The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Redox status changes exert critical impacts on necrotic/apoptotic and normal cellular processes. We report here a widely expressed Ca2+-permeable cation channel, LTRPC2, activated by micromolar levels of H2O2 and agents that produce reactive oxygen/nitrogen species. This sensitivity of LTRPC2 to redox state modifiers was attributable to an agonistic binding of nicotinamide adenine dinucleotide (beta-NAD+) to the MutT motif. Arachidonic acid and Ca2+ were important positive regulators for LTRPC2. Heterologous LTRPC2 expression conferred susceptibility to death on HEK cells. Antisense oligonucleotide experiments revealed physiological involvement of "native" LTRPC2 in H2O2- and TNFalpha-induced Ca2+ influx and cell death. Thus, LTRPC2 represents an important intrinsic mechanism that mediates Ca2+ and Na+ overload in response to disturbance of redox state in cell death.

Among the various disorders manifesting dementia, gait disturbance, and urinary incontinence in the elderly population, idiopathic normal pressure hydrocephalus (iNPH) is becoming of great importance. After the publication of the first edition of the Guidelines for Management of Idiopathic Normal Pressure Hydrocephalus in 2004 (the English version was published in 2008), clinical awareness of iNPH has risen dramatically, and the number of shunt surgeries has increased rapidly across Japan. Clinical and basic research on iNPH has increased significantly, and more high-level evidence has since been generated. The second edition of the Japanese Guidelines was thus published in July 2011, to provide a series of timely evidence-based recommendations related to iNPH. The revision of the Guidelines has been undertaken by a multidisciplinary expert working group of the Japanese Society of Normal Pressure Hydrocephalus in conjunction with the Japanese Ministry of Health, Labour and Welfare research project on``Studies on the epidemiology, pathophysiology, and treatment of normal pressure hydrocephalus.'' This English version of the second edition of the Guidelines was made to share these ideas with the international community and to promote international research on iNPH.

Background and Purpose: Microvascular perfusion defects may accompany sustained occlusion and subsequent reperfusion of the middle cerebral artery; however, the nature of such "no-reflow" defects remains unclear.Methods: In the absence of antithrombotic pretreatment, we documented lenticulostriatal microvascular flow integrity following 3-hour middle cerebral artery occlusion and 1-hour reperfusion in a baboon occlusion/reperfusion model by two methods identifying 1) microvascular occlusion and 2) microvascular patency.Results: Microvascular "no-reflow" involved capillaries (vessels of 4.0-7.5 /un diameter) of the lenticulostriatal territory. Capillary reflow included 27-39% of all capillaries in two subjects, indicating a significant reduction of perfusion from normal (2p=0.045). In identical experimental preparations, single polymorphonuclear leukocytes completely occluded 4.7% of microvessels of capillary diameter in randomly selected fields, partially occluded 33% of postcapillary venules, and occluded 40% (four of 10) of capillaries in linear reconstruction along a 110 /*m length. Circumferential contact between polymorphonuclear leukocytes and the luminal endothelial cell membranes was documented, with an intercellular gap of, at most, 160 nm. Fibrin was found with degranulated platelets when the latter were associated with granulocytes, but not with polymorphonuclear leukocytes alone.Conclusions: The rinding of capillary-obstructing polymorphonuclear leukocytes in the microvascular bed following middle cerebral artery reperfusion in focal ischemia in this model satisfies an essential requirement for postulating their role in early microvascular injury and the "no-reflow" phenomenon. {Stroke 1991 ;22:1276-1283)

In patients receiving 0.6 mg/kg alteplase, the outcome and the incidence of sICH were comparable to published data for 0.9 mg/kg. These findings indicate that alteplase, when administered at 0.6 mg/kg to Japanese patients, might offer a clinical efficacy and safety that are compatible with data reported in North America and the European Union for a 0.9 mg/kg dose.

BackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a treatable neurological syndrome in the elderly. Although the magnetic resonance imaging (MRI) findings of tight high-convexity and medial subarachnoid spaces and the ventriculo-peritoneal (VP) shunt with programmable valve are reportedly useful for diagnosis and treatment, respectively, their clinical significance remains to be validated. We conducted a multicenter prospective study (Study of Idiopathic Normal Pressure Hydrocephalus on Neurological Improvement: SINPHONI) to evaluate the utility of the MRI-based diagnosis for determining the 1-year outcome after VP shunt with the Codman-Hakim programmable valve.MethodsTwenty-six centers in Japan were involved in this study. Patients aged between 60 and 85 years with one or more of symptoms (gait, cognitive, and urinary problems) and MRI evidence of ventriculomegaly and tight high-convexity and medial subarachnoid spaces received VP shunt using the height/weight-based valve pressure-setting scheme. The primary endpoint was a favorable outcome (improvement of one level or more on the modified Rankin Scale: mRS) at one year after surgery, and the secondary endpoints included improvement of one point or more on the total score of the iNPH grading scale. Shunt responder was defined by more than one level on mRS at any evaluation point in one year.ResultsThe full analysis set included 100 patients. A favorable outcome was achieved in 69.0% and 80.0% were shunt responders. When measured with the iNPH grading scale, the one-year improvement rate was 77.0%, and response to the surgery at any evaluation point was detected in 89.0%. Serious adverse events were recorded in 15 patients, three of which were events related to surgery or VP shunt. Subdural effusion and orthostatic headache were reported as non-serious shunt-related adverse events, which were well controlled with readjustment of pressure.ConclusionsThe MRI-based diagnostic scheme is highly useful. Tight high-convexity and medial subarachnoid spaces, and enlarged Sylvian fissures with ventriculomegaly, defined as disproportionately enlarged subarachnoid-space hydrocephalus (DESH), are worthwhile for the diagnosis of iNPH. This study is registered with ClinicalTrials.gov, number NCT00221091.

Canonical transient receptor potential (TRPC) channels control influxes of Ca 2؉ and other cations that induce diverse cellular processes upon stimulation of plasma membrane receptors coupled to phospholipase C (PLC). Invention of subtype-specific inhibitors for TRPCs is crucial for distinction of respective TRPC channels that play particular physiological roles in native systems. Here, we identify a pyrazole compound (Pyr3), which selectively inhibits TRPC3 channels. Structure-function relationship studies of pyrazole compounds showed that the trichloroacrylic amide group is important for the TRPC3 selectivity of Pyr3. Electrophysiological and photoaffinity labeling experiments reveal a direct action of Pyr3 on the TRPC3 protein. In DT40 B lymphocytes, Pyr3 potently eliminated the Ca 2؉ influx-dependent PLC translocation to the plasma membrane and late oscillatory phase of B cell receptorinduced Ca 2؉ response. Moreover, Pyr3 attenuated activation of nuclear factor of activated T cells, a Ca 2؉ -dependent transcription factor, and hypertrophic growth in rat neonatal cardiomyocytes, and in vivo pressure overload-induced cardiac hypertrophy in mice. These findings on important roles of native TRPC3 channels are strikingly consistent with previous genetic studies. Thus, the TRPC3-selective inhibitor Pyr3 is a powerful tool to study in vivo function of TRPC3, suggesting a pharmaceutical potential of Pyr3 in treatments of TRPC3-related diseases such as cardiac hypertrophy.Ca 2ϩ signaling ͉ pyrazole compounds ͉ TRPC channels ͉ TRPC3

Background and Purpose-The Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) Japan was organized to determine the safety and clinical efficacy of intraarterial infusion of urokinase (UK) in patients with stroke within 6 hours of onset. Methods-Patients with ischemic stroke presenting within 6 hours of onset and displaying occlusions of the M1 or M2 portion of the middle cerebral artery on carotid angiography were randomized to the UK or control groups. Clinical outcome was assessed by the modified Rankin Scale, National Institutes of Health Stroke Scale, and Barthel Index. Results-The Independent Monitoring Committee recommended stopping the trial after approval of intravenous infusion of recombinant tissue plasminogen activator in Japan. A total of 114 patients underwent randomization, 57 patients in each group. Background characteristics were comparable between the 2 groups. The primary end point of favorable outcome (modified Rankin Scale 0 to 2) at 90 days was somewhat more frequent in the UK group than in the control group (49.1% and 38.6%, OR: 1.54, 95% CI: 0.73 to 3.23) but did not reach a significant level (Pϭ0.345). However, excellent functional outcome (modified Rankin Scale 0 to 1) at 90 days, a preplanned secondary end point, was more frequent in the UK group than in the control group (42.1% and 22.8%, Pϭ0.045, OR: 2.46, 95% CI: 1.09 to 5.54). There were significantly more patients with National Institutes of Health Stroke Scale 0 or 1 at 90 days in the UK group than the control group (Pϭ0.017). The 90-day cumulative mortality was 5.3% in the UK group and 3.5% in the control group (Pϭ1.000), and intracerebral hemorrhage within 24 hours of treatment occurred in 9% and 2%, respectively (Pϭ0.206). Conclusions-The trial was aborted prematurely and the primary end point did not reach statistical significance.Nevertheless, the secondary analyses suggested that intraarterial fibrinolysis has the potential to increase the likelihood of excellent functional outcome.