Cerebrospinal Fluid Biomarkers for the Diagnosis of Alzheimer Disease in South Korea.

Laboratory-specific reference values for cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers are necessary. Our objective was to apply well-known CSF biomarkers and redetermine their diagnostic cutoff values for AD in South Korea. CSF samples from matched control subjects (n=71), patients with AD dementia (ADD, n=76), and other neurological disorders with cognitive decline (OND, n=47) were obtained from 6 Korean dementia clinics according to a standardized protocol. CSF biomarker concentrations were measured using enzyme-linked immunosorbent assay. CSF biomarkers differed significantly between the ADD and control groups (P<0.001 for all), and between the ADD and OND groups (P<0.001 for all). The areas under the curve in differentiation of ADD from control subjects were 0.97 for Aß42, 0.93 for total tau (tTau), 0.86 for pTau, and 0.99 for both tTau/Aß42 and pTau/Aß42 ratios. Our revised cutoff value for Aß42 was higher than our previous one, whereas the values for the Tau proteins were similar. The tTau/Aß42 ratio had the highest accuracy, 97%. Our findings highlight the usefulness of CSF AD biomarkers in South Korea, and the necessity of continually testing the reliability of cutoff values.

Tuning the Biointerface: Low-Temperature Surface Modification Strategies for Orthopedic Implants to Enhance Osteogenic and Antimicrobial Activity.

As both the average life expectancy and incidence of bone tissue reconstruction increases, development of load-bearing implantable materials that simultaneously enhance osseointegration while preventing postoperative infection is crucial. To address this need, significant research efforts have been dedicated to developing surface modification strategies for metallic load-bearing implants and scaffolds. Despite the abundance of strategies reported, many address only one factor, for example, surface chemistry or topography. Furthermore, the incorporation of surface features to increase osteocompatibility can increase the probability of infection, by encouraging the formation of bacterial biofilms. To truly advance this field, research efforts must focus on developing multifunctional coatings that concurrently address these complex and competing requirements. In addition, particular emphasis should be placed on utilizing surface modification processes that are versatile, low cost, and scalable, for ease of translation to mass manufacturing and clinical use. The aim of this short Review is to highlight recent advances in scalable and multifunctional surface modification techniques that obtain a programmed response at the bone tissue/implant interface. Low-temperature approaches based on macromolecule immobilization, electrochemical techniques, and solution processes are discussed. Although the strategies discussed in this Review have not yet been approved for clinical use, they show great promise toward developing the next generation of ultra-long-lasting biomaterials for joint and bone tissue repair.

Femtosecond laser induced nano-textured micropatterning to regulate cell functions on implanted biomaterials.

Posterior capsular opacification (PCO) is the most common complication of cataract surgery. PCO is due to the proliferation, migration, and epithelial-to-mesenchymal transition of the residual lens epithelial cells (LECs) within the lens capsule. As surface topography influences cellular response, we investigated the effect of modulating the dimensions of periodic nano-textured patterns on the surface of an intraocular lens material to regulate lens epithelial cell functions such as cell adhesion, migration, orientation, and proliferation. Patterned poly(HEMA) samples were prepared by a femtosecond laser microfabrication, and the behaviors of human B-3 LECs were observed on groove/ridge patterns with widths varying from 5 to 40 µm. In the presence of ridge and groove patterns, the adherent cells elongated along the direction of the patterns, and f-actin of the cells was spread to a lesser extent on the nano-textured groove surfaces. Both single and collective cell migrations were significantly inhibited in the perpendicular direction of the patterns on the nano-textured micro-patterned samples. We also fabricated the patterns on the curved surface of a commercially available intraocular lens for in vivo evaluation. In vivo results showed that a patterned IOL could help suppress the progression of PCO by inhibiting cell migration from the edge to the center of the IOL. Our reports demonstrate that nano- and microscale topographical patterns on a biomaterial surface can regulate cellular behavior when it is implanted into animals.

Quantitative autonomic function test in differentiation of multiple system atrophy from idiopathic Parkinson disease.

BACKGROUND: Differential diagnosis of idiopathic Parkinson disease (IPD) and multiple system atrophy-Parkinson type (MSA-P) is challenging since they share clinical features with parkinsonism and autonomic dysfunction. To distinguish MSA-P from IPD when the symptoms are relatively mild, we investigated the usefulness of the quantitative fractionalized autonomic indexes and evaluated the correlations of autonomic test indexes and functional status. METHODS: Thirty-six patients with parkinsonism (22 with IPD and 14 with MSA-P) in Soonchunhyang University Bucheon Hospital from February 2014 to June 2015 were prospectively enrolled in the study. We compared fractionalized autonomic indexes and composite autonomic scoring scale between patients with IPD and MSA-P with Hoehn and Yahr (H&Y) score ≤3. Parasympathetic indexes included expiratory/inspiratory ratio during deep breathing, Valsalva ratio (VR), and regression slope of systolic blood pressure (BP) in early phase II (vagal baroreflex sensitivity) during Valsalva maneuver. Sympathetic adrenergic indexes were pressure recovery time (PRT) and adrenergic baroreflex sensitivity (BRSa) (BP decrement associated with phase 3 divided by the PRT), sympathetic index 1, sympathetic index 3, early phase II mean BP drop, and pulse pressure reduction rate. Additionally, we compared the unified multiple system atrophy rating scale (UMSARS) and H&Y scores and the autonomic indexes in all patients. RESULTS: PRT was significantly different between the IPD and MSA-P groups (P = 0.004) despite the similar BP drop during tilt. Cut-off value of PRT was 5.5 s (sensitivity, 71.4%; specificity, 72.7%). VR (r = -0.455, P = 0.009) and BRSa (r = -0.356, P = 0.036) demonstrated a significant correlation with UMSARS and H&Y scores. CONCLUSIONS: Among the cardiovascular autonomic indexes, PRT can be a useful parameter in differentiating the early stage of MSA-P from that of IPD. Moreover, VR, and BRSa may be the optimal indexes in determining functional symptom severity.

The Correlation Study between Plasma Aß Proteins and Cerebrospinal Fluid Alzheimer's Disease Biomarkers.

BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß proteins (Aß). In this study we explored the correlation of plasma Aß40 and Aß42 concentrations with Aß42, total tau (tTau) and phosphorylated tau 181 (pTau181) levels in cerebrospinal fluid (CSF) in AD and control subjects to further understand the characteristics of plasma Aß proteins levels. METHODS: The consecutive subjects (44 AD and 47 controls) in this study were recruited. The plasma levels of Aß40 and Aß42 were measured using a commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kits. And the corresponding CSFs were analyzed in terms of Aß42, tTau and pTau181 concentrations using INNOTEST ELISA kits. Further, the albumin levels were measured both in serum and CSF and albumin ratio was obtained to check the integrity of blood-brain barrier. RESULTS: CSF Aß42 concentrations were significantly decreased while tTau and pTau181 levels were significantly increased in AD subjects. The plasma levels of Aß42 were significantly lower (p=0.007), while the Aß40/Aß42 ratio was significantly higher (p<0.001) in AD patients than in controls. The overall plasma Aß42 levels showed a positive correlation with those of CSF Aß42 (p=0.001), but not with the others in CSF. In subgroup analysis, the CSF Aß42 demonstrated positive correlation with not only plasma Aß42 but also Aß40 levels in controls. However, no significant relationship was noted between plasma and CSF Aß proteins in AD group. CONCLUSIONS: The plasma Aß42 and Aß40 concentrations were shown to have a close relationship with CSF Aß42 levels in controls, but not in AD subjects. Our results suggest that the correlation between plasma Aß40 and CSF Aß42 levels is perturbed in AD.

Ultrathin Metal Films with Defined Topographical Structures as In Vitro Cell Culture Platforms for Unveiling Vascular Cell Behaviors.

Implanted material surfaces make direct contact with body tissues to work on its own purpose. Therefore, studies of the surface properties of implantable materials that determine cell fate are very important for successful implantation. Although numerous studies have addressed the relationship between cells and material surfaces, nonmetallic surfaces and metallic surfaces likely produce different cellular responses because of their intrinsic differences in surface energy, roughness, and chemical composition. Moreover, given the nontransparent property of metal materials, which hampers the real-time imaging of cellular behavior, a detailed cellular-level analysis at the metal-tissue interface has not been performed. In this study, metal-based cell culture platforms (MCPs) with defined microscale topographical patterns are developed using a combination of photolithography and direct current magnetron sputtering techniques. The MCPs allow to observe vascular cells on metals in real time and identify the selective regulation of human aortic smooth muscle cells and Human umbilical vein endothelial cells (HUVECs) by metallic surface topography. Additionally, atomic force microscopy, contact angles, and energy-dispersive X-ray spectroscopy analyses show that the MCPs exhibit nearly identical chemical properties with their bulk counterparts, demonstrating that MCPs can be utilized as an in vitro cell culture platform system for understanding the cellular behavior on metal substrates.

Developing a culturally appropriate depression prevention program: the family coping skills program.

Depression is a disorder that can have particularly deleterious effects on individuals from racial/ethnic minority and low-income backgrounds. Culturally appropriate prevention programs offer a way to provide accessible and effective mental health services to these underserved populations. The authors introduce the Family Coping Skills Program (FCSP), a novel depression prevention program developed specifically for low-income Latina mothers. The authors present the theoretical underpinnings of the FCSP and describe their efforts to make the program culturally appropriate and to enhance recruitment and retention of participants. Initial outcome data from an uncontrolled trial were promising and support continued development and evaluation of the FCSP and other similar programs.

Isolated axial lateropulsion with ipsilesional subjective visual vertical tilt in caudal lateral medullary infarction.

The isolated body lateropulsion has been well recognized in caudal lateral medullary infarction and postulated to result from the involvement of ipsilateral dorsal spinocerebellar tract which is known to convey proprioception of trunk and legs. However, there has been no case accompanied by the tilt of the subjective visual vertical in caudal lateral medullary infarction. Recently, it has been suggested that a lesion in the ipsilateral graviceptive vestibulothalamic pathway can lead to alteration of subjective visual vertical without ocular tilt reaction in various brainstem lesions. Here we describe two cases of caudal lateral medullary infarction with ipsilesional body lateropulsion and subjective visual vertical tilt but without limb ataxia or ocular tilt reaction. It could be hypothesized that the ascending graviceptive information from the spinal cord may run adjacent to the dorsal spinocerebellar tract or perception of the visual vertical can be influenced by ascending spinal proprioception.

Elevation of the Plasma Aß40/Aß42 Ratio as a Diagnostic Marker of Sporadic Early-Onset Alzheimer's Disease.

BACKGROUND: Although plasma amyloid-ß (Aß) levels have been evaluated as a possible diagnostic marker of Alzheimer's disease (AD), the findings are inconsistent. OBJECTIVE: The present study aimed to validate plasma levels of Aß40, Aß42, and the Aß40/Aß42 ratio as biomarkers of AD in subjects with early-onset AD (EOAD) without familial AD genetic mutations. METHODS: Patients with sporadic EOAD (sEOAD) were prospectively recruited by nine neurology clinics. Plasma levels of Aß40 and Aß42 were measured using a sandwich enzyme-linked immunosorbent assay (ELISA) in 100 sEOAD (50-69 year-old) and 46 age-matched normal control subjects (50-72 year-old). Cerebrospinal fluid (CSF) was obtained from 32 sEOAD subjects and 25 controls. The integrity of the blood-brain barrier was assessed using the CSF/plasma albumin ratio. RESULTS: The plasma levels of Aß42 were significantly lower, while the Aß40/Aß42 ratio was significantly higher in sEOAD patients than in controls. The levels of Aß40, Aß42, and the Aß40/Aß42 ratio did not differ in relation to the APOEɛ4 allele. The CSF/plasma albumin ratio was comparable between the two groups, and the plasma parameters of Aß proteins were not significantly associated. A multivariate analysis revealed that an increased Aß40/Aß42 ratio is valuable for the discrimination of sEOAD from controls (ß=0.344, p=0.000). The area under the ROC curve for the Aß40/Aß42 ratio was 0.76, and a cut-off ratio of 5.87 was suggested to have 70% sensitivity and 68% specificity. CONCLUSION: The plasma Aß40/Aß42 ratio had moderate validity for the discrimination of sEOAD patients from age-matched controls.

In vivo imaging of human adipose-derived stem cells in Alzheimer's disease animal model.

Stem cell therapy is a promising tool for the treatment of diverse conditions, including neurodegenerative diseases such as Alzheimer's disease (AD). To understand transplanted stem cell biology, in vivo imaging is necessary. Nanomaterial has great potential for in vivo imaging and several noninvasive methods are used, such as magnetic resonance imaging, positron emission tomography, fluorescence imaging (FI) and near-infrared FI. However, each method has limitations for in vivo imaging. To overcome these limitations, multimodal nanoprobes have been developed. In the present study, we intravenously injected human adipose-derived stem cells (hASCs) that were labeled with a multimodal nanoparticle, LEO-LIVE™-Magnoxide 675 or 797 (BITERIALS, Seoul, Korea), into Tg2576 mice, an AD mouse model. After sequential in vivo tracking using Maestro Imaging System, we found fluorescence signals up to 10 days after injection. We also found strong signals in the brains extracted from hASC-transplanted Tg2576 mice up to 12 days after injection. With these results, we suggest that in vivo imaging with this multimodal nanoparticle may provide a useful tool for stem cell tracking and understanding stem cell biology in other neurodegenerative diseases.

Preparation and diagnostic utility of a hemagglutination inhibition test antigen derived from the baculovirus-expressed hemagglutinin-neuraminidase protein gene of Newcastle disease virus.

A recombinant hemagglutinin-neuraminidase (rHN) protein from Newcastle disease virus (NDV) with hemagglutination (HA) activity was expressed in Spodoptera frugiperda cells using a baculovirus expression system. The rHN protein extracted from infected cells was used as an antigen in a hemagglutination inhibition (HI) test for the detection and titration of NDV-specific antibodies present in chicken sera. The rHN antigen produced high HA titers of 2(13) per 25 µL, which were similar to those of the NDV antigen produced using chicken eggs, and it remained stable without significant loss of the HA activity for at least 12 weeks at 4°C. The rHN-based HI assay specifically detected NDV antibodies, but not the sera of other avian pathogens, with a specificity and sensitivity of 100% and 98.0%, respectively, in known positive and negative chicken sera (n = 430). Compared with an NDV-based HI assay, the rHN-based HI assay had a relative sensitivity and specificity of 96.1% and 95.5%, respectively, when applied to field chicken sera. The HI titers of the rHN-based HI assay were highly correlated with those in an NDV-based HI assay (r = 0.927). Overall, these results indicate that rHN protein provides a useful alternative to NDV antigen in HI assays.

p35 deficiency accelerates HMGB-1-mediated neuronal death in the early stages of an Alzheimer's disease mouse model.

The activities of CDK5 and p35 are thought to be important in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). We studied the effect of p35 deletion in Tg2576 mice, which is an AD animal model. To obtain the desired mice, we crossed p35(-/-) with Tg2576 mice. The resulting p35(-/-)/Tg2576 (KO/Tg) mice displayed higher mortality rates and exhibited impaired spatial learning and memory at 6 months of age. Using immunohistochemical and biochemical approaches, we observed a reduction in the expression of pre- and post-synaptic markers such as NMDAR1, synaptophysin and GluR1. In addition, the intensity of MAP-2-positive dendrites extending from neuronal cell bodies was significantly decreased in KO/Tg mice compared with KO/WT and WT/Tg mice. We also detected increased neuronal cell death in the hippocampus, along with thinned and collapsed morphological changes in the alveus region and a dramatic increase in the number of microglial cells. Microglial infiltration in the hippocampus could result in the increased secretion of the soluble high mobility group box-1 protein (HMGB-1). The secretion of HMGB-1 is increased by Aß, and secretion of HMGB-1 promotes neuronal cell death. Moreover, we found that HMGB-1 secretion induced by Aß in KO/Tg mice gave rise to ER-mediated cell death. In summary, during the stages of KO/Tg mice model, the microglial infiltration and secretion of soluble HMGB-1 were significantly increased in the hippocampus. These conditions promote neuronal death, synaptic destruction and behavioral deficits.

Effective psychotherapy with low-income clients: The importance of attending to social class.

The purpose of this article is to explore some of the issues associated with conducting psychotherapy with low-income clients. Throughout the article, we draw from our specific clinical experiences working with low-income Latina mothers in a depression prevention program. The themes that we address regarding class and psychotherapy are in the areas of assessment of social class, integration of class issues into the therapy process, and managing differences in social class between therapists and clients. As we discuss these themes, we provide concrete recommendations in order to advance awareness and effectiveness in working with economically disadvantaged populations.

Therapeutic potentials of neural stem cells treated with fluoxetine in Alzheimer's disease.

Recent studies have proposed that chronic treatment with antidepressants increases neurogenesis in the adult hippocampus. However, the effect of antidepressants on fetal neural stem cells (NSCs) has not been well defined. Our study shows the dose-dependent effects of fluoxetine on the proliferation and neural differentiation of NSCs. Fluoxetine, even at nanomolar concentrations, stimulated proliferation of NSCs and increased the number of ßIII-tubulin (Tuj 1)- and neural nucleus marker (NeuN)-positive cells, but not glial fibrillary acidic protein (GFAP)-positive cells. These results suggest that fluoxetine can enhance neuronal differentiation. In addition, fluoxetine has protective effects against cell death induced by oligomeric amyloid beta (Aß(42)) peptides. Taken together, these results clearly show that fluoxetine promotes both the proliferation and neuronal differentiation of NSCs and exerts protective effects against Aß(42)-induced cytotoxicities in NSCs, which suggest that the use of fluoxetine is applicable for cell therapy for various neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases by its actions in NSCs.

The preventive and therapeutic effects of intravenous human adipose-derived stem cells in Alzheimer's disease mice.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid plaques and neurofibrillary tangles accompanied by cognitive dysfunction. The aim of the present study was to elucidate preventive and therapeutic potential of stem cells for AD. Among stem cells, autologous human adipose-derived stem cells (hASCs) elicit no immune rejection responses, tumorigenesis, or ethical problems. We found that intravenously transplanted hASCs passed through the BBB and migrated into the brain. The learning, memory and pathology in an AD mouse model (Tg2576) mice greatly improved for at least 4 months after intravenous injection of hASC. The number of amyloid plaques and Aß levels decreased significantly in the brains of hASC-injected Tg mice compared to those of Tg-sham mice. Here, we first report that intravenously or intracerebrally transplanted hASCs significantly rescues memory deficit and neuropathology, in the brains of Tg mice by up-regulating IL-10 and VEGF and be a possible use for the prevention and treatment of AD.

Biphasic electrical currents stimulation promotes both proliferation and differentiation of fetal neural stem cells.

The use of non-chemical methods to differentiate stem cells has attracted researchers from multiple disciplines, including the engineering and the biomedical fields. No doubt, growth factor based methods are still the most dominant of achieving some level of proliferation and differentiation control--however, chemical based methods are still limited by the quality, source, and amount of the utilized reagents. Well-defined non-chemical methods to differentiate stem cells allow stem cell scientists to control stem cell biology by precisely administering the pre-defined parameters, whether they are structural cues, substrate stiffness, or in the form of current flow. We have developed a culture system that allows normal stem cell growth and the option of applying continuous and defined levels of electric current to alter the cell biology of growing cells. This biphasic current stimulator chip employing ITO electrodes generates both positive and negative currents in the same culture chamber without affecting surface chemistry. We found that biphasic electrical currents (BECs) significantly increased the proliferation of fetal neural stem cells (NSCs). Furthermore, BECs also promoted the differentiation of fetal NSCs into neuronal cells, as assessed using immunocytochemistry. Our results clearly show that BECs promote both the proliferation and neuronal differentiation of fetal NSCs. It may apply to the development of strategies that employ NSCs in the treatment of various neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases.

Gatekeeping and homophobia: from bouncers in bars to the macro-social, interpersonal, and intrapsychological practices of homophobia.

There are links between the theoretical construct of gatekeeping and Madureira's conceptualization of homophobia as a boundary phenomenon. The gatekeeping phenomenon exposes the process through which borders and boundaries of social conduct are regulated and maintained. Hence a focus on gatekeeping practices reveals how conduct becomes scrutinized and restricted in crucial gated sites. Following Madureira's model, these gated areas can be identified and analyzed at macro-social, interpersonal, and intrapsychological levels.

The Latino mental health project: a local mental health needs assessment.

In this article, we present the results of a local needs assessment of the mental health experiences, service needs, and barriers to treatment-seeking of the Latino population in Worcester, Massachusetts. Overall, participants reported relatively high rates of experiences with symptoms of mental health problems, they indicated using a range of both formal and alternative mental health services, and they noted a variety of instrumental, attitudinal, and culturally-specific barriers to seeking mental health services. Findings are discussed with regards to the role that community-driven research can play in advancing efforts to provide relevant services to underserved populations.