Stimulation-Dependent Intraspinal Microtubules and Synaptic Failure in Alzheimer's Disease: A Review

There are many microtubules in axons and dendritic shafts, but it has been thought that there were fewer microtubules in spines. Recently, there have been four reports that observed the intraspinal microtubules. Because microtubules originate from the centrosome, these four reports strongly suggest a stimulation-dependent connection between the nucleus and the stimulated postsynaptic membrane by microtubules. In contrast, several pieces of evidence suggest that spine elongation may be caused by the polymerization of intraspinal microtubules. This structural mechanism for spine elongation suggests, conversely, that the synapse loss or spine loss observed in Alzheimer's disease may be caused by the depolymerization of intraspinal microtubules. Based on this evidence, it is suggested that the impairment of intraspinal microtubules may cause spinal structural change and block the translocation of plasticity-related molecules between the stimulated postsynaptic membranes and the nucleus, resulting in the cognitive deficits of Alzheimer's disease

Computational Fluid Dynamics in Unruptured Intracranial Aneurysms

Introduction and Objective: Intracranial aneurysm, also known as brain aneurysm, is a cerebrovascular disorder in which weakness in the wall of a cerebral artery causes a localized dilation or ballooning of the blood vessel. There is no objective way, device or tools, of predicting rupture of aneurysm so far. Computational fluid dynamics (CFDs) was proposed as a tool to identify the rupture risk. Purpose of study: To reveal the correlation of CFD findings with intraoperative microscopic findings and prove the relevance of CFDin the prediction of rupture risk and in the management of unruptured intracranial aneurysms. Subjects and Methods: A prospective cohort study was conducted inNeurosurgery department of Fujita Health University Banbuntane Hotokukai Hospital, Nagoya, Japanduring a 3?month period in 2018,from January to March, Ten patientswere diagnosed unruptured intracranial aneurysms (UIA). In diagnosis computed tomography (CT) angiogram, CFD and digital subtraction angiogram were included. Intraoperatively microscopic examination of the aneurysm wall was carried out and images recorded. The correlation between microscopic dome morphology and CFD information was performed. Results: Nine cases were found intraoperatively to have a higher risk of rupture based on the thinning of the wall. One cases had an atherosclerotic wall. All cases had low wall shear stress (WSS). In 90 % of cases Low WSS was able to predict the potency rupture risk in the near future. Conclusions: This study of CFD and its correlation with intraoperativefindings of the aneurysm suggested that low WSS of the aneurysm wall is associated with thin wall aneurysm and hence increased risk of aneurysm rupture. Thus CFD can be used to predict the risk of rupture of unruptured aneurysm and for planning of its treatment

Long term prognosis of ventriculoatrial shunt for idiopathic normal pressure hydrocephalus in the elderly

Objective: A retrospective study was conducted to access the long-term prognosis of inserting the Ventriculoatrial (VA) shunt in the elderly for the idiopathic normal pressure hydrocephalus (iNPH). Material and Methods: Retrospective data is collected from April 2004 to August 2015, and 1065 patients were selected. Patients who underwent surgical examination or surgery in suspected iNPH were included. Tap test is done in all cases and found to be effective for 968 cases and 656 VA shunts for 614 cases. Out of 614 cases there are 440 cases in which patient age were over 75 years. Of these 440 cases only 141 cases were able to observe 03 years or more after the surgery, 37 deaths and 05 cases with survival and unknown prognosis were found among them. So we analyzed this group mainly in 99 cases that the prognosis after 03 years was known. We access the outcome of VA shunt by the modified Rankin scale (mRS), iNPH grading scale (iNPHGS) and complications in the operative 656 cases and in 03 years follow up of 141 patients. Results: Of 141, there are 78 males and 63 females. Age at the time of VA shunt insertion was 81.5±4.1 years and age at final follow-up was 85.2±4.4 years. The proportion of patients who achieved a favorable outcome by complications was 97.9% in 03 years follow-up period and 87.7% in which follow-up is less than 03 years. At the time of VA shunt insertion out of 141, 57 patients lies between 75-79 years, 57 between 80-84, 24 between 85 to 89, and only 03 were found to be 90 years or more. At the time of final follow-up at 03 years, 15 patients lies between 75 to 79 years, 56 between 80 to 84 years, 57 between 85 to 89 years and 23 patents were found to be 90 years or greater. 70 cases or almost 50% exceeded 85 years. At the time of VA shunt 1, 11, 39, 51, 36, 3, 0 patients were in 0 to 6 modified Rankin Scale Score respectively and at 03 years follow-up 8, 19, 32, 29, 9, 2, 37 were in 0 to 6 mRS respectively. Comparison of the study is done with SIPHONI study on VP shunt and LP shunt. Conclusion: Patients suspected of having idiopathic normal pressure hydrocephalus were treated by VA shunt and found no significant difference in serious adverse effects. This study shows that VA shunt is an effective choice for iNPH in the late elderly population, but it needs more randomized control trial to establish its efficacy

High Flow Bypass for Cavernous Carotid Aneurysms

Introduction and objective: High flow extracranial to intracranial (HF EC–IC) cerebral revascularisation may be necessary in the management of complex skull base tumours and intracranial aneurysms. Bypass grafting can be considered high flow when a radial artery or the saphenous vein is interposed between the extracranial carotids arteries and intracranial vessels. The decision as to whether to use a low flow or high flow bypass is determined by the anticipated cerebral blood flow needed and the availability of a supply source. In this study, we have used this method to bypass for two cases of giant aneurysms of the cavernous sinus part of the ICA. Methods: Two cases of giant ICE aneurysm not amenable to clipping or coiling were taken since 2016. Patients were treated in Neurosurgery department of Fujita Health University Banbuntane Hotokukai Hospital, Nagoya, Japan. During bypass surgery, intraoperative methods were used to determine the patency of the graft artery: Doppler sonography and indocyanine green (ICG) Dual-Image Videoangiography (DIVA). Results: Two patients with symptomatic large and giant cavernous carotid aneurysms were evaluated as not amenable for clipping or endovascular treatment due to location and size of the aneurysm and associated high morbidity risk with these treatment options. In both cases radial artery graft was used for high-flow EC-MCA bypass and proximal internal carotid artery was ligated. Additionally, for high-flow bypass was performed superficial temporal artery (STA) to middle cerebral artery (MCA) bypass. DIVA, ICG and Doppler sonography were used multiple times to assess the patency of graft artery. In one case there was not complete ligation of the IC after postop DSA, the next day was performed reintervention to completely ligate IC. Postoperative course was uneventful, there were no mortality or morbidity. Follow-up showed good recovery and postoperative CT and DSA showed complete occlusion of ligated IC and patent functioning arterial graft. Conclusions: Cavernous carotid aneurysms (CCA) are rare and pose considerable challenges in management. A bypass procedure before parent artery occlusion, preferable to reduce the risks of postocclusion stroke. Intraoperative Doppler sonography and DIVA makes it easy to check the patency of the graft. DIVA is superior over Doppler or ICG in terms of better visualization of related anatomical structures

Real-time patency verification during clipping aneurysm and STA-MCA by-pass with dual-image videoangiography

The dual-image videoangiography (DIVA) is a new tool which helps identify ves-sels and surrounding structure. This method is based on use of indocyanine green video angiography (ICG-VA) technology on real time microscopic operative image. In this two case, we report of using DIVA in STA-MCA bypass surgery of 46 years old, female patient of stenosis of right MCA. And using DIVA during clipping ICA paraclinod aneurysm of 35 years old, female. During surgery, it helped in identifying temporal and frontal branches of the STA and there careful selection. After anastomosis, DIVA was used to refine vessel patency and functioning of the anastomosis. DIVA has the potential to replace ICG-VA as a tool for checking the patency of graft during bypass procedures and obliteration of aneurysm along with surgical procedures for AVM and d-AVF. DIVA allows visualization of vessels against a background of normal brain and has better visualization at greater depth and high magnification. This is particularly important during bypass surgery, which very often is performed in deep surgical fields and high magnification

Severe Aortic Stenosis in Dialysis Patients

Background: Characteristics and prognosis of hemodialysis patients with severe aortic stenosis have not yet been well defined. Methods and Results: The CURRENT AS (contemporary outcomes after surgery and medical treatment in patients with severe aortic stenosis) registry, a Japanese multicenter registry, enrolled 3815 consecutive patients with severe aortic stenosis. There were 405 hemodialysis patients (initial aortic valve replacement [AVR] group: N=135 [33.3%], and conservative group: N=270) and 3410 nonhemodialysis patients (initial AVR group: N=1062 [31.1%], and conservative group: N=2348). The median follow‐up duration after the index echocardiography was 1361 days, with 90% follow‐up rate at 2 years. The cumulative 5‐year incidence of all‐cause death was significantly higher in hemodialysis patients than in nonhemodialysis patients in both the entire cohort (71% versus 40%, P<0.001) and in the initial AVR group (63.2% versus 17.9%, P<0.001). Among hemodialysis patients, the initial AVR group as compared with the conservative group was associated with significantly lower cumulative 5‐year incidences of all‐cause death (60.6% versus 75.5%, P<0.001) and sudden death (10.2% versus 31.7%, P<0.001). Nevertheless, the rate of aortic valve procedure–related death, which predominantly occurred within 6 months of the AVR procedure, was markedly higher in the hemodialysis patients than in the nonhemodialysis patients (21.2% and 2.3%, P<0.001). Conclusions: Among hemodialysis patients with severe aortic stenosis, the initial AVR strategy as compared with the conservative strategy was associated with significantly lower long‐term mortality risk, particularly the risk for sudden death, although the effect size for the survival benefit of the initial AVR strategy was smaller than that in the nonhemodialysis patients

Decline in Left Ventricular Ejection Fraction during Follow-up in Patients with Severe Aortic Stenosis

Objectives: The aim of this study was to investigate the prognostic impact of the decline in left ventricular ejection fraction (LVEF) at 1-year follow-up in patients with severe aortic stenosis (AS) managed conservatively. Background: No previous study has explored the association between LVEF decline during follow-up and clinical outcomes in patients with severe AS. Methods: Among 3, 815 patients with severe AS enrolled in the multicenter CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry in Japan, 839 conservatively managed patients who underwent echocardiography at 1-year follow-up were analyzed. The primary outcome measure was a composite of AS-related deaths and hospitalization for heart failure. Results: There were 91 patients (10.8%) with >10% declines in LVEF and 748 patients (89.2%) without declines. Left ventricular dimensions and the prevalence of valve regurgitation and atrial fibrillation or flutter significantly increased in the group with declines in LVEF. The cumulative 3-year incidence of the primary outcome measure was significantly higher in the group with declines in LVEF than in the group with no decline (39.5% vs. 26.5%; p 10% declines in LVEF at 1 year after diagnosis had worse AS-related clinical outcomes than those without declines in LVEF under conservative management. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140

Initial Surgical Versus Conservative Strategies in Patients With Asymptomatic Severe Aortic Stenosis

AbstractBackgroundCurrent guidelines generally recommend watchful waiting until symptoms emerge for aortic valve replacement (AVR) in asymptomatic patients with severe aortic stenosis (AS).ObjectivesThe study sought to compare the long-term outcomes of initial AVR versus conservative strategies following the diagnosis of asymptomatic severe AS.MethodsWe used data from a large multicenter registry enrolling 3,815 consecutive patients with severe AS (peak aortic jet velocity >4.0 m/s, or mean aortic pressure gradient >40 mm Hg, or aortic valve area <1.0 cm2) between January 2003 and December 2011. Among 1,808 asymptomatic patients, the initial AVR and conservative strategies were chosen in 291 patients, and 1,517 patients, respectively. Median follow-up was 1,361 days with 90% follow-up rate at 2 years. The propensity score–matched cohort of 582 patients (n = 291 in each group) was developed as the main analysis set for the current report.ResultsBaseline characteristics of the propensity score–matched cohort were largely comparable, except for the slightly younger age and the greater AS severity in the initial AVR group. In the conservative group, AVR was performed in 41% of patients during follow-up. The cumulative 5-year incidences of all-cause death and heart failure hospitalization were significantly lower in the initial AVR group than in the conservative group (15.4% vs. 26.4%, p = 0.009; 3.8% vs. 19.9%, p < 0.001, respectively).ConclusionsThe long-term outcome of asymptomatic patients with severe AS was dismal when managed conservatively in this real-world analysis and might be substantially improved by an initial AVR strategy. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140

Current use of inotropes according to initial blood pressure and peripheral perfusion in the treatment of congestive heart failure: findings from a multicentre observational study

OBJECTIVES: Current guidelines restrict the use of inotropes for the treatment for heart failure (HF) unless the patients are hypotensive or hypoperfused because of safety concerns. This study sought to characterise the contemporary real-world use of inotropes and associated long-term outcomes according to systolic blood pressure (sBP) and perfusion status. DESIGN: A multicentre prospective cohort study. SETTING: This study was nested from the Kyoto Congestive Heart Failure registry, which included consecutive Japanese patients admitted for HF. PARTICIPANTS: We categorised 3995 patients into two groups: sBP ≥90 mm Hg and warm profile group, and sBP <90 mm Hg or cold profile group. In each group, patients were stratified across the use of inotropes within 24 hours of hospital presentation. PRIMARY AND SECONDARY OUTCOMES: The primary outcome was all-cause death throughout follow-up. Secondary outcomes included cardiovascular death throughout follow-up, all-cause death during index hospitalisation and after discharge, and HF hospitalisation. RESULTS: A total of 793 patients (20%) presented with sBP <90 mm Hg or cold profile, whereas 3202 patients had sBP ≥90 mm Hg and warm profile; 276 patients (35%) in the sBP <90 mm Hg/cold group and 312 patients (10%) in the sBP ≥90 mm Hg/warm group received initial inotropic treatment. Adjusted excess risk of inotrope use relative to no inotrope for the primary outcome measure was significant in the sBP ≥90 mm Hg/warm group (adjusted HR), 1.36; 95% CI 1.09 to 1.72, p=0.006) but not in the sBP <90 mm Hg/cold group (adjusted HR, 1.28, 95% CI 0.96 to 1.69, p=0.09). Risk for postdischarge all-cause death and HF hospitalisation was not significantly different between the patients with inotropes and no inotropes in both groups. CONCLUSION: Inotrope use in the absence of hypotension and hypoperfusion is still common, but associated with a worse long-term prognosis. TRIAL REGISTRATION NUMBER: UMIN000015238

A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care.

To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma's compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed