Quality of life after brain injury-overall scale, Japanese version: assessment of reliability and validity.

This study analyzed the linguistic and psychometric validation of the Japanese version of the Quality of Life after Brain Injury-Overall Scale (QOLIBRI-OS) consisting of six items which cover several TBI-relevant domains. We hypothesized that the Japanese version has good reliability, convergent validity, and divergent validity, compared with its long version, the 37-item QOLIBRI. The QOLIBRI-OS Japanese version was forward and back-translated from the English version. In total, 129 individuals participated in this study after experiencing a traumatic brain injury and attending clinics, rehabilitation centers, and support centers in Japan. The structure of the QOLIBRI-OS was investigated by confirmatory factor analyses and compared with the QOLIBRI. Only one factor was extracted, and a model with one underlying factor had a good fit. The QOLIBRI-OS showed good-to-excellent internal consistency and test-retest reliability. The QOLIBRI-OS was positively correlated with the QOLIBRI, Short Form Health Survey-36 version 2, and Glasgow Outcome Scale Extended, and negatively correlated with the Hospital Anxiety and Depression Scale. The results suggest that the QOLIBRI-OS Japanese version is a reliable and valid tool for assessing disease-specific health-related QOL in individuals after traumatic brain injury in Japan.

Stroke Patients with Nearly Independent Transfer Ability are at High Risk of Falling.

OBJECTIVES: To examine the relationship between patients' transfer ability and fall risk in stroke patients during hospitalization. MATERIALS AND METHODS: We retrospectively enrolled 237 stroke patients who were transferred to a convalescent rehabilitation ward from acute wards in the same hospital. Using incident reports, we investigated their fall rates and activity status at the falls according to their transfer abilities, which were assessed with Functional Independence Measure (FIM) transfer scores. The bi-weekly time trend of fall rates in all patients and in three subgroups based on FIM transfer scores of 1-3, 4-5, and 6-7, and activity status at the falls, were investigated. In addition, changes of patients' transfer ability on admission, at the first fall, and at discharge were investigated among falling patients. RESULTS: The fall rate was the greatest in patients with a FIM transfer score of 4 (14.3 times/1000 person-days). The majority of falls for patients with a FIM transfer score of 1 occurred at the activity status of "on the bed" and "sitting", while three quarters of patients with a FIM score of 7 had falls during "standing" and "walking". No longitudinal trend in fall rates was found overall; however, the fall rate trends differed depending on the FIM transfer score. The majority of the patients who fell required full assistance for transfers upon admission but required no assistance at discharge. CONCLUSIONS: Fall risk differed among patients with various transfer abilities; the greatest risk was in those who needed minimal assistance for transfers.

ECHO-liveFISH: in vivo RNA labeling reveals dynamic regulation of nuclear RNA foci in living tissues.

Elucidating the dynamic organization of nuclear RNA foci is important for understanding and manipulating these functional sites of gene expression in both physiological and pathological states. However, such studies have been difficult to establish in vivo as a result of the absence of suitable RNA imaging methods. Here, we describe a high-resolution fluorescence RNA imaging method, ECHO-liveFISH, to label endogenous nuclear RNA in living mice and chicks. Upon in vivo electroporation, exciton-controlled sequence-specific oligonucleotide probes revealed focally concentrated endogenous 28S rRNA and U3 snoRNA at nucleoli and poly(A) RNA at nuclear speckles. Time-lapse imaging reveals steady-state stability of these RNA foci and dynamic dissipation of 28S rRNA concentrations upon polymerase I inhibition in native brain tissue. Confirming the validity of this technique in a physiological context, the in vivo RNA labeling did not interfere with the function of target RNA nor cause noticeable cytotoxicity or perturbation of cellular behavior.

FGF8 acts as a classic diffusible morphogen to pattern the neocortex.

Gain- and loss-of-function experiments have demonstrated that a source of fibroblast growth factor (FGF) 8 regulates anterior to posterior (A/P) patterning in the neocortical area map. Whether FGF8 controls patterning as a classic diffusible morphogen has not been directly tested. We report evidence that FGF8 diffuses through the mouse neocortical primordium from a discrete source in the anterior telencephalon, forms a protein gradient across the entire A/P extent of the primordium, and acts directly at a distance from its source to determine area identity. FGF8 immunofluorescence revealed FGF8 protein distributed in an A/P gradient. Fate-mapping experiments showed that outside the most anterior telencephalon, neocortical progenitor cells did not express Fgf8, nor were they derived from Fgf8-expressing cells, suggesting that graded distribution of FGF8 results from protein diffusion from the anterior source. Supporting this conclusion, a dominant-negative high-affinity FGF8 receptor captured endogenous FGF8 at a distance from the FGF8 source. New FGF8 sources introduced by electroporation showed haloes of FGF8 immunofluorescence indicative of FGF8 diffusion, and surrounding cells reacted to a new source of FGF8 by upregulating different FGF8-responsive genes in concentric domains around the source. Reducing endogenous FGF8 with the dominant-negative receptor in the central neocortical primordium induced cells to adopt a more posterior area identity, demonstrating long-range area patterning by FGF8. These observations support FGF8 as a classic diffusible morphogen in neocortex, thereby guiding future studies of neocortical pattern formation.

EFFECTS OF REHABILITATION PROGRAM FOCUSED ON IMPROVING REAL-LIFE DAILY ACTIVITIES OF PATIENTS WITH MILD COGNITIVE IMPAIRMENTS OR DEMENTIA AND THEIR CAREGIVERS.

Objective: To evaluate the effectiveness of a dyadic outpatient rehabilitation program focused on improving the real-life daily activities of patients with mild cognitive impairments or dementia and their caregivers. Design: Retrospective study. Subjects: Eight patients with mild cognitive impairments or dementia and their caregivers. Methods: The rehabilitation program comprised eight 1-hour sessions by occupational therapists with patients and his/her caregivers. Patients were assessed for motor function, cognitive function, and quality of life, and their caregivers were assessed for depression and caregiver burden. Participants were assessed at pre-program and post-program, and 3-month follow-up. Results: The scores of caregiver-assessed Quality of life in Alzheimer's disease scale in patients significantly improved at post-program (median [interquartile range], 30.0 [7.0]) compared with pre-program (27.0 [2.8], effect size = 0.77, p = 0.029). In caregivers, the Zarit Caregiver Burden Interview scores decreased significantly at post-program (16.5 [13.0]) compared with pre-program (22.0 [17.5], effect size = 0.72, p = 0.042). There were no significant differences in other assessments. Conclusions: The rehabilitation program focused on real daily activities and demonstrated to improve patients' quality of life and caregivers' depression and caring burden through patient-caregiver interaction. Future enhanced follow-up systems are warranted.

The role of Fgf8 in telencephalic and diencephalic patterning.

Correct patterning of the developing brain is crucial importance for accurate wiring and function. Although the adult brain contains many complex structures, it begins with a simple structure-the neural tube. As it develops, the neural tube is divided into several regions, including the telencephalon, diencephalon, midbrain, and hindbrain. In each of these regions, signaling molecules are secreted from discrete zones, which establish positional information and regulate regional growth. There are many mechanistic questions that remain to be resolved about the action of these growth and differentiation factors. The cellular factors mediating patterning in response to these factors are largely unknown. Furthermore, identical differentiation factors are expressed in different regions of the brain and yet control significantly different patterning mechanisms, and the factors that control region-specific responses to these factors are mostly obscure. Furthermore, differentiation factors also show dramatically different expression patterns in different vertebrate species that may underlie changes in brain structure, but the mechanisms by which these changes in gene expression occur poorly understood. To address these issues, we discuss the role of Fgf8, which controls anterior/posterior patterning in different regions of the developing brain. We also discuss how modifications of Fgf8 expression in the diencephalon controlled by retrotransposons can change the shape and function of the brain in various species.

Activation of Ras-ERK pathway by Fgf8 and its downregulation by Sprouty2 for the isthmus organizing activity.

In the previous studies, we showed that strong Fgf8 signaling activates the Ras-ERK pathway to induce cerebellum. Here, we show importance of negative regulation following activation of this pathway for proper regionalization of mesencephalon and metencephalon in chick embryos. 'Prolonged' activation of ERK by misexpression of Fgf8b and dominant-negative Sprouty2 (dnSprouty2) did not change the fate of the mesencephalic alar plate. Downregulation of ERK activity using an MEK inhibitor, U0126, or by tetracycline-dependent Tet-off system after co-expression of Fgf8b and dnSprouty2 forced the mesencephalic alar plate to differentiate into cerebellum. We then paid attention to Mkp3. After misexpression of dnMkp3 and Fgf8b, slight downregulation of ERK activity occurred, which may be due to Sprouty2, and the mesencephalon transformed to the isthmus-like structure. The results indicate that ERK must be once upregulated and then be downregulated for cerebellar differentiation and that differential ERK activity level established by negative regulators receiving Fgf8 signal may determine regional specificity of mesencephalon and metencephalon.

Isthmus organizer for mesencephalon and metencephalon.

The vertebrate central nervous system is elaborated from a simple neural tube. Brain vesicles formation is the first sign of regionalization. Classical transplantation using quail and chick embryos revealed that the mesencephalon-metencephalon boundary (isthmus) functions as an organizer of the mesencephalon and metencephalon. Fgf8 is accepted as a main organizing molecule of the isthmus. Strong Fgf8 signal activates the Ras-ERK signaling pathway to differentiate the cerebellum. In this review, the historical background of the means of identifying the isthmus organizer and the molecular mechanisms of signal transduction for tectum and cerebellum differentiation is reviewed.

A SINE-derived element constitutes a unique modular enhancer for mammalian diencephalic Fgf8.

Transposable elements, including short interspersed repetitive elements (SINEs), comprise nearly half the mammalian genome. Moreover, they are a major source of conserved non-coding elements (CNEs), which play important functional roles in regulating development-related genes, such as enhancing and silencing, serving for the diversification of morphological and physiological features among species. We previously reported a novel SINE family, AmnSINE1, as part of mammalian-specific CNEs. One AmnSINE1 locus, named AS071, showed an enhancer property in the developing mouse diencephalon. Indeed, AS071 appears to recapitulate the expression of diencephalic fibroblast growth factor 8 (Fgf8). Here we established three independent lines of AS071-transgenic mice and performed detailed expression profiling of AS071-enhanced lacZ in comparison with that of Fgf8 across embryonic stages. We demonstrate that AS071 is a distal enhancer that directs Fgf8 expression in the developing diencephalon. Furthermore, enhancer assays with constructs encoding partially deleted AS071 sequence revealed a unique modular organization in which AS071 contains at least three functionally distinct sub-elements that cooperatively direct the enhancer activity in three diencephalic domains, namely the dorsal midline and the lateral wall of the diencephalon, and the ventral midline of the hypothalamus. Interestingly, the AmnSINE1-derived sub-element was found to specify the enhancer activity to the ventral midline of the hypothalamus. To our knowledge, this is the first discovery of an enhancer element that could be separated into respective sub-elements that determine regional specificity and/or the core enhancing activity. These results potentiate our understanding of the evolution of retroposon-derived cis-regulatory elements as well as the basis for future studies of the molecular mechanism underlying the determination of domain-specificity of an enhancer.

Dynamic spatiotemporal gene expression in embryonic mouse thalamus.

The anatomy of the mammalian thalamus is characterized by nuclei, which can be readily identified in postnatal animals. However, the molecular mechanisms that guide specification and differentiation of neurons in specific thalamic nuclei are still largely unknown, and few molecular markers are available for most of these thalamic subregions at early stages of development. We therefore searched for patterned gene expression restricted to specific mouse thalamic regions by in situ hybridization during the onset of thalamic neurogenesis (embryonic [E] days E10.5-E12.5). To obtain correct regional information, we used Shh as a landmark and compared spatial relationships with the zona limitans intrathalamica (Zli), the border of the p2 and p3 compartments of the diencephalon. We identified genes that are expressed specifically in the ventricular zone of the thalamic neuroepithelium and also identified a number of genes that already exhibited regional identity at E12.5. Although many genes expressed in the mantle regions of the thalamus at E12.5 showed regionally restricted patterns, none of these clearly corresponded to individual thalamic nuclei. We next examined gene expression at E15.5, when thalamocortical axons (TCAs) project from distinct regions of the thalamus and reach their targets in the cerebral cortex. Regionally restricted patterns of gene expression were again seen for many genes, but some regionally bounded expression patterns in the early postnatal thalamus had shifted substantially by E15.5. These findings reveal that nucleogenesis in the developing thalamus is associated with selective and complex changes in gene expression and provide a list of genes that may actively regulate the development of thalamic nuclei.

Regulation of isthmic Fgf8 signal by sprouty2.

Fgf8 functions as an organizer at the mes/metencephalic boundary (isthmus). We showed that a strong Fgf8 signal activates the Ras-ERK signaling pathway to organize cerebellar differentiation. Sprouty2 is expressed in an overlapping manner to Fgf8, and is induced by Fgf8. Its function, however, is indicated to antagonize Ras-ERK signaling. Here, we show the regulation of Fgf8 signaling in relation to Sprouty2. sprouty2 expression was induced very rapidly by Fgf8b, but interfered with ERK activation. sprouty2 misexpression resulted in a fate change of the presumptive metencephalon to the mesencephalon. Misexpression of a dominant negative form of Sprouty2 augmented ERK activation, and resulted in anterior shift of the posterior border of the tectum. The results indicate that Fgf8 activates the Ras-ERK signaling pathway to differentiate the cerebellum, and that the hyper- or hypo-signaling of this pathway affects the fate of the brain vesicles. Sprouty2 may regulate the Fgf8-Ras-ERK signaling pathway for the proper regionalization of the metencephalon and mesencephalon.