Validation of an immersive virtual reality system for training near and far space neglect in individuals with stroke: a pilot study

Background: Unilateral spatial neglect (USN) is defined as impaired ability to attend and see on one side, and when present, it interferes seriously with daily life. These symptoms can exist for near and far spaces combined or independently, and it is important to provide effective intervention for near and far space neglect.

Objective: The purpose of this pilot study was to propose an immersive virtual reality (VR) rehabilitation program using a head-mounted display that is able to train both near and far space neglect, and to validate the immediate effect of the VR program in both near and far space neglect.

Methods: Ten USN patients underwent the VR program with a pre–post design and no control. In the virtual environment, we developed visual searching and reaching tasks using an immersive VR system. Behavioral inattention test (BIT) scores obtained pre- and immediate post-VR program were compared.

Results: BIT scores obtained pre- and post-VR program revealed that far space neglect but not near space neglect improved promptly after the VR program. This effect for far space neglect was observed in the cancelation task, but not in the line bisection task.

Conclusions: Positive effects of the immersive VR program for far space neglect are suggested by the results of the present pilot study. However, further studies with rigorous designs are needed to validate its clinical effectiveness.     

Unmanipulated Reduced-Intensity Stem Cell Transplantation from a Haploidentical Donor Mismatched at 3 HLA Antigens to a Patient with Leukemic Transformation of Myelodysplastic Syndrome: Successful Second Transplantation after Graft Rejection

We present the case of a patient with myelodysplastic syndrome who experienced leukemia transformation and subsequently underwent transplantation of unmanipulated peripheral blood stem cells from a haploidentical sibling mismatched at 3 HLA antigens, along with a reduced-intensity regimen (fludarabine, busulfan, and anti-T-lymphocyte globulin) and tacrolimus-containing graft-versus-host disease (GVHD) prophylaxis. The patient experienced graft rejection but successfully underwent a second transplantation from the same donor with a slightly intensified conditioning regimen. Although the patient developed life-threatening cytomegalovirus (CMV) pneumonia following the second transplantation, he recovered completely from the pneumonia with intensive supportive therapy. He is still in complete remission past day 1000 in the absence of GVHD. As far as we know, this report is the first to describe a successful second transplantation that was performed for graft rejection following HLA-haploidentical nonmyeloablative stem cell transplantation. Furthermore, we emphasize that patients should be carefully monitored for CMV infection when reduced-intensity conditioning is given repeatedly over a short period.     

The vomeronasal chemosensory system as a route of neuroinvasion by herpes simplex virus

We have investigated the potential of neurotropic microbes to invade the central nervous system (CNS) via the peripheral nervous system. Herpes simplex virus type 1 (HSV-1) strain KH6 and herpes simplex virus type 2 (HSV-2) strain 186 were found to infect chemosensory neurons in the vomeronasal organ (the pheromone detector) following intranasal inoculation of mice. HSV-1 strain KH6 infection was further transmitted to the accessory olfactory bulb (first relay), the medial amygdala (second relay), and the bed nucleus of the stria terminalis and the ventromedial hypothalamus (third relay). HSV-1 strain KH6 also targeted the olfactory and trigeminal systems. HSV-2 strain 186 predominantly attacked the brainstem including the trigeminal system. While both viruses did not induce apoptosis in infected chemosensory neurons, they did in infected brain tissue. These results suggest that neurotropic viruses can invade the brain by infecting vomeronasal chemosensory neurons and that the restrained induction of apoptosis in the infected neurons may facilitate viral transmission to the CNS.     

Nicotine suppresses 1-methyl-4-phenylpyridinium ion-induced hydroxyl radical generation in rat striatum

The present study examined the ability of antioxidant effects of nicotine on 1-methyl-4-phenylpyridinium ion (MPP(+))-induced hydroxyl radical (*OH) formation of rat striatum. Rats were anesthetized and sodium salicylate in Ringer's solution (0.5 nmol/microl per min) was infused through a microdialysis probe to detect the generation of.OH as reflected by non-enzymatic formation trapped as 2,3-dihydroxybenzoic acid (DHBA) in the striatum. MPP(+) enhanced generation of.OH formation trapped as DHBA. However, nicotine (100 microM) significantly suppressed.OH formation induced by MPP(+). Iron (II) (2, 5 and 10 microM) increased the levels of DHBA in a concentration-dependent manner. However, in the presence of nicotine (100 microM), the effect of nicotine was suppressed. These results suggest that nicotine has a preventive effect on.OH generation by MPP(+) in rat striatum.     

Sequential compound exocytosis of large dense-core vesicles in PC12 cells studied with TEPIQ (two-photon extracellular polar-tracer imaging-based quantification) analysis

We investigated exocytosis of PC12 cells using two-photon excitation imaging and extracellular polar tracers (TEP imaging) at the basal region of PC12 cells adjacent to the glass cover slip. TEPIQ (two-photon extracellular polar-tracer imaging-based quantification) analysis revealed that most exocytosis was mediated by large dense-core vesicles (LVs) with a mean diameter of 220 nm, and that exocytosis of LVs occurred slowly with a mean latency of ∼7 s even though exocytosis was induced with large increases in cytosolic Ca²⁺ concentration by uncaging of a caged-Ca²⁺ compound. We also found that 97% of exocytic LVs remained poised at the plasma membrane, 72% maintained their fusion pores in an open conformation for more than 30 s, and 76% triggered sequential compound exocytosis of vesicles that were located deeper in the cytosol. Sequential compound exocytosis by PC12 cells was confirmed by electron microscopic investigation with photoconversion of diaminobenzidine by FM1-43 (a polar membrane tracer). Our data suggest that pre-stimulus docking of LVs to the plasma membrane does not necessarily hasten the fusion reaction, while docking and resulting stability of exocytic LVs facilitates sequential compound exocytosis, and thereby allowing mobilization of deep vesicles.     

In vivo labeling of amyloid with BF-108

Detection of aggregated amyloid-beta (Abeta) with a non-invasive imaging modality such as positron emission tomography (PET) was suggested to be ideal for the diagnosis of Alzheimer's disease (AD) prior to the onset of clinical symptoms. We have been searching for imaging probe candidates with a high affinity for aggregated Abeta in vitro and in vivo and high lipophilicity, a characteristic that allows for the permeation of the blood-brain barrier (BBB). As analyzed by Thioflavin T (ThT) assay and octanol/water partition coefficient test (PC), 3-diethylamino-6-(2-fluoroethyl)ethylaminoacridine (BF-108) were found to have high affinity for Abeta aggregates in vitro and high lipophilicity. Intravenously administrated BF-108 labeled Abeta aggregates injected into the amygdala as observed under a fluorescence microscope, showing this compound's permeability of BBB and an ability to label Abeta in vivo. BF-108 also labeled neuritic senile plaques (SPs), neurofibrillary tangles, and amyloid-laden vessels in temporal and hippocampal sections from AD patients. Following intravenous administration of BF-108 to an APP23 transgenic (TG) mouse, in vivo labeling of endogenous plaques was seen in brain sections by fluorescence microscopy. These properties suggest the potential utility of BF-108 for in vivo imaging of AD pathology.     

Effects of magnesium on prostacyclin synthesis and intracellular free calcium concentration in vascular cells.

This study investigated the effects of extracellular magnesium concentration ([Mg2+]e; 0.3-3 mM) on intracellular free calcium concentration ([Ca2+]i) and prostacyclin (PGI2) production in cultured human umbilical vein endothelial cells (HUVEC) and vascular smooth muscle cells from rats (VSMC) under basal and agonist-stimulated conditions. We used histamine as agonist which increases [Ca2+]i and PGI2 production in HUVEC, norepinephrine in VSMC. [Mg2+]e dose-dependently increased basal and agonist-stimulated PGI2 production in both cells. [Mg2+]e dose-dependently reduced basal [Ca2+]i in VSMC, but did not influence in HUVEC. In both cells, increasing [Mg2+]e reduced agonist-stimulated [Ca2+]i responses. Furthermore, [Mg2+]e dose-dependently reduced agonist-stimulated [Ca2+]i in Ca(2+)-free buffer, indicating intracellular Ca2+ release. In VSMC, 10(-6) M diltiazem and 10(-7) M nifedipine, Ca2+ channel blockers, reduced agonist-stimulated [Ca2+]i as well as 3 mM Mg2+, but did not affect PGI2 production. [Mg2+]e amplified dose-dependently arachidonic acid-induced PGI2 production in both cells, suggesting the activation of cyclooxygenase and/or PGI2 synthetase. Our results suggest that [Mg2+]e influences intracellular Ca2+ mobilization of not only vascular smooth muscle cells but also endothelial cells by inhibiting both Ca2+ influx and intracellular Ca2+ release. [Mg2+]e enhances PGI2 production in both types of cells, although the mechanism is likely to be independent from Ca2+ mobilization.     

ARK5 expression in colorectal cancer and its implications for tumor progression

A novel member of the human AMPK family, ARK5, was recently discovered to be a key molecule in mediating cancer cell migration activity in human pancreas cancer cell line PANC-1, and its activation was found to be induced by Akt-dependent phosphorylation at Ser 600. DNA array analysis with 241 paired cDNAs from 13 different types of tumors and corresponding normal tissues derived from cancer patients revealed ARK5 overexpression in the samples of colorectal cancer. ARK5 expression was measured and an in vitro invasion assay was performed in six human colorectal cancer cell lines, WiDr, HCT-15, DLD-1, SW620, LoVo, and SW480, and since high invasion activity was concordant with higher ARK5 expression, ARK5 expression was examined in relation to tumor progression and metastatic activity in clinical samples. In 56 clinical samples of primary colorectal cancers and their liver metastases, higher ARK5 expression was observed in the samples from more advanced cases, and much higher expression was observed in the liver metastases. In situ hybridization analysis showed ARK5 overexpression in tumor cells. Based on these findings, we propose that ARK5 overexpression is involved in tumor progression of colon cancer clinically.     

Human herpesvirus 8 (HHV8) sequence variations in HHV8 related tumours in Okinawa, a subtropical island in southern Japan

BACKGROUND: Although rare in mainland Japan, classic Kaposi's sarcoma (KS) is frequently reported in Okinawa, a subtropical island in southern Japan. Human herpesvirus 8 (HHV8) has been identified in the tumours and geographical differences occur. Aim: To sequence HHV8 in classic and AIDS associated KS in Okinawa. MATERIALS/METHODS: Eight classic KS cases, one AIDS associated KS, five granuloma pyogenicum cases, two inflammatory pseudotumours, two Castleman's disease cases, one angiosarcoma, and one primary effusion lymphoma (PEL) were studied. As a control, HHV8 positive cultured PEL cells (TY-1) were used. The presence of HHV8 sequences was evaluated by PCR and in situ hybridisation. PCR products were sequenced. RESULTS: There were no histological differences among KS resulting from the different virus genotypes. HHV8 was detected in all cases of KS, in one PEL, and one granuloma pyogenicum. Eight classic KS cases and one granuloma pyogenicum were infected with HHV8 genotype II/C (K1 region) or subtype C (ORF26 region), which had a five amino acid deletion at K1 VR2 region. An AIDS associated KS and a PEL were infected with type I/A virus. CONCLUSION: In Okinawa, classic KS cases and one granuloma pyogenicum case were infected with HHV8 genotype II/C, also classified as subtype C. AIDS associated KS and PEL were infected with a different HHV8 (genotype I/A), similar to that found in the USA. In Okinawa, HHV8 infection is more than four times higher than in mainland Japan, resulting in many cases of KS because of HHV8 genotype II/C infection.