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Introduction: Adolescent scar contracture kyphoscoliosis is a very rare disease.Methods and Results: Here, we present the case of a 21-year-old man who was scalded due to ebullient water when he was 10 years old. Moreover, kyphoscoliosis was found when he was 12 years old and developed rapidly. Thereafter, no management was proposed before his consultation at our center. On examination, kyphoscoliosis was detected in thoracolumbar, the trunk deviated to the right on standing view, extensive contractured scar presented on the right side of the back, abdomen, chest wall, hip, right thighs and armpit anterior, especially in the right flank. A one-stage correction was deemed too risky, we therefore released contractured scar during the first stage with the defect of soft tissue protected by vacuum sealing drainage and then performed skeletal traction with halo and bilateral femoral pins. A reasonable correction was achieved without any neurological deficits 1 month after traction. Next, a second-stage operation was taken to translate a free anterolateral thigh myocutaneous flap to overlay the extensive defect of soft tissue. 1.5 months later, a third posterior segmental pedicle screw instrumented fusion with Smith-Peterson osteotomy between T9 and L2 was performed. Postoperative recovery was uneventful and as there were no complications, he was discharged 10 days after the third surgery. At 2-year follow-up the patient's outcome is excellent with balance and correction of the deformity.Conclusion: Based this grand round case and relevant literature, we discuss the different options for the treatment of adolescent scar contracture scoliosis. [ABSTRACT FROM AUTHOR]

Background and Aim: Angelica sinensis (Oliv.) Diels (Danggui, DG), exhibits potential in myocardial infarction (MI) treatment. However, research on its synergistic combinations for cardioprotective effects has been limited owing to inadequate approaches., Experimental Procedure: We identified certain phenolic acids and phthalein compounds in DG. Network pharmacology analysis and experimental validation revealed the components that protected H9c2 cells and reduced lactate dehydrogenase levels. Subsequently, a combination of computational experimental strategies and a secondary phenotypic optimization platform was employed to identify effective component combinations with synergistic interactions. The Chou-Talalay and Zero Interaction Potency (ZIP) models were utilized to quantify the synergistic relationships. The optimal combination identified, Z -Ligustide and Chlorogenic acid (Z-LIG/CGA), was evaluated for its protective effects on cardiac function and cardiomyocytes apoptosis induced by inflammatory in a mouse model of induced by left anterior descending coronary artery ligation. Flow cytometry was further utilized to detect the polarization ratio of M1/M2 macrophages and the expression of inflammatory cytokines in serum was measured, assessing the inhibition of inflammatory responses and pro-inflammatory signaling factors by Z-LIG/CGA., Key Results: Quadratic surface analysis revealed that the Z-LIG/CGA combination displayed synergistic cardioprotective effects (combination index value <1; ZIP value >10). In vivo , Z-LIG/CGA significantly improved cardiac function and reduced the fibrotic area in mice post-MI, surpassing the results in groups treated with Z-LIG or CGA alone. Compared to the MI group, the Z-LIG/CGA group exhibited decreased ratios of the myocardial cell apoptosis-related proteins BAX/Bcl-2 and Cleaved Caspase-3/Caspase-3 in mice. Further research revealed that Z-LIG/CGA treatment significantly increased IL-1R2 levels, significantly decreased IL-17RA levels, and inhibited the activation of p-STAT1, thereby alleviating cell apoptosis after MI. Additionally, the Z-LIG/CGA combination significantly inhibited the ratio of M1/M2 macrophages and suppressed the expression levels of pro-inflammatory cytokines IL-1β, IL-6, IL-17, and TNF-α in the serum., Conclusion and Implications: We successfully identified a synergistic drug combination, Z-LIG/CGA, which improves MI outcomes by inhibiting cardiomyocyte apoptosis and inflammatory damage through modulating macrophage polarization and regulating the IL-1R2/IL-17RA/STAT1 signaling pathway. This study provides a charming paradigm to explore effective drug combinations in traditional Chinese medicine and a promising treatment for MI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Fan, Wei, Chai, Li, Gao, Liu and Guo.)

Backgrounds: Nonalcoholic fatty liver disease (NAFLD) exhibits a close association with osteoporosis. This work aims to assess the potential effects of NAFLD on the progression of osteopenia in animal models., Methods: Forty-eight C57BL/6 female mice were randomly divided to wild-type (WT) group and high-fat diet (HFD) group. The corresponding detections were performed after sacrifice at 16, 24 and 32 weeks, respectively., Results: At 16 weeks, an remarkable increase in body weight and lipid aggregation in the hepatocytes of HFD group was observed compared to the WT group, while the bone structure parameters showed no significant difference. At 24 weeks, the levels of TNF-α and IL-6 in NAFLD mice were significantly increased, while the level of osteoprotegerin mRNA in bone tissue was decreased, and the level of receptor activator of nuclear factor Kappa-B ligand mRNA was increased. Meanwhile, the function of osteoclasts was increased, and the bone microstructure parameters showed significant changes. At 32 weeks, in the HFD mice, the mRNA levels of insulin-like growth factor-1 (IGF-1), runt-related transcription factor 2, and osterix mRNA were reduced, while the insulin-like growth factor binding protein-1 (IGFBP-1) level was increased. Simultaneously, the osteoblast function was decreased, and the differences of bone structure parameters were more significant, showing obvious osteoporosis., Conclusions: The bone loss in HFD mice is pronounced as NAFLD progresses, and the changes of the TNF-α, IL-6, IGF-1, and IGFBP-1 levels may play critical roles at the different stages of NAFLD in HFD., (© 2023. The Author(s).)

Atherosclerosis is a chronic disease that thickens the blood vessel walls and narrows the lumen. Venous thrombosis is a blood clot that forms in the body's deep veins or pulmonary arteries. However, the relationship between NDUFB11 and NDUFS3 and atherosclerosis and venous thrombosis is unclear. We employed data files that combined atherosclerosis and chronic stress groups. Subsequently, we conducted differential gene expression analysis (DEGs) and performed weighted gene co-expression network analysis (WGCNA). We constructed and analyzed a protein-protein interaction (PPI) network. Further analyses included functional enrichment analysis, gene set enrichment analysis (GSEA), gene expression heatmaps, immune infiltration analysis, and mRNA analysis. By comparing our findings with the Comparative Toxicogenomics Database (CTD), we identified the most relevant diseases associated with the core genes. Additionally, we utilized TargetScan to screen for miRNAs regulating the central DEGs. To validate our results, we conducted Western Blot experiments at the cellular level. A total of 1747 DEGs were co-identified. According to the Gene Ontology (GO) analysis of differentially expressed genes, they were primarily enriched in mitochondrial gene expression, mitochondrial envelope, organelle membrane, and mitochondrial inner membrane categories. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the target cells were mainly enriched in metabolic pathways, ribosomes, and histidine metabolism. The intersection of enriched terms from both GO and KEGG analyses showed significant enrichment in mitochondrial gene expression, mitochondrial envelope, organelle inner membrane, ribosomal structural constituents, histidine metabolism, and oxidative phosphorylation. Eight core genes were identified, including NDUFS5, UQCRQ, COX6C, COX7B, ATP5ME, NDUFS3, NDUFA3, and NDUFB11. The gene expression heatmap demonstrated that core genes (NDUFB11 and NDUFS3) were downregulated in atherosclerosis with venous thrombosis samples and upregulated in normal samples. CTD analysis revealed that the core genes NDUFB11 and NDUFS3 were associated with pain, arterial diseases, atherosclerosis, arteritis, venous thrombosis formation, and venous thromboembolism. We added Western Blot basic cell experiment for verification. NDUFB11 and NDUFS3 are downregulated in atherosclerosis and venous thrombosis, associated with poorer prognosis, and may serve as potential biomarkers for both diseases., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Sulfonamide antibiotics (SAs) are serious pollutants to ecosystems and environments. Previous studies showed that microbial degradation of SAs such as sulfamethoxazole (SMX) proceeds via a sad-encoded oxidative pathway, while the sulfonamide-resistant dihydropteroate synthase gene, sul, is responsible for SA resistance. However, the co-occurrence of sad and sul genes, as well as how the sul gene affects SMX degradation, was not explored. In this study, two SMX-degrading bacterial strains, SD-1 and SD-2, were cultivated from an SMX-degrading enrichment. Both strains were Paenarthrobacter species and were phylogenetically identical; however, they showed different SMX degradation activities. Specifically, strain SD-1 utilized SMX as the sole carbon and energy source for growth and was a highly efficient SMX degrader, while SD-2 did could not use SMX as a sole carbon or energy source and showed limited SMX degradation when an additional carbon source was supplied. Genome annotation, growth, enzymatic activity tests, and metabolite detection revealed that strains SD-1 and SD-2 shared a sad-encoded oxidative pathway for SMX degradation and a pathway of protocatechuate degradation. A new sulfonamide-resistant dihydropteroate synthase gene, sul918, was identified in strain SD-1, but not in SD-2. Moreover, the lack of sul918 resulted in low SMX degradation activity in strain SD-2. Genome data mining revealed the co-occurrence of sad and sul genes in efficient SMX-degrading Paenarthrobacter strains. We propose that the co-occurrence of sulfonamide-resistant dihydropteroate synthase and sad genes is crucial for efficient SMX biodegradation. KEY POINTS: • Two sulfamethoxazole-degrading strains with distinct degrading activity, Paenarthrobacter sp. SD-1 and Paenarthrobacter sp. SD-2, were isolated and identified. • Strains SD-1 and SD-2 shared a sad-encoded oxidative pathway for SMX degradation. • A new plasmid-borne SMX resistance gene (sul918) of strain SD-1 plays a crucial role in SMX degradation efficiency., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We report herein the regioselective synthesis of all-carbon lemniscular nanohoops bis-po -CC and bis-pm -TC by the rational control of ring closures at the different positions of planar chiral tetrasubstituted [2.2]paracyclophane. Topological analyses reveal that bis-pm -TC is topologically chiral while bis-po -CC is topologically achiral. X-ray crystal analysis demonstrates that bis-pm -TC adopts a lemniscular conformation with a contiguous conjugation. CD and CPL measurements further reveal that the chiroptical properties of bis-pm -TC are obviously different from those of bis-po -CC due to their different topological chiralities., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Biomass materials are perceived as sustainable, carbon-rich precursors for the fabrication of carbon materials. In this study, we demonstrated the capacitance performance of biomass-derived carbon, produced by using golden shower tree seeds (GTs) as carbon precursors and potassium ferrate (K 2 FeO 4 ) as the activation agent. The as-prepared porous carbon (GTPC) possessed an ultrahigh specific surface area (1915 m 2 g -1 ) and abundant pores. They also exhibited superior electrochemical performance, owing to their well-constructed porous structure, high surface area, and optimized porous structure. Optimized activated carbon (GTPC-1) was used to assemble a symmetric solid-state supercapacitor device with poly(vinyl alcohol) (PVA)/H 2 SO 4 as a solid-state gel electrolyte. The device exhibited a maximum areal energy density of 42.93 µWh cm -2 at a power density of 520 µW cm -2 .

Background: The risk of early mortality of patients who start dialysis urgently is high; however, in patients with diabetes undergoing urgent-start peritoneal dialysis (USPD), the risk of, and risk factors for, early mortality are unknown., Aim: To identify risk factors for mortality during high-risk periods in patients with diabetes undergoing USPD., Methods: This retrospective cohort study enrolled 568 patients with diabetes, aged ≥ 18 years, who underwent USPD at one of five Chinese centers between 2013 and 2019. We divided the follow-up period into two survival phases: The first 6 mo of USPD therapy and the months thereafter. We compared demographic and baseline clinical data of living and deceased patients during each period. Kaplan-Meier survival curves were generated for all-cause mortality according to the New York Heart Association (NYHA) classification. A multivariate Cox proportional hazard regression model was used to identify risk factors for mortality within the first 6 mo and after 6 mo of USPD., Results: Forty-one patients died within the first 6 mo, accounting for the highest proportion of mortalities (26.62%) during the entire follow-up period. Cardiovascular disease was the leading cause of mortality within 6 mo (26.83%) and after 6 mo (31.86%). The risk of mortality not only within the first 6 mo but also after the first 6 mo was higher for patients with obvious baseline heart failure symptoms than for those with mild or no heart failure symptoms. Independent risk factors for mortality within the first 6 mo were advanced age [hazard ratio (HR: 1.908; 95%CI: 1.400-2.600; P < 0.001), lower baseline serum creatinine level (HR: 0.727; 95%CI: 0.614-0.860; P < 0.001), higher baseline serum phosphorus level (HR: 3.162; 95%CI: 1.848-5.409; P < 0.001), and baseline NYHA class III-IV (HR: 2.148; 95%CI: 1.063-4.340; P = 0.033). Independent risk factors for mortality after 6 mo were advanced age (HR: 1.246; 95%CI: 1.033-1.504; P = 0.022) and baseline NYHA class III-IV (HR: 2.015; 95%CI: 1.298-3.130; P = 0.002)., Conclusion: To reduce the risk of mortality within the first 6 mo of USPD in patients with diabetes, controlling the serum phosphorus level and improving cardiac function are recommended., Competing Interests: Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Droplet vitrification has emerged as a promising ice-free cryopreservation approach to provide a supply chain for off-the-shelf cell products in cell therapy and regenerative medicine applications. Translation of this approach requires the use of low concentration (i.e., low toxicity) permeable cryoprotectant agents (CPA) and high post cryopreservation viability (>90%), thereby demanding fast cooling and warming rates. Unfortunately, with traditional approaches using convective heat transfer, the droplet volumes that can be successfully vitrified and rewarmed are impractically small (i.e., 180 picoliter) for <2.5 m permeable CPA. Herein, a novel approach to achieve 90-95% viability in micro-liter size droplets with 2 m permeable CPA, is presented. Droplets with plasmonic gold nanorods (GNRs) are printed onto a cryogenic copper substrate for improved cooling rates via conduction, while plasmonic laser heating yields >400-fold improvement in warming rates over traditional convective approach. High viability cryopreservation is then demonstrated in a model cell line (human dermal fibroblasts) and an important regenerative medicine cell line (human umbilical cord blood stem cells). This approach opens a new paradigm for cryopreservation and rewarming of dramatically larger volume droplets at lower CPA concentration for cell therapy and other regenerative medicine applications., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Objective: The clock-drawing test (CDT) is a widely used screening tool for detecting cognitive decline. However, normative data for Chinese individuals are scarce. Our study aimed to provide standardized values for the three quantitative CDT scoring methods that were tailored for Chinese-speaking adults in Shijiazhuang City and explore the discriminant validity of the CDT scores in patients with acute ischemic stroke., Methods: We conducted the CDT among 418 healthy individuals aged between 35 and 84 years. The CDT was administered and scored by five raters using the method derived from the Montreal Cognitive Assessment (MoCA), Rouleau's, and Babins' scoring systems. The influence of age, education, and sex on the performance in the CDT was analyzed. Furthermore, 336 patients with acute ischemic stroke were enrolled to explore the discriminant validity of CDT scores., Results: In all three scoring systems, CDT scores were significantly correlated with age and years of education but not with sex. Normative data stratified for age and years of education were established. Interrater and intersystem reliability were high in our study. CDT total scores and subscores showed significant differences between stroke patients and healthy individuals., Conclusions: Our study provides CDT normative data using three quantitative scoring methods for Chinese-speaking adults in Shijiazhuang City. Age and education level were the key factors that affected the CDT scores. CDT total scores and subscores provided good discriminant validity for patients with acute ischemic stroke., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

In this paper, a salamo-based copper(ii) complex probe L-Cu 2+ was synthesized, which combined with copper(ii) ions to form L-Cu 2+ for the detection of S 2- and had a good fluorescence chemical response. Through spectral analysis, we found that S 2- could be identified with high sensitivity and selectivity in the presence of various anions and could be used for the detection of S 2- by the naked eye. With the addition of S 2- , the solution color changed from colorless to bright yellow. UV absorption, fluorescence and other characterization methods were carried out, and the mechanism of action was determined. In addition, we performed a visual inspection of H 2 S gas, and the probe L-Cu 2+ could detect S 2- in the gas molecules, revealing its potential application value in biology and medicine., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Neuroticism is a core personality trait and a major risk factor for several mental and physical diseases, particularly in females, who score higher on neuroticism than men, on average. However, a better understanding of the expression profiles of proteins in the circulating blood of different neurotic female populations may help elucidate the intrinsic mechanism of neurotic personality and aid prevention strategies on mental and physical diseases associated with neuroticism., Methods: In our study, female subjects were screened for inclusion by the Eysenck Personality Questionnaire (EPQ), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) scales and routine physical examination. Subjects who passed the examination and volunteered to participate were grouped by neuroticism using EPQ scores (0 and 1 = low neuroticism group; > 5 = high neuroticism group). Proteins in serum samples of the two neuroticism groups were identified using isobaric tags for relative and absolute quantification (iTRAQ) technology., Results: A total of 410 proteins exhibited significant differences between high and low neuroticism, 236 proteins were significantly upregulated and 174 proteins were significantly downregulated. Combine the results of GO and KEGG enrichment analysis of differences proteins between high and low neuroticism with the PPI network, it could be observed that the Alpha-synuclein (SNCA), ATP7A protein (ATP7A), Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (GNG2), cyclin-dependent kinase 6 (CDK6), myeloperoxidase (MPO), azurocidin (AZU1), Histone H2B type 1-H (HIST1H2BH), Integrin alpha-M (ITGAM) and Matrix metalloproteinase-9 (MMP9) might participate in the intrinsic mechanism of neuroticism by regulating response to catecholamine stimulus, catecholamine metabolic process, limbic system development and transcriptional misregulation in cancer pathway., Conclusions: Our study revealed the characteristics of the neurotic personality proteome, which might be intrinsic mechanism of the neurotic population., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)

The traditional Chinese herb Lonicerae Japonicae Flos has shown significant clinical benefits in the treatment of heart failure, but the mechanism remains unclear. As the main active ingredient found in the plasma after oral administration of Lonicerae Japonicae Flos, chlorogenic acid (CGA) has been reported to possess anti-inflammatory, anti-oxidant and anti-apoptosis function. We firstly confirmed the cardioprotective effects of CGA in transverse aortic constriction (TAC)-induced heart failure mouse model, through mitigating the TNF-α-induced toxicity. We further used TNF-α-induced cardiac injury in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to elucidate the underlying mechanisms. CGA pre-treatment could reverse TNF-α-induced cellular injuries, including improved cell viability, increased mitochondrial membrane potential and inhibited cardiomyocytes apoptosis. We then examined the NF-κB/p65 and major mitogen-activated protein kinases (MAPKs) signalling pathways involved in TNF-α-induced apoptosis of hiPSC-CMs. Importantly, CGA can directly inhibit NF-κB signal by suppressing the phosphorylation of NF-κB/p65. As for the MAPKs, CGA suppressed the activity of only c-Jun N-terminal kinase (JNK), but enhanced extracellular signal-regulated kinase1/2 (ERK1/2) and had no effect on p38. In summary, our study revealed that CGA has profound cardioprotective effects through inhibiting the activation of NF-κB and JNK pathway, providing a novel therapeutic alternative for prevention and treatment of heart failure., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

New thoughts are warranted to develop efficient diagnosis and optimal therapeutics to combat unstable angina (UA)/myocardial infarction (MI). Therefore, the gene data of patients with UA or MI were used in this study to identify the optimal pathways which can provide comprehensive information for UA/MI development. Differentially expressed genes (DEGs) between UA and MI were detected using LIMMA package, and pathway enrichment analysis was conducted for the DEGs, based on the DAVID tool, to detect the significant pathways. Then, differential co-expression network (DCN) and sub-DCN for the DEGs were constructed. Subsequently, informative pathways were extracted using guilt-by-association (GBA) principle relying on the area under the curve (AUC), and the pathway categories with AUC >0.8 were defined as the informative pathways. Finally, we selected the optimal pathways based on the traditional pathway analysis and the sub-DCN-based-GBA pathway prediction method. A total of 203 and 266 DEGs were identified from the expression profile of blood of MI samples comparing with UAs in the time-point 1 and time-point 2 groups. Moreover, 7 and 10 informative pathway terms were identified based on AUC>0.8. Significantly, cytokine-cytokine receptor interaction, as well as MAPK signaling pathway were the common optimal pathways in the two groups. Calcium signaling pathway was unique to the whole blood of patients with acute coronary syndrome (ACS) taken at 30 days post-ACS. In conclusion, the optimal pathways (MAPK signaling pathway, cytokine-cytokine receptor interaction, and calcium signaling pathway) might play important roles in the progression of UA/MI.

Silibinin, also known as silybin, is the major flavonolignan isolated from Silybum marianum . Although previous reports demonstrated that silibinin exhibits significant tumor suppressor activities in various cancers by promoting cell apoptosis, it was also shown to trigger autophagy to counteract apoptosis induced by exogenous stresses in several types of cells. However, there is no report to address the role of silibinin induced autophagy in human A172 and SR glioblastoma cells. Our study showed that silibinin treatment not only inhibited the metabolic activities of glioblastoma cells but also promoted their apoptosis through the regulation of caspase 3 and PARP-1 in concentration- and time-dependent manners. Meanwhile, silibinin induced autophagy through upregulation of microtubule-associated protein a light chain 3- (LC3-) II. And autophagy inhibition with chloroquine, a lysosomotropic agent, significantly enhanced silibinin induced glioblastoma cell apoptosis. Moreover, silibinin dose-dependently downregulated the phosphorylation levels of mTOR at Ser-2448, p70S6K at Thr-389, and 4E-BP1 at Thr-37/46. Furthermore, the expression of YAP, the downstream effector of Hippo signal pathway, was also suppressed by silibinin. These results suggested that silibinin induced glioblastoma cell apoptosis concomitant with autophagy which might be due to simultaneous inhibition of mTOR and YAP and silibinin induced autophagy exerted a protective role against cell apoptosis in both A172 and SR cells.

Background: Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease yet with no effective treatment available. The sigma-1 receptor (S1R), a ligand-regulated chaperone, emerges as a potential retina-protective therapeutic target. In particular, pharmacological activation of S1R was recently shown to rescue cones in the rd10 mouse, a rod Pde6b mutant that recapitulates the RP pathology of autonomous rod degeneration followed by secondary death of cones. The mechanisms underlying the S1R protection for cones are not understood in detail., Methods: By rearing rd10/S1R -/- and rd10/S1R +/+ mice in dim light to decelerate rapid rod/cone degeneration, we were able to compare their retinal biochemistry, histology and functions throughout postnatal 3-6 weeks (3 W-6 W)., Results: The receptor-interacting protein kinases (RIP1/RIP3) and their interaction (proximity ligation) dramatically up-regulated after 5 W in rd10/S1R -/- (versus rd10/S1R +/+ ) retinas, indicative of intensified necroptosis activation, which was accompanied by exacerbated loss of cones. Greater rod loss in rd10/S1R -/- versus rd10/S1R +/+ retinas was evidenced by more cleaved Caspase3 (4 W) and lower rod electro-retinographic a-waves (4 W-6 W), concomitant with reduced LC3-II and CHOP (4 W-6 W), markers of autophagy and endoplasmic reticulum stress response, respectively. However, the opposite occurred at 3 W., Conclusion: This study reveals previously uncharacterized S1R-associated mechanisms during rd10 photoreceptor degeneration, including S1R's influences on necroptosis and autophagy as well as its biphasic role in rod degeneration upstream of cone death.

The aim of the present study was to observe the in vivo targeting characteristic of angiopoietin 2-small interfering RNA (Ang2-siRNA) plasmid/chitosan magnetic nanoparticles in an established nude mouse model of malignant melanoma (MM) under an external magnetic field. The nude mouse MM model was first established, then divided into 3 groups, including the control group, the non-targeting group and the target group, the control group was given normal saline and the non-targeting and targeting groups were administrated particles through the tail vein; the non-targeting group was not under external magnetic field and the control group and the targeting group were under external magnetic field for 60 min. The mice were then sacrificed and the tumor tissues were stained with hematoxylin and eosin and Prussian blue in order to verify the particle distributions in the tumor tissues. The control group exhibited negative Prussian blue staining in the tumor tissues, the non-targeting group demonstrated weakly positive Prussian blue staining in tumor tissues and the targeting group revealed strongly positive Prussian blue staining in tumor tissues. Ang2-siRNA plasmid vector/chitosan magnetic nanoparticles directly moved towards tumor tissues under the action of external magnetic field, thus it demonstrated good targeting characteristic.

Although the neurovascular unit was originally developed as a conceptual framework for stroke, it is now recognized that these cell-cell interactions play critical roles in many other CNS disorders as well. In brain trauma, perturbations within the neurovascular unit may be especially important. Changes in neurovascular coupling may disrupt blood flow and metabolic regulation. Disruption of transmitter release-reuptake kinetics in neurons and astrocytes may augment excitotoxicity. Alterations in gliovascular signaling may underlie blood-brain barrier disruptions and traumatic edema. Perturbations in cell-cell signaling between all neuronal, glial, and vascular compartments may increase susceptibility to cell death. Finally, repairing the brain after trauma requires the integrated restoration of all neural, glial, and vascular connectivity for effective functional recovery. Just as in stroke, saving neurons alone may also be insufficient for treating brain trauma. In this minireview, we attempt to briefly highlight some of these pathways to underscore the importance of rescuing the entire neurovascular unit in brain trauma., (© 2014 John Wiley & Sons Ltd.)

Objective: To explore the effects on the standardized management of patients with coronary atherosclerotic heart disease complicated with chronic heart failure., Methods: A total of 823 patients discharged from our department were randomly enrolled. Among 734 patients with follow-up consents, they were divided into management and control groups (n = 440, 294). The management group received standardized out-of-hospital management, regular health education and follow-ups of telephone and outpatient visits., Results: Compared with the control group, the management group had lower rates of all-cause mortality, cardiac death and readmission due to cardiovascular events (CVE) declining by 26.5%, 32.2% and 57.0% respectively. Over a 4-year period, the annular survival rate of management group was 92%, 85%, 83% and 82% while that of control group 95%, 89%, 82% and 75% respectively. Patient compliance of digoxin and diuretics in the control group was inferior to that in the management group., Conclusion: Through standardized out-of-hospital management, the patients with coronary atherosclerotic heart disease plus chronic heart failure may achieve significant benefits through reducing the rates of all-cause mortality, cardiac death and readmission due to CVE and improving survival rate.

Chalcones, which have characteristic 1,3-diaryl-2-propen-1-one skeleton, are mainly produced in roots, rhizomes, heartwood, leaves, and seeds of genera Angelica, Sophora, Glycyrrhiza, Humulus, Scutellaria, Parartocarpus, Ficus, Dorstenia, Morus, Artocarpus, and so forth. They have become of interest in the research and development of natural antitumor agents over the past decades due to their broad range of mechanisms including anti-initiation, induction of apoptosis, antiproliferation, antimetastasis, antiangiogenesis, and so forth. This review summarizes the studies on the antitumor activity of naturally occurring chalcones and their underlying mechanisms in detail during the past decades.

Background: Hand, foot and mouth disease (HFMD) is an emerging public health problem in China, not only threatening the health of children, but also causing tremendous loss and burden to both families and society. The aim of this study was to characterize the epidemiology and clinical features of HFMD, and to understand the key factors affecting HFMD in the Harbin region to provide scientific evidence for effective prevention and control strategies., Methods: Epidemiological and clinical information from 2379 randomly chosen cases of HFMD treated at the Harbin Center for Disease Control and Prevention from May 2008 to November 2011 were analyzed. All cases were separated into common and severe HFMD, with key factors for severe HFMD analyzed using multivariable Logistic regression., Results: Among the 2379 patients, 1798 were common cases and 581 severe cases, 14 of which resulted in death. Most cases were in children younger than 5 years. Morbidity peaked in July and was higher in the surrounding country and cities than in Harbin proper. Medical expenses were significantly higher for severe than for common cases (P < 0.001). The primary clinical symptoms were fever and erythema; laboratory examination showed leucocytosis together with pneumonia, carditis, and abnormal electrocardiogram and electroencephalogram in severe cases. Multivariable Logistic regression analysis showed that the key factors for severe HFMD were age, morbidity location, morbidity area, fever duration, mouth mucosal symptoms, and abnormal serum levels of neutrophils (NEUT), hemoglobin and glucose (P < 0.05)., Conclusions: To improve prognosis, reduce medical expense and prevent the development of severe cases, we should improve the epidemiological detection of HFMD to treat patients quickly. We should also closely monitor children with the EV71 virus, who present with continuous fever as well as abnormal laboratory results, from areas highly susceptible to HFMD attacks.

Stroke is not only more prevalent but is also associated with more severe adverse functional outcomes among patients with sleep apnea. Monocarboxylate transporters (MCT) are important regulators of cellular bioenergetics, have been implicated in brain susceptibility to acute severe hypoxia (ASH), and could underlie the unfavorable prognosis of cerebrovascular accidents in sleep apnea patients. Rodents were exposed to either intermittent hypoxia (IH) during sleep, a characteristic feature of sleep apnea, or to sustained hypoxia (SH), and expression of MCT1 and MCT2 was assessed. In addition, the functional recovery to middle cerebral artery occlusion (MCAO) in rats and hMCT2 transgenic mice and of hippocampal slices subjected to ASH was assessed, as well as the effects of MCT blocker and MCT2 antisense oligonucleotides and siRNAs. IH, but not SH, induced significant reductions in MCT2 expression over time at both the mRNA and protein levels and in the functional recovery of hippocampal slices subjected to ASH. Similarly, MCAO-induced infarcts were significantly greater in IH-exposed rats and mice, and overexpression of hMCT2 in mice markedly attenuated the adverse effects of IH. Exogenous pyruvate treatment reduced infarct volumes in normoxic rats but not in IH-exposed rats. Administration of the MCT2 blocker 4CN, but not the MCT1 antagonist p-chloromercuribenzene sulfonate, increased infarct size. Thus, prolonged exposures to IH mimicking sleep apnea are associated with increased CNS vulnerability to ischemia that is mediated, at least in part, by concomitant decreases in the expression and function of MCT2. Efforts to develop agonists of MCT2 should provide opportunities to ameliorate the overall outcome of stroke.

Objective: Diabetes is an independent risk factor for stroke. However, the underlying mechanism of how diabetes confers that this risk is not fully understood. We hypothesize that secretion of neurotrophic factors by the cerebral endothelium, such as brain-derived neurotrophic factor (BDNF), is suppressed in diabetes. Consequently, such accrued neuroprotective deficits make neurons more vulnerable to injury., Research Design and Methods: We examined BDNF protein levels in a streptozotocin-induced rat model of diabetes by Western blotting and immunohistochemistry. Levels of total and secreted BDNF protein were quantified in human brain microvascular endothelial cells after exposure to advanced glycation end product (AGE)-BSA by enzyme-linked immunosorbent assay and immunocytochemistry. In media transfer experiments, the neuroprotective efficacy of conditioned media from normal healthy endothelial cells was compared with AGE-treated endothelial cells in an in vitro hypoxic injury model., Results: Cerebrovascular BDNF protein was reduced in the cortical endothelium in 6-month diabetic rats. Immunohistochemical analysis of 6-week diabetic brain sections showed that the reduction of BDNF occurs early after induction of diabetes. Treatment of brain microvascular endothelial cells with AGE caused a similar reduction in BDNF protein and secretion in an extracellular signal-related kinase-dependent manner. In media transfer experiments, conditioned media from AGE-treated endothelial cells were less neuroprotective against hypoxic injury because of a decrease in secreted BDNF., Conclusions: Taken together, our findings suggest that a progressive depletion of microvascular neuroprotection in diabetes elevates the risk of neuronal injury for a variety of central nervous system diseases, including stroke and neurodegeneration.

Aims: the role of nuclear factor (NF)-κB in heart failure (HF) is not well defined. We sought to determine whether myocyte-localized NF-κB p65 activation in HF exacerbates post-infarction remodelling and promotes maladaptive endoplasmic reticulum (ER) stress., Methods and Results: non-transgenic (NTg) and transgenic (Tg) mice with myocyte-restricted overexpression of a phosphorylation-resistant inhibitor of κBα (IκBα(S32A,S36A)) underwent coronary ligation (to induce HF) or sham operation. Over 4 weeks, the remote myocardium of ligated hearts exhibited robust NF-κB activation that was almost exclusively p65 beyond 24 h. Compared with sham at 4 weeks, NTg HF hearts were dilated and dysfunctional, and exhibited hypertrophy, fibrosis, up-regulation of inflammatory cytokines, increased apoptosis, down-regulation of ER protein chaperones, and up-regulation of the ER stress-activated pro-apoptotic factor CHOP. Compared with NTg HF, Tg-IκBα(S32A,S36A) HF mice exhibited: (i) improved survival, chamber remodelling, systolic function, and pulmonary congestion, (ii) markedly diminished NF-κB p65 activation, cytokine expression, and fibrosis, and (iii) a three-fold reduction in apoptosis. Moreover, Tg-IκBα(S32A,S36A) HF hearts exhibited maintained expression of ER chaperones and CHOP when compared with sham. In cardiomyocytes, NF-κB activation was required for ER stress-mediated apoptosis, whereas abrogation of myocyte NF-κB shifted the ER stress response to one of adaptation and survival., Conclusion: persistent myocyte NF-κB p65 activation in HF exacerbates cardiac remodelling by imparting pro-inflammatory, pro-fibrotic, and pro-apoptotic effects. p65 modulation of cell death in HF may occur in part from NF-κB-mediated transformation of the ER stress response from one of adaptation to one of apoptosis.

Background: Genomic amplification of the human telomerase RNA gene (hTERC), located in the chromosome 3q26 region, has been documented in tumorigenesis. The present study was designed to detect hTERC amplification in cervical lesions and evaluate whether this might serve as a supportive biomarker to cytopathology or histopathology in the diagnosis of cervical lesions., Methods: Liquid-based thin-layer cytopathologic examination and detection of amplification by fluorescence in situ hybridization (FISH) was conducted in 130 women, along with assessment of human papillomavirus DNA, colposcopy with biopsy, and histopathologic examination., Results: In cytopathologic examinations, hTERC amplification rates for negative for intraepithelial lesion or malignancy (NILM),atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL) and squamous cell carcinoma (SCC) cases were 0% (0/10), 4% (1/25), 20% (6/30), 77% (27/35), and 100% (10/10), respectively. The difference among abnormal cellular change groups was statistically significant (P< 0.05). In histopathologic examinations, hTERC amplification rates in normal squamous cell with or without inflammatory, cervical intraepithelial neoplasia 1 (CIN 1), CIN 2, CIN 3 and SCC cases were 3.8% (2/52), 18.2% (6/33), 66.7% (6/9), 84.6% (22/26), 100% (10/10), respectively. There were significant differences among CIN1, CIN2, CIN3 and SCC cases (P< 0.05). The hTERC amplification was more specific than HPV positivity in differentiating lowgrade from high-grade cervical disorders (specificity: 88.5% vs. 70.8%, P< 0.05)., Conclusions: FISH detection of hTERC amplification could be an effective adjunct to cytopathologic or histopathologic examination for differential diagnosis of low- and high-grade cervical squamous cell disorders.

Neuroglobin (Ngb) is a recently discovered globin that affords protection against hypoxic/ischemic-induced cell injury in brain. Hypoxic/ischemic injury is associated with accumulation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS). In previous studies, we found that Ngb has antioxidative properties, and protects PC-12 cells against hypoxia- and β-amyloid-induced cell death. To further delineate the potential role of Ngb in protection against cerebral ischemia-reperfusion injury in vivo, we developed a transgenic mouse line that overexpresses Ngb. Hippocampal ischemia-reperfusion injury was induced by a 10-minute bilateral occlusion of the common carotid arteries, and the animal brains were assessed 3 days later. CA1 neural injury was determined by cresyl violet staining. Lipid peroxidation was assessed using a malonyldialdehyde assay kit, whereas ROS/RNS accumulation was determined by Het staining in the CA1 hippocampal region. Hippocampal Ngb mRNA and protein expressions were assessed by reverse transcriptase-PCR and western blotting, respectively. Neuroglobin was successfully overexpressed in the hippocampus of Ngb transgenic mice. After ischemia-reperfusion, CA1 ROS/RNS production and lipid peroxidation were markedly decreased in Ngb transgenic mice compared with wild-type mice. Furthermore, CA1 neuronal injury was also markedly reduced. Thus, Ngb may confer protection against ischemia-reperfusion injury in the brain through its intrinsic antioxidant properties.

Objective: To evaluate the effect of out-hospital normalized management of coronary heart disease (CAD) on the end point events such as mortality, readmission, etc, and on the compliance of patients through normalized management by an alliance of community and hospital., Methods: The samples were comprised of a total of 2000 patients in 15 communities. And 1642 patients agreed to a follow-up and signed a consent form. Ten communities were chosen as the intensive management group in which community clinicians were trained and the patient management plan was proposed and carried out. The remaining 5 communities were taken as the control group in which the community clinicians were not trained and the patients received only general management. Both groups received a follow-up of 23 months., Results: Compared with the control group, the intensive manage group showed a lower risk of all-cause death, cardiac death and readmission due to cardiovascular events (CVE). They declined by 36.5% (OR 0.635, 95%CI 0.478-0.854), 41.5% (OR 0.585, 95%CI 0.428-0.800) and 56.1% (OR 0.439, 95%CI 0.315-0.612) respectively. The proportion of patients with NYHA III in the intensive management and control groups increased by 3.6% and 7.7% while that of the counterparts of NYHAIV in two groups increased by 1.6% and 6.4% respectively. The cardiac function in the patients of intensive management group was significantly superior to that in control group. Patients in both groups displayed an acceptable compliance to cardiac medications except for aspirin. The proportion of aspirin in the intensive management and control groups increased by 8.4% and 8.7% respectively (P<0.05)., Conclusion: Through normalized management provided by an alliance of community and hospital, the rates of all-cause death and readmission due to CVE decrease significantly concurrently with an improvement of cardiac function and quality of life in CAD patients.

Study Design: Acellular spinal cord was prepared through chemical extraction, and its biocompatibility was studied., Objective: Acellular scaffolds have been developed from various materials for tissue reconstruction, except for spinal cord. The objective of this study was to prepare acellular spinal cord and examine the biocompatibility of the scaffold., Setting: This study was conducted at the Department of Orthopedics, Xinqiao Hospital, The Third Military Medical University, Chongqing, China., Methods: The morphology of the acellular segments was revealed by scanning electron microscopy, immunohistochemistry, and hematoxylin and eosin stain. Biocompatibility was studied by immunohistochemistry., Results: Results show that in spinal cord scaffolds, cells, myelin sheath and axon of nerve fibers were eliminated, and three-dimensional supports of extracellular matrix were reserved. The component analytical results of the acellular spinal cord indicate that they contain laminin, fibronectin and collagen, which can facilitate and induce the regeneration of injured nerves, and enhance the adhesion and proliferation of cells. The acellular spinal cord has a three-dimensional structure and excellent biocompatibility., Conclusion: Our data indicate that acellular spinal cord has certain biological properties and it may be a potential alternative scaffold for spinal cord tissue engineering.

Background: Granulocyte colony-stimulating factor (G-CSF) seems to improve cardiac function and perfusion when used systemically through mobilization of stem cells into peripheral blood, but results of previous clinical trials remain controversial. This study was designed to investigate safety and efficacy of subcutaneous injection of G-CSF on left ventricular function in patients with impaired left ventricular function after ST-segment elevation myocardial infarction (STEMI)., Methods: Thirty-three patients (22 men; age, (68.5 +/- 6.1) years) with STEMI and with comorbidity of leukopenia were included after successful primary percutaneous coronary intervention within 12 hours after symptom onset. Patients were randomized into G-CSF group who received G-CSF (10 microg/kg of body weight, daily) for continuous 7 days and control group. Results of blood analyses, echocardiography and angiography were documented as well as possibly occurred adverse events., Results: No severe adverse events occurred in both groups. Mean segmental wall thickening in infract segments increased significantly at 6-month follow up compared with baseline in both groups, but the longitudinal variation between two groups had no significant difference (P > 0.05). The same change could also be found in longitudinal variation of wall motion score index of infarct segments (P > 0.05). At 6-month follow-up, left ventricular end-diastolic volume of both groups increased to a greater extent, but there were no significant differences between the two groups when comparing the longitudinal variations (P > 0.05). In both groups, left ventricular ejection fraction measured by echocardiography ameliorated significantly at 6-month follow-up (P < 0.05), but difference of the longitudinal variation between two groups was not significant (P > 0.05). When pay attention to left ventricular ejection fraction measured by angiocardiography, difference of the longitudinal variation between groups was significant (P = 0.046). Early diastolic mitral flow velocity deceleration time changed significantly at 6- month follow-up in both groups (P = 0.05)., Conclusions: Mobilization of stem cells by G-CSF after reperfusion of infarct myocardium is safe and seems to offer a pragmatic strategy for recovery of myocardial global function.

Homogeneous and stable magnetic nanofluids containing γ-Fe2O3 nanoparticles were prepared using a two-step method, and their thermal transport properties were investigated. Thermal conductivities of the nanofluids were measured to be higher than that of base fluid, and the enhanced values increase with the volume fraction of the nanoparticles. Viscosity measurements showed that the nanofluids demonstrated Newtonian behavior and the viscosity of the nanofluids depended strongly on the tested temperatures and the nanoparticles loadings. Convective heat transfer coefficients tested in a laminar flow showed that the coefficients increased with the augment of Reynolds number and the volume fraction.

Objective: To investigate the effects of Notch signaling on scars in a rabbit ear model of hypertrophic scarring., Methods: The hypertrophic scar of rabbits' ears was reproduced. The left rabbit's ear wounds as the N-[N-(3,5-difluorophenacetyl-L-alanyl)]-(S)-phenylglycine t-butyl ester (DAPT) treated group were treated intradermally with the gamma-secretase inhibitor DAPT to inhibit the activation of Notch at 1, 3, 7 and 14 day time points. The right ears as the control group were treated with normal saline at the same time points. Experimental and control wounds were harvested on days 14, 21, 28 and 35 post wounding, and then examined histologically to quantify hypertrophic index and fibroblasts. The expression of epidermal differentiation markers-keratin 14 (K14), keratin 19 (K19), Involucrin and Notch downstream molecules-P21, P63 were examined and analyzed with immunohistochemistry staining., Results: Both hypertrophic index (1.93 +/- 0.32, 1.82 +/- 0.36, 1.79 +/- 0.25) and number of fibroblasts [(4.08 +/- 0.88), (3.30 +/- 0.53), (3.19 +/- 0.73) x 10(3)/mm(2)] in the DAPT treated group were significantly reduced on days 21, 28 and 35, compared with the control group [2.56 +/- 0.29, 2.61 +/- 0.30, 2.58 +/- 0.39, and (5.45 +/- 0.99), (4.80 +/- 1.13), (4.43 +/- 1.17) x 10(3)/mm(2), all P < 0.01)]. The K19, K14 and P63 increased their expression in the DAPT treated group (28.6% +/- 5.7%, 53.1% +/- 4.5%, 57.0% +/- 5.8%) relative to the control group (10.1% +/- 2.8%, 30.8% +/- 4.9%, 16.5% +/- 2.2%, all P < 0.01) on day 14 post wounding, while the Involucrin and P21 decreased their expression in the DAPT treated group (12.3% +/- 1.9%, 11.0% +/- 1.7%) relative to the control group (29.3% +/- 4.6%, 44.3% +/- 3.5%, both P < 0.01)., Conclusion: Inactivation of Notch signaling will inhibit scar epidermis to over-differentiation, and thereby inhibit proliferation of hypertrophic scars in the rabbit ears.

Background: Previous studies showed that preservation of microvascular integrity after myocardial ischemia was associated with myocardial viability. Real-time myocardial contrast echocardiography (RT-MCE) is a promising modality for non-invasive evaluation of microcirculation perfusion. Thus, it provides a unique tool to detect myocardial viability. We sought in this study to investigate the role of RT-MCE in predicting left ventricular (LV) functional recovery and remodeling after revascularization in patients with ischemic heart disease., Methods: Thirty-one patients with ischemic heart disease and resting regional LV dysfunction were included. LV volume, global and regional function were evaluated by echocardiography before and 6 - 9 months after revascularization. RT-MCE was performed before revascularization using low mechanical index power modulation imaging. Myocardial contrast opacification of dysfunctional segments was scored on a 3-point scale and mean contrast score in dysfunctional segments was calculated. Patients were divided into 2 groups according to mean contrast score in dysfunctional segments: group A, patients with mean contrast score = 0.5 (n = 19); group B, patients with mean contrast score < 0.5 (n = 12)., Results: Wall motion improvement was found to be 94.5%, 45.5% and 16.1% respectively (P < 0.01) in homogenous, patchy and absent contrast opacification segments. At baseline, there was no significant difference in LV volume and global function between the two groups. After revascularization, group B had significantly larger LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV), lower LV ejection fraction (LVEF) and higher wall motion score index (WMSI) than those of group A (all P < 0.05). Revascularization was followed by significant improvement of LV volume and recovery of global LV function in group A (all P < 0.01); however, in group B, after revascularization, deterioration of LVEDV (P < 0.05) was observed, moreover LVESV, WMSI and LVEF did not change significantly., Conclusions: The maintenance of myocardial microcirculation detected by RT-MCE can predict functional recovery and LV remodeling after revascularization in patients with ischemic heart disease, which might be helpful in clinical decision-making and risk stratification.

Background and Purpose: Hemorrhagic conversion after tissue plasminogen activator (tPA) stroke therapy has been linked with elevations in matrix metalloproteinase-9 (MMP-9) at the neurovascular interface. Here, we test the idea that statins may directly ameliorate tPA-induced MMP-9 dysregulation., Methods: Recombinant human tPA (5 microg/mL) was added to primary rat cortical astrocytes. Zymography was used to quantify MMP-9 levels in conditioned media. Effects of simvastatin or the Rho kinase inhibitor Y-27632 were assessed by pretreating cells before tPA exposure., Results: Simvastatin (1 to 10 micromol/L) significantly reduced tPA-induced MMP-9 in cortical astrocytes. This effect may be mediated via the Rho kinase pathway because tPA-induced activation of Rho signaling was suppressed by simvastatin, and tPA-induced MMP-9 levels were similarly reduced by the Rho kinase inhibitor Y-27632 (1 to 10 micromol/L)., Conclusions: Statins reduce tPA-induced MMP-9 dysregulation by inhibiting the Rho signaling pathway. Statins may ameliorate tPA-associated MMP imbalances in stroke.

X-linked hypohidrotic ectodermal dysplasia (HED) is a rare disease characterized by the hypoplasia or absence of eccrine glands, dry skin, scant hair, and dental abnormalities. Here, we report a Mongolian family with congenital absence of teeth inherited in an X-linked fashion. The affected members of the family did not show other HED characteristics, except hypodontia. We successfully mapped the affected locus to chromosome Xq12-q13.1, and then found a novel missense mutation, c.193C>G, in the ectodysplasin A (EDA) gene in all affected males and carrier females. The mutation causes arginine to be replaced by glycine in codon 65 (R65G) in the juxtamembrane region of EDA. In addition, 33% (3/9) of female carriers have a skewed X-chromosome inactivation pattern. Our result strongly suggests that the c.193C>G mutation is the disease-causing mutation in this family.

Background: Quantitatively assessing myocardial perfusion and its reserve is of great importance for the diagnosis and stratification of patients with coronary artery disease (CAD), and represents an important goal of myocardial contrast echocardiography. In this study we sought to test the usefulness of low dose dobutamine stress real-time myocardial contrast echocardiography (RT-MCE) in the assessment of CAD, and to explore the relationship between perfusion reserve and contractile reserve., Methods: Twenty-six patients with suspected or clinical diagnosed CAD were enrolled and underwent RT-MCE at baseline and under low dose dobutamine stress, and subsequent coronary angiography. RT-MCE images were analyzed quantitatively from microbubble replenishment curves for myocardial perfusion and its reserve., Results: At baseline, significant differences in beta (0.28 +/- 0.12, 0.25 +/- 0.09, 0.22 +/- 0.06, 0.20 +/- 0.07 respectively, P < 0.01) and A x beta (1.37 +/- 0.46, 1.28 +/- 0.47, 1.13 +/- 0.37, 0.91 +/- 0.32, respectively, P < 0.01) were observed among four segment groups with graded coronary artery stenosis severity (normal; 30% - 69% stenosis; 70% - 90% stenosis; and beyond 90% stenosis), but not observed in parameter A. When under stress, significant differences in A (5.73 +/- 1.28, 5.63 +/- 1.01, 4.96 +/- 0.81, 4.57 +/- 0.62, respectively, P < 0.01), beta (0.67 +/- 0.17, 0.55 +/- 0.19, 0.32 +/- 0.13, 0.25 +/- 0.08, respectively, P < 0.01) and A x beta (3.81 +/- 1.20, 3.11 +/- 1.17, 1.59 +/- 0.82, 1.12 +/- 0.37, respectively, P < 0.01) were observed among the formerly mentioned groups. Graded decreases in A reserve (1.20 +/- 0.53, 1.11 +/- 0.16, 0.98 +/- 0.12, 0.99 +/- 0.13, respectively, P < 0.01), beta reserve (2.65 +/- 1.07, 2.32 +/- 0.82, 1.44 +/- 0.40, 1.29 +/- 0.34, respectively, P < 0.01) and A x beta reserve (3.05 +/- 1.63, 2.59 +/- 1.01, 1.42 +/- 0.44, 1.27 +/- 0.34, respectively, P < 0.01) could also be observed with increasing coronary stenosis severity. In five segments groups scored by WMS (1 - 5), concordance between contractile function and myocardial perfusion could be found both at rest (beta: 0.28 +/- 0.11, 0.22 +/- 0.08, 0.21 +/- 0.05, 0.17 +/- 0.05, 0.19 +/- 0.06, respectively, P < 0.01; A x beta: 1.29 +/- 0.48, 0.98 +/- 0.45, 0.94 +/- 0.29, 0.76 +/- 0.30, 0.92 +/- 0.32, respectively, P < 0.01) and under stress (beta: 0.59 +/- 0.20, 0.35 +/- 0.15, 0.27 +/- 0.08, 0.17 +/- 0.05, 0.20 +/- 0.05, respectively, P < 0.01; A x beta: 3.07 +/- 1.38, 1.62 +/- 0.82, 1.28 +/- 0.40, 0.78 +/- 0.24, 0.93 +/- 0.22, respectively, P < 0.01). This concordance is also valid in terms of the reserves, and the MCE parameters in segments with ameliorated contractile function are significantly higher than in those without., Conclusions: Quantitative RT-MCE in conjunction with dobutamine stress shows promise in identifying and stratifying CAD and in exploring the perfusion-contractile correlation.

Calcium/calmodulin-dependent kinase II (CaMKII) is an ubiquitous second messenger that is highly expressed in neurons, where it has been implicated in some of the pathways regulating neuronal discharge as well as N-methyl-d-aspartate receptor-mediated synaptic plasticity. The full expression of the mammalian hypoxic ventilatory response (HVR) requires intact central relays within the nucleus of the solitary tract (NTS), and neural transmission of hypoxic afferent input is mediated by glutamatergic receptor activity, primarily through N-methyl-D-aspartate receptors. To examine the functional role of CaMKII in HVR, KN-93, a highly selective antagonist of CaMKII, was microinjected in the NTS via bilaterally placed osmotic pumps in freely behaving adult male Sprague-Dawley rats for 3 days. Vehicle-loaded osmotic pumps were surgically placed in control animals, and adequate placement of cannulas was ascertained for all animals. HVR was measured using whole body plethysmography during exposure to 10% O(2)-balance N(2) for 20 min. Compared with control rats, KN-93 administration elicited marked attenuations of peak HVR (pHVR) but did not modify normoxic minute ventilation. Differences in pHVR were primarily attributable to diminished respiratory frequency recruitments during pHVR without significant differences in tidal volume. These findings indicate that CaMKII activation in the NTS mediates respiratory frequency components of the ventilatory response to acute hypoxia; however, CaMKII activity does not appear to underlie components of normoxic ventilation.

Tyrosine hydroxylase, a hypoxia-regulated gene, may be involved in tissue adaptation to hypoxia. Intermittent hypoxia, a characteristic feature of sleep apnea, leads to significant memory deficits, as well as to cortex and hippocampal apoptosis that are absent after sustained hypoxia. To examine the hypothesis that sustained and intermittent hypoxia induce different catecholaminergic responses, changes in tyrosine hydroxylase mRNA, protein expression, and activity were compared in various brain regions of male rats exposed for 6 h, 1 day, 3 days, and 7 days to sustained hypoxia (10% O(2)), intermittent hypoxia (alternating room air and 10% O(2)), or normoxia. Tyrosine hydroxylase activity, measured at 7 days, increased in the cortex as follows: sustained > intermittent > normoxia. Furthermore, activity decreased in the brain stem and was unchanged in other brain regions of sustained hypoxia-exposed rats, as well as in all regions from animals exposed to intermittent hypoxia, suggesting stimulus-specific and heterotopic catecholamine regulation. In the cortex, tyrosine hydroxylase mRNA expression was increased, whereas protein expression remained unchanged. In addition, significant differences in the time course of cortical Ser(40) tyrosine hydroxylase phosphorylation were present in the cortex, suggesting that intermittent and sustained hypoxia-induced enzymatic activity differences are related to different phosphorylation patterns. We conclude that long-term hypoxia induces site-specific changes in tyrosine hydroxylase activity and that intermittent hypoxia elicits reduced tyrosine hydroxylase recruitment and phosphorylation compared with sustained hypoxia. Such changes may not only account for differences in enzyme activity but also suggest that, with differential regional brain susceptibility to hypoxia, recruitment of different mechanisms in response to hypoxia will elicit region-specific modulation of catecholamine response.

Objective: To investigate the feasibility of transplanted endothelial progenitor cells transfected with VEGF165 gene to ischemic flap with increased neovascularization and augmented the survival areas., Methods: EPCs were isolated from human cord blood and cultured in vitro. Plasmid PcDNA3.1(-)/VEGF165 containing VEGF gene was transfected into the EPCs. EPCs transfected with blank plasmid, and EPCs without transfection were used as controls. ELISA was used to detect the expression of VEGF protein in the culture fluids. The EPCs were dyed with CM-DiI 7 days later. Ischemic skin flaps were made on the backs of 27 nude mice. The mice were randomly divided into 3 equal groups with their skin flaps being transplanted with EPCs transfected with 3.1(-)/VEGF165 plasmid, EPCs not transfected with 3.1(-)/VEGF165 plasmid, and injected with M199 medium at the basal part. Four days after the peduncles of the skin flaps were cut. Seven days after the cutting-off of the peduncles the survival rate of skin flap was observed and the blood perfusion was observed with laser Doppler flowmetry, 10 days after the density of capillary arteries were observed with microcirculation microscope. Three specimens of skin flap were taken 7 and 11 days after the skin flaps were made to undergo histological examination to detect the density of capillary arteries by CD34 immunohistochemistry and to observe the proliferation of EPCs with fluorescence microscopy. Peripheral blood samples were collected 1, 4, 7, 14, and 28 days after the skin flaps were made to undergo ELISA to detect the levels of VEGF protein, Results: The VEGF levels in the culture supernatants of the groups A, B, and C were 352 ng/L +/- 35 ng/L, 45 ng/L +/- 5 ng/L, and 0 ng/L respectively with significant difference between any 2 groups (all P < 0.05). The skin flap survival rates of the three groups were 97.2%, 60.3%, and 34.2% respectively with significant difference between any 2 groups (all P < 0.05) and the survival quality of the group A was the best. The capillary density of the group A was greater than those of the groups B and C. The VEGF levels at any time point of the group A were all significantly higher than those of the group B and C (all P < 0.05) and there was not a significant difference between the groups B and C. The capillary density levels at different time points decreased progressively in the order of groups A, B, and C with significant difference between any 2 groups (all P < 0.05). No EPC was shown by fluorescence microscopy in the skin flaps of the group C. The EPC density in skin flap 7 and 11 days after the flaps were made were 136 +/- 10 and 75 +/- 6/mm(2) and 305 +/- 26 and 199 +/- 18/mm(2) respectively with significant differences between the groups A and B. (both P < 0.05)., Conclusion: The EPCs from human cord blood, especially those transfected with VEGF165 gene increases the neovascularization in ischemic skin flaps and augments their survival rate.

Aim: To study the signal roles of protein kinase C (PKC) and protein kinase A (PKA) in the influence of interferon-gamma (IFN-gamma) on proliferation and collagen synthesis of fibroblasts derived from hypertrophic scar (HS-FB) and normal skin (NS-FB)., Methods: HS-FB and NS-FB were cultured and passaged in Dulbecco modified Eagles medium (DMEM). Activity of PKC and PKA were assayed by transferring phosphorus (32P) into substrate after treatment with IFN-gamma 1000 kU/L at 10, 30, 60, and 120 min. Cell proliferation was determined with MTT assay. The collagen synthesis was measured with [3H]proline incorporation and Type III pre-collagen was determined with radioimmunoassay., Results: After exposure to IFN-gamma 1000 kU/L for 30 min, PKC activity of HS-FB and NS-FB increased from 2.57 +/- 0.14 and 2.13 +/- 0.12 nmol x min(-1) x g(-1) of control to 3.75 +/- 0.19 and 3.36 +/- 0.16 nmol x min(-1) x g(-1), respectively (P < 0.05). After exposure to IFN-gamma 1000 kU/L for 60 and 120 min, PKA activities of HS-FB increased gradually from 0.82 +/- 0.04 nmol x min(-1) x g(-1) of control to 1.03 +/- 0.05 and 1.23 +/- 0.06 nmol x min(-1) x g(-1), respectively (P<0.05). The PKA activities of NS-FB also increased from 0.52 +/- 0.03 nmol x min(-1) x g(-1) of control to 0.68 +/- 0.03 and 0.89 +/- 0.05 nmol x min(-1) x g(-1), respectively (P<0.05). The proliferation and collagen synthesis were enhanced by PKC activator (containing phosphatidylserine, diacylglycerol and Ca2+) and PKA inhibitor [H(7)250 micromol/L, 1-(5-isoquinolinylsulfonyl)-2-methyl piperazine], and inhibited by PKC inhibitor (GF109 250 micromol/L) and PKA activator (cAMP 25 micromol/L) (P<0.01). GF109 abrogated increased proliferation and collagen synthesis by IFN-gamma but it did not affect the inhibitory effects of IFN-gamma. At 120 min H7 reversed the inhibitory functions of IFN-gamma., Conclusion: IFN-gamma transiently increased proliferation and collagen synthesis of HS-FB and NS-FB by activation of PKC and subsequently inhibited proliferation and collagen synthesis by activation of PKA., (Copyright 2004 Acta Pharmacologica Sinica)

In previous single-labeling experiments, we showed that neurons in the nucleus ambiguous (NA) and the dorsal moto nucleus of the vagus (DmnX) project to intrinsic cardiac ganglia. Neurons in these two motor nuclei differ significantly in the size of their projection fields, axon caliber, and endings in cardiac ganglia. These differences in NA and DmnX axon cardiac projections raise the question as to whether they target the same, distinct, or overlapping populations of cardiac principal neurons. To address this issue, we examined vagal terminals in cardiac ganglia and trace injection sites in the brain stem using two different anterograde t ace s 1,1-dioleyl-3,3,3,3-tetramethylindocarbocyanine methanesulfonate and 4-[4-(dihexadecylamino)-styryl]-N-methylpyridinium iodide] and confocal microscopy in male Sprague-Dawley rats. We found that 1) NA and DmnX neurons innervate the same cardiac ganglia, but these axons target separate subpopulations of principal neurons and 2) axons arising from neurons in the NA and DmnX in the contralateral sides of the brain stem enter the cardiac ganglionic plexus through separate bundles and preferentially innervate principal neurons near their entry regions, providing topographic mapping of vagal motor neurons in left and right brain stem vagal nuclei. Because the NA and DmnX project to distinct populations of cardiac principal neurons, we propose that they may play different roles in controlling cardiac function.

Chronic intermittent hypoxia, a characteristic feature of sleep-disordered breathing, induces hypertension through augmented sympathetic nerve activity and requires the presence of functional carotid body arterial chemoreceptors. In contrast, chronic sustained hypoxia does not alter blood pressure. We therefore analyzed the biosynthetic pathways of catecholamines in peripheral nervous system structures involved in the pathogenesis of intermittent hypoxia-induced hypertension, namely, carotid bodies, superior cervical ganglia, and adrenal glands. Rats were exposed to either intermittent hypoxia (90 seconds of room air alternating with 90 seconds of 10% O2) or to sustained hypoxia (10% O2) for 1 to 30 days. Dopamine, norepinephrine, epinephrine, dihydroxyphenylacetic acid, and 5-hydroxytyptamine contents were measured by high-performance liquid chromatography. Expression of tyrosine hydroxylase and its phosphorylated forms, dopamine beta-hydroxylase, phenylethanolamine N-methyltransferase, and GTP cyclohydrolase-1 were determined by Western blot analyses. Both sustained and intermittent hypoxia significantly increased dopamine and norepinephrine content in carotid bodies but not in sympathetic ganglia or adrenal glands. In carotid bodies, both types of hypoxia augmented total levels of tyrosine hydroxylase protein and its phosphorylation on serines 19, 31, 40, as well as levels of GTP cyclohydrolase-1. However, the effects of intermittent hypoxia on catecholaminergic pathways were significantly smaller and delayed than those induced by sustained hypoxia. Thus, attenuated induction of catecholaminergic phenotype by intermittent hypoxia in carotid body may play a role in development of hypertension associated with sleep-disordered breathing. The effects of both types of hypoxia on expression of catecholaminergic enzymes in superior cervical neurons and adrenal glands were transient and small.

The effects of chronic sustained hypoxia (SH) on ventilation have been thoroughly studied. However, the effects of intermittent hypoxia (IH), a more prevalent condition in health and disease are currently unknown. We hypothesized that the ventilatory consequences of SH and IH may differ and be related to changes in N-methyl-D-aspartate (NMDA) glutamate receptor subunit expression. To examine these issues, Sprague-Dawley adult male rats were exposed to 30 days of either SH (10% O2) or IH (21% and 10% O2 alternations every 90 s) or to normoxia (RA), at the end of which ventilatory and O2 consumption responses to a 20-min acute hypoxic challenge (10% O2) were conducted. In addition, dorsocaudal brain stem tissue lysates were harvested at 1 h, 6 h, 1 day, 3 days, 7 days, 14 days, and 30 days of SH and IH and analyzed for NR1, NR2A, and NR2B NMDA glutamate receptor expression by immunoblotting. Normoxic ventilation was higher after both SH and IH (P < 0.001). Peak hypoxic ventilatory response was higher after SH but not after IH compared with RA. However, hypoxic ventilatory decline was more prominent after SH than IH (P < 0.001). NR1 expression showed a biphasic pattern of expression over time that was essentially identical after IH and SH (P value not significant). However, NR2A and NR2B expression was higher in IH compared with SH and RA (P < 0.01). We conclude that long-lasting exposures to SH and IH enhance normoxic ventilation but are associated with different time domains of ventilation during acute hypoxia that may be accounted in part by changes in NMDA glutamate receptor subunit expression.

Intermittent hypoxia (IH) during sleep, a critical feature of sleep apnea, induces significant neurobehavioral deficits in the rat. Cyclooxygenase (COX)-2 is induced during stressful conditions such as cerebral ischemia and could play an important role in IH-induced learning deficits. We therefore examined COX-1 and COX-2 genes and COX-2 protein expression and activity (prostaglandin E2 [PGE2] tissue concentration) in cortical regions of rat brain after exposure to either IH (10% O2 alternating with 21% O2 every 90 seconds) or sustained hypoxia (10% O2). In addition, the effect of selective COX-2 inhibition with NS-398 on IH-induced neurobehavioral deficits was assessed. IH was associated with increased COX-2 protein and gene expression from Day 1 to Day 14 of exposure. No changes were found in COX-1 gene expression after exposure to hypoxia. IH-induced COX-2 upregulation was associated with increased PGE2 tissue levels, neuronal apoptosis, and neurobehavioral deficits. Administration of NS-398 abolished IH-induced apoptosis and PGE2 increases without modifying COX-2 mRNA expression. Furthermore, NS-398 treatment attenuated IH-induced deficits in the acquisition and retention of a spatial task in the water maze. We conclude that IH induces upregulation and activation of COX-2 in rat cortex and that COX-2 may play a role in IH-mediated neurobehavioral deficits.

Intermittent hypoxia (IH), one of the hallmarks of obstructive sleep apnea, occurs more frequently during pregnancy. We hypothesized that IH may lead to persistent postnatal changes in respiratory responses to acute hypoxia and may also lead to adverse effects on spatial function learning as revealed by the Morris water maze. To examine this issue, time-pregnant Sprague-Dawley rats were exposed to IH and room air (IHRA; 21 and 10% O2 alternations every 90 seconds) or to normoxia (RARA) until delivery. Ventilatory and metabolic responses to a 20-minute acute hypoxic challenge (10% O2) were conducted at postnatal ages 5, 10, 15, and 30 days. In addition, spatial task learning was assessed in the water maze at 1 and 4 months of age. Normoxic ventilation was higher at all time points in IHRA rats than in RARA rats (p < 0.01). Peak hypoxic ventilatory responses were attenuated in IHRA rats at 5 days of age and hypoxic ventilatory depression was accentuated at this age as well. However, ventilatory equivalents (minute ventilation/oxygen consumption) revealed significant reductions in peak hypoxic ventilatory responses of IHRA rats and hypoxic ventilatory depression at all postnatal ages (p < 0.01). Acquisition and retention of a spatial task were similar in the IHRA and RARA groups at both 1 and 4 months of age. We conclude that gestational intermittent hypoxia elicits long-lasting alterations in the control of breathing. We postulate that such IH-induced respiratory plasticity may create selective vulnerability to hypoxia during development.

The nucleus of the solitary tract (NTS) plays a pivotal role in the ventilatory response to hypoxia (HVR). However, the effects of excitotoxic lesions and the potential for functional recovery and plasticity remain unknown. Domoic acid (DA) or vehicle were bilaterally injected within the NTS of adult male Sprague Dawley rats. HVR (10% O(2)) and anatomical changes were assessed at 5-90 d after surgery. DA induced dose-dependent HVR attenuations ( approximately 70% at peak effect) that exhibited saturation at concentrations of 0.75-1.0 mm. However, although sodium cyanide-induced ventilatory responses were virtually abolished, DA did not modify baroreceptor gain. Consistent with ventilatory reductions, NTS neurons showed a significant degeneration 3 d after DA injection. In addition, the projection fields and the density of vagal afferent terminals to the NTS, and the motor neurons in the dorsal motor nucleus of the vagus were substantially reduced at 15 d. At 30 d, no functional or neural recovery were apparent. However, at day 60, the reduction in HVR was only approximately 40% of control, and at 90 d, HVR returned to control levels, paralleling regeneration of vagal afferent terminals within the NTS. The regeneration was particularly prominent in the commissural and dorsomedial subnuclei in the absence of cellular recovery. Thus, the integrity of the NTS is critical for HVR, spontaneous HVR recovery occurs after excitotoxic lesions in the NTS, and vagal-glossopharyngeal terminal sprouting in the NTS may underlie the anatomical substrate for such spontaneous functional recovery. The adult brainstem/NTS has self-repairing capabilities and will compensate for functional losses after structural damage by rewiring of its neural circuitry.

Gangliogliomas are rare tumors of the central nervous system that account for approximately 1% of all brain tumors. Histologically, gangliogliomas are composed of intimately admixed glial and neuronal components, the pathological origins of which remain to be characterized. Clonal analysis through examination of the pattern of the X chromosome inactivation allows one to distinguish monoclonal differentiation of a genetically abnormal progenitor cell from parallel, but independent, clonal expansion of two different cell types during tumorigenesis in biphasic neoplasms, such as gangliogliomas. In the present study, we investigated the clonality of eight gangliogliomas from female patients using both methylation- and transcription-based clonality assays at the androgen receptor locus (HUMARA) on the X chromosome. Among tumors from seven patients who were heterozygous at the HUMARA locus, five were identified as monoclonal with the methylation-based clonality assay, and the results were confirmed by the transcription-based method, whereas two were shown to be polyclonal by the methylation-based clonality assay but monoclonal by transcription-based clonality analysis. We conclude that the predominant cell types in most gangliogliomas are monoclonal in origin and derive from a common precursor cell that subsequently differentiates to form neoplastic glial and neuronal elements.