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Few reports have described the successful treatment of stroke caused by acute vertebral artery (VA) origin occlusion by endovascular surgery. We describe the case of a 68-year-old man who experienced stroke due to left acute VA origin occlusion. Cerebral angiography showed that the left VA was occluded at its origin, the right VA had hypoplastic and origin stenosis, and the basilar artery was occluded by a thrombus. The VA origin occlusion was initially passed through with a 0.035-inch guide wire. An angioplasty was performed, and a coronary stent was appropriately placed. The VA origin was successfully recanalized. A balloon-assisted guiding catheter was navigated through the stent and a thrombectomy was performed using the Penumbra system. The patient's symptoms gradually improved postoperatively. Balloon-assisted catheter guidance through a vertebral artery stent permitted a successful thrombectomy using the Penumbra system and may be useful for treating stroke due to VA origin occlusion.

Macrophages are heterogeneous and include classically activated M1 and alternatively activated M2 macrophages, characterized by pro- and anti-inflammatory functions, respectively. Macrophages that express heme oxygenase-1 also exhibit anti-inflammatory effects. We assessed the anti-inflammatory effects of statin in experimental anti-glomerular basement membrane glomerulonephritis and in vitro, focusing on the macrophage heterogeneity. Rats were induced anti-glomerular basement membrane glomerulonephritis and treated with atorvastatin (20 mg/kg/day) or vehicle (control). Control rats showed infiltration of macrophages in the glomeruli at day 3 and developed crescentic glomerulonephritis by day 7, together with increased mRNA levels of the M1 macrophage-associated cytokines, interferon-γ, tumor necrosis factor-α, and interleukin-12. In contrast, statin reduced the level of proteinuria, reduced infiltration of macrophages in glomeruli with suppression of monocyte chemotactic protein-1 expression, and inhibited the formation of necrotizing and crescentic lesions. The number of glomerular ED3-positive macrophages decreased with down-regulation of M1 macrophage-associated cytokines. Furthermore, statin augmented ED2-positive M2 macrophages with up-regulation of the M2 macrophage-associated chemokines and cytokines, chemokine (C-C motif) Iigand-17 and interleukin-10. Statin also increased the glomerular interleukin-10-expressing heme oxygenase-1-positive macrophages. Statin inhibited macrophage development, and suppressed ED3-positive macrophages, but augmented ED2-positive macrophages in M2-associated cytokine environment in vitro. We conclude that the anti-inflammatory effects of statin in glomerulonephritis are mediated through inhibition of macrophage infiltration as well as augmentation of anti-inflammatory macrophages.

Defect of growth hormone receptor (GHR) is classically known to cause Laron syndrome, characterized by short stature, specific facial appearance, elevated serum growth hormone levels, and decreased insulin-like growth factor I levels. In addition, an increased cardiovascular risk due to elevated plasma total and LDL cholesterol levels marks another feature of the disease. Growth hormone (GH) plays an important role in the regulation of lipoprotein metabolism. GH status was found to be an independent determinant of plasma total cholesterol and triglyceride levels in humans. We studied a total of 207 members of eight-generation extended family of familial hypercholesterolemia (FH) in which affected members presented with various lipoprotein phenotypes. Intra-familial correlation analysis of a modifier effect of a Leu526Ile substitution in GHR gene was carried out among 95 carriers for LDL receptor gene (LDLR) mutation and 112 non-carriers. When plasma high-density lipoprotein cholesterol (HDL-c) levels in the LDLR-mutation carriers were compared, a significant lowering effect of HDL-c was observed with the Leu allele; the values were lowest among Leu/Leu homozygotes (mean ± SD = 37 ± 2 mg/dl), highest in Ile/Ile homozygotes (50 ± 4 mg/dl), and intermediate among Leu/Ile heterozygotes (41 ± 2 mg/dl) (P = 0.0021). The results indicate a significant modification of the phenotype of FH with the defective LDLR allele, by GHR Leu variation in the kindred studied. © 2003 Wiley-Liss, Inc.

The optimal hematocrit (Hctopt) in hemodialysis (HD) patients has yet to be determined based on the etiology and complications of their endstage renal disease (ESRD). To investigate this problem, we compared regional cerebral oxygen supply (rCOS) in diabetic (DM group) and non-diabetic HD patients (non-DM group) with data from subjects without renal disease or DM (control group) Regional cerebral blood flow (rCBF) was measured with single-photon emission computed tomography (SPECT) by the N-isopropyl-p-[123I]-iodoamphetamine (123I-IMP)-autoradiographic (ARG) method, and both the O2content (O2CT) of arterial blood and hematocrit (Hct) were evaluated. Using the regression lines of rCBF vs Hct and O2CT vs Hct, we established a convex curve between rCOS and Hct. The peak of the curve indicates the maximum rCOS (rCOSmax) and Hctoptfor rCOSmax The rCBF in both the DM and non-DM groups was lower than that of the control group at the same Hct level, and the DM group had the lowest values. The rCOSmaxvalues in the DM and non-DM groups were nearly equal, but both were lower than in controls. The Hctopt in the DM group was lower than that in the non-DM group by 6.3%±3.3% Although the difference in Hctoptvalues in the DM and non-DM groups was 6.3%, the rCOSmaxvalues in both groups were nearly equal. This suggests that differences in the Hctoptmay depend on complications or causes of ESRD. The optimal Hct in the DM group was 22.6%±1.9%, and that for the non-DM group was 29.0%±1.8%

The therapeutic efficacy of ozagrel sodium (ozagrel), alone and in combination with heparin, and its therapeutic time window were studied in a photochemically induced thrombotic cerebral infarction rat model. Cerebral artery thrombosis was induced by irradiating the brain with green light through intact skull using rose bengal as the photosensitizing dye. One set of animals was treated immediately after thrombosis with (1) vehicle, (2) 10 mg/kg ozagrel in saline, intravenously (i.v.), (3) 150 U/kg unfractioned heparin, subcutaneously (s.c.), or (4) ozagrel, i.v. plus heparin, s.c. Infarct volume was significantly smaller and edema was reduced in the ozagrel-treated groups compared to the vehicle-treated group; heparin did not convey additional benefit. In another set of animals, rats were given either vehicle or 10 mg/kg ozagrel in saline, i.v., 60 min or 120 min after induction of thrombosis. Ozagrel reduced infarct volume, but its effect diminished with delayed administration. The therapeutic window was determined to be less than 60 minutes after induction of thrombosis.

To date, three loci for autosomal recessive hereditary spastic paraplegia (ARHSP) linked to chromosomes 8p12-q13, 16qter, and 15q13–15 have been characterized. We have clinically characterized 13 Japanese ARHSP families and performed genetic linkage analyses. All 13 families were classified as having the “complicated” form, which manifests with mental impairment and thin corpus callosum. Linkage to the 8p12-q13 and 16qter loci was excluded, although 10 of the 13 families showed marker data consistent with linkage to the 15q13–15 locus. The multipoint LOD score of the 10 families linked to chromosome 15 was above 9.00 in the 3-centimorgan segment flanked by D15S994 and D15S659, with a maximum multipoint LOD score of 9.68 at a position 1.2 centimorgans telomeric from D15S994 to D15S659. We have shown that ARHSP with thin corpus callosum, a subtype of recessive spastic paraplegia, maps to chromosome 15q13–15. Ann Neurol 2000;48:108–112

To date, three loci for autosomal recessive hereditary spastic paraplegia (ARHSP) linked to chromosomes 8p12‐q13, 16qter, and 15q13–15 have been characterized. We have clinically characterized 13 Japanese ARHSP families and performed genetic linkage analyses. All 13 families were classified as having the “complicated” form, which manifests with mental impairment and thin corpus callosum. Linkage to the 8p12‐q13 and 16qter loci was excluded, although 10 of the 13 families showed marker data consistent with linkage to the 15q13–15 locus. The multipoint LOD score of the 10 families linked to chromosome 15 was above 9.00 in the 3‐centimorgan segment flanked by D15S994 and D15S659, with a maximum multipoint LOD score of 9.68 at a position 1.2 centimorgans telomeric from D15S994 to D15S659. We have shown that ARHSP with thin corpus callosum, a subtype of recessive spastic paraplegia, maps to chromosome 15q13–15. Ann Neurol 2000;48:108–112

Abstract: Background. Diabetic nephropathy is one of the major complications in patients with diabetes mellitus. We investigated the urinary excretion of the vitronectin receptor (VNR; integrin αυβ3) to determine whether it would be a useful indicator of diabetic nephropathy. Methods. We measured the urinary excretion of β3 originating from VNR in 217 patients with non-insulin dependent diabetes mellitus (NIDDM; normoalbuminuria; n = 75, microalbuminuria; n = 75, macroalbuminuria; n = 67) and 44 healthy controls by immunoblotting analysis. Immunofluorescence microscopy analysis for VNR was also performed, using urinary sediments from patients with macroalbuminuria as samples. Results. The amount of urinary β3 originating from VNR significantly increased with the development of diabetic nephropathy. Immunofluorescence microscopy revealed the expression of β3 in the urinary sediments of the NIDDM patients. Conclusion. We conclude that urinary VNR level may be a useful index of diabetic nephropathy in NIDDM.

Abstract: We present here a case of variant Gerstmann-Strussler syndrome (GSS) with a codon 105 mutation of the prion protein gene. A 57-year-old woman developed dementia and gait disturbance dissimilar to the spastic paraparesis that is observed in most cases with codon 105 mutation. The clinical course of the disease in this case was 12 years. The brain weighed 900 g, and the frontal lobe, pallidum and thalamus were markedly atrophic. Severe neuronal loss was observed in the deep layer of the frontal and temporal cortices, and fibrillary gliosis and a marked loss of neurons was observed in the globus pallidus, thalamus and substantia nigra. Many amyloid plaques and some ballooned neurons were present in the frontal, temporal and parietal cortices. However, no spongiform changes were seen. The cerebellum was relatively well preserved. Numerous neurofibrillary tangles (NFTs) were recognized in the cerebral cortices, and scattered NFTs were observed in the basal nucleus of Meynert, thalamus, substantia nigra, periaqueductal gray matter, raphe nuclei and locus ceruleus. The case presented here indicates the presence of variations in the pathological findings of cases with codon 105 mutation, and that the formation of cortical and brain stem NFTs might have something to do with the duration of illness and/or the degree of brain tissue destruction that had occurred.

We investigated the hypothesis that bradykinin generation may induce ischemic brain edema in spontaneously hypertensive rats.

We examined the autopsied brains of cases of 6 types of tauopathy: parkinsonism-dementia complex of Guam (PDC), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Pick disease, Alzheimer disease (AD), and myotonic dystrophy together with Guamanian controls. Light microscopy sections of these brains were examined using anti-tau antibodies. Tau-positive fine granules (TFGs) were globe-shaped, and 3 to 6 μm in diameter, were observed predominantly in the frontal white matter in 30 of the 35 patients with PDC. However, no TFGs were found in association with PSP, myotonic dystrophy, Pick disease, AD, or CBD. Western blot analysis of frozen brain tissue taken from the PDC cases revealed that the frontal cortex was hyperphosphorylated and contained 6 tau isoforms (3R + 4R tau). However, in the present study, it was revealed that the novel TFGs in the white matter of patients with PDC was composed of 4R tau. Western blot analysis of sarkosyl-insoluble tau from the white matter of the PDC cases showed 2 major bands of 60 and 64 kDa and one minor band of 67 kDa. After dephosphorylation, these bands resolved into one major band of 4-repeat (4R) tau isoform and 3 minor bands of 3-repeat (3R) and 4R tau isoforms. Moreover, the TFGs observed in cases in which the number of neurofibrillary tangles (NFTs) was higher than the threshold level were not correlated with the presence of cortical NFTs. In conclusion, these novel TFGs were found almost exclusively in PDC brains and could therefore be considered as a characteristic neuropathologic marker of this particular tauopathy. The TFGs were hyperphosphorylated tau-positive structures that may be formed by a different mechanism from that used to produce cortical NFTs.

We investigated by immunohistochemistry the deposition of α-synuclein in the brains of deceased patients with the parkinsonism-dementia complex (PDC) of Guam. Five of 13 PDC brains showed numerous α-synuclein positive neuronal inclusions and abnormal neurites, chiefly in the amygdala. Similar α-synuclein positive lesions were observed, although to a lesser extent, in the entorhinal cortex and the dorsal vagal nucleus. No α-synuclein positive inclusions were observed in motor cortex or locus coeruleus, and only a small number of positive inclusions were found in the Sommer's sector, temporal cortex, or substantia nigra. Some of the α-synuclein positive inclusions were reminiscent of cortical Lewy bodies (LB), but many of those in the amygdala coexisted with tau-positive pretangles and/or neurofibrillary tangles (NFT) within the same neurons. In these neurons, tau-positive shells encapsulated α-synuclein positive central cores or irregularly shaped α-synuclein-positive deposition intermingled with pretangles/NFT. Thus, the present study suggests that a common mechanism may govern aggregation of α-synuclein and tau in the amygdala, and that aggregation of α-synuclein may play some role in the neurodegenerative process of a tauopathy (i.e. PDC) in which Aβ deposition is virtually absent.