Yuan Ting Sun

Deficiency of electroneutral K+-Cl- cotransporter 3 causes a disruption in impulse propagation along peripheral nerves.

Nerve conduction requires the fine tuning of ionic currents through delicate interactions between axons and Schwann cells. The K+–Cl− cotransporter (KCC) family includes four isoforms (KCC1–4) that play an important role in the maintenance of cellular osmotic homeostasis via the coupled electroneutral movement of K+ and Cl− with concurrent water flux. Mutation in SLC12A6 gene encoding KCC3 results in an autosomal recessive disease, known as agenesis of the corpus callosum associated with peripheral neuropathy. Nevertheless, the role of KCC3 in nerve function remains a puzzle. In this study, the microscopic examination of KCC isoforms expressed in peripheral nerves showed high expression of KCC2–4 in nodal segments of the axons and in the perinucleus and microvilli of Schwann cells. The KCC inhibitor [[(dihydroindenyl)oxy]alkanoic acid] but not the Na+–K+–2Cl−‐cotransport inhibitor (bumetanide) dose‐dependently suppressed the amplitude and area of compound muscle action potential, indicating the involvement of KCC activity in peripheral nerve conduction. Furthermore, the amplitude and area under the curve were smaller, and the nerve conduction velocity was slower in nerves from KCC3−/− mice than in nerves from wild‐type mice, while the expression pattern of KCC2 and KCC4 was similar in KCC3 kockout and wild‐type strains. KCC3−/− mice also manifested a prominent motor deficit in the beam‐walking test. This is the first study to demonstrate that the K+–Cl− cotransporter activity of KCC3 contributes to the propagation of action potentials along peripheral nerves.

K+–Cl− cotransport mediates the bactericidal activity of neutrophils by regulating NADPH oxidase activation

•  Neutrophilic phagocytosis is essential for innate immunity against the bacterial infection. •  During phagocytosis, the generation of bactericidal hypochlorous acid requires superoxide produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to kill the internalized pathogens. •  We show that NADPH oxidase complexes are associated with K+–Cl− cotransporter (KCC) at the plasma membrane of activated neutrophils and are internalized to form phagosomes, where KCC activity and expression level affect the production of oxidants. •  This study supports the notion that KCC, in particular KCC3, is involved in the early stages of the hosts defence against microorganisms.

Outcome of Acute Ischemic Stroke in Very Elderly Patients: Is Intravenous Thrombolysis Beneficial?

Background/Aims: Intravenous tissue plasminogen activator (tPA) treatment is recommended in acute stroke within 3 h of onset; however, the benefit of its use in the elderly remains uncertain. We assessed the safety and efficacy of tPA treatment in elderly patients. Methods: We recruited 97 elderly Chinese patients aged ≧80 years with cerebral ischemia presenting within 3 h of onset. Favorable outcomes were defined as discharge to home and modified Rankin Scale (mRS) ≤2 at discharge. Results: For moderate to severe patients (NIHSS ≧6), the baseline characteristics between the tPA (n = 30) and non-tPA (n = 41) group were not different. The proportion of patients discharged home was 56.7 and 61%, respectively (p = 0.72). For patients with baseline mRS ≤2, the frequency of discharged mRS ≤2 was not different (27.3% of the tPA group and 26.9% of the non-tPA group; p = 1.00). Symptomatic intracranial hemorrhage was 6.7 and 2.4%, respectively (p = 0.31). For minor stroke patients (NIHSS ≤5), tPA was not considered and the outcome of those discharged home and mRS ≤2 was 73 and 88%, respectively. Conclusion: Elderly patients can be treated safely with intravenous tPA, whereas our data did not support routine thrombolysis. Further randomized trials in the elderly are encouraged.

Variations of brain activities of acupuncture to TE5 of left hand in normal subjects

This paper presents the evident effects of acupoint stimulation, using EEG (electroencephalogram) measurements. With acupuncture stimulation and the EEG measurement on the same meridian, EEG is able to accurately detect the effects of acupunctural point stimulation on brain waves. In this study, 24 subjects without heart or neural diseases were randomly separated into two groups of 12, named test and control groups. Similar procedures are performed; the subjects lay on a bed with eyes closed for ten minutes as the baseline. The test group received acupuncture at their Waiguan points (TE5) on their left hands for 20 minutes, while the control group did not. EEGs are recorded during pre-acupuncture, acupuncture stimulation and post-acupuncture stimulation periods. The EEG electrodes are at the T3, T4, O1 and O2 locations. Continuous wavelet transformation analysis is adopted; therefore, EEGs are divided into the following bands: δ (0.5-4HZ), θ (4-8HZ), α (8-13HZ) and β (13-30HZ). During acupuncture stimulation, the θ energy is increased and had statistical differences at all electrode points, T3, T4, O1 and O2. Upon removing the needle, the energy at the T3 and T4 points slowly declined and revealed obvious statistical differences. During acupuncture, only α energy has been noted to have statistical difference and it was increased at the T3 point. However, the energy was decreased and had no statistical difference after five minutes. Acupuncture is proven to be able to affect brain waves, as the stimulation might have changed the tissues between the cranium and scalp; therefore, the brain waves are detected more easily.

Stroke suggests increased risk of dementia

BACKGROUND Stroke is a major cause of disability in the elderly and considerably increases the risk of dementia, which is another important source of disability. This population-based study aimed to examine the risk of dementia in patients with stroke compared with non-stroke cases with similar comorbidities. METHODS Using the Taiwan National Health Insurance databank covering the period 2001-2007, this retrospective cohort study evaluated the risk of dementia in 10,884 patients with first stroke who had no history of dementia. In this study, we performed a 1:5 case-control matched analysis, in which cases were matched to controls based on their estimated propensity scores, which were estimated with demographics and associated risk factors. This approach reduced selection bias. Cox proportional hazards regression analysis was then used to estimate the risk of dementia in stroke patients. RESULTS During the 5-year follow-up period, 1,487 (13.74%) stroke and 1,402 (2.59%) non-stroke patients suffered dementia. Stroke was independently associated with a 6.09 (95% confidence interval [CI], 5.66 to 6.55) times greater risk of dementia 5 years after stroke. Older age was associated with a higher incidence of dementia after stroke. Each stroke type had different impacts on the occurrence of dementia. The hazard ratio of dementia among hemorrhagic stroke patients was much higher than those of ischemic stroke and controls. CONCLUSION The findings of this study suggest that stroke confers an increased risk of dementia, especially in the elderly and in patients with hemorrhagic stroke. We advocate the need for close observation and enhanced health education programs to benefit patients with stroke.

Usefulness of vascular wall deformation for assessment of carotid arterial stiffness and association with previous stroke in elderly

BACKGROUND Carotid arterial stiffness measured by techniques of speckle tracking echocardiography is helpful to assess vascular wall deformation. We conducted a study to investigate the relationship between vascular deformation of the carotid artery and ischemic stroke in the elderly. METHODS We recruited 89 consecutive individuals aged ≥60 years (mean age = 72±6 years; 31 men) from a community health survey program. Ten (11%) had a history of ischemic stroke. Carotid B-mode images were acquired using a high-resolution vascular probe equipped on an echocardiographic system. Circumferential strain (CS) and strain rate (CSR) were obtained by speckle tracking techniques with a region of interest covering the entire depth of the common carotid arterial wall. RESULTS Both CS and CSR were significantly correlated with beta index and distensibility but not with carotid intima-medial thickness and pulse wave velocity. In the comparison between patients with or without history of stroke, carotid CS (1.46% ± 0.54% vs. 2.75% ± 1.23%; P = 0.002) and CSR (0.30±0.13 1/s vs. 0.47±0.18 1/s; P = 0.007) were significantly lower in patients with stroke. Multivariable analysis showed that both carotid CS and CSR were independent factors associated with previous strokes. CONCLUSIONS Carotid wall deformation indices are useful for assessment of local carotid arterial stiffness. CS and CSR of carotid artery measured by speckle tracking techniques were associated with previous ischemic stroke in the elderly.

Remote cerebellar hemorrhage following supratentorial craniotomy.

Abstract Objective: Cerebellar hemorrhage remote from the site of surgery may complicate neurosurgical procedure. The exact pathophysiology of this type of hemorrhage is poorly understood. We retrospectively compared 16 patients who had remote cerebellar hemorrhage (RCH) with a case-matched control cohort, to determine the significance of perisurgical and surgical factors that may predispose patients to such bleeding events. Methods: From 1 June 2005 to 31 December 2008, postoperative routine head computed tomographic (CT) scan was performed in our institution and 16 patients with RCH after supratentorial neurosurgical procedure were identified. The medical charts of these 16 cases and a control cohort of 64 patients were recorded. All parameters were analyzed with regards to various variables. Results: The incidence RCH after supratentorial craniotomy increased after postoperative computed tomographic scan. The mechanism of cerebellar hemorrhage in this series of patients is most likely multifactorial. Several variables showed a significant association with the occurrence of RCH. Multivariate analysis indicated that the following two factors independently correlated with occurrence of RCH: (1) postoperative epidural drainage amount; and (2) history of previous cerebrovascular accident (CVA) with cerebral atrophy. All cases with RCH underwent medical treatment and no neurological sequelae associated with RCH. Conclusions: Postoperative epidural drainage amount and history of previous CVA with cerebral atrophy can reliably predict the occurrence of cerebellar hemorrhage after supratentorial craniotomy. One of the most important strategies to minimize hazardous complications is to be aware of these potential risk factors and to take action to prevent them.

Sequential appearance and disappearance of hemianopia, palinopsia and metamorphopsia: A case report and literature review

We report a case with a sequential appearance and disappearance of homonymous hemianopsia, palinopsia and metamorphopsia in the defective visual field within two days. She had a stroke nine months ago and recovered completely. During that episode, dizziness and unsteadiness happened suddenly and was followed by above-mentioned visual symptoms. Brain image and blood perfusion studies showed an old right occipital lesion with hemodynamic changes. Electroencephalograms performed immediately just after the disappearance of all the above-mentioned symptoms subsided and four months later showed similar findings, some isolated independent sharp waves over bilateral temporal areas, with right posterior extension. These were independent of her visual symptoms. The pathophysiologies of our case could be a sequential hemodynamic change in the right occipital area, from hypoperfusion to transient hyperperfusion and finally to normal perfusion. Potential mechanisms are discussed with literature review.

Integrating Image-Based High-Content Screening with Mouse Models Identifies 5-Hydroxydecanoate as a Neuroprotective Drug for Paclitaxel-Induced Neuropathy

Chemotherapy-induced neurotoxicity is a common adverse effect of cancer treatment. No medication has been shown to be effective in the prevention or treatment of chemotherapy-induced neurotoxicity. This study aimed to discover potential neuroprotective drugs for paclitaxel-induced neurotoxicity. An image-based high-content platform was first developed to screen for potential neuroprotective drugs. The screening system comprised of automated image acquisition and multiparameter analysis, including neuronal viability, neurite outgrowth, and synaptogenesis. By this platform, we obtained a candidate list from compound libraries. In the drug screening from compound libraries of ion channel ligands, REDOX and GABAergic ligands, 5-hydroxydecanoate (5-HD) exhibited the most significant neuroprotective effects against paclitaxel-induced neurotoxicity in both cortical and dorsal root ganglion (DRG) neurons. In mouse behavioral tests, 5-HD restored the thermal sensitivity and alleviated mechanical allodynia induced by paclitaxel. Electron micrographs of sciatic nerve revealed that 5-HD reduced the damages caused by paclitaxel in the nonmyelinated and smaller myelinated fibers. The mechanistic study on DRG neurons suggested that 5-HD rescued the dysregulation of intracellular calcium homeostasis provoked by paclitaxel. Importantly, 5-HD did not jeopardize the antitumor effect of paclitaxel in tumor xenograft models. In conclusion, we established an imaged-based high-content screening platform and a protocol for verifying the neuroprotective effect in vivo, by which 5-HD was identified and validated as a potential neuroprotective drug for paclitaxel-induced neuropathy. Mol Cancer Ther; 14(10); 2206–14. ©2015 AACR.

TDP-43 proteolysis is associated with astrocyte reactivity after traumatic brain injury in rodents

The aggregation and deposition of transactivation response DNA-binding protein 43 (TDP-43) in neurons and astrocytes is characteristic in a number of neurodegenerative diseases including Alzheimers disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Nevertheless, the exact role of TDP-43 in astrocytes is unknown. Recently, TDP-43 was identified in neurons but not astrocytes after traumatic brain injury (TBI) in humans. In the present study, we evaluated TDP-43 expression and proteolysis in astrocytes in a rat model of TBI. We assessed TDP-43 fragment expression, astrocyte morphology, neuronal population numbers, and motor function after TBI with or without intracerebroventricular administration of a caspase-3 inhibitor. Motor dysfunction was observed after TBI in potential association astrocytic TDP-43 short fragment mislocalization and accumulation, astrogliosis, and neuronal loss. Notably, caspase-3 inhibition prevented these changes after TBI. Our findings suggest that TDP-43 proteolysis in astrocytes is related to astrogliosis and subsequent neuronal loss in TBI, and that TDP-43 may be an important therapeutic target for preventing motor dysfunction after TBI.