A pilot study of autologous CD34-depleted bone marrow mononuclear cell transplantation via the hepatic artery in five patients with liver failure

Background aimsMany rodent experiments and human studies on stem cell therapy have shown promising therapeutic approaches to liver diseases. We investigated the clinical outcomes of five patients with liver failure of various causes who received autologous CD34-depleted bone marrow-derived mononuclear cell (BM-MNC) transplantation, including mesenchymal stromal cells, through the hepatic artery.MethodsCD34-depleted BM-MNCs were obtained from five patients waiting for liver transplantation by bone marrow aspiration and using the CliniMACS CD34 Reagent System (Miltenyi Biotech, Bergisch Gladbach, Germany), and autologous hepatic artery infusion was performed. The causes of hepatic decompensation were hepatitis B virus (HBV), hepatitis C virus (HCV), propylthiouracil-induced toxic hepatitis and Wilson disease.ResultsSerum albumin levels improved 1 week after transplantation from 2.8 g/dL, 2.4 g/dL, 2.7 g/dL and 1.9 g/dL to 3.3 g/dL, 3.1 g/dL, 2.8 g/dL and 2.6 g/dL. Transient liver elastography data showed some change from 65 kPa, 33 kPa, 34.8 kPa and undetectable to 46.4 kPa, 19.8 kPa, 29.1 kPa and 67.8 kPa at 4 weeks after transplantation in a patient with Wilson disease, a patient with HCV, and two patients with HBV. Ascites decreased in two patients. One of the patients with HBV underwent liver transplantation 4 months after the infusion, and the hepatic progenitor markers (cytokeratin [CD]-7, CD-8, CD-9, CD-18, CD-19, c-Kit and epithelial cell adhesion molecule [EpCAM]) were highly expressed in the explanted liver.ConclusionsSerum albumin levels, liver stiffness, liver volume, subjective healthiness and quality of life improved in the study patients. Although these findings were observed in a small population, the results may suggest a promising future for autologous CD34-depleted BM-MNC transplantation as a bridge to liver transplantation in patients with liver failure.     

Therapeutic angiogenesis of three-dimensionally cultured adipose-derived stem cells in rat infarcted hearts

Background aimsTo successfully treat myocardial infarction (MI), blood must be resupplied to the ischemic myocardium by inducing angiogenesis. Many studies report enhanced angiogenesis using stem cells; however, the therapeutic efficacy of cell transplant remains low because transplanted cells may not survive, be retained at the site of transplant, or develop into vascular tissue. In this study, we assessed the therapeutic potential of three-dimensional cell masses (3DCM) composed of human adipose-derived stem cells (hASC) in a rat MI model.MethodsFor formation of 3DCM, hASC were cultured on a substrate with immobilized fibroblast growth factor 2. The morphology and phenotypes of 3DCM were analyzed 1 day after culture. The cells (hASC and 3DCM, 5 × 10⁵ cells) were injected into ischemic regions after ligation of the left coronary artery (n = 6 in each group). Cell retention ratio, therapeutic efficacy and vascularization were evaluated 4 weeks after transplant.ResultsA spheroid-type 3DCM, which included vascular cells (CD34⁺/CD31⁺/KDR⁺/α-SMA⁺) with high production of human vascular endothelial growth factor, was obtained. Infarct size and cardiomyocyte apoptosis were reduced in the 3DCM-injected group compared with the hASC-injected group. The retention ratio of hASC was 14-fold higher in the 3DCM-injected group. Many transplanted cells differentiated into endothelial and smooth muscle cells and formed vascular networks incorporated into host vessels.ConclusionsTransplant of 3DCM may be useful for angiogenic cell therapy to treat MI.     

Loss of VHL promotes progerin expression,leading to impaired p14/ARF function and suppression of p53 activity

Renal cell carcinomas (RCCs) are frequently occurring genitourinary malignancies in the aged population. A morphological characteristic of RCCs is an irregular nuclear shape, which is used to index cancer grades. Other features of RCCs include the genetic inactivation of the von Hippel-Lindau gene, VHL, and p53 genetic-independent inactivation. An aberrant nuclear shape or p53 suppression has not yet been demonstrated. We examined the effect of progerin (an altered splicing product of the LMNA gene linked to Hutchinson Gilford progeria syndrome; HGPS) on the nuclear deformation of RCCs in comparison to that of HGPS cells. In this study, we showed that progerin was suppressed by pVHL and was responsible for nuclear irregularities as well as p53 inactivation. Thus, progerin suppression can ameliorate nuclear abnormalities and reactivate p53 in response to genotoxic addition. Furthermore, we found that progerin was a target of pVHL E3 ligase and suppressed p53 activity by p14/ARF inhibition. Our findings indicate that the elevated expression of progerin in RCCs results from the loss of pVHL and leads to p53 inactivation through p14/ARF suppression. Interestingly, we showed that progerin was expressed in human leukemia and primary cell lines, raising the possibility that the expression of this LMNA variant may be a common event in age-related cancer progression.     

The Effect of Static Stretch on Elastin Degradation in Arteries

Previously we have shown that gradual changes in the structure of elastin during an elastase treatment can lead to important transition stages in the mechanical behavior of arteries [1]. However, in vivo arteries are constantly being loaded due to systolic and diastolic pressures and so understanding the effects of loading on the enzymatic degradation of elastin in arteries is important. With biaxial tensile testing, we measured the mechanical behavior of porcine thoracic aortas digested with a mild solution of purified elastase (5 U/mL) in the presence of a static stretch. Arterial mechanical properties and biochemical composition were analyzed to assess the effects of mechanical stretch on elastin degradation. As elastin is being removed, the dimensions of the artery increase by more than 20% in both the longitude and circumference directions. Elastin assays indicate a faster rate of degradation when stretch was present during the digestion. A simple exponential decay fitting confirms the time constant for digestion with stretch (0.11±0.04 h⁻¹) is almost twice that of digestion without stretch (0.069±0.028 h⁻¹). The transition from J-shaped to S-shaped stress vs. strain behavior in the longitudinal direction generally occurs when elastin content is reduced by about 60%. Multiphoton image analysis confirms the removal/fragmentation of elastin and also shows that the collagen fibers are closely intertwined with the elastin lamellae in the medial layer. After removal of elastin, the collagen fibers are no longer constrained and become disordered. Release of amorphous elastin during the fragmentation of the lamellae layers is observed and provides insights into the process of elastin degradation. Overall this study reveals several interesting microstructural changes in the extracellular matrix that could explain the resulting mechanical behavior of arteries with elastin degradation.     

Intermittent Hypoxia Can Aggravate Motor Neuronal Loss and Cognitive Dysfunction in ALS Mice

Background

Patients with ALS may be exposed to variable degrees of chronic intermittent hypoxia. However, all previous experimental studies on the effects of hypoxia in ALS have only used a sustained hypoxia model and it is possible that chronic intermittent hypoxia exerts effects via a different molecular mechanism from that of sustained hypoxia. No study has yet shown that hypoxia (either chronic intermittent or sustained) can affect the loss of motor neurons or cognitive function in an in vivo model of ALS.

Objective

To evaluate the effects of chronic intermittent hypoxia on motor and cognitive function in ALS mice.

Methods

Sixteen ALS mice and 16 wild-type mice were divided into 2 groups and subjected to either chronic intermittent hypoxia or normoxia for 2 weeks. The effects of chronic intermittent hypoxia on ALS mice were evaluated using the rotarod, Y-maze, and wire-hanging tests. In addition, numbers of motor neurons in the ventral horn of the spinal cord were counted and western blot analyses were performed for markers of oxidative stress and inflammatory pathway activation.

Results

Compared to ALS mice kept in normoxic conditions, ALS mice that experienced chronic intermittent hypoxia had poorer motor learning on the rotarod test, poorer spatial memory on the Y-maze test, shorter wire hanging time, and fewer motor neurons in the ventral spinal cord. Compared to ALS-normoxic and wild-type mice, ALS mice that experienced chronic intermittent hypoxia had higher levels of oxidative stress and inflammation.

Conclusions

Chronic intermittent hypoxia can aggravate motor neuronal death, neuromuscular weakness, and probably cognitive dysfunction in ALS mice. The generation of oxidative stress with activation of inflammatory pathways may be associated with this mechanism. Our study will provide insight into the association of hypoxia with disease progression, and in turn, the rationale for an early non-invasive ventilation treatment in patients with ALS.     

Prevalence of and Factors Associated with Albuminuria in the Korean Adult Population: The 2011 Korea National Health and Nutrition Examination Survey

Background

Microalbuminuria is associated with increased risk of renal disease and cardiovascular diseases even in non-diabetic subjects. High incidence rates of microalbuminuria have been found in a number of population-based studies. However, the prevalence and risk factors associated with microalbuminuria in the general population in Korea are unclear.

Objectives

The present study was performed to estimate the prevalence of microalbuminuria and investigate the associated risk factors in the general adult population using the Fifth Korea National Health and Nutrition Examination Survey (KNHANES V-2) data from 2011.

Methods

A total of 5,202 participants (mean age, 45.6 years; men, 2,337; women, 2,865) were included in the analysis. Microalbuminuria was evaluated in participants of KNHANES V-2 based on the urine albumin–creatinine ratio. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease study equation.

Results

The weighted prevalence of microalbuminuria was 5.2% (95% CI, 4.4–6.1) in the general population. The prevalence of albuminuria is increased with age. After adjustment for age and sex, the presence of albuminuria was associated with increased waist circumference, systolic and diastolic blood pressure, aspartate aminotransferase, triglyceride, fasting plasma glucose, and the presence of hypertension and diabetes. In logistic regression analyses, older age, female sex, diabetes, hypertension, and serum aspartate aminotransferase were independently associated with the presence of albuminuria.

Conclusion

The prevalence of microalbuminuria was found to be 5.2%, and conventional risk factors for cardiovascular diseases are closely related to the presence of microalbuminuria in Korea. Microalbuminuria may be a useful marker to identify individuals with increased risk of cardiovascular disease.     

Acute Histologic Chorioamnionitis Is a Risk Factor for Adverse Neonatal Outcome in Late Preterm Birth after Preterm Premature Rupture of Membranes

Background

The objective of this study was to determine whether acute histologic chorioamnionitis is associated with adverse neonatal outcomes in late preterm infants who were born after preterm PROM.

Methodology/Principal Findings

The relationship between the presence of acute histologic chorioamnionitis and adverse neonatal outcome was examined in patients with preterm PROM who delivered singleton preterm newborns between 34 weeks and 36 6/7 weeks of gestation. Nonparametric statistics were used for data analysis. The frequency of acute histologic chorioamnionitis was 24% in patients with preterm PROM who delivered preterm newborns between 34 weeks and 36 6/7 weeks of gestation. Newborns born to mothers with histologic chorioamnionitis had significantly higher rates of adverse neonatal outcome (74% vs 51%; p<0.005) than those without histologic chorioamnionitis. This relationship remained significant after adjustment for gestational age at preterm PROM, gestational age at delivery, and exposure to antenatal corticosteroids.

Conclusions/Significance

The presence of acute histologic chorioamnionitis is associated with adverse neonatal outcome in late preterm infants born to mothers with preterm PROM.     

The Smartphone Addiction Scale: Development and Validation of a Short Version for Adolescents

Objective

This study was designed to investigate the revised and short version of the smartphone addiction scale and the proof of its validity in adolescents. In addition, it suggested cutting off the values by gender in order to determine smartphone addiction and elaborate the characteristics of smartphone usage in adolescents.

Method

A set of questionnaires were provided to a total of 540 selected participants from April to May of 2013. The participants consisted of 343 boys and 197 girls, and their average age was 14.5 years old. The content validity was performed on a selection of shortened items, while an internal-consistency test was conducted for the verification of its reliability. The concurrent validity was confirmed using SAS, SAPS and KS-scale. Receiver operating characteristics analysis was conducted to suggest cut-off.

Results

The 10 final questions were selected using content validity. The internal consistency and concurrent validity of SAS were verified with a Cronbach''s alpha of 0.911. The SAS-SV was significantly correlated with the SAS, SAPS and KS-scale. The SAS-SV scores of gender (p<.001) and self-evaluation of smartphone addiction (p<.001) showed significant difference. The ROC analysis results showed an area under a curve (AUC) value of 0.963(0.888–1.000), a cut-off value of 31, sensitivity value of 0.867 and specificity value of 0.893 in boys while an AUC value of 0.947(0.887–1.000), a cut-off value of 33, sensitivity value of 0.875, and a specificity value of 0.886 in girls.

Conclusions

The SAS-SV showed good reliability and validity for the assessment of smartphone addiction. The smartphone addiction scale short version, which was developed and validated in this study, could be used efficiently for the evaluation of smartphone addiction in community and research areas.     

Protein tyrosine phosphatase controls breast cancer invasion through the expression of matrix metalloproteinase-9

The expression of matrix metalloproteinases (MMPs) produced by cancer cells has been associated with the high potential of metastasis in several human carcinomas, including breast cancer. Several pieces of evidence demonstrate that protein tyrosine phosphatases (PTP) have functions that promote cell migration and metastasis in breast cancer. We analyzed whether PTP inhibitor might control breast cancer invasion through MMP expression. Herein, we investigate the effect of 4-hydroxy-3,3-dimethyl-2H benzo[g]indole-2,5(3H)-dione (BVT948), a novel PTP inhibitor, on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 expression and cell invasion in MCF-7 cells. The expression of MMP-9 and cell invasion increased after TPA treatment, whereas TPA-induced MMP-9 expression and cell invasion were decreased by BVT948 pretreatment. Also, BVT948 suppressed NF-κB activation in TPA-treated MCF-7 cells. However, BVT948 didn’t block TPA-induced AP-1 activation in MCF-7 cells. Our results suggest that the PTP inhibitor blocks breast cancer invasion via suppression of the expression of MMP-9. [BMB Reports 2013; 46(11): 533-538]