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OBJECTIVE Amyotrophic lateral sclerosis(ALS)is a fetal neurodegenerative disease characterized by the progressive loss of upper and lower motor neu-rons,leading to skeletal muscle atrophy,weakness,and paralysis.Oxidative stress plays a crucial role in ALS pathogenesis,including the familial forms of the disease arising from mutations in the gene coding for superox-ide dismutase(SOD1).Additionally,the abnormal accu-mulation of TAR DNA-binding protein of 43 ku(TDP-43)is a pathological feature present in almost all patients,even though the pathogenesis of ALS is unclear.Current-ly,there is no drug that can cure ALS/FTLD.Tetramethyl-pyrazine nitrone(TBN)is a derivative of tetramethylapyr-azine,derived from traditional Chinese medicine Ligusti-cum chuanxiong,which has been extensively proven to have therapeutic effects on various models of neurode-generative diseases.METHODS We investigated the therapeutic effect of TBN in the SOD1G93A and TDP-43M337V ALS mouse models.In the SOD1G93A trans-genic mouse model,TBN was administered to mice via intraperitoneal or intragastric injection after the onset of motor deficits.We injected the TDP-43M337V virus into the striatum of mice unilaterally and bilaterally,and then administered TBN 30 mg·kg-1 intragastrically to observe changes in behavior and survival rate of mice.RESULTS TBN slowed the progression of motor neuron disease,as evidenced by improved motor performance,reduced spi-nal motor neuron loss and associated glial response,and decreased skeletal muscle fiber denervation and fibrosis.TBN treatment activated mitochondrial antioxidant activity through the PGC-1α/Nrf2/HO-1 pathway and decreased the expression of human SOD1.In the mice with unilateral injection of TDP-43M337V into the striatum,TBN improved motor deficits and cognitive impairment in the early stages of disease progression.In mice with bilateral injection of TDP-43M337V into the striatum,TBN not only improved motor function but also prolonged survival.Moreover,we demonstrate that its therapeutic effect may be through activation of the Akt/mTOR/GSK-3β and AMPK/PGC-1α/Nrf2 signaling pathways.CONCLUSION TBN shows promise as an agent for the treatment of ALS/FTLD.TBN is currently undergoing clinical investigation for several indications,including a Phase Ⅱ trial for ALS.
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Objectives:To investigate the clinical impacts of chronic total occlusion (CTO) in acute non-ST segment elevation myocardial infarction (NSTEMI) patients underwent primary percutaneous coronary intervention (PCI).Methods:A total of 2 271 acute NSTEMI patients underwent primary PCI from China Acute Myocardial Infarction Registry were enrolled in this study and divided into the CTO group and the non-CTO group according to the angiography. The primary endpoint was in-hospital mortality and mortality during a 2-year follow-up. The secondary endpoint was major adverse cardiovascular events (MACE) including revascularization, death, re-myocardial infarction, heart failure readmission, stroke and major bleeding.Results:Thirteen-point four percent of the total acute NSTEMI patients had concurrent CTO. In-hospital mortality (3.6% vs. 1.4%, P<0.01) and 2-year mortality (9.0% vs. 5.1%, P<0.01) were significantly higher in the CTO group than those in the non-CTO group, respectively. Multiple regression analyses showed that chronic obstructive pulmonary disease ( HR 7.28, 95% CI 1.50-35.35, P=0.01) was an independent risk factor of in-hospital mortality, and advanced age ( HR 1.04, 95% CI 1.01-1.07, P<0.01), and low levels of ejection fraction ( HR 0.95, 95% CI 0.93-0.98, P<0.01) were independent risk factors of 2-year mortality. CTO ( HR1.67, 95% CI 1.10-2.54, P=0.02) was an independent risk factor of revascularization, but not a risk factor of mortality. Conclusions:Although acute NSTEMI patients concurrent with CTO had higher mortality, CTO was only an independent risk factor of revascularization, but not of mortality. Advanced age and low levels of ejection fraction were independent risk factors of long-term death among acute NSTEMI patients.
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Proton nuclear magnetic resonance (1H NMR) based metabolomics was applied to characterize the fecal metabolic profiles of chronic unpredictable mild stress (CUMS)-depression (CUMS-D) and CUMS-resilience (CUMS-R) rats. The fecal biomarkers and metabolic pathways involved in CUMS-D and CUMS-R were screened and identified, revealing the underlying mechanisms of two different responses of the body to the same stresses. Firstly, the classic depression model, i.e. CUMS, was constructed. According to the fecal metabolomics profiles, the model rats were divided into two groups, i.e. the CUMS-D group and the CUMS-R group. And then, the depression statuses of CUMS-D rats and CUMS-R rats were verified by their sucrose preference rates. Lastly, multivariate data analysis was applied to clarify the fecal biomarkers and corresponding metabolic pathways involving in CUMS-D and CUMS-R. The results show that compared with the control rats, the sucrose preference rates of CUMS-D rats were significantly reduced. By contrast, the sucrose preference rates of CUMS-R rats had no significant difference. At the same time, CUMS-D and CUMS-R showed both unique and shared biomarkers and pathways. Three pathways are significantly related to CUMS-D, including taurine and hypotaurine metabolism, alanine, aspartate and glutamate metabolism, and arginine and proline metabolism. Glycerolipid metabolism and tryptophan metabolism are specific pathways related to CUMS-R. This study explores the mechanisms of the emergence of susceptible and resilience of rats under the same stimulus from a metabolomics perspective. The current findings provide not only a new perspective for studying depression, and personalized and precision treatments in clinic, but also the research and development of antidepressants.
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In vitro studies have established the prevalent theory that the mitochondrial kinase PINK1 protects neurodegeneration by removing damaged mitochondria in Parkinson's disease (PD). However, difficulty in detecting endogenous PINK1 protein in rodent brains and cell lines has prevented the rigorous investigation of the in vivo role of PINK1. Here we report that PINK1 kinase form is selectively expressed in the human and monkey brains. CRISPR/Cas9-mediated deficiency of PINK1 causes similar neurodegeneration in the brains of fetal and adult monkeys as well as cultured monkey neurons without affecting mitochondrial protein expression and morphology. Importantly, PINK1 mutations in the primate brain and human cells reduce protein phosphorylation that is important for neuronal function and survival. Our findings suggest that PINK1 kinase activity rather than its mitochondrial function is essential for the neuronal survival in the primate brains and that its kinase dysfunction could be involved in the pathogenesis of PD.
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Objective:To investigate the percutaneous permeability of sinomenine hydrochloride （SNH） and optimize the parameters of electroporation to achieve the best permeation enhancing effect on SNH. Method:The percutaneous permeability of SNH and the enhancement effect of electroporation were studied by <italic>in vitro</italic> diffusion cell method， and the enhancement effect of electroporation was further evaluated by <italic>in vivo</italic> study in mice. Result:Under steady-state condition， the permeation rates of SNH in stripped skin and intact skin of hairless mice were （385.81±12.88）， （0.88±0.20） μg·cm<sup>-2</sup>·h<sup>-1</sup>， respectively. The permeation rate in stripped skin was 438 times higher than that in intact skin. The results of percutaneous permeation kinetics analysis showed that the solubility and diffusion coefficient of SNH in stratum corneum were relatively low， which were （70.82±9.63）×10<sup>3</sup> g·m<sup>-3</sup> and （3.07±1.52）×10<sup>-14</sup> cm<sup>2</sup>·s<sup>-1</sup>， respectively. Under the optimized electroporation conditions （voltage of 72 V， time of 60 min）， the 24 h cumulative permeation amount of SNH through skin of mice was （10 008.39±1 961.57） μg·cm<sup>-2</sup>， and the steady-state permeation rate was （456.01±51.26） μg·cm<sup>-2</sup>·h<sup>-1</sup>， which were 5.4 times and 5.1 times higher than those of blank group， respectively. <italic>In vivo</italic> studies in mice showed that the contents of SNH in skin and muscle of electroporation group were 2.0 times and 1.5 times higher than those of blank group. Conclusion:The low solubility and low diffusion coefficient of SNH in the stratum corneum are the main factors hindering the percutaneous permeation of SNH. Electroporation can significantly increase the percutaneous permeation of SNH and its retention in skin and muscle of mice.
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Objective:To investigate the clinical efficacy of Zhang's acupoint pressure therapy plus electroacupuncture (EA) in treating post-traumatic knee osteoarthritis.Methods:A total of 98 eligible patients with post-traumatic knee osteoarthritis were divided into group A and B by the random number table, 49 cases in each group. Group A was intervened by Zhang's acupoint pressure therapy plus EA; group B was given medicinal fumigation. The clinical efficacies of the two groups were compared.Results:The markedly effective rate of group A was significantly higher than that of group B.Conclusion:Zhang's acupoint pressure therapy plus EA can produce a satisfactory clinical efficacy in treating post-traumatic knee osteoarthritis, and is worth promotion.
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Gefitinib is used as a first-line treatment for advanced non-small cell lung cancer (NSCLC). Unfortunately, most NSCLC patients inevitably develop gefitinib resistance during treatment. In addition to EGFR mutation status, the mechanisms involved are largely unknown. In this study, we showed that miR-124, a tumor suppressor, was significantly down-regulated in gefitinib-resistant NSCLC patients and cell lines compared with gefitinib-sensitive patients and cell lines. In addition, the miR-124 depletion induced gefitinib resistance, and miR-124 overexpression sensitized gefitinib-resistant cells to gefitinib. Mechanistic analysis revealed that miR-124 decreased SNAI2 and STAT3 expression by directly targeting their 3'UTRs and that knocking down SNAI2 or STAT3 partly reversed the gefitinib resistance induced by miR-124 depletion. Our data demonstrate that the miR-124 plays a new critical role in acquired resistance to gefitinib and that the manipulation of miR-124 might provide a therapeutic strategy for reversing acquired gefitinib resistance.
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Humans , 3' Untranslated Regions , Antineoplastic Agents , Pharmacology , Therapeutic Uses , Carcinoma, Non-Small-Cell Lung , Drug Therapy , Genetics , Metabolism , Cell Line, Tumor , Drug Resistance, Neoplasm , Genetics , HEK293 Cells , Lung Neoplasms , Drug Therapy , Genetics , Metabolism , MicroRNAs , Genetics , Quinazolines , Pharmacology , Therapeutic Uses , STAT3 Transcription Factor , Genetics , Metabolism , Snail Family Transcription Factors , Genetics , MetabolismABSTRACT
OBJECTIVE@#To describe our experience in the clinical manifestation and treatment of malignant tumors of the external and middle ear.@*METHOD@#The study reviewed 39 patients between 1994-2011 in our hospital, including 15 pinna tumors, 18 external canal tumors and 6 middle ear tumors. 23 males and 16 females were enrolled in this study. The mean age of patients at the time of surgery was 59. Radiotherapy or radiotherapy and chemotherapy were the only possible treatment in 6 cases. Thirty-three patients were treated surgically, and 9 patients also received radiotherapy after surgery.@*RESULT@#All of the patients had been followed up over 3 years, except for 1 case of external canal and 1 case of middle ear tumor. The 3-year survival of pinna, external canal and middle ear tumors were 86.7%, 82.4% and 60.0% respectively. At the last follow up, the pinna tumors showed that the survival rate was 100% in T1, T2 and Tx stage, and 0% in T4 stage; the external canal tumors showed that the survival rate was 90% in T1 stage, and 66.7% in T2, T3 stage; the middle ear tumors showed that the survival rate was 100% in T1 and T2 stage, 0% in T3 stage.@*CONCLUSION@#The T staging system is for an important prognostic factor, and it is important for an early diagnosis and radical surgery to achieve a better therapeutical result.
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Female , Humans , Male , Ear Auricle , Pathology , Ear Canal , Pathology , Ear Neoplasms , Pathology , Ear, Middle , Pathology , Neoplasm Staging , Retrospective Studies , Survival RateABSTRACT
Objective To study the correlation between laryngopharyngeal reflux (LPR) and voice disorders . Methods One hundred and three patients with reflux -related symptoms were recruited .The patients were evalu-ated with reflux symptom index (RSI) ,reflux finding score (RFS) evaluation and 24-hour dural-probe pH moni-toring .Eighty -nine cases with voice disorders were divided into 5 groups :vocal process granuloma (n=18) chron-ic pharyngolaryngitis (n=19) ,vocal polyps (n=15) ,vocal fold leukoplakia (n=21) and Reinke's edema (n=16) . The other 14 patients without voice disorders were the control subjects .Results According 24-hour dural -probe pH monitoring assessments ,48 .3% of the patients with voice disorders showed LPR positive .The positive rate in the vocal fold leukoplakia group (71 .4% ) and Reinke's edema group (75 .0% ) were significantly higher than the control group (35 .7% ) .RSI and RFS of the patients with Reinke's edema were both significantly higher than the control group(P=0 .020 ,P=0 .009) .RSI of the patients with chronic pharyngolaryngitis were significantly higher than the control group (P=0 .019) .The acid reflux episodes ,acid reflux time which except in the supine position of the vocal fold leukoplakia group were significantly higher than the control group .The acid reflux episodes ,acid ex-posure and acid reflux time which all except in the supine position of the Reinke's edema group were significantly higher than the control group .Conclusion The correlations between Reinke's edema ,vocal fold leukoplakia and LPR were stronger .In these two groups ,the acid reflux episodes were higher and acid reflux times were longer .
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<p><b>BACKGROUND</b>Idiopathic flexible flatfoot in children most frequently improves with age and remains asymptomatic. It is a physiological variation of the normality that does not require treatment unless it becomes symptomatic. The aim of this research was to investigate the reason why some individuals with flexible flatfoot become symptomatic by analysis of the differences in the relative alignment of each segment of the foot between symptomatic and asymptomatic patients with idiopathic flexible flatfoot using radiographic measurements.</p><p><b>METHODS</b>One hundred patients with idiopathic flexible flatfoot were retrospectively identified and divided into two groups: asymptomatic (n = 50) and symptomatic (n = 50). Standing anteroposterior and lateral radiographs of the foot were analyzed. Five measurements were calculated to describe the alignment of the foot. An independent-samples t-test and Logistic regression test were used for statistical analysis.</p><p><b>RESULTS</b>Age and sex were similar in the two groups. The independent-samples test revealed significant differences in two parameters: the anteroposterior talonavicular coverage angle and the lateral talo-first metatarsal angle. When the Logistic regression test was performed, only the talonavicular coverage angle showed statistical significance.</p><p><b>CONCLUSIONS</b>The lateral displacement of the navicular bone, measured by the anteroposterior talonavicular coverage angle, seems to be related to the onset of symptoms. In individuals with otherwise normal flexible flatfoot, an increase in this angle might be an important risk factor for developing symptoms.</p>
Subject(s)
Adolescent , Child , Female , Humans , Male , Biomechanical Phenomena , Flatfoot , Diagnostic Imaging , Pathology , Therapeutics , Logistic Models , Radiography , Retrospective Studies , Weight-BearingABSTRACT
<p><b>OBJECTIVE</b>In order to find out the cause of molar intrusion and how to avoid molar intrusion, we analyze the movement tendency of tooth by changing the angles of upper accentuated-curve and the height of free traction hook.</p><p><b>METHODS</b>Spiral CT scanning and Mimics 10.0 software were employed in this study to construct the three dimensional finite element model of maxillary teeth, periodontal ligaments and alveolar bone as well as the inch stainless steel upper accentuated-curve archwires with different angles (5 degrees, 10 degrees, 15 degrees, 20 degrees, 25 degrees) and the free traction hook with different height (2.1, 4.0, 5.5 mm). By exerting 1.5 N backward force to analysis the displacement trend of maxillary tooth.</p><p><b>RESULTS</b>Upper accentuated-curve archwires made the incisors labially tip, intruse, distally upright and mesilabially torsion; made the canines labially tip, prolong, mesial-tipped and mesi-labially torsion; made the second premolars and the first molars buccal tip, intruse, distal upright and mesi-labially torsion. With the angle of upper accentuated-curve archwires increased, all tooth movement tendency increased; while with the height of free traction hook increased, all tooth movement tendency decreased.</p><p><b>CONCLUSION</b>When the angle of upper accentuated-curve archwires increased, the extent of molar intrusion increased, but when the height of free traction hook increased, the degree of molar intrusion decreased. The degree of molar intrusion was minimum using 5 degrees upper accentuated-curve archwires cooperated with 5.5 mm free traction hook.</p>
Subject(s)
Humans , Bicuspid , Bone Screws , Finite Element Analysis , Incisor , Maxilla , Molar , Periodontal Ligament , Tooth , Tooth Movement TechniquesABSTRACT
<p><b>OBJECTIVE</b>To build the physical model of four suturae which are related to the growth of maxilla in the three-dimensional finite-element model of maxillofacial bones.</p><p><b>METHODS</b>A 16 years old volunteer with individual normal occlusion, good periodontium health condition and without diseases of temporomandibular joint was chosen to be the material of modeling. The three-dimensional finite-element model of the volunteer's maxillofacial bones was built using the CT scan and the finite-element modeling method. Finally we built the physical model of four suturae which were related to the growth of maxilla in the model of maxillofacial bones.</p><p><b>RESULTS</b>The model of maxillofacial bones with 86,575 nodes and 485,915 elements was generated. This model contained four suturae including sutura frontomaxillaris, sutura zygomaticomaxillaris, sutura temporozygomatica and sutura pterygopalatine.</p><p><b>CONCLUSION</b>A three-dimensional finite-element model of maxillofacial bones with good biological similarity was developed.</p>
Subject(s)
Humans , Male , Bone and Bones , Cranial Sutures , Finite Element Analysis , Head , Maxilla , Skull , Temporomandibular Joint , Tomography, X-Ray ComputedABSTRACT
Fruit ripening is associated with a number of physiological and biochemical changes. They include degradation of chlorophyll, synthesis of flavor compounds, carotenoid biosynthesis, conversion of starch to sugars, cell wall solublisation and fruit softening. These changes are brought about by the expression of specific genes. People are interested in the molecular mechanism involved in the regulation of gene transcription during fruit ripening. Many fruit-specific promoters such as PG, E4, E8, and 2A11 have been characterized and shown to direct ripening-specific expression of reporter genes. AGPase plays the key role in catalyzing the biosynthesis of starch in plants. It is a heterotetrameric enzyme with two small subunits and two large subunits, which are encoded by different genes. In higher plants, small subunits are highly conserved among plant species and expressed in all tissues. And the large subunits are present at multiple isoforms and expressed in a tissue-specific pattern. In fruits, the expression pattern of the large subunits varies with plant species. That made it important to study the transcriptional regulation of the large subunits of AGPase in different plant species. Northern-blot analysis indicates in watermelon, an isoform of the large subunits Wml1 expressed specifically in fruits, not in leaves. The 5' flanking region of Wml1, which covers 1573bp, has been isolated through the method of uneven PCR. And transient expression assay has shown that the 1573bp (named WSP) can direct fruit-specific expression of GUS gene. Our goal in this study was to scan the promoter region for main regulatory regions involved in fruit-specific expression. A chimaeric gene was constructed containing the WSP promoter, the beta-glucuronidase (GUS) structural sequence as a reporter gene and the nopaline synthase polyadenylation site (NOS-ter). The plasmid pSPA was digested with Hind III + Hinc II and promoter fragment of 1573bp (from 180bp to 1752bp) was cut out and cloned into Sma I sites of pBluescript SK(-), to produce pBSPA-16. The same insert was then cut out with Hind III + BamH I, and ligated with transient expression vector pBI426 digested by HindIII + Bgl II to produce pISPA-16. Three 5'-end deletions of the promoter were obtained and fused to GUS gene in plant transient expression vector pBI426: the 1201bp fragment (from 551bp to 1752bp) was generated by digestion of pBSPA-16 with BamH I + SnaB I, the 898bp fragment (from 854bp to 1752bp) by BamH I + EcoRV. Both fragments were ligated with pBluescript SK(-) digested by BamH I + Sma I, to produce pBSPA-12 and pBS-PA-9. The inserts were cut out with HindmIII + BamH I and ligated with pBI426 digested by Hind III + Bgl II, to produce pISPA-12 and pISPA-9. The 795bp fragment (from 957bp to 1752bp) was generated by digestion of pSPA with Hinc II + EcoR I, promoter fragment was cut out and cloned into Sma I sites of pBluescript SK(-), to produce pBSPA-8. The same insert were cut out with Hind III + BamH I, and ligated with transient expression vector pBI426 digested by Hind III + Bgl II. The 1573bp fragment and three 5'-end deletions were delivered into watermelon leaf, stem, flower and fruit of different development stages (5, 10, 20 days after pollination) via particle bombardment using a biolistic PDS-1000/He particle gun. Bombardment parameters were as follows: a helium pressure of 1200 psi, vacuum of 91432.23Pa, 7 cm between the stopping screen and the plate. Histochemical assay were done on all the tissues bombarded after incubation for 2 days. The 1573bp fragment had the strongest promoter activity, and can induce GUS expression in fruits of 5 and 20 days after anthesis and flowers, but not in fruits of 10 days after anthesis, leaves and stems. Fragments of 1201bp and 898bp can induce GUS expression only in fruits of 20 days after anthesis, and with lower expression levels than 1573bp. Fragment of 795bp was not able to direct GUS expression in any of the tissues bombarded (data not shown). It can be concluded that of the 1573bp, 1201 bp, 898bp Wml1 5'flanking regions include the necessary information directing fruit-specific expression. Deletion from 180bp to 551bp doesn't affect the fruit-specificity of the promoter, but lowered the expression level. There may be some cis-acting elements located in this region, which can enhance external gene expression in later stages of fruit development. Deletion from 854bp and 958bp led to loss of GUS expression. This region includes the necessary information needed for gene expression as well as the regulatory elements for fruit-specific transcription.