Safety and Tolerability of Intra-Articular Injection of Adipose-Derived Mesenchymal Stem Cells GXCPC1 in 11 Subjects With Knee Osteoarthritis: A Nonrandomized Pilot Study Without a Control Arm.

The current study aimed to determine the safety profile of intra-articular-injected allogeneic adipose-derived mesenchymal stem cells (ADSCs) GXCPC1 in subjects with knee osteoarthritis (OA) and its preliminary efficacy outcome. The 3 + 3 phase I study was designed with two dose-escalation cohorts: low dose (6.7 × 106 GXCPC1, N = 5) and high dose (4 × 107 GXCPC1, N = 6). The primary endpoint was safety, which was evaluated by recording adverse events throughout the trial; the secondary endpoints included total, pain, stiffness, and function subscales of the Western Ontario and McMaster Universities Arthritis Index (WOMAC), Visual Analogue Scale (VAS) for pain, and 12-Item Short Form (SF-12) health survey questionnaire. The GXCPC1 treatment was found to be safe after 1 year of follow-up with no treatment-related severe adverse events observed. When compared to baseline, subjects in both the low- and high-dose cohorts demonstrated improving trends in pain and knee function after receiving GXCPC1 treatment. Generally, the net change in pain (95% confidence interval (CI) = -7.773 to -2.561t at 12 weeks compared to baseline) and knee function (95% CI = -24.297 to -10.036t at 12 weeks compared to baseline) was better in subjects receiving high-dose GXCPC1. Although this study included a limited number of subjects without a placebo arm, it showed that the intra-articular injection of ADSCs was safe and well-tolerated in subjects with therapeutic alternatives to treat knee OA. However, a larger scale study with an appropriate control would be necessary for clinical efficacy in the following study.

Consistencies among miscellaneous scales for evaluation of post-stroke dysphagia.

PURPOSE: Post-stroke dysphagia (PSD) is the most common type of dysphagia. Stroke patients with sustained dysphagia have poorer outcomes. The severity of PSD is assessed using miscellaneous scales with unknown consistencies. We aim to investigate the consistencies among miscellaneous scales, which could aid in the assessment of PSD. METHODS: A total of 49 PSD patients were enrolled. Functional Oral Intake Scale (FOIS), Dysphagia Severity Scale (DSS), Ohkuma Questionnaire, Eating Assessment Tool-10, and Repetitive Saliva Swallowing Test were performed. FOIS was performed by physicians, and DSS was conducted by both the physicians and nurses; the physicians used either videofluoroscopy (VF) or videoendoscopy (VE) for evaluation; while, the nurses assessed PSD by observation and subjective judgment. RESULTS: When using VF (VF-DSS and VF-FOIS) as the gold standard for the evaluation, VE-FOIS (κ = 0.625, 95% CI 0.300-0.950, p < 0.001) has a substantial agreement with VF-FOIS, and VE-DSS (κ = 0.381, 95% CI 0.127-0.636, p = 0.007) has a fair agreement with VF-DSS. The weighted kappa of FOIS to DSS in VE (weighted κ = 0.577, 95% CI 0.414-0.740, p < 0.001) is not lower than that in VF (weighted kappa = 0.249, 95% CI 0.136-0.362, p < 0.001). CONCLUSION: For both DSS and FOIS, only VE has a statistically significant agreement with VF. Though VF has been viewed as the traditional gold standard of dysphagia screening, it has the limitations of being invasive and equipment dependent. For PSD, VE could be considered as a substitution when VF is not available or suitable.

Pharmacological Management of Dysphagia in Patients with Alzheimer's Disease: A Narrative Review.

Alzheimer's disease (AD) and dysphagia are important health and socioeconomic problems in the aging population. Currently, the medical treatment of dysphagia in AD patients remains insufficient, and there are significant gaps in the management and clinical needs to postpone tube feeding. Literatures published over the last 30 years were searched in the PubMed and Embase databases. All relevant and promising pharmacological management studies were included. Because of the heterogeneity in design and methodology, only narrative reports were mentioned. Nine studies were included with two case reports, two case series, and two observational and three randomized controlled trials. The key approaches and clinical problems related to dysphagia include onset pattern, dementia stage, review of offending drugs and polypharmacy, and comorbidities (cerebrovascular disease, hypertension, parkinsonism, depression, and anorexia). The corresponding strategies of pharmacological treatments are further proposed and discussed comprehensively, with transient receptor potential channel modulators as promising treatment. With the integration of adequate and potential pharmacomanagement, AD patients with dysphagia can achieve a good prognosis and postpone tube feeding to maintain a better quality of life. More rigorous studies are needed to verify the effectiveness of innovative strategies and develop targets for neurostimulation.

Mesenchymal Stem Cell Secreted-Extracellular Vesicles are Involved in Chondrocyte Production and Reduce Adipogenesis during Stem Cell Differentiation.

BACKGROUND: Extracellular vesicles (EVs) are derived from internal cellular compartments, and have potential as a diagnostic and therapeutic tool in degenerative disease associated with aging. Mesenchymal stem cells (MSCs) have become a promising tool for functional EVs production. This study investigated the efficacy of EVs and its effect on differentiation capacity. METHODS: The characteristics of MSCs were evaluated by flow cytometry and stem cell differentiation analysis, and a production mode of functional EVs was scaled from MSCs. The concentration and size of EVs were quantitated by Nanoparticle Tracking Analysis (NTA). Western blot analysis was used to assess the protein expression of exosome-specific markers. The effects of MSC-derived EVs were assessed by chondrogenic and adipogenic differentiation analyses and histological observation. RESULTS: The range of the particle size of adipose-derived stem cells (ADSCs)- and Wharton's jelly -MSCs-derived EVs were from 130 to 150 nm as measured by NTA, which showed positive expression of exosomal markers. The chondrogenic induction ability was weakened in the absence of EVs in vitro. Interestingly, after EV administration, type II collagen, a major component in the cartilage extracellular matrix, was upregulated compared to the EV-free condition. Moreover, EVs decreased the lipid accumulation rate during adipogenic induction. CONCLUSION: The results indicated that the production model could facilitate production of effective EVs and further demonstrated the role of MSC-derived EVs in cell differentiation. MSC-derived EVs could be successfully used in cell-free therapy to guide chondrogenic differentiation of ADSC for future clinical applications in cartilage regeneration.

A One-Step, Monolayer Culture and Chemical-Based Approach to Generate Insulin-Producing Cells From Human Adipose-Derived Stem Cells to Mitigate Hyperglycemia in STZ-Induced Diabetic Rats.

The global population of individuals afflicted with diabetes mellitus has been increasing year by year, and this disease poses a serious threat to human health as well as the economies worldwide. Pancreatic or islet transplantations provide one of the most effective and long-term therapies available to treat diabetes, but the scarcity and quality of pancreatic islets limit their use in treatments. Here, we report the development of a one-step, monolayer culture, and chemical-based protocol that efficiently mediates the differentiation of human adipose-derived stem cells (hADSCs) into insulin-producing cells (IPCs). Our data indicate that hADSCs in monolayer culture that are allowed to differentiate into IPCs are superior to those in suspension cultures with respect to insulin secretion capacity (213-fold increase), cell viability (93.5 ± 3.27% vs. 41.67 ± 13.17%), and response to glucose stimulation. Moreover, the expression of genes associated with pancreatic lineage specification, such as PDX1, ISL1, and INS (encoding insulin), were expressed at significantly higher levels during our differentiation protocol (6-fold for PDX1 and ISL1, 11.5-fold for INS). Importantly, in vivo studies demonstrated that transplantation with IPCs significantly mitigated hyperglycemia in streptozotocin-induced diabetic rats. Our results indicate that this one-step, rapid protocol increases the efficiency of IPC generation and that the chemical-based approach for IPC induction may reduce safety concerns associated with the use of IPCs for clinical applications, thereby providing a safe and effective cell-based treatment for diabetes.

Intracerebral transplantation of autologous adipose-derived stem cells for chronic ischemic stroke: A phase I study.

Current therapy does not provide significant benefits for patients with chronic stroke. Pre-clinical studies suggested that autologous adipose-derived stem cells have benefits for the treatment of chronic stroke. This Phase I open-label study was conducted to demonstrate the safety and efficacy of autologous adipose-derived stem cells (GXNPC1) in chronic stroke. Three patients with chronic stroke were treated with stereotactic implantation of autologous adipose-derived stem cells (1 × 108 cells). The primary endpoints of safety evaluation included adverse events, over a 6 months post-implantation period. The secondary endpoints included improvements in neurological functions. Evolutional change of brain parenchyma was also followed with magnetic resonance imaging (MRI). All three participants improved significantly at 6 months follow-up. The extent of improvement from pre-treatment was: National Institutes of Health Stroke Scale improved 5-15 points, Barthel Index: 25-50 points, Berg balance scale 0-21 points and Fugl-Meyer modified sensation 3-28 points. All three patients had signal change along the implantation tract on MRI one month after surgery. There is no related safety issue through 6 months observation. Clinical measures of neurological symptoms of these patients with chronic stroke improved at 6 months without adverse effects after implantation of autologous adipose-derived stem cells (GXNPC1), which might be correlated with post-implantation changes on brain MRI. Clinical Trial Registration-URL: https://clinicaltrials.gov/ct2/show/NCT02813512?term=ADSC&cond=Stroke&cntry=TW&draw=2&rank=1 Unique identifier: NCT02813512.

Intramyocardial injection of human adipose-derived stem cells ameliorates cognitive deficit by regulating oxidative stress-mediated hippocampal damage after myocardial infarction.

Cognitive impairment is a serious side effect of post-myocardial infarction (MI) course. We have recently demonstrated that human adipose-derived stem cells (hADSCs) ameliorated myocardial injury after MI by attenuating reactive oxygen species (ROS) levels. Here, we studied whether the beneficial effects of intramyocardial hADSC transplantation can extend to the brain and how they may attenuate cognitive dysfunction via modulating ROS after MI. After coronary ligation, male Wistar rats were randomized via an intramyocardial route to receive either vehicle, hADSC transplantation (1 × 106 cells), or the combination of hADSCs and 3-Morpholinosydnonimine (SIN-1, a peroxynitrite donor). Whether hADSCs migrated into the hippocampus was assessed by using human-specific primers in qPCR reactions. Passive avoidance test was used to assess cognitive performance. Postinfarction was associated with increased oxidative stress in the myocardium, circulation, and hippocampus. This was coupled with decreased numbers of dendritic spines as well as a significant downregulation of synaptic plasticity consisting of synaptophysin and PSD95. Step-through latency during passive avoidance test was impaired in vehicle-treated rats after MI. Intramyocardial hADSC injection exerted therapeutic benefits in improving cardiac function and cognitive impairment. None of hADSCs was detected in rat's hippocampus at the 3rd day after intramyocardial injection. The beneficial effects of hADSCs on MI-induced histological and cognitive changes were abolished after adding SIN-1. MI-induced ROS attacked the hippocampus to induce neurodegeneration, resulting in cognitive deficit. The remotely intramyocardial administration of hADSCs has the capacity of improved synaptic neuroplasticity in the hippocampus mediated by ROS, not the cell engraftment, after MI. KEY MESSAGES: Human adipose-derived stem cells (hADSCs) ameliorated injury after myocardial infarction by attenuating reactive oxygen species (ROS) levels. Intramyocardial administration of hADSCs remotely exerted therapeutic benefits in improving cognitive impairment after myocardial infarction. The improved synaptic neuroplasticity in the hippocampus was mediated by hADSC-inhibiting ROS, not by the stem cell engraftment.

Pharmacological blood pressure control and outcomes in patients with hypertensive crisis discharged from the emergency department.

Pharmacological blood pressure (BP) intervention for high blood pressure is controversial for a wide spectrum of hypertensive crisis in the emergency department (ED). We evaluated whether medical control of BP altered the short- and long-term outcomes among patients with hypertensive crisis who were discharged from the ED under universal health care. This retrospective cohort comprised 22 906 adults discharged from the ED of a tertiary hospital with initial systolic BP ≥ 180 mmHg or diastolic BP ≥ 120 mmHg between 2010 and 2016. The main exposure was the use of antihypertensive medication during the ED stay. Clinical endpoints were revisits to the ED or inpatient admission (at 7, 30, and 60 days), cardiovascular mortality (at 1, 3, and 5 years), and incident stroke (at 1, 3, and 5 years). The associations between pharmacological intervention for BP and outcomes were evaluated using multivariable Cox proportional-hazards models. Of the patient data analyzed, 72.2% were not treated pharmacologically and 68.4% underwent evaluation of end-organ damage. Pharmacological intervention for BP was significantly associated with a 11% and 11% reduced risk of hospital revisits within 30 or 60 days of discharge from ED, respectively, particularly among patients with polypharmacy. No association between pharmacological intervention for BP and incident stroke and cardiovascular mortality was observed. A revision of diagnostic criteria for hypertensive crisis is essential. Although pharmacological intervention for BP may not alter the long-term risk of cardiovascular mortality, it significantly reduces short-term health care utilization.

The prevalence of esophageal cancer after caustic and pesticide ingestion: A nationwide cohort study.

Habits such as smoking and alcohol drinking and existing esophageal malfunction are considered the main risk factors for esophageal carcinogenesis. Caustic ingestion of acidic or alkaline agents or strong irritants can induce severe esophageal corrosive injury and increase esophageal cancer risk. We studied the relationship between esophageal carcinoma and acute detergent or pesticide poisoning by using nationwide health insurance data. Methodology/Principle findings: We compared a pesticide/detergent intoxication cohort (N = 21,840) and an age- and gender-matched control cohort (N = 21,840) identified from the National Health Insurance Research Database between 2000 and 2011. We used the multivariable Cox proportional model to determine esophageal carcinoma risk. The overall incidence density of esophageal cancer was 1.66 per 10,000 person-years in the comparison cohort and 4.36 per 10,000 person-years in the pesticide/detergent intoxication cohort. The corresponding adjusted hazard ratio (HR) for esophageal cancer was 2.33 (95% confidence interval [CI] = 1.41-3.86) in the pesticide/detergent intoxication cohort compared with the control cohort. Patients with corrosive and detergent intoxication did not have a higher risk of esophageal cancer (adjusted HR = 0.98, 95% CI = 0.29-3.33) than those without pesticide/detergent intoxication. However, patients with pesticide intoxication had a significantly higher risk of esophageal cancer (adjusted HR = 2.52, 95% CI = 1.52-4.18) than those without pesticide/detergent intoxication. Conclusion: In the present study, after adjusting for conventional risk factors, we observed that pesticide intoxication could exert substantial effects through increased esophageal cancer risk. However, patients with detergent intoxication may not have an increased risk of esophageal cancer.

An Ingestible Electronics for Continuous and Real-Time Intraabdominal Pressure Monitoring.

Abdominal compartment syndrome can be treated through decompressive surgery if intraabdominal hypertension (IAH) can be detected in time. Treatment delays due to manual, conventional intravesical pressure (IVP) monitoring using a Foley catheter have been reported. In this work, we present an innovative gastrointestinal intraluminal pressure (GIP) measurement-based method to monitor and improve pressure-guided relief of intraabdominal pressure (IAP). A novel algorithm for detecting IAH in the gastrointestinal tract of a live porcine model is reported. A wireless pressure-sensing capsule (10 × 13 mm) was developed for absolute measurement. The IAP was estimated during artificial pneumoperitoneum. The pressure waveform-based measurements indicated that the wireless pressure sensor could be used to predict IAP. To enhance GIP monitoring for predicting IAH, the proposed continuous ingestible wireless electronics-based pressure waveform measurement device can be used as a complement to existing modalities. The use of the proposed pressure measurement and communication technology can help provide valuable data for digital health platforms.

Host pre-conditioning improves human adipose-derived stem cell transplantation in ageing rats after myocardial infarction: Role of NLRP3 inflammasome.

Functional decline of stem cell transplantation in ageing hosts is well documented. The mechanism for this is poorly understood, although it is known that advancing age does not provide an optimal milieu for exogenous stem cells to survive, engraft and differentiate. We showed that n-butylidenephthalide improved human adipose-derived stem cell (hADSC) engraftment via attenuating the production of reactive oxygen species (ROS). It remained unclear whether pre-treated hosts with n-butylidenephthalide can rejuvenate the ageing heart and improve hADSC engraftment by regulating the ROS/NLRP3 inflammasome-mediated cardiac fibrosis after myocardial infarction. One hour after coronary ligation, hADSCs were transplanted into the hearts of young and ageing Wistar rats that were pre-treated with or without n-butylidenephthalide for 3 days. At day 3 after infarction, myocardial infarction was associated with an increase in ROS levels and NLRP3 inflammasome activity with age. hADSC transplant effectively provided a significant decrease in ROS levels, NLRP3 inflammasome activity, IL-1ß levels and cardiac fibrosis in either young or old infarcted rats. However, the beneficial effects of hADSCs were greater in young compared with old rats in terms of NLRP3 inflammasome activity. The infarcted ageing rats pre-conditioned by n-butylidenephthalide improved engraftment and differentiation of hADSCs and additionally attenuated cardiac fibrosis compared with hADSCs alone. The anti-inflammation effects of n-butylidenephthalide were reversed by SIN-1. In conclusions, the increased NLRP3 inflammasome activity plays the pathogenesis of ageing-related functional hADSC decline in the ageing hosts. n-butylidenephthalide-pre-treated ageing hosts reversibly ameliorate the harsh microenvironments, improve stem cell engraftment and attenuate cardiac fibrosis after myocardial infarction.

Transplantation with GXHPC1 for Liver Cirrhosis: Phase 1 Trial.

Currently, the only effective therapy for cirrhosis of the liver is liver transplantation. However, finding a compatible liver is difficult due to the low supply of healthy livers and the ever-increasing demand. However, stem-cell therapy may offer a solution for liver cirrhosis; for example, GXHPC1 therapy preparation contains adipose-derived mesenchymal stem cells (AD-MSCs) and was developed for the treatment of liver cirrhosis. In our previous report, animal studies suggested that treatment of a diseased liver via GXHPC1 transplantation can abrogate liver fibrosis and facilitate recovery of liver function. In our current human trial, patients with liver cirrhosis were included. Their adipose tissue was harvested from the subcutaneous fat of the abdominal wall during surgery. AD-MSCs were cultured and suspended at a concentration of 100 million cells in 1 ml of physiological saline (i.e., GXHPC1). This human study passed the Taiwan Food and Drug Administration IND inspection and received Phase I clinical trial permission. The trial was conducted with six patients with liver cirrhosis to demonstrate the safety and efficacy of administering GXHPC1. Intrahepatic injection of GXHPC1 did not cause any safety issues in the analysis of adverse drug reactions and suspected unexpected serious adverse reactions, and showed a tendency for improvement of liver function, METAVIR score, Child-Pugh score, MELD score, and quality of life for patients with liver cirrhosis.

Factors of post-stroke dementia: A nationwide cohort study in Taiwan.

AIM: We investigated the long-term risk of dementia for up to 10 years in patients with stroke and broadened the correlates. METHODS: We carried out a case-control study using the Taiwan National Health Insurance Research database in 2000 with a sampled population of 1 million. The study cohort comprised 8236 patients with stroke and no dementia history. We carried out a 1:1 case-control matched analysis on estimated propensity scores. Cox proportional hazards regressions were carried out to estimate the risk of dementia during the 5- and 10-year follow-up periods. The risk factors were also investigated. RESULTS: The stroke cohort was significantly at more risk of dementia during the 5- and 10-year follow-up periods, with adjusted hazard ratios 1.87 and 1.53, respectively. The patients with ischemic stroke, transient ischemic attack and intracerebral hemorrhage had a significantly higher risk of dementia after 5 and 10 years, with adjusted hazard ratios of 1.81 and 1.49, 1.92 and 1.61, and 2.14 and 1.61, respectively. The significant risk factors of dementia were age ≥60 years, resident in southern and eastern regions, having low insurance range, and antiplatelet use. CONCLUSIONS: Stroke and the subtypes, including ischemic stroke, transient ischemic attack and intracerebral hemorrhage, increase the long-term risk of dementia. The incidence of post-stroke dementia increases yearly, but the relative risk decreases gradually. Older adults, residents in southern and eastern regions, having low insurance range and antiplatelet use were prominent risk factors of post-stroke dementia in Taiwan. Careful management of stroke and risk factors of post-stroke dementia with long-term follow up of cognition should be reinforced. Geriatr Gerontol Int 2019; 19: 815-822.

Remote transplantation of human adipose-derived stem cells induces regression of cardiac hypertrophy by regulating the macrophage polarization in spontaneously hypertensive rats.

Left ventricular hypertrophy (LVH) in hypertension has prognostic significance on cardiovascular mortality and morbidity. Recently, we have shown that n-butylidenephthalide (BP) improves human adipose-derived stem cell (hADSC) engraftment via attenuated reactive oxygen species (ROS) production. This prompted us to investigate whether remote transplantation of BP-pretreated hADSCs confers attenuated LVH at an established phase of hypertension. Male spontaneously hypertensive rats (SHRs) aged 12 weeks were randomly allocated to receive right hamstring injection of vehicle, clinical-grade hADSCs, and BP-preconditioned hADSCs for 8 weeks. As compared with untreated SHRs, naïve hADSCs decreased the ratio of LV weight to tibia, cardiomyocyte cell size, and collagen deposition independent of hemodynamic changes. These changes were accompanied by attenuated myocardial ROS production and increased p-STAT3 levels. Compared with naïve hADSCs, BP-preconditioned hADSCs provided a further decrease of ROS and LVH and an increase of local hADSC engraftment, STAT3 phosphorylation, STAT3 activity, STAT3 nuclear translocation, myocardial IL-10 levels, and the percentage of M2 macrophage infiltration. SIN-1 or S3I-201 reversed the effects of BP-preconditioned ADSCs increase on myocardial IL-10 levels. Furthermore, SIN-1 abolished the phosphorylation of STAT3, whereas superoxide levels were not affected following the inhibition of STAT3. Our results highlighted the feasibility of remote transplantation of hADSCs can be considered as an alternative procedure to reverse cardiac hypertrophy even at an established phase of hypertension. BP-pretreated hADSCs polarize macrophages into M2 immunoregulatory cells more efficiently than naïve hADSCs via ROS/STAT3 pathway.

Escitalopram oxalate inhibits proliferation and migration and induces apoptosis in non-small cell lung cancer cells.

Population-based cohort studies have revealed that neuroleptic medications are associated with a reduced cancer risk. Recent studies have demonstrated that selective serotonin reuptake inhibitors (SSRIs) have an antiproliferative or cytotoxic effect on certain cancer types. Known as a superior SSRI, escitalopram oxalate exhibits favorable tolerability with generally mild and temporary adverse events. The present study aimed to examine the effects of escitalopram oxalate on non-small cell lung cancer (NSCLC) cells. The experimental results revealed that escitalopram oxalate significantly inhibited the proliferation and invasion of A549, and H460 cells compared with BEAS-2B cells. Additionally, escitalopram oxalate significantly increased the sub-G1 population and caspase-3 activity of A549, and H460 cells. Furthermore, escitalopram oxalate significantly induced mitochondria-dependent apoptotic signaling cascades in A549 and H460 cells, which included increases in the protein expression levels of apoptosis regulator Bax, truncated BH3-interacting domain death agonist, cytochrome c, apoptotic protease-activating factor 1, and cleaved caspase-9. These findings suggest that escitalopram oxalate could serve a therapeutic agent for the treatment of NSCLC due to its antiproliferative and apoptotic effects.

Targeting the pathway of GSK-3ß/nerve growth factor to attenuate post-infarction arrhythmias by preconditioned adipose-derived stem cells.

Adipose-derived stem cell (ADSC) transplantation is a promising new therapy to improve cardiac function after myocardial infarction. However, its low efficacy of transdifferentiation hampers its usefulness. Glycogen synthase kinase-3ß (GSK-3ß) signal has been shown to play a role in preconditioning-induced cardioprotection. We assessed whether n-butylidenephthalide (BP) primed ADSCs can attenuate arrhythmias by a GSK-3ß-dependent pathway after myocardial infarction. Male Wistar rats after coronary ligation was randomly allocated to receive intramyocardial injection of vehicle, ADSCs, BP-preconditioned ADSCs, (BP+lithium)-preconditioned ADSCs, (BP+SB216763)-preconditioned ADSCs, and (BP+LY294002)-preconditioned ADSCs. ADSCs were primed for 16h before implantation. After 4weeks of implantation, ADSCs were retained in myocardium, reduced fibrosis and improved cardiac function. Sympathetic hyperinnervation was blunted after administering ADSCs, assessed by immunofluorescent analysis, and Western blotting and real-time quantitative RT-PCR of nerve growth factor. Arrhythmic scores during programmed stimulation in the ADSC-treated infarcted rats were significantly lower than vehicle. BP-preconditioned ADSCs had superior cardioprotection, greater ADSC engraftment and transdifferentiation, and antiarrhythmic effects compared with ADSCs alone. Simultaneously, BP increased the levels of phospho-Akt and down-regulated GSK-3ß activity. The effects of BP against sympathetic hyperinnervation were blocked by LY294002, a PI3K inhibitor. Addition of either lithium or SB216763 did not have additional effects compared with BP alone. Compared with ADSC alone, BP-primed ADSC implantation improved stem cell engraftment and attenuated sympathetic hyperinnervation and arrhythmias through a PI3K/Akt/GSK-3ß-dependent pathway, suggesting that a synergic action was achieved between BP pretreatment and ADSCs.

Commercial Production of Autologous Stem Cells and Their Therapeutic Potential for Liver Cirrhosis.

Human adipose-derived stem cells (hADSCs) are a promising source of autologous stem cells for personalized cell-based therapies. Culture expansion of ADSCs provides an attractive opportunity for liver cirrhosis patients. However, safety and stability issues can pose big challenges for personalized autologous stem cell products. In the present study, we addressed whether the commercial production program could provide a consistent product for liver cirrhosis therapy. We collected adipose tissue from three human donors by lipoaspirate and isolated ADSCs, which were expanded in culture to reach 1 × 108 cells (an approximately 1,000-fold expansion) within four passages. We then examined their morphology, chromosome stability, surface markers, and differentiation ability after culture. Next, we explored their therapeutic potential using a rat model of thioacetamide-induced liver cirrhosis. Culture-expanded ADSCs were injected intrahepatically, and their biodistribution was tracked by immunohistochemistry using an antibody against human mitochondria. Finally, we tested for tumor development by subcutaneously injecting a 100-fold dose range of cultured ADSCs into immunocompromised mice. Taken together, we find that culture expansion of autologous ADSCs is a potentially suitable stem cell product for personalized cell-based therapy for patients with liver cirrhosis.

Predictors of Carotid Intima-Media Thickness and Plaque Progression in a Chinese Population.

AIM: Atherosclerotic diseases are the leading cause of death worldwide. Longitudinal changes in carotid intima-media thickness (IMT) and plaque are being increasingly used as markers of atherosclerosis progression and may predict future cardiovascular events. This study aimed to investigate the predictors of carotid IMT and plaque progression in a Chinese population and to determine whether these predictors differ by gender. METHODS: Segment-specific carotid IMT and plaque were measured in 712 stroke- and myocardial infarction-free subjects at baseline and after an average interval of 4.3±0.9 years. Multivariate linear regression and logistic regression analyses were conducted to investigate the predictive effect of age, gender, and cardiovascular risk factors on carotid IMT and plaque progression. Gender-specific analyses were also performed. RESULTS: Overall, age and smoking were predictors of common carotid artery IMT progression (adjusted p＜0.001 and p=0.045, respectively). Age, hypertension, and use of antihypertensive medication were predictors of bifurcation IMT progression (adjusted p＜0.001, p=0.033, and p＜0.001, respectively). The use of antihypertensive medication was associated with less annual IMT progression in hypertensive subjects than in those who did not take medication, which was most prominent in the bifurcation segment. In addition, most predictors of IMT progression were identified in women in a gender-specific analysis. For plaque progression, age and gender were independent predictors. CONCLUSIONS: The predictors of carotid atherosclerosis progression were gender and segment specific. The detection and control of hypertension may prevent atherosclerosis progression, particularly in women.

Chloroacetic acid triggers apoptosis in neuronal cells via a reactive oxygen species-induced endoplasmic reticulum stress signaling pathway.

Chloroacetic acid (CA), a chlorinated analog of acetic acid and an environmental toxin that is more toxic than acetic, dichloroacetic, or trichloroacetic acids, is widely used in chemical industries. Furthermore, CA has been found to be the major disinfection by-products (DBPs) of drinking water. CA has been reported to be highly corrosive and to induce severe tissue injuries (including nervous system) that lead to death in mammals. However, the effects and underlying mechanisms of CA-induced neurotoxicity remain unknown. In the present study, we found that CA (0.5-2.0 mM) significantly increased LDH release, decreased the number of viable cells (cytotoxicity) and induced apoptotic events (including: increases in the numbers of apoptotic cells, the membrane externalization of phosphatidylserine (PS), and caspase-3/-7 activity) in Neuro-2a cells. CA (1.5 mM; the approximate to LD50) also triggered ER stress, which was identified by monitoring several key molecules that are involved in the unfolded protein responses (including the increase in the expressions of p-PERK, p-IRE-1, p-eIF2α, ATF-4, ATF-6, CHOP, XBP-1, GRP 78, GRP 94, and caspase-12) and calpain activity. Transfection of GRP 78- and GRP 94-specific si-RNA effectively abrogated CA-induced cytotoxicity, caspase-3/-7 and caspase-12 activity, and GRP 78 and GRP 94 expression in Neuro-2a cells. Additionally, pretreatment with 2.5 mM N-acetylcysteine (NAC; a glutathione (GSH) precursor) dramatically suppressed the increase in lipid peroxidation, cytotoxicity, apoptotic events, calpain and caspase-12 activity, and ER stress-related molecules in CA-exposed cells. Taken together, these results suggest that the higher concentration of CA exerts its cytotoxic effects in neuronal cells by triggering apoptosis via a ROS-induced ER stress signaling pathway.

A walk-in screening of dementia in the general population in Taiwan.

Alzheimer's disease (AD) has increased in its prevalence due to the increasing aged population. Currently there is no updated data on the prevalence of dementia including its very mild stage in Taiwan. Under the extensive coverage of Mentality Protection Center (MPC), Fo Guang Shan, Taiwan, the volunteers of MPC have conducted the medicine-related services and the screening of dementia by AD8 (ascertainment of dementia 8) that can screen the dementia even at its very mild stage in general population in all Taiwan. From 2011 to 2013, in total, 2,171 participants, 368 in the northern, 549 in the central, 877 in the southern, and 377 in the eastern part, were recruited with the mean age being 66.9 ± 10.2 years old. The ratio of suspected dementia patients, AD8 score greater than or equal to 2, was 13.6% of all recruited participants with their mean AD8 score being 2.9 ± 1.3, mean age being 69.4 ± 10.8 years old, and female predominance being 73.0%. Although this is a screening study, it has extensive coverage of all Taiwan and the use of AD8 is capable of screening very mild dementia. A further study with a randomized sampling to examine the prevalence and incidence of dementia including its very mild stage is encouraged.