Myocardial ischemia/reperfusion injury is the major cause of morbidity and mortality for cardiovascular diseases. Dopamine D2 receptors are expressed in cardiac tissues. However, the roles of dopamine D2 receptors in myocardial ischemia/reperfusion injury and cardiomyocyte apoptosis are unclear. Here we investigated the effects of both dopamine D2 receptors agonist (bromocriptine) and antagonist (haloperidol) on apoptosis of cultured neonatal rat ventricular myocytes induced by ischemia/reperfusion injury.
Myocardial ischemia/reperfusion injury was simulated by incubating primarily cultured neonatal rat cardiomyocytes in ischemic (hypoxic) buffer solution for 2 h. Thereafter, these cells were incubated for 24 h in normal culture medium.
Treatment of the cardiomyocytes with 10 μM bromocriptine significantly decreased lactate dehydrogenase activity, increased superoxide dismutase activity, and decreased malondialdehyde content in the culture medium. Bromocriptine significantly inhibited the release of cytochrome c, accumulation of [Ca2+]i, and apoptosis induced by ischemia/reperfusion injury. Bromocriptine also down-regulated the expression of caspase-3 and -9, Fas and Fas ligand, and up-regulated Bcl-2 expression. In contrast, haloperidol (10 μM) had no significant effects on the apoptosis of cultured cardiomyocytes under the aforementioned conditions.
These data suggest that activation of dopamine D2 receptors can inhibit apoptosis of cardiomyocytes encountered during ischemia/reperfusion damage through various pathways.
A DFT-SOFM-RBFNN method is proposed to improve the accuracy of DFT calculations
on Y-NO (Y = C, N, O, S) homolysis bond dissociation energies (BDE) by
combining density functional theory (DFT) and artificial intelligence/machine
learning methods, which consist of self-organizing feature mapping neural
networks (SOFMNN) and radial basis function neural networks (RBFNN). A
descriptor refinement step including SOFMNN clustering analysis and correlation
analysis is implemented. The SOFMNN clustering analysis is applied to classify
descriptors, and the representative descriptors in the groups are selected as
neural network inputs according to their closeness to the experimental values
through correlation analysis. Redundant descriptors and intuitively biased
choices of descriptors can be avoided by this newly introduced step. Using RBFNN
calculation with the selected descriptors, chemical accuracy (≤1
kcal·mol−1) is achieved for all 92 calculated
organic Y-NO homolysis BDE calculated by DFT-B3LYP, and the mean absolute
deviations (MADs) of the B3LYP/6-31G(d) and B3LYP/STO-3G methods are reduced
from 4.45 and 10.53 kcal·mol−1 to 0.15 and 0.18
kcal·mol−1, respectively. The improved results
for the minimal basis set STO-3G reach the same accuracy as those of 6-31G(d),
and thus B3LYP calculation with the minimal basis set is recommended to be used
for minimizing the computational cost and to expand the applications to large
molecular systems. Further extrapolation tests are performed with six molecules
(two containing Si-NO bonds and two containing fluorine), and the accuracy of
the tests was within 1 kcal·mol−1. This study shows
that DFT-SOFM-RBFNN is an efficient and highly accurate method for Y-NO
homolysis BDE. The method may be used as a tool to design new NO carrier
Y-NO bond; homolysis bond dissociation energies; density functional theory; self-organizing feature mapping neural network; radial basis function neural network
The extracellular calcium-sensing receptor (CaSR) belongs to family C of the G protein coupled receptors. Whether the CaSR is expressed in the pulmonary artery (PA) is unknown.
The expression and distribution of CaSR were detected by RT-PCR, Western blotting and immunofluorescence. PA tension was detected by the pulmonary arterial ring technique, and the intracellular calcium concentration ([Ca2+]i) was detected by a laser-scanning confocal microscope.
The expressions of CaSR mRNA and protein were found in both rat pulmonary artery smooth muscle cells (PASMCs) and PAs. Increased levels of [Ca2+]o (extracellular calcium concentration) or Gd3+ (an agonist of CaSR) induced an increase of [Ca2+]i and PAs constriction in a concentration-dependent manner. In addition, the above-mentioned effects of Ca2+ and Gd3+ were inhibited by U73122 (specific inhibitor of PLC), 2-APB (specific antagonist of IP3 receptor), and thapsigargin (blocker of sarcoplasmic reticulum calcium ATPase).
CaSR is expressed in rat PASMCs, and is involved in regulation of PA tension by increasing [Ca2+]i through G-PLC-IP3 pathway.
Producing large-scale graphene films with controllable patterns is an essential component of graphene-based nanodevice fabrication. Current methods of graphene pattern preparation involve either high cost, low throughput patterning processes or sophisticated instruments, hindering their large-scale fabrication and practical applications. We report a simple, effective, and reproducible approach for patterning graphene films with controllable feature sizes and shapes. The patterns were generated using a versatile photocoupling chemistry. Features from micrometres to centimetres were fabricated using a conventional photolithography process. This method is simple, general, and applicable to a wide range of substrates including silicon wafers, glass slides, and metal films.
Studies on the risk of chromosomal abnormalities in early spontaneous abortion after assisted reproductive technology (ART) are relatively controversial and insufficient. Thus, to obtain a more precise evaluation of the risk of embryonic chromosomal abnormalities in first-trimester miscarriage after ART, we performed a meta-analysis of all available case–control studies relating to the cytogenetic analysis of chromosomal abnormalities in first-trimester miscarriage after ART.
Literature search in the electronic databases MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) based on the established strategy. Meta-regression, subgroup analysis, and Galbraith plots were conducted to explore the sources of heterogeneity.
A total of 15 studies with 1,896 cases and 1,186 controls relevant to the risk of chromosomal abnormalities in first- trimester miscarriage after ART, and 8 studies with 601 cases and 602 controls evaluating frequency of chromosome anomaly for maternal age≥35 versus <35 were eligible for the meta-analysis. No statistical difference was found in risk of chromosomally abnormal miscarriage compared to natural conception and the different types of ART utilized, whereas the risk of fetal aneuploidy significantly increased with maternal age≥35 (OR 2.88, 95% CI: 1.74–4.77).
ART treatment does not present an increased risk for chromosomal abnormalities occurring in a first trimester miscarriage, but incidence of fetal aneuploidy could increase significantly with advancing maternal age.
In this randomized controlled trial we tested the efficacy of an intervention program (CARE: Creating Avenues for Relative Empowerment) for improving outcomes of hospitalized older adults and their family caregivers. Family caregiver-patient dyads (n=407) were randomized into two groups. The CARE group received a two-session empowerment-educational program 1-2 days post-admission and 1-3 days pre-discharge. The attention control group received a generic information program during the same timeframe. Follow-up was at 2 weeks and 2 months post-discharge. There were no statistically significant differences in patient or family caregiver outcomes. However, inconsistent evidence of role outcome differences suggests that CARE may benefit certain family caregiver subgroups instead of being a one-size-fits-all intervention strategy. Closer examination of CARE's mechanisms and effects is needed.
RCT; family caregivers; older adult patients; hospital care
The purpose of our study is to evaluate the clinical results of anatomical reconstruction of the lateral ligaments with semitendinosus allograft.
Thirty-six patients with chronic lateral instability underwent anatomical reconstruction of the lateral ligaments of the ankle with semitendinosus allograft. The American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale score (AOFAS score) and the Karlsson score were used to evaluate the clinical results before and after surgery.
A total of 35 patients (97.2 %) (36 ankles) were followed up for a mean of 37.9 months. The mean AOFAS score improved from 42.3 ± 4.9 points preoperatively to 90.4 ± 6.7 postoperatively. The mean Karlsson score improved from 38.5 ± 3.2 preoperatively to 90.1 ± 7.8 postoperatively.
Anatomical reconstruction of the lateral ligaments with semitendinosus allograft achieves a satisfactory surgical outcome for chronic ankle instability.
This study aimed to investigate the impact of the combined use of the nuclear factor-κB (NF-κB) inhibitors pyrrolidine dithiocarbamate (PDTC), bortezomib or SN50, and the chemotherapy agents arsenic acid (As2O3), fluorouracil (5FU), oxaliplatin or paclitaxel on the growth and apoptosis of HT-29 cells. Cell morphology was observed using inverted microscopy, and cell viability and apoptosis were assessed using the MTT assay and flow cytometry, respectively. The activities of NF-κB were analyzed by western blotting and electrophoretic mobility shift assay (EMSA). Cell growth was significantly inhibited by As2O3, oxaliplatin and paclitaxel in a time- and concentration-dependent manner (P<0.05), while 5FU inhibited cell growth in a time-dependent manner only (P<0.05). The growth inhibition rate and apoptosis induction ratio were increased following the combined treatment of the chemotherapy agent and NF-κB inhibitor. The expression of NF-κB p65 was upregulated when cells were treated with a chemotherapy drug, however it was downregulated following combined treatment or treatment with an NF-κB inhibitor alone. In conclusion, an NF-κB inhibitor combined with a chemotherapy drug effectively inhibited cell proliferation, induced cell apoptosis and inhibited NF-κB activity to enhance the chemotherapeutic sensitivity of HT-29 cells.
colon cancer; NF-κB inhibitor; chemotherapy; bortezomib; pyrrolidine dithiocarbamate; SN50
To establish an ultra-performance liquid chromatography (UPLC) fingerprinting method for quality control of Phragmitis rhizoma from Baiyangdian.
Materials and Methods:
Ultrasonic extraction with 70% methanol was performed on 10 samples of P. rhizoma collected from 10 different villages in Baiyangdian. The sample solutions were analyzed by Waters UPLC equipped with the ACQUITY UPLC BEH C18 column and photodiode array (PDA) detector, and gradient eluted with acetonitrile/water as the mobile phase. The flow rate was set to 0.1 mL/min; the column temperature was set to 25°C; and the detection wavelength was set to 285 nm.
The chromatograms of the 10 samples showed 27 common peaks, of which one was identified as the ferulic acid standard. The similarity indexes were all above 0.82. Hierarchical cluster analysis showed that the constituents and their quantities differed according to the diameter of the original plant, which is related to its age.
The UPLC fingerprinting method had the advantages of being fast, accurate, and highly efficient; this indicated that it can be used for quality control of P. rhizoma produced in Baiyangdian. Also, the relation between the quality and diameter/age of the plant needs to be further investigated.
Baiyangdian; fingerprint; Phragmitis rhizoma; ultra-performance liquid chromatography
Isoalantolactone is a sesquiterpene lactone compound isolated from the roots of Inula helenium L. Previous studies have demonstrated that isoalantolactone possesses antifungal, anti-bacterial, anti-helminthic and anti-proliferative properties in a variety of cells, but there are no studies concerning its effects on head and neck squamous cell carcinoma (HNSCC). In the present study, an MTT assay demonstrated that isoalantolactone has anti-proliferative activity against the HNSCC cell line (UM-SCC-10A). Immunostaining identified that this compound induced UM-SCC-10A cell apoptosis but not necrosis. To explain the molecular mechanisms underlying its effects, flow cytometry and western blot analysis showed that the apoptosis was associated with cell cycle arrest during the G1 phase, up-regulation of p53 and p21, and down-regulation of cyclin D. Furthermore, our results revealed that induction of apoptosis through a mitochondrial pathway led to up-regulation of pro-apoptotic protein expression (Bax), down-regulation of anti-apoptotic protein expression (Bcl-2), mitochondrial release of cytochrome c (Cyto c), reduction of mitochondrial membrane potential (MMP) and activation of caspase-3 (Casp-3). Involvement of the caspase apoptosis pathway was confirmed using caspase inhibitor Z-VAD-FMK pretreatment. Together, our findings suggest that isoalantolactone induced caspase-dependent apoptosis via a mitochondrial pathway and was associated with cell cycle arrest in the G1 phase in UM-SCC-10A cells. Therefore, isoalantolactone may become a potential drug for treating HNSCC.
DNA repair gene X-ray repair cross complementing group 1 (XRCC1) plays an important role in the maintenance of the genomic integrity and protection of cells from DNA damage. Sequence variation in XRCC1 gene may alter head and neck cancer (HNC) susceptibility. However, these results are inconclusive. To derive a more precise estimation of the relationship between XRCC1 polymorphism and HNC risk, we undertook a meta-analysis involving 16,344 subjects.
A search of the literature by PubMed, Embase, Web of Science and China National Knowledge Infrastructure was performed to identify studies based on the predetermined inclusion criteria. The odds ratio (OR) with 95% confidence interval (CI) was combined using a random-effects model or a fixed-effects model.
Twenty-nine studies consisting of 6,719 cases and 9,627 controls were identified and analyzed. Overall, no evidence of significant association was observed between XRCC1 Arg194Trp, XRCC1 Arg280His, XRCC1 Arg399Gln genotypes and the risk of HNC in any genetic models. Subgroup analyses according to ethnicity, tumor site, publication year, genotyping method also detected no significant association in any subgroup, except that oral cancer was associated with Arg194Trp variant in recessive model. Furthermore, no significant effect of these polymorphisms interacted with smoking on HNC risk was detected but Arg194Trp homozygous variant.
In conclusion, this meta-analysis suggests that the XRCC1 Arg194Trp, Arg280His and Arg399Gln polymorphism may not involve in HNC susceptibility. Further studies about gene-gene and gene-environment interactions in different populations are required.
Among the most common human congenital anomalies, cleft lip and palate (CL/P) affects up to 1 in 700 live births. MicroRNA (miR)s are small, non-coding RNAs that repress gene expression post-transcriptionally. The miR-17-92 cluster encodes six miRs that have been implicated in human cancers and heart development. We discovered that miR-17-92 mutant embryos had severe craniofacial phenotypes, including incompletely penetrant CL/P and mandibular hypoplasia. Embryos that were compound mutant for miR-17-92 and the related miR-106b-25 cluster had completely penetrant CL/P. Expression of Tbx1 and Tbx3, the DiGeorge/velo-cardio-facial (DGS) and Ulnar-mammary syndrome (UMS) disease genes, was expanded in miR-17-92 mutant craniofacial structures. Both Tbx1 and Tbx3 had functional miR seed sequences that mediated gene repression. Analysis of miR-17-92 regulatory regions uncovered conserved and functional AP-2α recognition elements that directed miR-17-92 expression. Together, our data indicate that miR-17-92 modulates expression of critical T-box transcriptional regulators during midface development and is itself a target of Bmp-signaling and the craniofacial pioneer factor AP-2α. Our data are the first genetic evidence that an individual miR or miR cluster is functionally important in mammalian CL/P.
CL/P are very common birth defects in humans. The genetic mechanism underlying CL/P pathogenesis is poorly understood. MiRs, small non-coding RNAs that function to post-transcriptionally regulate gene expression, have been identified as pivotal modulators of various developmental events and diseases. To date, there is no individual miR or miR cluster that has been identified as functionally essential in mammalian CL/P. Here, we have discovered that deletion of miR-17-92 cluster in mice results in craniofacial malformations including CL/P. Importantly, MIR-17-92 is located on a critical human chromosome region associated with 13q deletion syndrome, a chromosomal disorder that presents with defects including CL/P, suggesting the advantages of our animal model to study human disease. Moreover, our work demonstrated that miR-17-92 cluster directly repressed T-box factors, which have critical functions during craniofacial development. We further showed that miR-17-92 was directly activated by Bmp-signaling and transcription factor AP-2α. Together, our work identified a novel miR-mediated transcriptional network underlying CL/P, providing new insights into craniofacial developmental biology.
Chilling tolerance was increased in seed germination and root growth of wheat seedlings grown in media containing 20 µg/mL cerebroside C (CC), isolated from the endophytic Phyllosticta sp. TG78. Seeds treated with 20 µg/mL CC at 4°C expressed the higher germination rate (77.78%), potential (23.46%), index (3.44) and the shorter germination time (6.19 d); root growth was also significantly improved by 13.76% in length, 13.44% in fresh weight and 6.88% in dry mass compared to controls. During the cultivation process at 4°C for three days and the followed 24 h at 25°C, lipid peroxidation, expressed by malondialdehyde (MDA) content and relative membrane permeability (RMP) was significantly reduced in CC-treated roots; activities of lipoxygenase (LOX), phospholipid C (PLC) and phospholipid D (PLD) were inhibited by 13.62–62.26%, 13.54–63.93% and 13.90–61.17%, respectively; unsaturation degree of fatty acids was enhanced through detecting the contents of CC-induced linoleic acid, linolenic acid, palmitic acid and stearic acid using GC-MS; capacities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were individually increased by 7.69–46.06%, 3.37–37.96%, and −7.00–178.07%. These results suggest that increased chilling tolerance may be due, in part, to the reduction of lipid peroxidation and alternation of lipid composition of roots in the presence of CC.
Extracellular signals play essential roles in controlling the proliferation and differentiation of oligodendrocyte progenitor cells in the developing central nervous system. However, the intracellular pathways that transduce these extrinsic signals remain to be elucidated. In this study, we showed that conditional ablation of the nonreceptor tyrosine phosphatase Shp2 in Olig1-expressing oligodendrocyte lineage resulted in dramatic reduction in the generation and proliferation of oligodendrocyte progenitor cells in the spinal cord. Maturation and myelination of oligodendrocytes were also compromised in the Shp2 mutants. The deficits in oligodendrocyte development in Shp2 mutants nearly phenocopied those observed in PDGF-A mutants, suggesting that Shp2 is a crucial component in transducing PDGFRα signals in the control of oligodendrocyte proliferation and maturation.
Shp2; oligodendrocyte; spinal cord; proliferation; differentiation
Mounting evidence indicates that miRNAs play important roles in the control of glial cell development in the central nervous system. Suppression of miRNA formation disrupts the initial generation of oligodendrocyte progenitor cells from the ventricular neuroprogenitor cells in embryonic spinal cord. miRNAs also regulate the later events of oligodendrocyte development including cell proliferation, maturation and myelin formation. In addition, miRNAs are essential for the development of astrocytes, and inhibition of miRNA genesis completely blocks astrogliogenesis in the spinal cord.
Oligodendrocytes; astrocytes; spinal cord; miRNA; regulation
Microenvironment has been increasingly recognized as a critical regulator of cancer progression. In this study, we identified early changes in the microenvironment that contribute to malignant progression. Exposure of human bronchial epithelial cells (BEAS-2B) to methylnitrosourea (MNU) caused a reduction in cell toxicity and an increase in clonogenic capacity when the temperature was lowered from 37°C to 28°C. Hypothermia-incubated adipocyte media promoted proliferation in A549 cells. Although a hypothermic environment could increase urethane-induced tumor counts and Lewis lung cancer (LLC) metastasis in lungs of three breeds of mice, an increase in tumor size could be discerned only in obese mice housed in hypothermia. Similarly, coinjections using differentiated adipocytes and A549 cells promoted tumor development in athymic nude mice when adipocytes were cultured at 28°C. Conversely, fat removal suppressed tumor growth in obese C57BL/6 mice inoculated with LLC cells. Further studies show hypothermia promotes a MNU-induced epithelial-mesenchymal transition (EMT) and protects the tumor cell against immune control by TGF-β1 upregulation. We also found that activated adipocytes trigger tumor cell proliferation by increasing either TNF-α or VEGF levels. These results suggest that hypothermia activates adipocytes to stimulate tumor boost and play critical determinant roles in malignant progression.
The genome-wide presence of copy number variations (CNVs), which was shown to affect the expression and function of genes, has been recently suggested to confer risk for various human disorders, including Amyotrophic Lateral Sclerosis (ALS). We have performed a genome-wide CNV analysis using PennCNV tool and 733K GWAS data of 117 Turkish ALS patients and 109 matched healthy controls. Case-control association analyses have implicated the presence of both common (>5%) and rare (<5%) CNVs in the Turkish population. In the framework of this study, we identified several common and rare loci that may have an impact on ALS pathogenesis. None of the CNVs associated has been implicated in ALS before, but some have been reported in different types of cancers and autism. The most significant associations were shown for 41 kb and 15 kb intergenic heterozygous deletions (Chr11: 50,545,009–50,586,426 and Chr19: 20,860,930–20,875,787) both contributing to increased risk for ALS. CNVs in coding regions of the MAP4K3, HLA-B, EPHA3 and DPYD genes were detected however, after validation by Log R Ratio (LRR) values and TaqMan CNV genotyping, only EPHA3 deletion remained as a potential protective factor for ALS (p = 0.0065024). Based on the knowledge that EPHA4 has been previously shown to rescue SOD1 transgenic mice from ALS phenotype and prolongs survival, EPHA3 may be a promising candidate for therepuetic interventions.
Camellia, comprising more than 200 species, is a valuable economic commodity due to its enormously popular commercial products: tea leaves, flowers, and high-quality edible oils. It is the largest and most important genus in the family Theaceae. However, phylogenetic resolution of the species has proven to be difficult. Consequently, the interspecies relationships of the genus Camellia are still hotly debated. Phylogenomics is an attractive avenue that can be used to reconstruct the tree of life, especially at low taxonomic levels.
Seven complete chloroplast (cp) genomes were sequenced from six species representing different subdivisions of the genus Camellia using Illumina sequencing technology. Four junctions between the single-copy segments and the inverted repeats were confirmed and genome assemblies were validated by PCR-based product sequencing using 123 pairs of primers covering preliminary cp genome assemblies. The length of the Camellia cp genome was found to be about 157kb, which contained 123 unique genes and 23 were duplicated in the IR regions. We determined that the complete Camellia cp genome was relatively well conserved, but contained enough genetic differences to provide useful phylogenetic information. Phylogenetic relationships were analyzed using seven complete cp genomes of six Camellia species. We also identified rapidly evolving regions of the cp genome that have the potential to be used for further species identification and phylogenetic resolution.
In this study, we wanted to determine if analyzing completely sequenced cp genomes could help settle these controversies of interspecies relationships in Camellia. The results demonstrate that cp genome data are beneficial in resolving species definition because they indicate that organelle-based “barcodes”, can be established for a species and then used to unmask interspecies phylogenetic relationships. It reveals that phylogenomics based on cp genomes is an effective approach for achieving phylogenetic resolution between Camellia species.
The TRPM8 ion channel is expressed in sensory neurons and is responsible for sensing environmental cues such as cold temperatures and chemical compounds, including menthol and icilin. The channel functional activity is regulated by various physical and chemical factors, and is likely to be pre-conditioned by its molecular composition. Our studies indicate that TRPM8 channel forms a structural-functional complex with the polyester, poly-(R)-3hydroxybutyrate (PHB). We identified by mass spectrometry a number of PHB-modified peptides in the N-terminus of the TRPM8 protein and in its extracellular S3–S4 linker. Removal of PHB by enzymatic hydrolysis, and site-directed mutagenesis of both the serine residues that serve as covalent anchors for PHB and adjacent hydrophobic residues that interact with the methyl groups of the polymer, resulted in significant inhibition of TRPM8 channel activity. We conclude that the TRPM8 channel undergoes post-translational modification by PHB and that this modification is required for its normal function.
Transient Receptor Potential Melastatin 8 channel (TRPM8); Cold; Menthol; Icilin-sensation; Poly-(R)-3-hydroxybutyrate (PHB); PHB-depolymerase PhaZ7; Post-translational modification (PTM); Human Embryonic Kidney 293 cells (HEK-293)
Background and aim
Limitations of the currently recommended stepwise treatment pathway for type 2 diabetes mellitus (T2DM), especially the failure of monotherapies to maintain good glycemic control, have prompted use of early, more aggressive combination therapies.
The VISION study is designed to explore the efficacy and safety of vildagliptin as an add-on to metformin therapy compared with up-titration of metformin monotherapy in Chinese patients with T2DM.
VISION, a 24-week, phase 4, prospective, randomized, multicenter, open-label, parallel-group study, will include 3312 Chinese T2DM patients aged ≥18 years who are inadequately controlled (6.5% >HbA1c ≤9%) by metformin (750–1000 mg/day). Eligible patients will be randomized to receive either vildagliptin plus metformin or up-titration of metformin monotherapy (5:1). Patients will also be subgrouped (1:1:1:1) based on their age and body mass index (BMI): <60 years and <24 kg/m2; <60 years and ≥24 kg/m2; ≥60 years and <24 kg/m2; and ≥60 years and ≥24 kg/m2.
The VISION study will test the hypothesis that early use of combination therapy with vildagliptin and metformin will provide good glycemic control and will be better tolerated than up-titration of metformin monotherapy. The study will also correlate these benefits with age and BMI.
VISION study; Vildagliptin; Type 2 diabetes; Study design; DPP-IV inhibitors
Duchenne muscular dystrophy (DMD) caused by loss of cytoskeletal protein dystrophin is a devastating disorder of skeletal muscle. Primary deficiency of dystrophin leads to several secondary pathological changes including fiber degeneration and regeneration, extracellular matrix breakdown, inflammation, and fibrosis. Matrix metalloproteinases (MMPs) are a group of extracellular proteases that are involved in tissue remodeling, inflammation, and development of interstitial fibrosis in many disease states. We have recently reported that the inhibition of MMP-9 improves myopathy and augments myofiber regeneration in mdx mice (a mouse model of DMD). However, the mechanisms by which MMP-9 regulates disease progression in mdx mice remain less understood. In this report, we demonstrate that the inhibition of MMP-9 augments the proliferation of satellite cells in dystrophic muscle. MMP-9 inhibition also causes significant reduction in percentage of M1 macrophages with concomitant increase in the proportion of promyogenic M2 macrophages in mdx mice. Moreover, inhibition of MMP-9 increases the expression of Notch ligands and receptors, and Notch target genes in skeletal muscle of mdx mice. Furthermore, our results show that while MMP-9 inhibition augments the expression of components of canonical Wnt signaling, it reduces the expression of genes whose products are involved in activation of non-canonical Wnt signaling in mdx mice. Finally, the inhibition of MMP-9 was found to dramatically improve the engraftment of transplanted myoblasts in skeletal muscle of mdx mice. Collectively, our study suggests that the inhibition of MMP-9 is a promising approach to stimulate myofiber regeneration and improving engraftment of muscle progenitor cells in dystrophic muscle.
Pain and agitation are common in patients after craniotomy. They can result in tachycardia, hypertension, immunosuppression, increased catecholamine production and increased oxygen consumption. Dexmedetomidine, an alpha-2 agonist, provides adequate sedation without respiratory depression, while facilitating frequent neurological evaluation.
The study is a prospective, randomized, double-blind, controlled, parallel-group design. Consecutive patients are randomly assigned to one of the two treatment study groups, labeled ‘Dex group’ or ‘Saline group.’ Dexmedetomidine group patients receive a continuous infusion of 0.6 μg/kg/h (10 ug/ml). Placebo group patients receive a maintenance infusion of 0.9% sodium chloride for injection at a volume and rate equal to that of dexmedetomidine. The mean percentages of time in optimal sedation, vital signs, various and adverse events, the percentage of patients requiring propofol for rescue to achieve/maintain targeted sedation (Sedation-Agitation Scale, SAS 3 to 4) and total dose of propofol required throughout the study drug infusion are collected. The percentage of patients requiring fentanyl for additional rescue to analgesia and total dose of fentanyl required are recorded. The effects of dexmedetomidine on hemodynamic and recovery responses during extubation are measured. Intensive care unit and hospital length of stay also are collected. Plasma levels of epinephrine, norepinephrine, dopamine, cortisol, neuron-specific enolase and S100-B are measured before infusion (T1), at two hours (T2), four hours (T3) and eight hours (T4) after infusion and at the end of infusion (T5) in 20 patients in each group.
The study has been initiated as planned in July 2012. One interim analysis advised continuation of the trial. The study will be completed in July 2013.
ClinicalTrials (NCT): ChiCTR-PRC-12002903.
Dexmedetomidine; Analgesia; Sedation; Prophylactic; Delayed extubation; Craniotomy
According to the classic theory of Chinese medicine, pain is due to the blockage in meridian channels, and acupuncture was invented to treat pain by “dredging” the channels. To test the theory, a hyperalgesia model was made by injecting hydrogel into low hydraulic resistance channel (LHRC) in 12 anaesthetized minipigs. Tail-flick threshold and ear-flick threshold were measured using a thermal radiation dolorimeter, and relative flick threshold (RFT) was calculated. Hydraulic resistance (HR) was measured with a biological HR measuring instrument on low HR points on LHRC and on control points with higher HR located outside LHRC; readings were recorded before, during, and after acupuncture treatment. RFT decreased after blocking the LRHC and was still significantly decreased 2 days and 4 days afterwards. No significant changes occurred when injecting saline into the same points or injecting gel into points outside the channel. Subsequent acupuncture reduced HR on LRHC along meridians but had no significant effect on sites with higher HR located outside LHRC. One of the mechanisms of action of acupuncture treatment for chronic pain may be that acupuncture affects peripheral tissue by reducing the HR in LHRC along meridians, improving the flow of interstitial fluid and removing algogenic substances and thereby relieving pain.
To analyze the morphological change in the cartilage of the knee after anterior cruciate ligament (ACL) injury by comparing with that of the intact contralateral knee.
A total of 22 participants (12 male and 10 female patients) who had unilateral ACL injury underwent MRI scan of both the injured and intact contralateral knees. Sagittal plane images were segmented using a modeling software to determine cartilage volume and cartilage thickness in each part of the knee cartilage that were compared between the ACL-injured and the intact contra-lateral knees. Furthermore, the male and female patients’ data were analyzed in subgroups.
The ACL-injured knees had statistically significant lower total knee cartilage volume than the intact contralateral knees (P = 0.0020), but had similar mean thickness of total knee cartilage (not significant: n.s.). In the male subgroup, there was no significant difference in cartilage volume and thickness between normal and ACL-injured knees. In the female subgroup, the ACL-injured knees demonstrated statistically significant difference in total knee cartilage volume (P = 0.0004) and thickness (P = 0.0024) compared with the normal knees. The percentage change in the cartilage thickness in women was significantly greater than that in men.
Cartilage volume was significantly smaller in the ACL-injured knees than in the contralateral intact knees in this cohort. Women tended to display greater cartilage volume and thickness change after ACL injury than men. These findings indicated that women might be more susceptible to cartilage alteration after ACL injuries.
Level of evidence
MRI; Cartilage; Knee; Anterior cruciate ligament