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Berberina , Carcinoma Hepatocelular , Neoplasias Hepáticas , Células Neoplásicas Circulantes , Humanos , Carcinoma Hepatocelular/patologia , Células Neoplásicas Circulantes/patologia , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Recidiva Local de Neoplasia/patologia , Metástase NeoplásicaRESUMO
Objective: To investigate the effect of insertion technique and electrode array type on the insertion force of electrode array, and to provide a basis for further optimizing electrode design and facilitating mini-invasive electrode insertion. Methods: Three types of electrode array from Nurotron (Standard Electrode, Slim-medium Electrode, Slim-long Electrode) were studied. from July 2019 to December 2019. These electrode arrays were inserted into the phantom models of the cochlea, manually or robot-assisted(medium speed and low speed). The real-time force during electrode array insertion was recorded by ATI Nano 17 Ti sensors and was analyzed by accessory software. Origin 2020b software was used for statistical processing. Results: The insertion force of all electrode arrays progressively increased with the insertion depth. With the manual technique, the peak force of slim-medium electrode insertion was significantly smaller than that of the standard electrode insertion((71.0±16.6) mN vs (140.9±52.7) mN, Z=3.683, P<0.01), and the peak force of the slim-long electrode insertion was between the peak force of standard electrode and slim-medium electrode(P>0.05). No difference was found in the force variation of insertion among the three electrodes(P>0.05). With medium-speed and low-speed robotic assistance, the peak force characteristics of three electrodes were similar to those with the manual technique, but the force variation of standard electrode insertion ((83.9±9.7) mN/s) at medium speed was significantly larger than that of the slim-long electrode insertion ((69.2±4.0)mN/s), and the force variation of the standard electrode insertion at low speed was significantly greater than the other two electrodes. For the same electrode, robot-assisted insertion presented significantly lower peak force and force variation than manual insertion for each type of electrode array. But there was no difference in the peak force and force variation between two-speed levels of robot assistance (P>0.05). Conclusions: The insertion force of the electrode array will be lower when a slim electrode array or robot technique is applied. Long electrode array might make manual insertion difficult or less precise. Robot assistance has advantage on force control during electrode array insertion.
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Implante Coclear , Implantes Cocleares , Robótica , Cóclea/cirurgia , Eletrodos Implantados , HumanosRESUMO
Promoting beige adipocyte development within white adipose tissue (WAT) is a potential therapeutic approach to staunch the current obesity epidemic. Previously, we identified homeobox-containing transcription factor HOXC10 as a suppressor of browning in subcutaneous WAT. Here, we provide evidence for the physiological role of HOXC10 in regulating WAT thermogenesis. Analysis of an adipose-specific HOXC10 knockout mouse line with no detectable HOXC10 in mature adipocytes revealed spontaneous subcutaneous WAT browning, increased expression of genes involved in browning, increased basal rectal temperature, enhanced cold tolerance, and improved glucose homeostasis. These phenotypes were further exacerbated by exposure to cold or a ß-adrenergic stimulant. Mechanistically, cold and ß-adrenergic exposure led to reduced HOXC10 protein level without affecting its mRNA level. Cold exposure induced cAMP-dependent protein kinase-dependent proteasome-mediated degradation of HOXC10 in cultured adipocytes, and shotgun proteomics approach identified KCTD2, 5, and 17 as potential E3 ligases regulating HOXC10 proteasomal degradation. Collectively, these data demonstrate that HOXC10 is a gatekeeper of WAT identity, and targeting HOXC10 could be a plausible therapeutic strategy to unlock WAT thermogenic potentials.
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Adipócitos Brancos/metabolismo , Proteínas de Homeodomínio/metabolismo , Gordura Subcutânea/metabolismo , Termogênese/genética , Adipócitos Bege/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Linhagem Celular , Metabolismo Energético/fisiologia , Proteínas de Homeodomínio/genética , Camundongos , Camundongos KnockoutRESUMO
Objective: To describe the epidemiological characteristics and clinical features of patients with fatal coronavirus disease (COVID-19), in order to provide evidence for clinical diagnosis and treatment. Methods: In this retrospective study, we analyzed data on 141 fatal cases of confirmed COVID-19 that occurred among patients in Jinyintan Hospital in Wuhan, China, from January 20 to March 6, 2020. We analyzed their epidemiological characteristics, clinical and radiological features, laboratory results, and treatment. Results: Of the 141 patients (49 females, 92 males), the median age was 77 years (range: 24-92 years). The most likely source of exposure included the Huanan seafood market (n=3, 2%), family members (n=6, 4%), and hospital-acquired infection (n=8, 6%). The remaining 116 patients (72%) had no known source of exposure. Of the patients, 101 (72%) had chronic diseases. The most common comorbidities were hypertension, diabetes and coronary heart disease. The most common clinical manifestations were fever (n=121, 85%), dry cough (n=77, 54%), shortness of breath (n=23, 16%), and chest pain (n=15, 10%). Less common clinical manifestations included fatigue (n=7, 4%), headache (n=3, 2%), disorders of consciousness (n=2, 1%), diarrhea (n=2, 1%) and lumbago (n=1, 0.7%). In terms of laboratory tests, the absolute value of lymphocytes in most patients was reduced (n=132, 94%), but C-reactive protein (n=141, 100%), procalcitonin(n=121, 89%), serum amyloid (n=140, 99%) were significantly increased. The most common findings on imaging of the lungs were bilateral multiple mottling and ground-glass opacity (n=101, 72%), mainly in the lower lobes (n=15, 10%), with lesions being more common on the right. Other imaging findings included diffuse consolidation (n=4, 3%), ground-glass opacity and consolidation (n=20, 14%), and pneumothorax (n=1, 0.7%). All patients were treated with antibiotics and antiviral drugs. Other treatments included immunoglobulin (n=49, 35%), corticosteroids (n=45, 32%), continuous renal replacement therapy (n=24, 17%), and extracorporeal membrane oxygenation (n=12, 9%). All patients were treated with oxygen therapy. The mode of administration included invasive mechanical ventilation (n=61, 43%), noninvasive mechanical ventilation (n=65, 46%), and nasal catheter oxygen inhalation (n=15, 11%). The direct causes of death were acute respiratory distress syndrome (n=90, 64%), multiple organ failure (n=24, 17%), sudden cardiac arrest (n=11, 8%), viral myocarditis (n=8, 5%), acute myocardial infarction (n=4, 3%), cerebrovascular accident (n=3, 2%), and acute gastrointestinal bleeding (n=1, 0.7%). Conclusions: Risk factors for death due to COVID-19 included older age, male sex, and the presence of comorbidities. The most common direct causes of death were acute respiratory distress syndrome, multiple organ failure, sudden cardiac arrest, and viral myocarditis.
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COVID-19/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/patologia , China/epidemiologia , Comorbidade , Feminino , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
Objective: To evaluate the safety and outcomes of robot-assisted electrode insertion in cochlear implantation. Methods: We first reported the case of robot-assisted electrode insertion of cochlear implantation in October 2019. A new slim electrode array of Nurotron cochlear implant (CS-10A TM) and RobOtol(®) robot system were used in this case. The robotic assistance procedures, surgical outcomes were analyzed. Results: Robot-assisted electrode insertion was successfully performed in this adult patient. The preparation of robot system cost six minutes, the electrode array was slowly and fully inserted into tympanic scala with robot assistance. No damage in the surgical field occurred by the robotic instrument. Intraoperative electrode impedances and neural response measurements were normal. No postoperative complications occurred. Up to three months of follow up after implantation, the cochlear implant functioned well and rehabilitated hearing was satisfactory. Conclusion: Otological robot system shows its advantage in the elimination of human involuntary tremors and the augmentation of accuracy during micromanipulation, it could safely assist cochlear implantation to realize minimally invasive and full tympanic scala insertion of the electrode array, and to ensure the good preservation of the intracochlear fine structure.
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Implante Coclear , Implantes Cocleares , Robótica , Adulto , Cóclea/cirurgia , Eletrodos Implantados , Audição , HumanosRESUMO
AIMS: To determine the mechanism underlying the serum cholesterol reduction effect by probiotics isolated from local fermented tapioca (Tapai). METHODS AND RESULTS: Lactic acid bacteria strains were isolated and examined for acid tolerance, bile salt resistance and hypocholesterolemic properties. Among the isolates, Lactobacillus plantarum TAR4 showed the highest cholesterol reduction ability (48·01%). The focus in the in vivo trial was to elucidate the cholesterol balance from findings pertaining to serum cholesterol reduction in rat model fed with high fat diet via oral administration. Rats fed with high-cholesterol diet supplemented with Lact. plantarum TAR4 showed significant reduction in serum total cholesterol (29·55%), serum triglyceride (45·31%) and liver triglyceride (23·44%) as compared to high-cholesterol diet (HCD) group. There was a significant increment in faecal triglyceride (45·83%) and faecal total bile acid (384·95%) as compared to HCD group. CONCLUSIONS: The findings showed that probiotic Lact. plantarum TAR4 supplementation reduced the absorption of bile acids for enterohepatic recycling and increased the catabolism of cholesterol to bile acids and not by suppressing the rate of cholesterol synthesis. SIGNIFICANCE AND IMPACT OF STUDY: Probiotic supplements could provide a new nonpharmacological alternative to reduce cardiovascular risk factors.
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Colesterol/metabolismo , Suplementos Nutricionais , Alimentos Fermentados/microbiologia , Homeostase , Probióticos/administração & dosagem , Animais , Ácidos e Sais Biliares/metabolismo , Dieta Hiperlipídica/efeitos adversos , Homeostase/efeitos dos fármacos , Lactobacillales/classificação , Lactobacillales/isolamento & purificação , Lactobacillales/metabolismo , Lactobacillus plantarum/isolamento & purificação , Lactobacillus plantarum/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Manihot , Probióticos/farmacologia , Ratos , Triglicerídeos/metabolismoRESUMO
OBJECTIVE: Classical surgical management of jugular foramen (JF) tumors usually requires facial nerve rerouting which results in permanent facial palsy in most patients. The purpose of the article is to study the outcomes of different rerouting techniques, and to discuss their indications. MATERIAL AND METHODS: We retrospectively reviewed 98 patients with JF tumors operated at our center between January 2008 and December 2016 using different surgical approaches with the following procedures for facial nerve management: total anterior rerouting (TR), partial anterior rerouting (PR), and fallopian bridge (FB) technique. The data for facial nerve management, surgical outcome and postoperative facial nerve function were collected from the medical records. RESULTS: In the study, there were 48 males and 50 females. Of them, 61 (62.2%) were jugular paragangliomas, 22 (22.4%) schwannomas, and 15 (15.3%) meningiomas. Total tumor removal was achieved in 95 (96.9%) patients, while near-total removal was achieved in 3 (3.1%) paragangliomas. TR was applied in 31 (31.6%) patients with PR in 26 (26.5%) patients, and FB in 41 (41.8%) patients. The mean follow-up duration was 39.4±22.6 months, and 2 recurrences of paragangliomas were observed. Seventy-five patients (76.5%) had good facial function (HB I-II) at 1 year after surgery, the patients who received a TR approach presented significantly less HB I-II FN function (48.4%) than those with PR (82.6%, P<0.05) or those with FB technique (95.1%, P<0.001). 21 patients (21.4%) presented new-onset lower cranial nerve dysfunction of which 13 recovered at 1 year after surgery. CONCLUSION: Facial nerve management in JF tumors should be tailored individually. No-rerouting methods, such as the fallopian bridge technique, bring significantly better results in terms of facial nerve function, which might be performed first during surgery; its indication is based mainly on the tumor type and extent.
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Nervo Facial/cirurgia , Forâmen Jugular , Neoplasias da Base do Crânio/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Paralisia Facial/etiologia , Paralisia Facial/prevenção & controle , Feminino , Seguimentos , Humanos , Masculino , Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Pessoa de Meia-Idade , Neurilemoma/cirurgia , Paraganglioma/cirurgia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: MicroRNAs (miRNAs) play an essential role in the development and progression of colorectal cancer (CRC). Aberrant expression of miR-199a was associated with cancer development in many cancers. However, little was known about the clinical value of miR-199a in CRC. This study aimed to investigate the potential relationship between miR-199a expression and CRC prognosis. PATIENTS AND METHODS: Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) was carried out to detect miR-199a expression level in serum from 107 CRC patients and 60 healthy controls. RESULTS: Serum miR-199a levels were significantly lower in CRC patients, particularly in advanced stage CRC subjects. MiR-199a expression in patients with distant metastasis and lymph node metastasis was markedly reduced compared to those without. Moreover, low serum miR-199a expression was associated with various CRC clinicopathological parameters. The serum miR-199a levels in CRC patients were increased significantly after their treatment. Furthermore, the patients in low serum miR-199a expression group had both worse overall survival and disease-free survival. In the multivariate analysis, serum miR-199a was identified as an independent prognostic marker. CONCLUSIONS: Reduced serum miR-199a was associated with poor prognosis in CRC and it might be useful as a marker for diagnosis and prognosis in CRC.
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Biomarcadores Tumorais/sangue , Neoplasias Colorretais/diagnóstico , MicroRNAs/sangue , Adulto , Idoso , Neoplasias Colorretais/sangue , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Curva ROCRESUMO
OBJECTIVE: To examine the impact of integrated hybrid operating rooms for endoscope-assisted microsurgery using the presigmoid retrolabyrinthine (RL) approach, and to determine the value of simultaneous supervision of skull base endoscopic procedures by microscope. MATERIAL AND METHODS: We retrospectively reviewed endoscope-assisted surgery using the RL approach at our institution between September 2013 and January 2017. The simultaneous supervision of endoscopic procedures by microscope was realized using the integrated hybrid system. Intra- or postoperative complications and surgical outcomes were analyzed. All patients were followed for at least 1 year. RESULTS: In total, 32 patients were studied: 4 vestibular schwannomas, 5 cholesteatomas, 8 hemifacial spasms, 5 glossopharyngeal neuralgias, and 10 Ménière's disease. In patients with vestibular schwannoma or cholesteatoma, complete removal was performed in all patients. In patients with Ménière's disease, hemifacial spasm or glossopharyngeal neuralgia, satisfactory symptom relief was achieved in all patients. Two (6.3%) patients had hearing loss after surgery which did not recover. One (3.1%) patient with vestibular schwannoma had mild facial palsy (HB III) at 2 weeks after the operation and recovered to near normal facial nerve function (HB II) at 1 year after surgery. No permanent or transient dysfunction of the trigeminal nerve or the lower cranial nerves was observed during follow-up. No complications such as cerebrospinal fluid (CSF) leakage or meningitis were observed. CONCLUSION: The endoscope provided a clearer and larger view, which solved the limitations of surgery using the RL approach. Endoscopic surgery under simultaneous supervision by microscope was safe and efficient in hearing preservation as well as in preservation of facial nerve function. An integrated operation room provided better support and the ability to switch quickly between these various complex devices.
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Endoscópios , Microcirurgia/instrumentação , Microcirurgia/métodos , Adulto , Ângulo Cerebelopontino , Colesteatoma da Orelha Média/cirurgia , Descompressão Cirúrgica/métodos , Denervação/métodos , Feminino , Doenças do Nervo Glossofaríngeo/cirurgia , Espasmo Hemifacial/cirurgia , Humanos , Masculino , Doença de Meniere/cirurgia , Pessoa de Meia-Idade , Neuroma Acústico/cirurgia , Projetos Piloto , Complicações Pós-Operatórias , Estudos RetrospectivosRESUMO
Objective:To explore the gene promoter methylation profiles of nasal polyp, and to analysis the promoter methylation differences between the nasal polyp and the normal nasal mucosa.Method:Total DNA of the nasal polyp tissues and normal nasal mucosa were extracted. After immunoprecipitation and whole genome amplification, the DNA was labeled with Cy3/5 and hybridized in NimbleGen hybridization chamber. For array hybridization, Roche Nimblegen CpG Promoter array was used. The slides were scanned using the Axon GenePix 4000B microarray scanner. The different genes were analyzed through pathway and verified by Real-time PCR.Result:3010 genes were found to have promoter hypermethylation in normal nasal mucosa or nasal polyp.2,62%(79/3010) of the genes had promoter hypermethylation in all the nasal polyps, which were negative in normal nasal mucosa.10.66%(321/3010) of the genes had promoter hypermethylation in normal nasal mucosa, which were negative in all the nasal polyps. Three pathways were found in the promoter hypermethylation of the nasal polyps. Fourteen pathways were found in the negative hypermethylation of the nasal polyps.Conclusion:Genes promoter methylation plays an important role in the development of nasal polyps, and the gene promoter methylation profiling may yield new some clues on the mechanism of nasal polyps.
Assuntos
Metilação de DNA , Pólipos Nasais/genética , Regiões Promotoras Genéticas , Humanos , Mucosa Nasal , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Objective: To determine the personal dose level of radiation workers in medical institutions at the municipal level and below in a city, and to provide a scientific support for strengthening the radiation protection in the city's medical institutions. Methods: Information of the successful applicants for the "Radiation Worker Permit" from 174 medical institutions at the municipal level and below was collected from October 1, 2011 to December 31, 2014. The annual effective dose was calculated based on the personal dose monitoring report, and indicators including sex, permit application time, hospital level, type of occupational radiation, length of radiation work, blood test, and micronucleated lymphocyte rate were analyzed. Results: Of the 1 143 radiation worker permit applications submitted by medical institutions the municipal level and below in this city from 2011 to 2014, 1 123 provided at least one personal dose monitoring report. The annual effective dose of the radiation workers was 0-4.76 mSv (mean 0.31±0.40 mSv) , and the collective annual effective dose was 351.96 mSv. The annual effective dose was significantly different between radiation workers with different times of permit application, hospital levels, and types of occupational radiation (P<0.05) . Interventional radiology workers had the highest annual effective dose (0.63 mSv) , and annual effective dose was significantly different between interventional radiology workers with different lengths of radiation work (H=10.812, P<0.05) . Conclusion: The personal radiation dose of radiation workers in medical institutions at the municipal level and below in this city is maintained at a relatively low level, suggesting that the occupational environment is relatively safe for these workers. However, more focus should be placed on clinical interventional radiology workers.
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Exposição Ocupacional/efeitos adversos , Doses de Radiação , Monitoramento de Radiação , Proteção Radiológica , Humanos , Doenças Profissionais/prevenção & controle , Exposição Ocupacional/prevenção & controleRESUMO
Over the past 50 years, the focus of acoustic neuroma surgery has shifted from low mortality and tumor resection to retention of neurological function. Hearing preservation is another point in addition to facial nerve function preservation. Hearing preservation rates overall ranged from 2% to 93% in recent studies. Characteristics such as approach, pre-operative neurological function, tumor size, nerve of origin and fundal fluid of the internal auditory canal have been reported as possible influencing factors. This review provides a summary of recent studies and describes the prognostic factors that predict hearing preservation.
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Audição , Neuroma Acústico/cirurgia , Tratamentos com Preservação do Órgão/métodos , Orelha Interna , Humanos , Estudos RetrospectivosRESUMO
AIMS: To evaluate the effects of condensed tannins (CTs) fractions of differing molecular weights (MWs) from a Leucaena leucocephala hybrid-Rendang on the rumen protozoal community in vitro. METHODS AND RESULTS: The effects of unfractionated CTs (F0) and CT fractions of different MWs (F1 > F2 > F3 > F4 > F5) on protozoal population and community were evaluated in vitro using rumen microbes and ground guinea grass as the substrate. Higher-MW CT fractions F1 and F2 significantly (P < 0·05) decrease the number of ciliate protozoa. The real-time PCR analysis showed that the total protozoa was significantly (P < 0·05) lower in F0 and all CTs with fractions F1 and F2 having the lowest value. High-throughput sequencing of the partial 18S rRNA gene showed that the genus Entodinium significantly (P < 0·05) decreased with increasing MWs of CT, whereas Anoplodinium-Diplodinium were significantly (P < 0·05) increased. Inclusion of the highest MW CT fraction F1 decreased the relative abundance of the minor genera such as Eudiplodinium and Polyplastron compared to the control and CT fractions F2-F5. CONCLUSION: CTs of differing MWs could reduce and alter the rumen protozoa population in vitro. This effect was more pronounced for higher-MW CTs. SIGNIFICANCE AND IMPACT OF THE STUDY: The high MW CTs should be considered as a feed supplement in the ruminant diet to reduce the protozoal population which are known to be associated with methanogens as a means to mitigate methane production in the rumen.
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Objective: To evaluate the application of combination use of microscope and endoscope in cerebral pontine angle (CPA) surgery. Methods: A total of 72 patients undergone lateral skull base surgeries via endoscope under microscopic control from January 2006 to January 2015 was reviewed respectively. The patients including 35 males and 37 females were composed of 22 cases of vestibular swannnomas, 45 cases of cranial neuropathy and 5 cases of CPA chelesteatoma. Twenty cases of vestibular swannnomas, 15 cases of cranial neuropathy and 2 cases of CPA chelesteatoma undergone the surgery via retrosigmoid approach, while other cases undergone the surgery via retrolabyrinthine approach. Surgical procedures were accomplished under the control of microscope and different angular endoscope with imaging fusion. The surgical results were evaluated according to subjective and objective criteria, and all patients were followed up for 15 years. Results: The symptoms was disappeared in the cranial neuropathy patients, without facial paralysis, complication of other nerves or hearing loss. Twenty-two patients with vestibular schwannomas got total tumor removal without facial palsy or neurological deficits; useful hearing was preserved in 16 of 22 patients (72.7%), and no tumor recurrence was found during 1-5 years follow-up. There was also no facial palsy or other complications in 5 cases of CPA chelesteatoma, which gained completely surgical removal; useful hearing was preserved in 3 of 5 cases of these patients and no recurrence was occurred during 1-1.5 years follow-up. Conclusions: A combination use of endoscope and microscope could combine advantages and avoid disadvantages of two techniques. It can provide better exposure with minimal invasion in CPA surgery, and is especially applicable in surgery for cranial neuropathy, vestibular schwannoma and CPA cholesteatoma, which should be performed through retrosigmoid approach and retrolabyrinthine approach.
Assuntos
Ângulo Cerebelopontino/cirurgia , Endoscópios , Endoscopia/métodos , Microcirurgia/métodos , Neuroma Acústico/cirurgia , Feminino , Audição , Perda Auditiva , Humanos , Masculino , Microcirurgia/instrumentação , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/métodosRESUMO
Objective:The objective of this study is to investigate the methylation status of vascular endothelial cell growth factor B (VEGF-B) gene and to indentify the roles in pathogenesis,development and classification of nasal polyps.Method:The methylation status of VEGF-B gene of 28 nasal polyp tissues and 12 samples of inferior turbinate tissues were detected by methylationspecific-polymerase chain reaction (MS-PCR) and gene sequencing.Result:There was significant statistic diference between nasal polyp tissue group and control group (χ ²=4.096,P<0.05). The results of gene sequencing suggest that the VEGF-B gene promoter were hypomethylation status in the nasal polyps.Conclusion:Methylation status of VEGF-B promoter may play an important role in the pathogenetic mechanism of nasal polyps.
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Pólipos Nasais/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator B de Crescimento do Endotélio Vascular/genética , Estudos de Casos e Controles , Humanos , Inflamação/metabolismo , Metilação , Pólipos Nasais/patologia , Reação em Cadeia da Polimerase , Conchas Nasais/patologia , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator B de Crescimento do Endotélio Vascular/biossínteseRESUMO
KEY POINTS: Loss of function of the melanocortin 4 receptor (MC4R) results in hyperphagia, obesity and increased growth. Despite knowing that MC4Rs control food intake, we are yet to understand why defects in the function of the MC4R receptor contribute to rapid linear growth. We show that hyperphagia following germline loss of MC4R in male mice promotes growth while suppressing the growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis. We propose that hyperinsulinaemia promotes growth while suppressing the GH-IGF-1 axis. It is argued that physiological responses essential to maintain energy flux override conventional mechanisms of pubertal growth to promote the storage of excess energy while ensuring growth. ABSTRACT: Defects in melanocortin-4-receptor (MC4R) signalling result in hyperphagia, obesity and increased growth. Clinical observations suggest that loss of MC4R function may enhance growth hormone (GH)-mediated growth, although this remains untested. Using male mice with germline loss of the MC4R, we assessed pulsatile GH release and insulin-like growth factor-1 (IGF-1) production and/or release relative to pubertal growth. We demonstrate early-onset suppression of GH release in rapidly growing MC4R deficient (MC4RKO) mice, confirming that increased linear growth in MC4RKO mice does not occur in response to enhanced activation of the GH-IGF-1 axis. The progressive suppression of GH release in MC4RKO mice occurred alongside increased adiposity and the progressive worsening of hyperphagia-associated hyperinsulinaemia. We next prevented hyperphagia in MC4RKO mice through restricting calorie intake in these mice to match that of wild-type (WT) littermates. Pair feeding of MC4RKO mice did not prevent increased adiposity, but attenuated hyperinsulinaemia, recovered GH release, and normalized linear growth rate to that seen in pair-fed WT littermate controls. We conclude that the suppression of GH release in MC4RKO mice occurs independently of increased adipose mass, and is a consequence of hyperphagia-associated hyperinsulinaemia. It is proposed that physiological responses essential to maintain energy flux (hyperinsulinaemia and the suppression of GH release) override conventional mechanisms of pubertal growth to promote the storage of excess energy while ensuring growth. Implications of these findings are likely to extend beyond individuals with defects in MC4R signalling, encompassing physiological changes central to mechanisms of growth and energy homeostasis universal to hyperphagia-associated childhood-onset obesity.
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Hormônio do Crescimento/metabolismo , Hiperfagia/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Obesidade/metabolismo , Receptor Tipo 4 de Melanocortina/metabolismo , Animais , Encéfalo/metabolismo , Proteínas de Fluorescência Verde/genética , Hormônio do Crescimento/genética , Hormônio Liberador de Hormônio do Crescimento/genética , Insulina/sangue , Leptina/sangue , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Neurônios/metabolismo , Receptor Tipo 4 de Melanocortina/deficiência , Receptor Tipo 4 de Melanocortina/genéticaRESUMO
The plasticity of tumour-associated macrophages (TAMs) has implicated an influential role in hepatocellular carcinoma (HCC). Repolarisation of TAM towards M1 phenotype characterises an immune-competent microenvironment that favours tumour regression. To investigate the role and mechanism of TAM repolarisation in suppression of HCC by a natural compound baicalin, Orthotopic HCC implantation model was used to investigate the effect of baicalin on HCC; liposome-clodronate was introduced to suppress macrophage populations in mice; bone marrow-derived monocytes (BMDMs) were induced to unpolarised, M1-like, M2-like macrophages and TAM using different conditioned medium. We observed that oral administration of baicalin (50 mg/kg) completely blocked orthotopic growth of implanted HCC. Suppression of HCC by baicalin was diminished when mice macrophage was removed by clodronate treatment. Baicalin induced repolarisation of TAM to M1-like phenotype without specific toxicity to either phenotype of macrophages. Baicalin initiated TAM reprogramming to M1-like macrophage, and promoted pro-inflammatory cytokines production. Co-culturing of HCC cells with baicalin-treated TAMs resulted in reduced proliferation and motility in HCC. Baicalin had minimal effect on derivation of macrophage polarisation factors by HCC cells, while directly induced repolarisation of TAM and M2-like macrophage. This effect was associated with elevated autophagy, and transcriptional activation of RelB/p52 pathway. Suppression of autophagy or RelB abolished skewing of baicalin-treated TAM. Autophagic degradation of TRAF2 in baicalin-treated TAM might be responsible for RelB/p52 activation. Our findings unveil the essential role of TAM repolarisation in suppressive effect of baicalin on HCC, which requires autophagy-associated activation of RelB/p52.
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Carcinoma Hepatocelular/patologia , Flavonoides/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/patologia , Subunidade p52 de NF-kappa B/fisiologia , Fator de Transcrição RelB/fisiologia , Animais , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Polaridade Celular/efeitos dos fármacos , Flavonoides/uso terapêutico , Interleucina-12/genética , Interleucina-12/metabolismo , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Subunidade p52 de NF-kappa B/metabolismo , Transdução de Sinais , Fator de Transcrição RelB/metabolismo , Microambiente Tumoral , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The objectives of this study were to determine the molecular weight of condensed tannins (CT) extracted from mangosteen (Garcinia mangostana L) peel, its protein binding affinity and effects on fermentation parameters including total gas, methane (CH4) and volatile fatty acids (VFA) production. The average molecular weight (Mw) of the purified CT was 2,081 Da with a protein binding affinity of 0.69 (the amount needed to bind half the maximum bovine serum albumin). In vitro gas production declined by 0.409, 0.121, and 0.311, respectively, while CH4 production decreased by 0.211, 0.353, and 0.549, respectively, with addition of 10, 20, and 30 mg CT/500 mg dry matter (DM) compared to the control (p<0.05). The effects of CT from mangosteen-peel on in vitro DM degradability (IVDMD) and in vitro N degradability was negative and linear (p<0.01). Total VFA, concentrations of acetic, propionic, butyric and isovaleric acids decreased linearly with increasing amount of CT. The aforementioned results show that protein binding affinity of CT from mangosteen-peel is lower than those reported for Leucaena forages, however, the former has stronger negative effect on IVDMD. Therefore, the use of mangosteen-peel as protein source and CH4 mitigating agent in ruminant feed requires further investigations.
RESUMO
Atopic dermatitis (AD) has a high negative impact on quality of life. Acupuncture has antipruritic actions and may assist in treatment of AD; however, the current state of evidence for this remains unknown. We aimed to evaluate the efficacy of acupuncture against placebo/sham acupuncture in the management of AD. Electronic searches were conducted on a number of databases, from their inception until November 2013. Studies comparing the effects of acupuncture with those of placebo/sham acupuncture on severity of disease or symptoms/signs of AD were included. We did not find any studies that were eligible to be included in this systematic review. Among the excluded studies, there were two studies that evaluated the antipruritic effects of acupuncture and one study that evaluated the effects of acupuncture on IgE-mediated allergy. However, there were no randomized controlled trials evaluating the effects of acupuncture on AD as a disease. This finding therefore provides an indication of the current state of evidence of acupuncture in the management of AD, and highlights the research gap that exists, in that there is a lack of gold-standard studies (i.e. RCTs) to support valid conclusions. There is currently no evidence of the effects of acupuncture in the management of AD, and no evidence-based recommendations or conclusions can be made from this review. Several studies indicated that acupuncture may have a role in reducing itch or regulating IgE-mediated allergy, both of which are major characteristics of AD. However, there were no RCTs evaluating the effects of acupuncture on AD as a disease. There is therefore an urgent need for rigorously designed RCTs to assess the efficacy of acupuncture in the management of AD.