Aurora kinases are essential for regulation of chromosome segregation and cytokinesis during mitosis and play a role in growth and progression of human tumors, including ovarian cancer. Aurora A and Aurora B are frequently overexpressed in high-grade and low-grade ovarian cancers. Targeting Aurora kinases has great potential for improving the efficacy of chemotherapies of ovarian cancer. In this study, we investigated whether the Aurora kinase inhibitor, VE 465, can enhance the anti-tumor activity of carboplatin in human ovarian cancer cells. The antitumor activity of VE 465 was tested by MTT proliferative assay in multiple established human epithelial ovarian cancer cell lines of varying p53 status. VE 465 and carboplatin had a synergistic effect on cell viability in both platinum-sensitive and -resistant ovarian cancers. The growth-inhibitory effect was accompanied by reduction in expression of histone 3 and an increase in apoptosis. We conclude that VE 465 enhances the efficacy of carboplatin agents in ovarian carcinoma.
ovarian cancer; Aurora kinases; Aurora kinase inhibitors; chemosensitization
A porcine skin model was developed to characterize the dose-dependent response to high-dose radiation. The dorsal skin of a mini pig was divided into four paraspinal sections, with 11 small irradiation fields (2 cm × 2 cm) in each section, and a single fraction of 15, 30, 50 or 75 Gy was delivered to each section using a 6 MeV electron beam. A spectrophotometer measured gross skin changes, and a biopsy for each radiation dose was performed in the 1st, 2nd, 4th, 6th and 9th weeks for histology, immunostaining with anti-CD31, and western blotting with IL-6 and TGF-β1 to determine the degree of skin damage. After a 4-week latency period, erythema and dry desquamation, moist desquamation, and ulceration appeared at 4, 6 and 9 weeks, respectively. Gross skin toxicity was more pronounced, occurred early and continued to progress with irradiation >50 Gy, whereas complete healing was observed 12 weeks after 15 Gy. Spectrophotometry showed erythema indices rapidly increased during the first 4 weeks after irradiation. The number of eosinophils began rising sharply at 4 weeks and normalized after reaching peaks at 7–8 weeks. Microvessel density showed a biphasic pattern with a transient peak at 1 week, a nadir at 4–6 weeks, and maximum recovery at 9 weeks. Increase in the levels of IL-6 and TGF-β1 was detected soon after irradiation. Most of these parameters indicated complete healing of the skin 12 weeks after 15 Gy. Our porcine skin model provides an effective platform for studying high-dose radiation-induced skin injury, in particular histologic and molecular changes, during the early latency period.
radiation skin injury; porcine skin model; high-dose radiation
The Trail making test (TMT) is culture-loaded because of reliance on the Latin alphabet, limiting its application in Eastern populations. The Shape Trail Test (STT) has been developed as a new variant. This study is to examine the applicability of the STT in a senile Chinese population and to evaluate its potential advantages and disadvantages.
A total of 2470 participants were recruited, including 1151 cognitively normal control (NC), 898 amnestic mild cognitive impairment (aMCI), and 421 mild Alzheimer disease (AD) patients. Besides the STT, the Mini mental state examination and a comprehensive neuropsychological battery involving memory, language, attention, executive function and visuospatial ability were administered to all the participants. In a subgroup of 100 NC and 50 AD patients, both the STT and the Color Trail Test (CTT) were performed.
In NC, the time consumed for Part A and B (STT-A and STT-B) significantly correlated with age and negatively correlated with education (p<0.01). STT-A and B significantly differed among the AD, aMCI and NC. The number that successfully connected within one minute in Part B (STT-B-1 min) correlated well with STT-B (r = 0.71, p<0.01) and distinguished well among NC, aMCI and AD. In the receiver operating characteristic curve analysis, the AUCs (area under the curve) for STT-A, STT-B, and STT-B-1min in identifying AD were 0.698, 0.694 and 0.709, respectively. The STT correlated with the CTT, but the time for completion was longer.
The TMT is a sensitive test of visual search and sequencing. The STT is a meaningful attempt to develop a “culture-fair” variant of the TMT in addition to the CTT.
Danshen is a traditional Chinese medicine with many beneficial effects on cardiovascular diseases. The aim of this study was to evaluate the mechanisms responsible for the antiatherogenic effect of water soluble Danshen extracts (DEs). Rat vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs) were treated with DE. To evaluate the effects of DE in vivo, carotid balloon injury and tail vein thrombosis were induced in Sprague-Dawley (SD) rats and iliac artery stent was induced in New Zealand white rabbits. The inhibitory action of DE on platelet aggregation was confirmed with an impedance aggregometer. DE inhibited the production of reactive oxygen species, and the migration and proliferation of platelet-derived growth factor-BB stimulated VSMCs. Furthermore, DE prevented inflammation and apoptosis in HUVECs. Both effects of DE were reconfirmed in both rat models. DE treatment attenuated platelet aggregation in both in vivo and ex vivo conditions. Pretreatment with DE prevented tail vein thrombosis, which is normally induced by κ-carrageenan injection. Lastly, DE-treated rabbits showed decreased in-stent restenosis of stented iliac arteries. These results suggest that water soluble DE modulates key atherogenic events in VSMCs, endothelial cells, and platelets in both in vitro and in vivo conditions.
This editorial addresses the current challenges and future directions in the use of stem cells as an approach for treating amyotrophic lateral sclerosis. A wide variety of literature has been reviewed to enlighten the reader on the many facets of stem cell research that are important to consider before using them for a cell based therapy.
Stem cell therapy; Amyotrophic lateral sclerosis
Delayed recall of words in a verbal learning test is a sensitive measure for the diagnosis of amnestic mild cognitive impairment (aMCI) and early Alzheimer’s disease (AD). The relative validity of different retention intervals of delayed recall has not been well characterized. Using the Auditory Verbal Learning Test–Huashan version, we compared the differentiating value of short-term delayed recall (AVL-SR, that is, a 3- to 5-minute delay time) and long-term delayed recall (AVL-LR, that is, a 20-minute delay time) in distinguishing patients with aMCI (n = 897) and mild AD (n = 530) from the healthy elderly (n = 1215). In patients with aMCI, the correlation between AVL-SR and AVL-LR was very high (r = 0.94), and the difference between the two indicators was less than 0.5 points. There was no difference between AVL-SR and AVL-LR in the frequency of zero scores. In the receiver operating characteristic curves analysis, although the area under the curve (AUC) of AVL-SR and AVL-LR for diagnosing aMCI was significantly different, the cut-off scores of the two indicators were identical. In the subgroup of ages 80 to 89, the AUC of the two indicators showed no significant difference. Therefore, we concluded that AVL-SR could substitute for AVL-LR in identifying aMCI, especially for the oldest patients.
To analyze the clinical and radiological features of paragonimiasis in children and raise the awareness of this disease.
A total of 58 paragonimiasis patients were reviewed. They were 42 boys and 16 girls aged 2.0 to 15.3 years.
Among these patients, 20 were diagnosed in the recent 5 years, 46 with a history of raw water or food ingestion. Except 2 patients without any complaint, the most common features involved the systemic (41, 70.7%) and respiratory systems (43, 74.1%), followed by abdominal, cardiac and nervous systems, with rash and mass. Eosinophilia was noted in 46 (79.3%) patients, granulocytosis in 45 (77.6%), anemia in 14 (24.1%), and thrombocytopenia in 3. Imageology showed pneumonia in 26 (44.8%) patients, pleurisy in 28 (48.3%), hydropericardium in 17 (29.3%), ascites in 16 (27.6%), and celiac lymphadenitis in 13 (22.4%). Besides hepatomegaly and splenomegaly, calcification and multiple lamellar low echogenic areas in the liver were noted, each in one patient. Abnormal brain imaging was noted in 4 of 10 patients. Karyocyte hyperplasia with eosinophilia was noted in all the 19 patients who received bone marrow puncture.
Paragonimiasis should be considered in the differential diagnosis of patients with multiple organs or system lesions, especially those with eosinophilia, serous cavity effusion, respiratory, cardiac, digestive system, nervous system abnormality, and/or mass. Healthy eating habit is helpful for paragonimiasis prevention.
Paragonimiasis; Paragonimus; Metacercariae; Eosinophilia; China
The microanatomy of the inguinal spermatic cords has never been reported in Asia. The purpose of this study was to describe the number and relationship of the veins, arteries and lymphatics in the spermatic cord and to clarify the location of the vas deferens in Asian men. Fifty-one patients receiving 79 primary microsurgical varicocelectomies performed by a single surgeon from April 2011 to July 2012 were studied. The number of internal and external spermatic veins, testicular arteries and lymphatic channels preserved during the inguinal microsurgical varicocelectomy were recorded. The relationship between the right and left vascular anatomy during bilateral varicocelectomies was evaluated. The data showed that mean numbers of 1.5±0.9 arteries, 5.6±2.2 spermatic veins and 3.6±1.9 lymphatics were identified during the repairs. The internal spermatic arteries were surrounded by a dense complex of adherent veins in 81.2% of the cases. The external spermatic vein or veins were found in 60.8% of the cases. The vas deferens may be contained within the internal spermatic fascia. The results suggest that the number of veins may be highly variable and less than those reported in the English literature, but there is some similarity in the inguinal microanatomy of the right and left spermatic cords. Further research is warranted to clarify our results.
infertility; spermatic cord; varicocele
p33ING1b, a newly discovered candidate tumor suppressor gene and a nuclear protein, belongs to the inhibitor of growth gene family. Previous studies have shown that p33ING1b is involved in the restriction of cell growth and proliferation, apoptosis, tumor anchorage-independent growth, cellular senescence, maintenance of genomic stability and modulation of cell cycle checkpoints. Loss of nuclear p33ING1b has been observed in melanoma, seminoma, papillary thyroid carcinoma, oral squamous cell carcinoma, breast ductal cancer and acute lymphoblastic leukemia. Inactivation and/or decreased expression of p33ING1b have been reported in various types of cancer, including head and neck squamous cell, breast, lung, stomach, blood and brain malignancies. Since little is known about the clinicopathological significance of p33ING1b in esophageal squamous cell carcinoma (ESCC), this study aimed to investigate the association of p33ING1b expression with clinicopathological variables and particularly interesting new cysteine-histidine rich protein (PINCH) in patients with ESCC. p33ING1b expression was examined by immunohistochemistry in 20 normal esophageal mucosa and in 64 ESCC specimens. The results revealed that the positive expression of p33ING1b protein in normal squamous cells was localized in the nucleus alone and the positive rate was 95%, while in ESCCs, the positive expression was mainly in the cytoplasm, together with nuclear expression, and the positive rate was 36% (P<0.0001). Furthermore, the cases with lymph node metastasis showed a higher frequency of positive cytoplasmic expression than those without metastasis (P=0.001). The cytoplasmic expression of p33ING1b was positively related to PINCH expression (P<0.0001) in ESCC, and the cases positive for both proteins had a high lymph node metastasis rate (P=0.001). In conclusion, p33ING1b cellular compartmental shift from the nucleus to the cytoplasm may cause loss of normal cellular function and play a central role in the tumorigenesis and metastasis of ESCC.
immunohistochemistry; p33ING1b; PINCH; esophageal squamous cell carcinoma; metastasis
Mild cognitive impairment (MCI), defined as a transitional zone between normal cognition and dementia, requires a battery of formal neuropsychological tests administered by a trained rater for its diagnosis. The objective of this study was to develop a screening tool for MCI.
One hundred ninety seven cognitively normal controls (NC), one hundred sixteen patients with amnestic MCI –single domain (aMCI-sd), one hundred ninety five patients with amnestic MCI-multiple domain (aMCI-md), and two hundred twenty eight patients with mild Alzheimer’s disease (AD) were evaluated by comprehensive neuropsychological tests and by the Memory and Executive Screening (MES).
Correlation analysis showed that the three indicators of the MES were significantly negatively related with age (P<0.05), yet not related with education (P>0.05). There was no ceiling or floor effect. Test completion averaged seven minutes (421.14±168.31 seconds). The receiver operating characteristics (ROC) analyses performed on the aMCI-sd group yielded 0.89 for the area under the curve (AUC) (95% CI, 0.85–0.92) for the MES-total score, with sensitivity of 0.795 and specificity of 0.828. There was 81% correct classification rate when the cut-off was set at less than 75. Meanwhile, the aMCI-md group yielded 0.95 for the AUC (95% CI, 0.93–0.97) for the MES-total score, with sensitivity of 0.87 and specificity of 0.91, and 90% correct classification rate when the cut-off was set at less than 72.
The MES, minimally time-consuming, may be a valid and easily administered cognitive screening tool with high sensitivity and specificity for aMCI, with single or multiple domain impairment.
Mild cognitive impairment (MCI); Amnestic MCI-single domain (aMCI-sd); Amnestic MCI-multiple domain (aMCI-md); Alzheimer’s disease (AD); Memory and Executive Screening (MES); Mini-Mental State Examination (MMSE)
The cancer stem cell (CSC) hypothesis posits that deregulated neural stem cells (NSCs) form the basis of brain tumors such as glioblastoma multiforme (GBM). GBM, however, usually forms in the cerebral white matter while normal NSCs reside in subventricular and hippocampal regions. We attempted to characterize CSCs from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall.
We described isolating CSCs from a GBM involving the lateral ventricles and characterized these cells with in vitro molecular biomarker profiling, cellular behavior, ex vivo and in vivo techniques.
The patient’s MRI revealed a heterogeneous mass with associated edema, involving the left subventricular zone. Histological examination of the tumor established it as being a high-grade glial neoplasm, characterized by polygonal and fusiform cells with marked nuclear atypia, amphophilic cytoplasm, prominent nucleoli, frequent mitotic figures, irregular zones of necrosis and vascular hyperplasia. Recurrence of the tumor occurred shortly after the surgical resection. CD133-positive cells, isolated from the tumor, expressed stem cell markers including nestin, CD133, Ki67, Sox2, EFNB1, EFNB2, EFNB3, Cav-1, Musashi, Nucleostemin, Notch 2, Notch 4, and Pax6. Biomarkers expressed in differentiated cells included Cathepsin L, Cathepsin B, Mucin18, Mucin24, c-Myc, NSE, and TIMP1. Expression of unique cancer-related transcripts in these CD133-positive cells, such as caveolin-1 and −2, do not appear to have been previously reported in the literature. Ex vivo organotypic brain slice co-culture showed that the CD133+ cells behaved like tumor cells. The CD133-positive cells also induced tumor formation when they were stereotactically transplanted into the brains of the immune-deficient NOD/SCID mice.
This brain tumor involving the neurogenic lateral ventricular wall was comprised of tumor-forming, CD133-positive cancer stem cells, which are likely the driving force for the rapid recurrence of the tumor in the patient.
Glioblastoma multiforme; Primary tumors; Brain tumor stem cells; Cancer stem cells; Organotypic brain slice culture
Post-ischemic microglial activation may contribute to neuronal damage through the release of large amounts of pro-inflammatory cytokines and neurotoxic factors. The involvement of microRNAs (miRNAs) in the pathogenesis of disorders related to the brain and central nervous system has been previously studied, but it remains unknown whether the production of pro-inflammatory cytokines is regulated by miRNAs.
BV-2 and primary rat microglial cells were activated by exposure to oxygen-glucose deprivation (OGD). Global cerebral ischemia was induced using the four-vessel occlusion (4-VO) model in rats. Induction of pro-inflammatory and neurotoxic factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and nitric oxide (NO), were assessed by ELISA, immunofluorescence, and the Griess assay, respectively. The miRNA expression profiles of OGD-activated BV-2 cells were subsequently compared with the profiles of resting cells in a miRNA microarray. BV-2 and primary rat microglial cells were transfected with miR-181c to evaluate its effects on TNF-α production after OGD. In addition, a luciferase reporter assay was conducted to confirm whether TNF-α is a direct target of miR-181c.
OGD induced BV-2 microglial activation in vitro, as indicated by the overproduction of TNF-α, IL-1β, and NO. Global cerebral ischemia/reperfusion injury induced microglial activation and the release of pro-inflammatory cytokines in the hippocampus. OGD also downregulated miR-181c expression and upregulated TNF-α expression. Overproduction of TNF-α after OGD-induced microglial activation provoked neuronal apoptosis, whereas the ectopic expression of miR-181c partially protected neurons from cell death caused by OGD-activated microglia. RNAinterference-mediated knockdown of TNF-α phenocopied the effect of miR-181c-mediated neuronal protection, whereas overexpression of TNF-α blocked the miR-181c-dependent suppression of apoptosis. Further studies showed that miR-181c could directly target the 3′-untranslated region of TNF-α mRNA, suppressing its mRNA and protein expression.
Our data suggest a potential role for miR-181c in the regulation of TNF-α expression after ischemia/hypoxia and microglia-mediated neuronal injury.
Microglial activation; Hypoxia; Neuronal apoptosis; miR-181c; TNF-α
The purpose of this study was to test the efficacy of cyclic Arg-Gly-Asp (RGD) peptide conjugated with polyionic complex nanomicelles as targeted therapy for glioma.
A stable cyclic RGD polyionic complex nanostructure, ie, a c(RGDfC) polyionic complex micelle, was synthesized and its biocompatibility with cultured neurons was assessed using a cell viability assay. Targeted binding to cultured glioma cells was evaluated by the CdTe quantum dot marking technique and a cell viability assay. The inhibitory effect of the nanomicelles against glioma cells was also evaluated, and their targeted migration into rat brain glioma cells and apoptotic effects were traced by the CdTe quantum dot marking and immunohistochemical staining.
c(RGDfC) polyionic complex micelles did not affect the growth of neurons but bonded selectively to and inhibited proliferation of glioma cells in vitro. When tested in vivo, the micelles migrated into glioma cells, inducing apoptosis in the rat brain.
The c(RGDfC) polyionic complex micelle is an effective targeted therapy against glioma.
Arg-Gly-Asp; RGD; polyion complex; micelle; glioma; target therapy
The complete molecule of the title compound, C28H24N6, is generated by inversion symmetry with the inversion centre located at the mid-point of the central C–C bond of the butanediyl unit. The benzimidazole and pyridine rings are almost coplanar, the dihedral angle between their mean planes being 6.86 (11)°.
In ventricular fibrillation, the uncoupling of gap junctions slows conduction velocity and increases action-potential dispersion, which slows and diminishes defibrillation. We studied how the peptide ZP123, a gap-junction enhancer, might lower defibrillation-energy requirements during ventricular fibrillation in live pigs.
We randomly assigned 33 pigs into 3 groups: ZP123 (receiving a 1-µg/kg bolus and 10 µg/kg/hr of ZP123), control (receiving saline solution), and sham (undergoing a sham operation). After a 30-min administration of agents, ventricular fibrillation was induced and left untreated for 8 min. Biphasic defibrillation of 50 J was increased by 50-J increments as necessary. Defibrillation-energy requirements were defined as the lowest energy required to achieve defibrillation. Electrocardiographic values were obtained before and after the administration of agents. Western blot and immunofluorescence analyses were performed on ventricular myocardial samples.
All but one pig survived. The ZP123 treatment did not alter electrocardiographic variables. In the ZP123 group, the average required defibrillation energy was lower than that in the control group (327.28 ± 269.6 vs 610 ± 192.64 J; P=0.015), and the cumulative percentage of successful defibrillation at upper energy levels was higher (P <0.05). Supraventricular rhythm occurred more often in the ZP123 group than in the control group (72.7% vs 50%, P=0.042). Western-blot and immunofluorescence results showed that ZP123 did not alter the total amount of connexin43 but did prevent its dephosphorylation. We conclude that ZP123 can reduce defibrillation-energy requirements by preventing connexin43 remodeling during prolonged ventricular fibrillation.
Anti-arrhythmia agents/administration & dosage/therapeutic use; arrhythmias, cardiac/prevention & control; connexin 43/analysis/metabolism; gap junctions/drug effects/metabolism/physiology; models, cardiovascular; phosphorylation/drug effects; swine; treatment outcome; ventricular fibrillation/therapy
To investigate associations between MRI brain morphology, cerebrovascular risk (VR), clinical diagnosis and cognition among elders living in urban Shanghai.
Memory Disorders Clinic and community normal control (NC) subject recruitment.
Ninety-six older subjects, 32 with normal cognition, 30 with amnestic MCI (aMCI) and 34 with dementia.
Main outcome measures
Each subject received medical history, neurological/physical exams, neuropsychological evaluations, brain MRI and apolipoprotein E-ε4 (APOE -ε4) genotype test. MRI volumes were assessed using a semi-automatic method.
Brain volume (BV) was significantly smaller in the demented compared with NC (p < 0.001) or aMCI (p = 0.043). Hippocampal volume (HV) was lower, and white matter hyperintensity volume (WMH) was higher, in aMCI (HV: p = 0.028; WMH: p = 0.041) and dementia (HV: p < 0.001; WMH: p = 0.002) compared with NC. APOE -ε4 presence was significantly associated with reduced HV (p = 0.02). Systolic blood pressure was positively associated with VR score (p = 0.037); diastolic blood pressure (p = 0.021) and VR score (p = 0.036) were both positively associated with WMH. WMH (p = 0.029) and VR (p = 0.031) were both higher among the demented than NC.
MRI brain morphology changes were significantly associated clinical diagnosis, in addition, blood pressure was highly associated with VR score and WMH. These results suggest that MRI is a valuable measure of brain injury in a Chinese cohort and can serve to assess the effects of various degenerative and cerebrovascular pathologies.
Dementia; Mild Cognitive Impairment; Magnetic Resonance Imaging; white matter hyperintensities; hippocampal volume; cerebrovascular risk; apolipoprotein E genotype; cognition
Immunotherapy is often recommended as an adjuvant treatment to reduce the chance of cancer recurrence or metastasis. Interestingly, timing is very important for a successful immunotherapy against metastasis, although the precise mechanism is still unknown.
Methods and Findings
Using a mouse model of melanoma metastasis induced by intravenous injection of B16-F10 cells, we investigated the mechanism responsible for the diverse efficacy of the prophylactic or therapeutic TLR4 and TLR9 agonist complex against metastasis. We found that the activation of TLR4 and TLR9 prevented, but did not reverse, metastasis because the potency of this combination was neither sufficient to overcome the tumor cell-educated immune tolerance nor to induce efficacious autophagy in tumor cells. The prophylactic application of the complex promoted antimetastatic immunity, leading to the autophagy-associated death of melanoma cells via IFNγ/STAT1 activation and attenuated tumor metastasis. IFNγ neutralization reversed the prophylactic benefit induced by the complex by suppressing STAT1 activation and attenuating autophagy in mice. However, the therapeutic application of the complex did not suppress metastasis because the complex could not reverse tumor cell-induced STAT3 activation and neither activate IFNγ/STAT1 signaling and autophagy. Suppressing STAT3 activation with the JAK/STAT antagonist AG490 restored the antimetastatic effect of the TLR4/9 agonist complex. Activation of autophagy after tumor inoculation by using rapamycin, with or without the TLR4/9 agonist complex, could suppress metastasis.
Conclusion and Significance
Our studies suggest that activation of IFNγ/STAT1 signaling and induction of autophagy are critical for an efficacious anti-metastatic immunotherapy and that autophagy activators may overcome the timing barrier for immunotherapy against metastasis.
DJ-1 and α-synuclein are leading biomarkers for Parkinson disease diagnosis and/or monitoring disease progression. A few recent investigations have determined DJ-1 and α-synuclein levels in plasma or serum, a more convenient sample source than cerebrospinal fluid; but the results were variable or even contradictory. Besides limitations in detection technology and limited number of cases in some studies, inadequate control of several important confounders likely has contributed to these inconsistent results. In this study, the relative contribution of each blood component to blood DJ-1 and α-synuclein was evaluated, followed by quantification of plasma levels of both markers in a larger cohort of patients/subjects (~300 cases) whose cerebrospinal fluid DJ-1 and α-synuclein levels have been determined recently. The results demonstrated that the DJ-1 and α-synuclein in blood resided predominantly in red blood cells (>95%), followed by platelets (1-4%), white blood cells and plasma (≤1%), indicating that variations in hemolysis and/or platelet contamination could have a significant effect on plasma/serum DJ-1 and α-synuclein levels. Nonetheless, after adjusting for the age, although there was a trend of decrease in DJ-1 and α-synuclein in patients with Parkinson or Alzheimer disease compared with healthy controls, no statistical difference was observed in this cohort between any groups, even when the extent of hemolysis and platelet contamination were controlled for. Additionally, no correlation between DJ-1 or α-synuclein and Parkinson disease severity was identified. In conclusion, unlike in cerebrospinal fluid, total DJ-1 or α-synuclein in plasma alone is not useful as biomarkers for Parkinson disease diagnosis or progression/severity.
Biomarker; DJ-1; α-synuclein; plasma; Parkinson disease; Alzheimer disease
In this study, we investigated whether or not a new minimum contact locking compression plate (MC-LCP) can provide advantages over the limited contact dynamic compression plate (LC-DCP) in the context of interface contact area and force. Six matched pairs of cadaveric bones were used for each of three bone types of the humerus, radius and ulna. For each bone type, one of two bone plates was fixed to either of two matched cadaveric bones at the middle of the diaphysis. The interface contact area and force of the plate fixed to three types of human cadaveric bones were evaluated using Fuji prescale pressure sensitive film. Data were quantitated using computer-assisted image analysis. Results showed that the average force between the MC-LCP and humerus or radius was about half of that of the LC-DCP. And the average force between the MC-LCP and ulna was one third less than that of the LC-DCP. Meanwhile, the interface contact area between the MC-LCP and humerus or radius was also about half of that of the LC-DCP, and the interface contact area between the MC-LCP and ulna was less than one third of that of the LC-DCP. These results indicate that the MC-LCP has lower interface contact area and lower average force than that of the LC-DCP. Thus, the MC-LCP system may be a good alternate to treat forearm diaphyseal fractures.
Accumulating evidence suggests that extracellular α-synuclein (eSNCA) plays an important role in the pathogenesis of Parkinson's disease (PD) or related synucleinopathies by inducing neurotoxicity directly or indirectly via microglial or astroglial activation. However, the mechanisms by which this occurs remain to be characterized. To explore these mechanisms, we combined three biochemical techniques - Stable Isotope Labeling of Amino acid in Cell cultures (SILAC); biotin labeling of plasma membrane proteins followed by affinity purification; and analysis of unique proteins binding to SNCA peptides on membrane arrays. The SILAC proteomic analysis identified 457 proteins, of which, 245 or 172 proteins belonged to membrane or membrane associated proteins, depending on the various bioinformatics tools used for interpretation. In dopamine neuronal cells treated with eSNCA, the levels of 86 membrane proteins were increased and 35 were decreased compared with untreated cells. In peptide array analysis, 127 proteins were identified as possibly interacting with eSNCA. Of those, seven proteins were overlapped with the membrane proteins that displayed alterations in relative abundance after eSNCA treatment. One was ciliary neurotrophic factor receptor alpha (CNTFR-α), which appeared to modulate eSNCA-mediated neurotoxicity via mechanisms related to JAK1/STAT3 signaling but independent of eSNCA endocytosis.
Alpha-synuclein; Parkinson's disease; Proteomic
To determine apolipoprotein E (APOE)-ε4 and -ε2 frequencies and risk of mild cognitive impairment (MCI) and dementia in Shanghai, China.
A total of 34 MCI and 34 dementia cases were recruited from an urban Memory Disorders Clinic and 32 controls were recruited from a residential community served by the clinic. Apolipoprotein E was genotyped using standard methods.
Among controls, frequencies were ε2, 0.11; ε3, 0.84; and ε4, 0.05; among MCI, 0.05, 0.77, and 0.18; and for dementia, 0.02, 0.84, and 0.15, respectively. In education-adjusted models, the odds ratio (OR) = 5.6 for dementia (95% CI = 1.09–29.3) and 4.7 for MCI (95% CI = 0.90–25.2) associated with any ε4 allele. The ε2 allele was inversely associated with dementia (OR = 0.12, 95% CI = 0.013–0.997) and MCI (OR = 0.38, 95% CI = 0.08–1.61).
APOE-ε4 increases and -ε2 decreases the risk of dementia vs normal cognition. Similar trends were observed for amnestic mild cognitive impairment (aMCI).
apolipoprotein E; dementia; mild cognitive impairment; China
Biomarkers are urgently needed for the diagnosis and monitoring of disease progression in Parkinson’s disease. Both DJ-1 and α-synuclein, two proteins critically involved in Parkinson’s disease pathogenesis, have been tested as disease biomarkers in several recent studies with inconsistent results. These have been largely due to variation in the protein species detected by different antibodies, limited numbers of patients in some studies, or inadequate control of several important variables. In this study, the nature of DJ-1 and α-synuclein in human cerebrospinal fluid was studied by a combination of western blotting, gel filtration and mass spectrometry. Sensitive and quantitative Luminex assays detecting most, if not all, species of DJ-1 and α-synuclein in human cerebrospinal fluid were established. Cerebrospinal fluid concentrations of DJ-1 and α-synuclein from 117 patients with Parkinson’s disease, 132 healthy individuals and 50 patients with Alzheimer’s disease were analysed using newly developed, highly sensitive Luminex technology while controlling for several major confounders. A total of 299 individuals and 389 samples were analysed. The results showed that cerebrospinal fluid DJ-1 and α-synuclein levels were dependent on age and influenced by the extent of blood contamination in cerebrospinal fluid. Both DJ-1 and α-synuclein levels were decreased in Parkinson’s patients versus controls or Alzheimer’s patients when blood contamination was controlled for. In the population aged ≥65 years, when cut-off values of 40 and 0.5 ng/ml were chosen for DJ-1 and α-synuclein, respectively, the sensitivity and specificity for patients with Parkinson’s disease versus controls were 90 and 70% for DJ-1, and 92 and 58% for α-synuclein. A combination of the two markers did not enhance the test performance. There was no association between DJ-1 or α-synuclein and the severity of Parkinson’s disease. Taken together, this represents the largest scale study for DJ-1 or α-synuclein in human cerebrospinal fluid so far, while using newly established sensitive Luminex assays, with controls for multiple variables. We have demonstrated that total DJ-1 and α-synuclein in human cerebrospinal fluid are helpful diagnostic markers for Parkinson’s disease, if variables such as blood contamination and age are taken into consideration.
cerebrospinal fluid; Parkinson’s disease; biomarker; DJ-1; α-synuclein
Motor neuron loss is characteristic of cervical spinal cord injury (SCI) and contributes to functional deficit.
In order to investigate the amenability of the injured adult spinal cord to motor neuron differentiation, we transplanted spinal cord injured animals with a high purity population of human motor neuron progenitors (hMNP) derived from human embryonic stem cells (hESCs). In vitro, hMNPs displayed characteristic motor neuron-specific markers, a typical electrophysiological profile, functionally innervated human or rodent muscle, and secreted physiologically active growth factors that caused neurite branching and neuronal survival. hMNP transplantation into cervical SCI sites in adult rats resulted in suppression of intracellular signaling pathways associated with SCI pathogenesis, which correlated with greater endogenous neuronal survival and neurite branching. These neurotrophic effects were accompanied by significantly enhanced performance on all parameters of the balance beam task, as compared to controls. Interestingly, hMNP transplantation resulted in survival, differentiation, and site-specific integration of hMNPs distal to the SCI site within ventral horns, but hMNPs near the SCI site reverted to a neuronal progenitor state, suggesting an environmental deficiency for neuronal maturation associated with SCI.
These findings underscore the barriers imposed on neuronal differentiation of transplanted cells by the gliogenic nature of the injured spinal cord, and the physiological relevance of transplant-derived neurotrophic support to functional recovery.
In the title compound, [Cu2(C6H8O4)Cl2(C15H11N3)2]·4H2O, the dinuclear copper complex is located on a crystallographic inversion centre. Each Cu atom is in a distorted square-pyramidal coordination environment, with one O atom of an adipate dianion and three N atoms from the 2,2′:6′,2′′-terpyridine ligand occupying the basal plane, and one chlorine in the apical site. In addition, there is weak Cu—O interaction opposite of the chlorine with a distance of 2.768 (1) Å. The adipate ligand adopts a gauche–anti–gauche conformation. The interstitial water molecules form hydrogen-bonded tertramers that are connected to the complexes via O—H⋯O and O—H⋯Cl hydrogen bonds, thus leading to the formation of tightly hydrogen-bonded layers extending perpendicular to the b-axis direction.
Injurious mechanical ventilation can cause a pro‐inflammatory reaction in the lungs. Recent evidence suggests an association of the renin‐angiotensin system (RAS) with lung inflammation. A study was undertaken to investigate the pathogenic role of the RAS in ventilator‐induced lung injury (VILI) and to determine whether VILI can be attenuated by angiotensin converting enzyme (ACE) inhibition.
Male Sprague‐Dawley rats were mechanically ventilated for 4 h with low (7 ml/kg) or high (40 ml/kg) tidal volumes; non‐ventilated rats were used as controls. Lung injury and inflammation were measured by the lung injury score, protein leakage, myeloperoxidase activity, pro‐inflammatory cytokine levels and nuclear factor (NF)‐κB activity. Expression of the RAS components was also assessed. Some rats were pretreated with the ACE inhibitor captopril (10 mg/kg) for 3 days or received a concomitant infusion with losartan or PD123319 (type 1 or type 2 angiotensin II receptor antagonist) during mechanical ventilation to assess possible protective effects on VILI.
In the high‐volume group (n = 6) the lung injury score, bronchoalveolar lavage fluid protein concentration, pro‐inflammatory cytokines and NF‐κB activities were significantly increased compared with controls (n = 6). Lung tissue angiotensin II levels and mRNA levels of angiotensinogen and type 1 and type 2 angiotensin II receptors were also significantly increased in the high‐volume group. Pretreatment with captopril or concomitant infusion with losartan or PD123319 in the high‐volume group attenuated the lung injury and inflammation (n = 6 for each group).
The RAS is involved in the pathogenesis of ventilator‐induced lung injury. ACE inhibitor or angiotensin receptor antagonists can attenuate VILI in this rat model.