Unilateral spatial neglect (USN) may lead to poor functional rehabilitation outcomes. However, studies investigating the rehabilitation outcomes of right-sided USN are lacking. We aimed to ...investigate (1) the clinical impacts of USN, including right-sided USN, for stroke patients in sub-acute rehabilitation, and (2) evaluate the differences in clinical characteristics and rehabilitation outcomes between right- and left-sided USN patients. We retrospectively screened the medical records of 297 inpatients at the Tokyo-Bay Rehabilitation Hospital who experienced a cerebrovascular accident with supratentorial lesions between January 1st, 2014 and December 31st, 2016. We performed independent multiple regression analysis in patients with left and right hemisphere damage. The Behavioral Inattention Test was a significant independent variable for predicting the motor, cognitive, and total functional independence measure (FIM), compared to the Stroke Impairment Assessment Set and Mini-Mental State Examination. USN affects motor FIM recovery more than cognitive FIM recovery regardless of the damaged hemisphere. Our study results confirm that both right- and left-sided USN influence the functional recovery of stroke patients. USN occurs, slightly less frequently, following a left hemisphere stroke. However, USN negatively affected rehabilitation outcomes, regardless of the neglected side. Therefore, USN treatment is necessary for patients with left and right hemisphere damage.
Context: The process of epiphyseal fusion during puberty is regulated by estrogen, even in males.
Objective: Our objective was to investigate whether anastrozole, a potent aromatase inhibitor, could ...delay bone age acceleration and increase predicted adult height in adolescent boys with GH deficiency.
Methods: Fifty-two adolescent males with GH deficiency treated with GH were randomized to cotreatment with anastrozole or placebo daily for up to 36 months.
Results: Fifty subjects completed 12 months, 41 completed 24 months, and 28 completed 36 months. Linear growth was comparable between groups; however, there was a significantly slower increase in bone age advancement from baseline in the anastrozole group vs. placebo group after 2 yr (+1.8 ± 0.1 vs. +2.7 ± 0.1 yr, P < 0.0001) and after 3 yr (+2.5 ± 0.2 vs. +4.1 ± 0.1 yr, P < 0.0001). This resulted in a net increase in predicted adult height of +4.5 ± 1.2 cm in the anastrozole group at 24 months and +6.7 ± 1.4 cm at 36 months as compared with a 1-cm gain at both time points in the placebo group. Estradiol and estrone concentrations increased less in the anastrozole group compared with placebo group. All boys on the aromatase inhibitor had normal tempo of virilization. Safety data, including glucose, and plasma lipid concentrations were comparable between groups.
Conclusions: Anastrozole increases adult height potential of adolescent boys on GH therapy while maintaining normal pubertal progression after 2–3 yr. This treatment offers an alternative in promoting growth in GH-deficient boys in puberty. Long-term follow up is needed to elucidate fully the safety and efficacy of this approach.
Abstract Given potential differences between the skeletal and other effects of the third generation aromatase inhibitors (AIs), we conducted an open, randomised Phase I study, comparing the effects ...of three licensed AIs on bone turnover markers, lipid profiles and adrenal function. Treatment comparisons were undertaken in 90 healthy postmenopausal women with normal bone mineral density who received once daily oral anastrozole (1 mg, n = 29), letrozole (2.5 mg, n = 29) or exemestane (25 mg, n = 32) for 24 weeks with a subsequent 12 week washout period. All three AIs induced increases in bone resorption markers, but no significant differences were observed in their effects on bone turnover markers. Greater differences were observed in lipid metabolism. Notably, exemestane, but not anastrozole or letrozole, significantly increased the LDL:HDL cholesterol ratio by 12 weeks, largely mediated by a decrease in HDL-cholesterol. Further, long-term clinical studies are required to determine the impact, if any, of the differences observed between the AIs.
Purpose: In this study, we used the Japanese version of the Allen Cognitive Level Screen-5（ACLS-5） manual to determine its validity for use among occupational therapists in Japan by examining the ...relationship between the test results of the ACLS-5 in terms of the Mini Mental State Examination-Japanese, Functional Independence Measure, and bed-fast scale. Methods: We determined the Spearman’s rank correlation between the ACLS-5 and the bed-fast scale（widely used in Japan to assess activities of daily living）, the Functional Independence Measure（FIM）, and the Mini Mental State Examination-Japanese（MMSE-J）, which is used to measure cognitive function. In addition, we used the MMSE scores to divide the subjects into two groups: a healthy group with no cognitive problems （total MMSE-J≧28） and a group with cognitive problems（total MMSE-J≦27）. With our criterion variable thus set, we adjusted the ACLS-5 scores and added gender and age values, then performed a logistic regression analysis using the likelihood ratio test to ascertain the percentage of correct classifications（p ＜ 0.05）. Results: Our ACLS-5 measurement results were significantly correlated with the total bed-fast scale scores（ρ＝0.46）, total MMSE-J scores（ρ＝0.54）, and total FIM scores（ρ＝0.47）. In the logistic regression analysis, our ACLS-5 results were significant in terms of determining the presence or absence of cognitive problems, with a solid percentage of correct classifications（ 74.5％）. Conclusion: The measurement results for ACLS-5 and other evaluation methods obtained in this study confirm the validity of ACLS-5 for clinical use in Japan.
Background Mast cell (MC) progenitors leave the bone marrow, enter the circulation, and settle in the skin and other tissues. Their maturation in tissues is influenced by the surrounding ...microenvironment. Objective We tested the hypothesis that environmental factors play a role in MC maturation in the skin. Methods MCs were numerically, phenotypically, and functionally compared between germ-free (GF), specific pathogen-free, and GF mice reconstituted with microbiota. The maturity of MCs was then correlated with skin levels of stem cell factor (SCF), a critical MC differentiation factor, and lipoteichoic acid (LTA), a Toll-like receptor 2 ligand. MCs were also evaluated in mice with keratinocyte-specific deletion of Scf. Results We found that GF mice express abnormally low amounts of SCF, a critical MC differentiation factor, and contain MCs that are largely undifferentiated. Reconstituting the GF microbiota reverted this MC phenotype to normal, indicating that the phenotype is related to ongoing interactions of the microbiota and skin. Consistent with the immaturity of GF MCs, degranulation-provoking compound 48/80 induced less edema in the skin of GF mice than in conventional mice. Our results show that the skin microbiome drives SCF production in keratinocytes, which triggers the differentiation of dermal MCs. Because the skin microbiome is a rich source of LTA, a Toll-like receptor 2 ligand, we mimicked the GF microbiome's effect on MCs by applying LTA to the skin of GF mice. We also demonstrated that MC migration within the skin depends exclusively on keratinocyte-produced SCF. Conclusion This study has revealed a novel mechanism by which the skin microbiota signals the recruitment and maturation of MCs within the dermis through SCF production by LTA-stimulated keratinocytes.
Rare circulating tumor cells (CTCs) present in the bloodstream of patients with cancer provide a potentially accessible source for detection, characterization, and monitoring of nonhematological ...cancers. We previously demonstrated the effectiveness of a microfluidic device, the CTC-Chip, in capturing these epithelial cell adhesion molecule (EpCAM)-expressing cells using antibody-coated microposts. Here, we describe a high-throughput microfluidic mixing device, the herringbone-chip, or “HB-Chip,” which provides an enhanced platform for CTC isolation. The HB-Chip design applies passive mixing of blood cells through the generation of microvortices to significantly increase the number of interactions between target CTCs and the antibody-coated chip surface. Efficient cell capture was validated using defined numbers of cancer cells spiked into control blood, and clinical utility was demonstrated in specimens from patients with prostate cancer. CTCs were detected in 14 of 15 (93%) patients with metastatic disease (median = 63 CTCs/mL, mean = 386 ± 238 CTCs/mL), and the tumor-specific TMPRSS2-ERG translocation was readily identified following RNA isolation and RT-PCR analysis. The use of transparent materials allowed for imaging of the captured CTCs using standard clinical histopathological stains, in addition to immunofluorescence-conjugated antibodies. In a subset of patient samples, the low shear design of the HB-Chip revealed microclusters of CTCs, previously unappreciated tumor cell aggregates that may contribute to the hematogenous dissemination of cancer.
Oligodendrocyte precursor cells (OPCs) in the adult brain contribute to white matter homeostasis. After white matter damage, OPCs compensate for oligodendrocyte loss by differentiating into mature ...oligodendrocytes. However, the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that, during endogenous recovery from white matter ischemic injury, astrocytes support the maturation of OPCs by secreting brain-derived neurotrophic factor (BDNF). For in vitro experiments, cultured primary OPCs and astrocytes were prepared from postnatal day 2 rat cortex. When OPCs were subjected to chemical hypoxic stress by exposing them to sublethal CoCl2 for 7 d, in vitro OPC differentiation into oligodendrocytes was significantly suppressed. Conditioned medium from astrocytes (astro-medium) restored the process of OPC maturation even under the stressed conditions. When astro-medium was filtered with TrkB-Fc to remove BDNF, the BDNF-deficient astro-medium no longer supported OPC maturation. For in vivo experiments, we analyzed a transgenic mouse line (GFAP(cre)/BDNF(wt/fl)) in which BDNF expression is downregulated specifically in GFAP(+) astrocytes. Both wild-type (GFAP(wt)/BDNF(wt/fl) mice) and transgenic mice were subjected to prolonged cerebral hypoperfusion by bilateral common carotid artery stenosis. As expected, compared with wild-type mice, the transgenic mice exhibited a lower number of newly generated oligodendrocytes and larger white matter damage. Together, these findings demonstrate that, during endogenous recovery from white matter damage, astrocytes may promote oligodendrogenesis by secreting BDNF.
The repair of white matter after brain injury and neurodegeneration remains a tremendous hurdle for a wide spectrum of CNS disorders. One potentially important opportunity may reside in the response of residual oligodendrocyte precursor cells (OPCs). OPCs may serve as a back-up for generating mature oligodendrocytes in damaged white matter. However, the underlying mechanisms are still mostly unknown. Here, we use a combination of cell biology and an animal model to report a new pathway in which astrocyte-derived BDNF supports oligodendrogenesis and regeneration after white matter damage. These findings provide new mechanistic insight into white matter physiology and pathophysiology, which would be broadly and clinically applicable to CNS disease.
Trophic coupling between cerebral endothelium and their neighboring cells is required for the development and maintenance of blood-brain barrier (BBB) function. Here we report that oligodendrocyte ...precursor cells (OPCs) secrete soluble factor TGF-β1 to support BBB integrity. Firstly, we prepared conditioned media from OPC cultures and added them to cerebral endothelial cultures. Our pharmacological experiments showed that OPC-conditioned media increased expressions of tight-junction proteins and decreased in vitro BBB permeability by activating TGB-β-receptor-MEK/ERK signaling pathway. Secondly, our immuno-electron microscopic observation revealed that in neonatal mouse brains, OPCs attach to cerebral endothelial cells via basal lamina. And finally, we developed a novel transgenic mouse line that TGF-β1 is knocked down specifically in OPCs. Neonates of these OPC-specific TGF-β1 deficient mice (OPC-specific TGF-β1 partial KO mice: PdgfraCre/Tgfb1flox/wt mice or OPC-specific TGF-β1 total KO mice: PdgfraCre/Tgfb1flox/flox mice) exhibited cerebral hemorrhage and loss of BBB function. Taken together, our current study demonstrates that OPCs increase BBB tightness by upregulating tight junction proteins via TGF-β signaling. Although astrocytes and pericytes are well-known regulators of BBB maturation and maintenance, these findings indicate that OPCs also play a pivotal role in promoting BBB integrity.
Oligodendrocytes are one of the major cell types in cerebral white matter. Under normal conditions, they form myelin sheaths that encircle axons to support fast nerve conduction. Under conditions of ...cerebral ischemia, oligodendrocytes tend to die, resulting in white-matter dysfunction. Repair of white matter involves the ability of oligodendrocyte precursors to proliferate and mature. However, replacement of lost oligodendrocytes may not be the only mechanism for white-matter recovery. Emerging data now suggest that coordinated signaling between neural, glial, and vascular cells in the entire neurovascular unit may be required. In this mini-review, we discuss how oligodendrocyte lineage cells participate in signaling and crosstalk with other cell types to underlie function and recovery in various experimental models of subcortical white-matter injury.
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