Medication-based profiling of older orthopedic patients: a multicenter cross-sectional study.

BACKGROUND: Managing medication use in older orthopedic patients is imperative to extend their healthy life expectancy in an aging society. However, the actual situation regarding polypharmacy, the intake of potentially inappropriate medications (PIMs), and fall risk-increasing drugs (FRIDs) among older orthopedic patients is not well characterized. This study aimed to investigate the medication-based profiles of older orthopedic patients to highlight the critical points of concern. METHODS: We retrospectively reviewed the clinical data of consecutive patients aged ≥ 65 years who underwent orthopedic surgery at two acute care hospitals between April 2020 and March 2021. The cutoff number of prescribed drugs for polypharmacy was set at 6. According to the specified guidelines, 19 categories of drugs were identified as PIMs, and 10 categories were classified as FRIDs. RESULTS: A total of 995 older patients with orthopedic surgery were assessed, of which 57.4% were diagnosed with polypharmacy, 66.0% were receiving PIMs, and 41.7% were receiving FRIDs. The prevalence of FRID intake did not significantly differ among patients with degenerative spinal disease (n = 316), degenerative disease of extremities (n = 331), and fractures (n = 272). Compared with patients with degenerative disease of the extremities, the multivariable-adjusted prevalence ratios (PRs) of polypharmacy and PIM intake were significantly higher in patients with degenerative spinal disease (1.26 [confidence intervals (CI): 1.11-1.44] and 1.12 [CI: 1.00-1.25]), respectively. Use of antiemetic drugs (adjusted PR, 13.36; 95% CI: 3.14-56.81) and nonsteroidal anti-inflammatory drugs (adjusted PR, 1.37; 95% CI: 1.05-1.78) was significantly higher in patients with degenerative spinal disease. Among patients with degenerative spinal disease, the prevalence of antiemetic drug intake was 8.7% in lumbar spinal patients and 0% in cervical spinal patients. CONCLUSIONS: More than half of the orthopedic patients in this study were affected by polypharmacy, and approximately two-thirds were prescribed some form of PIMs. Patients with degenerative spinal disease showed a significantly higher prevalence of polypharmacy and PIM use compared with other orthopedic diseases. Particular attention should be paid to the high frequency of antiemetic drugs and nonsteroidal anti-inflammatory drugs intake among patients with degenerative lumbar spine conditions.

Polypharmacy of Older Surgical Patients With Extremity Fractures.

Introduction: Fractures are often caused by falls in older people. Among various causes of falls, polypharmacy is known to be a risk of falls. Furthermore, potentially inappropriate medicines (PIMs), which interact with polypharmacy, include the drugs involved in falls. Here, we primarily aimed to investigate the prescribed drugs in older surgical patients with extremity fractures to determine the frequency of polypharmacy and identify PIMs. The second aim was to clarify the characterization of prescribed drugs of older patients with hip fracture. Materials and Methods: We retrospectively collected the following clinical data of consecutive patients aged ≥65 years who underwent surgery for extremity fractures at our hospital between April 2019 and March 2021. A total of 19 categories were considered as PIMs. The Poisson regression models were used to examine the association between the number of prescribed drugs and hip fracture prevalence. Results: A total of 590 patients were reviewed. Our data showed that 55% of older patients with extremity fractures took ≥6 prescription drugs. The frequency of prescription of hypnotics, antithrombotic drugs, diuretics, and non-steroidal anti-inflammatory drugs was comparatively high among the 19 categories of PIMs. Multivariable analysis revealed that polypharmacy was significantly associated with hip fractures. Among PIMs, antithrombotic drugs and diuretics were significantly associated with the prevalence of hip fractures. Finally, we found a significant positive association between the prevalence of hip fracture and the number of drug categories of PIMs among older patients with extremity fractures. Conclusions: The present study clarified the characterization of the prescribed drugs in older surgical patients with extremity fractures. Special attention should be paid to hip fractures of older patients with polypharmacy or prescribed with many drugs categories of PIMs, particularly antithrombotic drugs and diuretics.

Incomplete accumulation of perilesional reactive astrocytes exacerbates wound healing after closed-head injury by increasing inflammation and BBB disruption.

Wound healing after closed-head injury is a significant medical issue. However, conventional models of focal traumatic brain injury, such as fluid percussion injury and controlled cortical impact, employ mechanical impacts on the exposed cerebral cortex after craniotomy. These animal models are inappropriate for studying gliosis, as craniotomy itself induces gliosis. To address this, we developed a closed-head injury model and named "photo injury", which employs intense light illumination through a thinned-skull cranial window. Our prior work demonstrated that the gliosis of focal cerebral lesion after the photo injury does not encompass artificial gliosis and comprises two distinct reactive astrocyte subpopulations. The reactive astrocytes accumulated in the perilesional recovery area actively proliferate and express Nestin, a neural stem cell marker, while those in distal regions do not exhibit these traits. The present study investigated the role of perilesional reactive astrocytes (PRAs) in wound healing using the ablation of reactive astrocytes by the conditional knockout of Stat3. The extensive and non-selective ablation of reactive astrocytes in Nestin-Cre:Stat3f/f mice resulted in an exacerbation of injury, marked by increased inflammation and BBB disruption. On the other hand, GFAP-CreERT2:Stat3f/f mice exhibited the partial and selective ablation of the PRAs, while their exacerbation of injury was at the same extent as in Nestin-Cre:Stat3f/f mice. The comparison of these two mouse strains indicates that the PRAs are an essential astrocyte component for wound healing after closed-head injury, and their anti-inflammatory and regenerative functions are significantly affected even by incomplete accumulation. In addition, the reporter gene expression in the PRAs by GFAP-CreERT2 indicated a substantial elimination of these cells and an absence of differentiation into other cell types, despite Nestin expression, after wound healing. Thus, the accumulation and subsequent elimination of PRA are proposed as promising diagnostic and therapeutic avenues to bolster wound healing after closed-head injury.

Determinants of Gait Parameters in Patients With Severe Hip Osteoarthritis.

OBJECTIVE: To investigate the characteristics and symptoms of patients with hip osteoarthritis that are associated with spatiotemporal gait parameters, including their variability and asymmetry. DESIGN: A retrospective, cross-sectional study. SETTING: University hospital. PARTICIPANTS: The study analyzed the gait analysis data of 155 patients (N=155) with hip osteoarthritis who were admitted to a university hospital for total hip replacement and were able to walk on a treadmill without a handrail. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The dependent variables were gait parameters during treadmill walking. These included gait speed, stride length, cadence, coefficient of variation of stride length and stride time, swing time symmetry index, and step symmetry index. Single and multiple regression analyses were conducted using independent variables of the characteristics and symptoms of the patients, including age, sex, height, pain, leg-length discrepancy, and muscle strength of the affected and normal sides measured with a hand-held dynamometer (iliopsoas, gluteus medius, and quadriceps). RESULTS: In the analysis, gait speed and stride were the dependent variables, whereas age, height, and muscle strength on the affected side were the significant independent variables (P<.05). Additionally, pain demonstrated a marginal association with gait speed (P=.053). Only the leg-length discrepancy correlated with cadence. When the coefficient of variation of the stride length was the dependent variable, age and muscle strength on the affected side were significant. For the swing time symmetry index, only the muscle strength on the affected side was significant. Furthermore, the step symmetry index only correlated with leg-length discrepancy. The muscle strength on the affected side was the only significant independent variable for the coefficient of variation of the stride time. CONCLUSIONS: The results revealed that each of the frequent clinical symptoms of hip osteoarthritis, such as pain, muscle weakness, and leg-length discrepancy, can explain different aspects of gait performance.

Modern Microscopic Approaches to Astrocytes.

Microscopy started as the histological analysis based on intrinsic optical properties of tissues such as the refractive index and light absorption, and is expanding to include the visualization of organelles by chemical staining, localization of molecules by immunostaining, physiological measurements such as Ca2+ imaging, functional manipulation by optogenetics, and comprehensive analysis of chemical composition by Raman spectra. The microscope is one of the most important tools in neuroscience, which aims to reveal the complex intercellular communications underlying brain function and pathology. Many aspects of astrocytes, including the structures of their fine processes and physiological activities in concert with neurons and blood vessels, were revealed in the course of innovations in modern microscopy. The evolution of modern microscopy is a consequence of breakthroughs in spatiotemporal resolutions and expansions in molecular and physiological targets due to the progress in optics and information technology, as well as the inventions of probes using organic chemistry and molecular biology. This review overviews the modern microscopic approach to astrocytes.

Evaluation and Manipulation of Neural Activity using Two-Photon Holographic Microscopy.

Recent advances in optical bioimaging and optogenetics have enabled the visualization and manipulation of biological phenomena, including cellular activities, in living animals. In the field of neuroscience, detailed neural activity related to brain functions, such as learning and memory, has now been revealed, and it has become feasible to artificially manipulate this activity to express brain functions. However, the conventional evaluation of neural activity by two-photon Ca2+ imaging has the problem of low temporal resolution. In addition, manipulation of neural activity by conventional optogenetics through the optic fiber can only simultaneously regulate the activity of neurons with the same genetic background, making it difficult to control the activity of individual neurons. To solve this issue, we recently developed a microscope with a high spatiotemporal resolution for biological applications by combining optogenetics with digital holographic technology that can modify femtosecond infrared laser beams. Here, we describe protocols for the visualization, evaluation, and manipulation of neural activity, including the preparation of samples and operation of a two-photon holographic microscope (Figure 1). These protocols provide accurate spatiotemporal information on neural activity, which may be useful for elucidating the pathogenesis of neuropsychiatric disorders that lead to abnormalities in neural activity.

Hospital-Wide Surveillance of Fracture Risk Assessment by Both FRAX and Medication Patterns in Acute Care Hospital.

To identify patients at a high risk for primary and secondary osteoporotic fractures using fracture risk assessments performed using the current method and the proposed method, in an acute care hospital and to identify departments where high-risk patients are admitted. This retrospective study included patients aged 40-90 years who were hospitalized at Fujita Health University Hospital. We collated the clinical data and prescriptions of all study participants. We also gathered data pertaining to risk factors according to Fracture Risk Assessment Tool (FRAX). Of the 1595 patients, the mean number of major osteoporotic fracture risk predicted using FRAX was 11.73%. The department of rheumatology showed the highest fracture risk (18.55 ± 16.81) and had the highest number of patients on medications that resulted in reduced bone mineral density (1.07 ± 0.98 medication). Based on the FRAX, the proportion of patients in the high-risk group in this department was significantly higher compared with those in the remaining departments with respect to glucocorticoid administration, rheumatoid arthritis, and secondary osteoporosis. However, the departments included in the high-risk group were not necessarily the same as the departments included in the top group, based on the administered medications. FRAX score is calculated based on various risk factors; however, only glucocorticoid corresponds to medications. We should focus on medication prescription patterns in addition to FRAX to improve fracture risk assessment in hospital-wide surveillance. Therefore, we recommend the use of FRAX along with the prescribed medications to identify departments that admit high-risk patients.

Effects of porous tantalum on periprosthetic bone remodeling around metaphyseal filling femoral stem: a multicenter, prospective, randomized controlled study.

Periprosthetic bone loss due to adaptive bone remodeling is an important unresolved issue in cementless total hip arthroplasty (THA). The use of porous tantalum on the proximal surface of the femoral stem is expected to decrease postoperative bone loss around the prosthesis through early fixation. We conducted a multicenter randomized controlled study to determine if porous tantalum could reduce periprosthetic bone loss after THA. From October 2012 to September 2014, 118 patients (mean age, 61.5 years; 107 females and 11 males) were prospectively enrolled and were randomly allocated at a ratio of 1:1 to either a metaphyseal filling stem with a proximal porous tantalum coating (Trabecular Metal) or a conventional metaphyseal filling stem with fiber mesh coating (VerSys). Patients underwent dual-energy x-ray absorptiometry scans within 1 week after surgery (baseline) and at 6, 12, and 24 months after surgery to assess periprosthetic bone mineral density (BMD) in the 7 Gruen zones. In addition, the Japanese Orthopaedic Association hip score was assessed before surgery and at 6, 12, and 24 months after surgery. In the proximal periprosthetic region (zones 1 and 7), the Trabecular Metal group had significantly smaller reductions in BMD than the VerSys group throughout the study period. In the VerSys group, significant reductions in BMD compared to baseline were seen at each measurement point in all regions, except in zone 6 at 24 months. In the Trabecular Metal group, no significant reductions in BMD relative to baseline were seen in zones 1, 5, or 6 throughout the study period. Both groups demonstrated similar improvement in Japanese Orthopaedic Association hip scores over the study period. This study demonstrated that a proximally coated stem with porous tantalum has superior results over a conventional stem with titanium fiber mesh in terms of periprosthetic bone remodeling.

Increased MFG-E8 at neuromuscular junctions is an exacerbating factor for sarcopenia-associated denervation.

Sarcopenia is an important health problem associated with adverse outcomes. Although the etiology of sarcopenia remains poorly understood, factors apart from muscle fibers, including humoral factors, might be involved. Here, we used cytokine antibody arrays to identify humoral factors involved in sarcopenia and found a significant increase in levels of milk fat globule epidermal growth factor 8 (MFG-E8) in skeletal muscle of aged mice, compared with young mice. We found that the increase in MFG-E8 protein at arterial walls and neuromuscular junctions (NMJs) in muscles of aged mice. High levels of MFG-E8 at NMJs and an age-related increase in arterial MFG-E8 have also been identified in human skeletal muscle. In NMJs, MFG-E8 is localized on the surface of terminal Schwann cells, which are important accessory cells for the maintenance of NMJs. We found that increased MFG-E8 at NMJs precedes age-related denervation and is more prominent in sarcopenia-susceptible fast-twitch than in sarcopenia-resistant slow-twitch muscle. Comparison between fast and slow muscles further revealed that arterial MFG-E8 can be uncoupled from sarcopenic phenotype. A genetic deficiency in MFG-E8 attenuated age-related denervation of NMJs and muscle weakness, providing evidence of a pathogenic role of increased MFG-E8. Thus, our study revealed a mechanism by which increased MFG-E8 at NMJs leads to age-related NMJ degeneration and suggests that targeting MFG-E8 could be a promising therapeutic approach to prevent sarcopenia.

Prescription drug survey of elderly patients with degenerative musculoskeletal disorders.

AIMS: Elderly patients with musculoskeletal disorders are generally expected to receive many prescription drugs for non-musculoskeletal comorbidities and for alleviating chronic musculoskeletal pains. The aims of this study were to review the use of prescription drugs in elderly patients with elective surgeries for musculoskeletal disorders and to identify the factors associated with polypharmacy in elderly patients with musculoskeletal disorders. METHODS: We retrospectively collected the clinical data of patients aged ≥65 years who underwent knee arthroplasty, total hip arthroplasty, or spinal surgery for lumbar or cervical degenerative disorders at our institution. The following data were evaluated: age, body mass index, sex, surgical site, prescription drugs used, American Society of Anesthesiologists physical status grade, and medical history, including hypertension, hyperlipidemia, diabetes, stroke, malignancy, and smoking. Polypharmacy was defined as the use of six or more drugs. RESULTS: In the present study, 767 consecutive patients were evaluated retrospectively. The prevalence of polypharmacy was >50% in the elderly patients with musculoskeletal disorders. The mean numbers of total drugs and pain relief medications were significantly higher in the lumbar surgery group than in the other surgery groups. Multivariable analysis revealed that the factors associated with polypharmacy were lumbar surgery, hypertension, hyperlipidemia, diabetes, and malignancy. CONCLUSIONS: This is the first study to cross-sectionally review the drugs prescribed to patients with degenerative musculoskeletal disorders. It clearly identified the factors associated with polypharmacy in elderly patients with degenerative musculoskeletal disorders. Particular attention should be paid to polypharmacy in elderly patients with lumbar degenerative disorders. Geriatr Gerontol Int 2022; 22: 121-126.

Impact of musculoskeletal disorders on healthy life expectancy in Japan.

BACKGROUND: Musculoskeletal disorders are a key cause of morbidity in elderly people. How musculoskeletal disorders relate to healthy life expectancy remain elusive. Hence, we aimed to estimate gains in healthy life expectancy from the elimination of musculoskeletal diseases and injuries by using recent national health statistics data in Japan. METHODS: Mortality data were taken from Japanese national life tables and death certificates in 2016. Information on medical diagnoses, injuries, and activity were obtained from the 2016 Comprehensive Survey of Living Conditions. We examined five disorders: rheumatoid arthritis, arthrosis, low back pain, osteoporosis, and fracture. The prevalence of limitations in activities of daily living (ADL) in the population after eliminating the disorder was estimated as the proportion of outpatients without the disorder and ADL limitations, inpatients without the disorder in hospitals and clinics, and people without the disorder who reside in long-term elderly care facilities. RESULTS: There were small gains in life expectancy from elimination of all selected musculoskeletal disorders (0.0-0.1 years). Elimination of rheumatoid arthritis, osteoporosis, and fracture slightly increased the expected years without activity limitation (0.1-0.4) and slightly decreased years with activity limitation (0.1-0.4 years). Meanwhile, elimination of arthrosis, low back pain, and arthrosis and low back pain moderately increased expected years without activity limitation (0.3-1.5 years) and decreased years with activity limitation (0.3-1.5 years). In addition, elimination of rheumatoid arthritis, arthrosis, low back pain, osteoporosis, and fracture decreased expected years with ADL limitations (0.0-0.8 years) and non-ADL limitations (0.0-0.3 years). A combination of arthrosis and low back pain showed a moderate decrease in expected years with both ADL limitations (0.7-1.1 years) and non-ADL limitations (0.3-0.4). CONCLUSIONS: These findings provide clinical evidence that among the musculoskeletal disorders low back pain and arthrosis are the key factors for the elongation of healthy life expectancy.

Preoperative prevalence of deep vein thrombosis in patients scheduled to have surgery for degenerative musculoskeletal disorders.

BACKGROUND: Although the incidence of symptomatic pulmonary thromboembolism after elective surgery for degenerative musculoskeletal disorders is comparatively low, it is extremely detrimental to both patients and health-care providers. Therefore, its prevention is mandatory. We aimed to perform a cross-sectional analysis of deep venous thrombosis (DVT) before elective surgery for degenerative musculoskeletal disorders, including total knee arthroplasty (TKA), total hip arthroplasty (THA), and spinal surgery, and identify the factors associated with the incidence of preoperative DVT. METHODS: The clinical data of patients aged ≥ 30 years who underwent TKA or THA, and spine surgery for lumbar or cervical degenerative disorders at our institution were retrospectively collected. D-dimer levels were measured preoperatively in all the patients scheduled for surgery. For the patients with D-dimer levels ≥ 1 µg/mL or who were determined by their physicians to be at high risk of DVT, the lower extremity vein was preoperatively examined for DVT on ultrasonography. RESULTS: Overall, we retrospectively evaluated 1236 consecutive patients, including 701 men and 535 women. Of the patients, 431 and 805 had D-dimer levels ≥ 1 and < 1 µg/mL, respectively. Of 683 patients who underwent lower extremity ultrasonography, 92 had proximal (n = 7) and distal types (n = 85) of DVT. The preoperative prevalence of DVT was 7.4 %. No patient had the incidence of postoperative symptomatic venous thromboembolism. A multivariate analysis revealed that age ≥ 80 years (odds ratio [OR], 95 % confidence interval [CI]: 2.8, 1.1-7.3), knee surgery (2.1, 1.1-4.0), American Society of Anesthesiologists (ASA) grade 2 (2.8, 1.2-6.8), ASA grades 3 or 4 (3.1, 1.0-9.4), and malignancy (1.9, 1.1-3.2) were significantly associated with DVT incidence. CONCLUSIONS: This is the first study to conduct a cross-sectional analysis of preoperative DVT data of patients scheduled for elective surgery for degenerative musculoskeletal disorders. Although whether screening for preoperative DVT is needed to prevent postoperative symptomatic pulmonary thromboembolism remains to be clarified, our data suggested that DVT should be noted before surgery in the patients with advanced age, knee surgery, high ASA physical status, and malignancy.

Effects of leptin on proliferation of astrocyte- and tanycyte-like neural stem cells in the adult mouse medulla oblongata.

Astrocyte- and tanycyte-like neural stem cells (NSCs) were recently detected in the area postrema (AP) and central canal (CC) of the adult medulla oblongata, respectively. The present study aimed to examine dynamical behaviors of the astrocyte- and tanycyte-like NSCs of the mouse medulla oblongata to leptin. The neurosphere assay identified astrocytes in the AP and tanycytes in the CC as NSCs based on their self-renewing neurospherogenic potential. Both NSCs in neurosphere cultures were multipotent cells that generate astrocytes, oligodendrocytes, and neurons. Astrocyte-like NSCs actively proliferated and tanycyte-like NSCs were quiescent under physiologically-relevant in vivo conditions. Chronic leptin treatment promoted proliferation of astrocyte-like NSCs in the AP both in vitro and in vivo. Leptin receptors were expressed in astrocyte-like, but not tanycyte-like NSCs. Food deprivation significantly diminished proliferation of astrocyte-like NSCs. Therefore, the present study indicates that proliferation of astrocyte-like, but not tanycyte-like NSCs is regulated by nutritional conditions.

Desloratadine inhibits heterotopic ossification by suppression of BMP2-Smad1/5/8 signaling.

Heterotopic ossification (HO) is a pathological condition in which ectopic bone forms within soft tissues such as skeletal muscle. Human platelet-derived growth factor receptor α positive (PDGFRα+) cells, which were proved to be the original cells of HO were incubated in osteogenic differentiation medium with Food and Drug Administration-approved compounds. Alkaline phosphatase activity was measured as a screening to inhibit osteogenic differentiation. For the compounds which inhibited osteogenic differentiation of PDGFRα+ cells, we examined dose dependency of its effect using alizarin red S staining and its cell toxicity using WST-8. In addition, regulation of bone morphogenetic proteins (BMP)-Smad signaling which is the major signal of osteogenic differentiation was investigated by Western blotting to elucidate the mechanism of osteogenesis inhibitory effect by the compound. In vivo experiment, complete transverse incision of Achilles tendons in mice was made and mice were fed the compound by mixing with drinking water after operation. Ten weeks after operation, we assessed and quantified HO by micro-computed tomography scan. Intriguingly, we discovered desloratadine inhibited osteogenic differentiation of PDGFRα+ cells using the drug repositioning method. Desloratadine inhibited osteogenic differentiation of the cells dose dependently without cell toxicity. Desloratadine suppressed phosphorylation of Smad1/5/8 induced by BMP2 in PDGFRα+ cells. In Achilles tenotomy mice model, desloratadine treatment significantly inhibited ectopic bone formation compared with control. In conclusion, we discovered desloratadine inhibited osteogenic differentiation using human PDGFRα+ cells and proved its efficacy using Achilles tenotomy ectopic bone formation model in vivo. Our study paved the way to inhibit HO in early clinical use because of its guaranteed safety.

Mesenchymal Bmp3b expression maintains skeletal muscle integrity and decreases in age-related sarcopenia.

Age-related sarcopenia constitutes an important health problem associated with adverse outcomes. Sarcopenia is closely associated with fat infiltration in muscle, which is attributable to interstitial mesenchymal progenitors. Mesenchymal progenitors are nonmyogenic in nature but are required for homeostatic muscle maintenance. However, the underlying mechanism of mesenchymal progenitor-dependent muscle maintenance is not clear, nor is the precise role of mesenchymal progenitors in sarcopenia. Here, we show that mice genetically engineered to specifically deplete mesenchymal progenitors exhibited phenotypes markedly similar to sarcopenia, including muscle weakness, myofiber atrophy, alterations of fiber types, and denervation at neuromuscular junctions. Through searching for genes responsible for mesenchymal progenitor-dependent muscle maintenance, we found that Bmp3b is specifically expressed in mesenchymal progenitors, whereas its expression level is significantly decreased during aging or adipogenic differentiation. The functional importance of BMP3B in maintaining myofiber mass as well as muscle-nerve interaction was demonstrated using knockout mice and cultured cells treated with BMP3B. Furthermore, the administration of recombinant BMP3B in aged mice reversed their sarcopenic phenotypes. These results reveal previously unrecognized mechanisms by which the mesenchymal progenitors ensure muscle integrity and suggest that age-related changes in mesenchymal progenitors have a considerable impact on the development of sarcopenia.

The Diversity of Intermediate Filaments in Astrocytes.

Despite the remarkable complexity of the individual neuron and of neuronal circuits, it has been clear for quite a while that, in order to understand the functioning of the brain, the contribution of other cell types in the brain have to be accounted for. Among glial cells, astrocytes have multiple roles in orchestrating neuronal functions. Their communication with neurons by exchanging signaling molecules and removing molecules from extracellular space takes place at several levels and is governed by different cellular processes, supported by multiple cellular structures, including the cytoskeleton. Intermediate filaments in astrocytes are emerging as important integrators of cellular processes. Astrocytes express five types of intermediate filaments: glial fibrillary acidic protein (GFAP); vimentin; nestin; synemin; lamins. Variability, interactions with different cellular structures and the particular roles of individual intermediate filaments in astrocytes have been studied extensively in the case of GFAP and vimentin, but far less attention has been given to nestin, synemin and lamins. Similarly, the interplay between different types of cytoskeleton and the interaction between the cytoskeleton and membranous structures, which is mediated by cytolinker proteins, are understudied in astrocytes. The present review summarizes the basic properties of astrocytic intermediate filaments and of other cytoskeletal macromolecules, such as cytolinker proteins, and describes the current knowledge of their roles in normal physiological and pathological conditions.

Neural stem cell phenotype of tanycyte-like ependymal cells in the circumventricular organs and central canal of adult mouse brain.

Tanycyte is a subtype of ependymal cells which extend long radial processes to brain parenchyma. The present study showed that tanycyte-like ependymal cells in the organum vasculosum of the lamina terminalis, subfornical organ and central canal (CC) expressed neural stem cell (NSC) marker nestin, glial fibrillar acidic protein and sex determining region Y. Proliferation of these tanycyte-like ependymal cells was promoted by continuous intracerebroventricular infusion of fibroblast growth factor-2 and epidermal growth factor. Tanycytes-like ependymal cells in the CC are able to form self-renewing neurospheres and give rise mostly to new astrocytes and oligodendrocytes. Collagenase-induced small medullary hemorrhage increased proliferation of tanycyte-like ependymal cells in the CC. These results demonstrate that these tanycyte-like ependymal cells of the adult mouse brain are NSCs and suggest that they serve as a source for providing new neuronal lineage cells upon brain damage in the medulla oblongata.

Three-dimensional fluorescence imaging using the transport of intensity equation.

We propose a nonscanning three-dimensional (3-D) fluorescence imaging technique using the transport of intensity equation (TIE) and free-space Fresnel propagation. In this imaging technique, a phase distribution corresponding to defocused fluorescence images with a point-light-source-like shape is retrieved by a TIE-based phase retrieval algorithm. From the obtained phase distribution, and its corresponding amplitude distribution, of the defocused fluorescence image, various images at different distances can be reconstructed at the desired plane after Fresnel propagation of the complex wave function. Through the proposed imaging approach, the 3-D fluorescence imaging can be performed in multiple planes. The fluorescence intensity images are captured with the help of an electrically tunable lens; hence, the imaging technique is free from motion artifacts. We present experimental results corresponding to microbeads and a biological sample to demonstrate the proposed 3-D fluorescence imaging technique.

VEGF- and PDGF-dependent proliferation of oligodendrocyte progenitor cells in the medulla oblongata after LPC-induced focal demyelination.

The myelin sheath is critical in maintaining normal functions of the adult central nervous system (CNS) and the loss of the myelin sheath results in various neurological diseases. Although remyelination is the intrinsic repair system against demyelination that new myelin sheath is formed around axons in the adult CNS, little has been reported on remyelination system in the medulla oblongata. In the present study, we showed that the proliferation of oligodendrocyte progenitor cells (OPCs) was increased in the medulla oblongata by lysophosphatidylcholine (LPC)-induced focal demyelination, but that of NSCs was not changed. The inhibition of vascular endothelial growth factor (VEGF)- and platelet-derived growth factor (PDGF)-signaling suppressed the proliferation of OPCs by LPC-induced demyelination. Thus, the present study indicates that resident OPCs contribute to focal remyelination and VEGF and PDGF signaling is required for the proliferation of OPCs in the medulla oblongata of the adult mouse.

Metabolic Plasticity of Astrocytes and Aging of the Brain.

As part of the blood-brain-barrier, astrocytes are ideally positioned between cerebral vasculature and neuronal synapses to mediate nutrient uptake from the systemic circulation. In addition, astrocytes have a robust enzymatic capacity of glycolysis, glycogenesis and lipid metabolism, managing nutrient support in the brain parenchyma for neuronal consumption. Here, we review the plasticity of astrocyte energy metabolism under physiologic and pathologic conditions, highlighting age-dependent brain dysfunctions. In astrocytes, glycolysis and glycogenesis are regulated by noradrenaline and insulin, respectively, while mitochondrial ATP production and fatty acid oxidation are influenced by the thyroid hormone. These regulations are essential for maintaining normal brain activities, and impairments of these processes may lead to neurodegeneration and cognitive decline. Metabolic plasticity is also associated with (re)activation of astrocytes, a process associated with pathologic events. It is likely that the recently described neurodegenerative and neuroprotective subpopulations of reactive astrocytes metabolize distinct energy substrates, and that this preference is supposed to explain some of their impacts on pathologic processes. Importantly, physiologic and pathologic properties of astrocytic metabolic plasticity bear translational potential in defining new potential diagnostic biomarkers and novel therapeutic targets to mitigate neurodegeneration and age-related brain dysfunctions.