinoic acid (RA). In the present study, the authors genetically engineered P19 cells to produce glial cell line-derived neurotrophic factor (GDNF), and grafted the cells in a rat model that had been rendered parkinsonian. METHODS: Undifferentiated P19 cells were grown in vitro and transduced with GDNF complementary DNA. The level of GDNF released from the transduced cells was measured using an enzyme-linked immunosorbent assay, and its neurotrophic activities were assessed by testing the effects on rat embryonic dopamine (DA) neurons in culture. After having been exposed to RA for 48 hours and allowed to differentiate into postmitotic neurons, the GDNF gene-transduced cells were implanted into the midbrain of immunosuppressed rats. A unilateral nigrostriatal lesion was then induced by intrastriatal infusions of 6-hydroxydopamine. Immunohistochemical analyses performed 4 weeks postgrafting revealed that the GDNF-producing cells expressed several neuronal markers without evidence of overgrowth. The grafts expressed GDNF protein and prevented the death of nigral DA neurons. Furthermore, the GDNF-producing cells implanted 4 weeks after nigrostriatal lesions restored the expression of tyrosine hydroxylase in injured DA neurons and induced their dendritic sprouting. CONCLUSIONS: The results indicate that the P19 cell line transduced with the GDNF gene can stably secrete functional levels of GDNF, even after being converted to postmitotic neurons. Because it is has been established that GDNF exerts trophic effects on DA neurons, the means currently used to deliver GDNF into the brain could be a viable strategy to prevent the death of nigral DA neurons in cases of Parkinson's disease.

Dephosphorylation-induced decrease of anti-apoptotic function of Bcl-2 in neuronally differentiated P19 cells following ischemic insults.

It is known that Bcl-2 has a protective effect against neuronal ischemia. Some reports speculate anti-apoptotic function of Bcl-2 depends not on the expression level but on the phosphorylation state. We found induction of apoptosis and CPP32 activation by energy impairment (3-nitropropionic acid (3-NP)-treatment or glucose-deprivation) in the neuronally differentiated P19 cells. Time course study of cell viability following ischemic insults showed that the number of viable cells decreased along with the increase in the amount of dephosphorylated Bcl-2 without obvious quantitative alteration of the protein. Then, we generated differentiated P19 cells overexpressing wild-type Bcl-2 (P19/wt. Bcl-2) or phosphorylation-negative Bcl-2 mutant (P19/mut.Bcl-2), in which alanine was substituted for serine 70. When the cell viability was examined within 24 h, P19/mut.Bcl-2 was more vulnerable to energy impairment as compared with P19/wt.Bcl-2. In addition, overexpression of wild-type Bcl-2 inhibited DNA laddering and CPP32 activation induced by the insults, while that of mutant Bcl-2 did not. These findings suggest that the phosphorylation state, as well as the expression level, of Bcl-2 plays an important role to modulate its protective effect against ischemic insults.

Presumed intraventricular meningioma treated by embolisation and the gamma knife.

A 58-year-old woman with a presumed incidentally discovered meningioma in the left lateral ventricle was treated by superselective embolisation and gamma knife therapy. The diameter of the tumour was 40 mm, and its main feeding artery was the left lateral posterior choroidal artery. This vessel was embolised with microcoils. At 8 months following embolisation, the diameter of the tumour had decreased and was stable. The gamma knife was chosen as an adjuvant therapy for the further control 13 months after embolisation. Embolisation and gamma knife therapy may be an alternative treatment for meningiomas where surgical resection appears difficult.

Enhancement of cisplatin sensitivity in high mobility group 2 cDNA-transfected human lung cancer cells.

To elucidate the role of high mobility group 2 protein (HMG2) in cis-diamminedichloroplatinum (II) (cisplatin, CDDP) sensitivity, we constructed a human HMG2-transfected human non-small cell lung cancer cell line, PC-14/HMG2. The HMG2 mRNA expression level was approximately twice those of parental PC-14 and mock-transfected PC-14/CMV. Gel mobility shift assay revealed a CDDP-treated DNA-protein complex in the nuclear extract of PC-14/HMG2, which was not found in the extracts of PC-14 and PC-14/CMV. This complex formation was subject to competition by CDDP-treated non-specific salmon sperm DNA, indicating that ectopic HMG2 recognizes CDDP-damaged DNA. PC-14/HMG2 showed more than 3-fold higher sensitivity to CDDP than PC-14 and PC-14/CMV. The intracellular platinum content of PC-14/HMG2 after exposure to 300 microM CDDP was 1.1 and 1.5 times that of PC-14 and PC-14/CMV, respectively. Cellular glutathione levels were not different in these cell lines. Repair of DNA interstrand cross-links determined by alkaline elution assay was decreased in PC-14/HMG2. These results suggest that HMG2 may enhance the CDDP sensitivity of cells by inhibiting repair of the DNA lesion induced by CDDP.

Endovascular treatment for internal carotid stenoses. long-term follow-up results and overall complications.

Seventy four cases of internal carotid stenoses greater than 60% were treated by PTA and/or stenting 86 times. Sixty one cases of cervical ICA stenosis were treated 71 times. 11 cases of high cervical - intracranial ICA stenosis were treated 13 times. Two cases of ICA dissection were treated by stent deployment. Stenotic ratio reduced from 79% to 29% in cervical ICA stenosis and 71 % to 32% in high cervical to intracranial ICA stenosis in average. Morbidity related to PTA and/or stenting was 2/74 (2.7%) and mortality was 0%. One was an ischemic complication and the other was a hemorrhagic complication due to hyperper fusion. Restenosis (stenosis greater than 70%) rate was 32%. Asymptomatic cerebral embolism were found in three cases (4.2%) on angiogram immediately after PTA and/or stenting. The complication rate related to PTA and/stenting was low but asymptomatic emboli were found in three cases. Considering these results, the indication for PTA and/stenting should be restricted to patients with high risk group, such as cases with high medical risks or difficult CEA cases, if appropriate protective systems for cerebral emboli were not available.

Endovascular treatment for vertebral dissecting aneurysm presenting with subarachnoid hemorrhage.

We report results and problems of the endovascular treatment in 12 cases of intradural vertebral dissecting aneurysm presenting with subarachnoid hemorrhage. There were four complications related to interventional procedure and conventional angiography. In three patients (25%), VDAs ruptured immediately after injection of contrast media or hypertension during the interventional procedure, which caused respiratory arrest. In a case of bilateral VA dissection (8%), after proximal VA occlusion had been performed for unilateral VDA, contralateral dissection extended to the basilar artery resulting in brain stem infarct. We suggest that the incidence of rebleeding of VDA during angiography and embolization is higher than that of usual saccular aneurysms. Careful injection of contrast media and strict blood pressure control seems to be more important to prevent rebleeding in VDAs than intracranial saccular aneurysms. Since unilateral VA occlusion may extend contralateral dissection in a case of bilateral VA dissection, it is necessary to check contralateral VA dissection before VA occlusion.

Percutaneous transluminal angioplasty for intracranial arteriosclerotic lesions.

We report 17 cases of intracranial arterial stenosis treated by percutaneous transluminal angioplasty (PTA), including 9 on the intracranial internal carotid (ICA), 4 on the middle cerebral (MCA), and 4 on vertebrobasilar artery (VBA) system. All patients had ischaemic brain symptoms and stenoses of more than 60% (calculated angiographically). We treated four patients by PTA for residual stenoses after thrombolysis for acute occlusion. We used PTA balloon catheters 2.0-3.5 mm in diameter for all procedures. As a rule, the balloon was inflated for 1 min at 6 atm. All arteries were successfully dilated (stenosis less than 50%) except for one treated by PTA for residual MCA stenosis after thrombolysis. The patient died of a massive infarct due to MCA reocclusion caused by arterial dissection. Stenosis recurred in 4 of 16 patients. Repeat PTA was successfully carried out in these cases. However, stenosis recurred in one of these patients 3 months after PTA, but the patient is being followed because he is asymptomatic. PTA of intracranial arteries is effective, but its indications should be based strictly on potential risks, such as acute occlusion derived from arterial dissection.

Carotid endarterectomy and simultaneous percutaneous transluminal angioplasty for tandem internal carotid stenoses.

We treated three patients with tandem internal carotid stenoses in single procedures including carotid endarterectomy (CEA) for the proximal stenosis and percutaneous transluminal angioplasty (PTA) for the distal stenosis. We devised a Y-shaped shunt tube for the CEA, through which a balloon catheter was introduced to perform PTA guided by mobile digital subtraction angiography. No cerebrovascular events occurred during follow-up. Our approach avoids the risk of a second procedure while effectively treating tandem stenoses.

The C-terminal domain of p53 catalyzes DNA-renaturation and strand exchange toward annealing between intact ssDNAs and toward eliminating damaged ssDNA from duplex formation through preferential recognition of damaged DNA by a duocarmycin.

The C-terminal domain of p53 may bind single-stranded (ss) DNA ends and catalyze renaturation of ss complementary DNA molecules, suggesting a possible direct role for p53 in DNA repair (Proc. Natl. Acad. Sci. USA, 92, 9455-9459, 1995). We found that DU-86, a duocarmycin derivative which alkylates DNA, bound ssDNA and enhanced the DNA binding activity of the p53 C-terminus. DU-86 weakened p53-mediated catalysis of complementary ssDNA renaturation. p53 C-terminus catalyzed DNA strand transfer toward annealing between intact ssDNAs and toward eliminating DU-86-damaged ssDNA from duplex formation. These results suggest that p53, via the C-terminal domain, may play a direct role in DNA repair by preferential recognization and elimination of damaged DNA.

Treatment of Restenosis after PTA for Internal Carotid Stenosis.

SUMMARY: Thirteen cases of restenosis occurred after percutaneous transluminal angioplasty (PTA) in 63 cases of internal carotid stenoses. They were treated by PTA or carotid endarterectomy. The patients were sufficiently informed of each treatment. Seven of them were initially treated by repeated PTA. The stenosis ratio improved from 82% to 30% after repeated PTA on average. However, one case in the PTA treated group resulted in restenosis and then carotid endarterectomy was performed. The other case also caused restenosis and was treated by PTA. Six cases were initially treated by carotid endarterectomy and all cases were successfully treated without difficulty. The success rate of the PTA was 2/7 (29%) in restenosis cases. One case causing re-restenosis had severe calcification in the arterial wall. PTA was thought to be effective for the restenosis cases after initial PTA if the arterial calcification was not severe.

Clinical Results and Problems in Embolization for Intracranial Aneurysms using Electrically Detachable Coils.

SUMMARY: Nineteen patients with intracranial aneurysm were treated using electrically detachable coils (GDC or IEDC) and angiographic results and complications were assessed. In 18 aneurysms treated by endosaccular occlusion, 11 (61%), 3 (17%) and 4 (22%) resulted in complete occlusion, neck remnant and dome filling, respectively. Neither haemorrhagic nor thromboembolic complications occurred in 19 patients. Embolization using electrically detachable coils seemed to be a safe and useful procedure without complications, but we should give attention to avoiding complications and incomplete occlusion in particular in a case of 1) wide-necked, 2) small (< 3 mm) or 3) complex- shaped aneurysms.

The strategy of dural arteriovenous fistula with isolated sinus.

SUMMARY: We treated 7 cases of dural arteriovenous fistulas (dAVF) with isolated sinus by transvenous direct embolization. The fistulas located in the transverse-sigmoid sinus in 5 cases, superior sagittal sinus in 1 case and transverse-sigmoid and superior sagittal sinus in 1 case. The initial symptoms were generalized convulsion in 2 cases, disturbed consciousness in 1 case, tinnitus in 2 cases and transient ischemic attack in 2 cases. We performed sinus packing with coils in all cases following transarterial embolization. All patients improved neurologically after the treatments and AVFs completely disappeared in all cases.

Vertebral arteriovenous fistula treated by embolization technique. Report of three cases.

SUMMARY: Three patients with vertebral arteriovenous fistulae are described. Transarterial embolization by microcoils and balloons was used in each case and the fistula was completely occluded in one case immediately after embolization. Another two cases with partial obliteration of the fistula were followed and showed complete occlusion of the fistula after a one year follow-up. After embolization of the fistula, each patient improved in clinical signs and symptoms and showed no complications. Transarterial embolization for vertebral arteriovenous fistula is a safe and effective treatment.