RESUMEN
BackgroundA novel coronavirus named as "SARS-CoV-2" has spread widely in many countries since December 2019, especially in China. This study aimed to quantify the age-specific transmissibility by using a mathematical model. MethodsAn age-specific susceptible - exposed - symptomatic - asymptomatic - recovered - seafood market (SEIARW) model was developed based on two suspected transmission routes (from market to person and person to person). The susceptible people from Wuhan City were divided into different age groups. We used the subscript i and j to represent age group 1 to 4 (i = j; 1: [≤] 14 years; 2: 15-44 years; 3: 45-64 years; 4: [≥] 65 years) and 1 to 5 (i = j; 1: [≤] 5 years; 2: 6-14 years; 3: 15-24 years; 4: 25-59 years; 4: [≥] 60 years), respectively. Data of reported COVID-19 cases were collected from one published literature from 26 November to 22 December, 2019 in Wuhan City, China. The age-specific transmissibility of the virus was estimated accordingly secondary attack rate (SAR). ResultsThe age-specific SEIARW model fitted with the reported data well by dividing the population into four age groups ({chi}2 = 4.99 x 10-6, P > 0.999), and five age groups ({chi}2 = 4.85 x 10-6, P > 0.999). Based on the four-age-group SEIARW model, the highest transmissibility occurred from age group 2 to 3 (SAR23 = 17.56 per 10 million persons), followed by from age group 3 to 2 (SAR32 = 10.17 per 10 million persons). The lowest transmissibility occurred from age group 1 to 2 (SAR12 = 0.002 per 10 million persons). Based on the five-age-group SEIARW model, the highest transmissibility occurred from age group 4 to 5 (SAR45 = 12.40 per 10 million persons), followed by from age group 5 to 4 (SAR54 = 6.61 per 10 million persons). The lowest transmissibility occurred from age group 3 to 4 (SAR34 = 0.0002 per 10 million persons). ConclusionsSARS-CoV-2 has high transmissibility among adults and elder people but low transmissibility among children and young people.
RESUMEN
OBJECTIVE: To summarize the theory about animal rule, in order to provide references for its implementation in industry. METHODS: The basic principles and main technology points of the animal rule are analyzed based on the guidance and other literatures issued by the Food and Drug Administration (FDA). RESULTS: FDA has formulated guidance, known simply as “animal rule”, which applies when clinical efficacy studies in humans cannot be ethically conducted and field efficacy studies are not feasible for certain chemical drugs and biological products including vaccines that are intended to treat or prevent serious or life-threatening diseases. Namely, those applications may be approved for marketing based on evidence of effectiveness derived from appropriate animal studies and any additional supporting data. This article introduces briefly how to carry out the critical animal effective studies and how to extrapolate human effective dose. CONCLUSION:Animal rule may provide a new registration strategy for drug candidates when their clinical efficacy studies in humans are not ethical or feasible but reasonably likely brings clinical benefits.
RESUMEN
OBJECTIVE To provide reference for the industry, introduce the experimental design of animal efficacy studies and human dosage extrapolating strategy about drugs and biological products (including vaccines) approved by FDA under animal rule. METHODS This article provides an overview catalogued by the indications of drugs (including vaccines), on experimental grouping, dosage regimen, critical efficacy endpoints and other elements in the adequate and well-controlled animal efficacy studies, and further analyses the strategy of extrapolating animals efficacy data. RESULTS The regulations commonly known as the animal rule allow for the licensure of drugs and biological products developed to reduce or prevent serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic chemical, biological, radiological, or nuclear substances, when human efficacy studies are not ethical and field trials to study the effectiveness of drugs or biological products are not feasible. CONCLUSION Under the animal rule, drug efficacy can be established based on adequate and well-controlled studies in animal models and the human dosing regimens can be extrapolated based on the animal data.
RESUMEN
<p><b>OBJECTIVE</b>To investigate the changes of left ventricular structure and function in patients with liver cirrhosis and their correlation with the model for end-stage liver disease (MELD) score.</p><p><b>METHODS</b>A total of 89 cirrhotic patients admitted between June, 2012 and June, 2014 and 30 healthy control subjects were enrolled in the study. According to MELD score, the cirrhotic patients were divided into 3 groups with MELD scores ≤9, between 10 and 19, and ≥20. The parameters of the left ventricle in resting state were measured using Doppler echocardiography, including left ventricular end systolic diameter (LVESD), left ventricular end diastolic diameter (LVEDD), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT), left atrial diameter (LAD), ejection fraction (LVEF), cardiac output (CO), mitral flow velocity, and E wave deceleration time (DT), and evaluated their relationship with MELD score.</p><p><b>RESULTS</b>Compared with the control subjects, the cirrhotic patients showed significantly increased LVESD, LVEDD, IVST, LAD, CO and DT but reduced VE/VA ratio (P<0.05 or 0.01). The values of LVESD, LVEDD, IVST, LAD and DT increased gradually with MELD scores (P<0.05 or 0.01). VE/VA ratio was higher in patients with MELD score of 10-19 than in those with MELD score ≤9, and decreased significantly in those with MELD score ≥20. Of the cirrhotic patients, 55% were found to have left atrial enlargement and 44% had a VE/VA ratio ≤1; left atrial enlargement and a VE/VA ratio below 1 were more common in patients with a MELD score ≥20 than in those with lower MELD scores. The LAD, LVEDD and DT were positively correlated with MELD scores (r=0.208, 0.319 and 0.197, respectively; P<0.05 or 0.01).</p><p><b>CONCLUSIONS</b>The patients with liver cirrhosis can have cardiac function deficiency manifested mainly by left ventricular diastolic dysfunction in positive correlation with the severity of liver disease.</p>
Asunto(s)
Humanos , Gasto Cardíaco , Estudios de Casos y Controles , Enfermedad Hepática en Estado Terminal , Atrios Cardíacos , Patología , Ventrículos Cardíacos , Cirrosis Hepática , Índice de Severidad de la Enfermedad , Función Ventricular IzquierdaRESUMEN
Hepatic fibrosis is a common disease caused by wound-healing response to a variety of chronic liver injuries; it is characterized by the imbalance of extracellular matrix synthesis and degradation. Angiotensin II is the major effector of the renin-angiotensin system. Increasing evidence has demonstrated that the interaction of angiotensin II with angiotensin receptor 1 plays an important role in the long-term liver injury-induced liver fibrosis by inducing the activation, proliferation and constriction of hepatic stellate cells, generation of the reactive oxygen species from activated hepatic stellate cells, and the synthesis and accumulation of collagen. In this article we focused on the role of angiotensin II and its receptor 1 in the pathogenesis, development and therapy of liver fibrosis in recent years.
RESUMEN
Autophagy dysregulation, mitochondrial dynamic abnormality and cell cycle re-entry are implicated in the vulnerable neurons of patients with Alzheimer's disease. This study was designed to testify the association among autophagy, mitochondrial dynamics and cell cycle in dividing neuroblastoma (N2a) cells. The N2a cells were cultured in vitro and treated with different concentrations of 3-methyladenine (3-MA). The cell viability was detected by methyl thiazolyl tetrazolium (MTT) assay. They were randomly divided into control group (cells cultured in normal culture medium) and 3-MA group (cells treated with 10 mmol/L 3-MA). The cell cycle was analyzed in the two groups 3, 6, 12, and 24 h after treatment by flow cytometry. Western blotting was used to evaluate the expression levels of mitofission 1 (Fis1), mitofusin 2 (Mfn2), microtubule-associated protein 1 light chain 3 (LC3), cell cycle-dependent kinase 4 (CDK4) and cdc2. The flow cytometry revealed that the proportion of cells in G(2)/M was significantly increased, and that in G0/G1 was significantly reduced in the 3-MA group as compared with the control group. Western blotting showed that the expression levels of Fis1, LC3, and CDK4 were significantly up-regulated in the 3-MA group at the four indicated time points as compared with the control group. Mfn2 was initially decreased in the 3-MA group, and then significantly increased at 6 h or 12 h. Cdc2 was significantly increased in the 3-MA group at 3 h and 6 h, and then dropped significantly at 12 h and 24 h. Our data indicated that 3-MA-induced suppressed autophagy may interfere with the cell cycle progression and mitochondrial dynamics, and cause cell death. There are interactions among cell cycle, mitochondrial dynamics and autophagy in neurons.
Asunto(s)
Humanos , Adenina , Apoptosis , Autofagia , Genética , Proteína Quinasa CDC2 , Ciclo Celular , Genética , División Celular , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Ciclina B , Quinasas Ciclina-Dependientes , Regulación de la Expresión Génica , Proteínas de la Membrana , Proteínas Asociadas a Microtúbulos , Dinámicas Mitocondriales , Genética , Proteínas Mitocondriales , Neuroblastoma , Transducción de SeñalRESUMEN
Autophagy dysregulation, mitochondrial dynamic abnormality and cell cycle re-entry are implicated in the vulnerable neurons of patients with Alzheimer's disease. This study was designed to testify the association among autophagy, mitochondrial dynamics and cell cycle in dividing neuroblastoma (N2a) cells. The N2a cells were cultured in vitro and treated with different concentrations of 3-methyladenine (3-MA). The cell viability was detected by methyl thiazolyl tetrazolium (MTT) assay. They were randomly divided into control group (cells cultured in normal culture medium) and 3-MA group (cells treated with 10 mmol/L 3-MA). The cell cycle was analyzed in the two groups 3, 6, 12, and 24 h after treatment by flow cytometry. Western blotting was used to evaluate the expression levels of mitofission 1 (Fis1), mitofusin 2 (Mfn2), microtubule-associated protein 1 light chain 3 (LC3), cell cycle-dependent kinase 4 (CDK4) and cdc2. The flow cytometry revealed that the proportion of cells in G(2)/M was significantly increased, and that in G0/G1 was significantly reduced in the 3-MA group as compared with the control group. Western blotting showed that the expression levels of Fis1, LC3, and CDK4 were significantly up-regulated in the 3-MA group at the four indicated time points as compared with the control group. Mfn2 was initially decreased in the 3-MA group, and then significantly increased at 6 h or 12 h. Cdc2 was significantly increased in the 3-MA group at 3 h and 6 h, and then dropped significantly at 12 h and 24 h. Our data indicated that 3-MA-induced suppressed autophagy may interfere with the cell cycle progression and mitochondrial dynamics, and cause cell death. There are interactions among cell cycle, mitochondrial dynamics and autophagy in neurons.
RESUMEN
<p><b>OBJECTIVE</b>To observe the clinical manifestations of bullous retinal detachment and analyze the etiological factors.</p><p><b>METHODS</b>A retrospective analysis of the clinical data was conducted in 22 patients with multifocal retinal pigment epitheliopathy (DRPE) and big bullous retinal detachment (BBRD), who were admitted between 2003 and 2008 in Zhongshan Ophthalmic Center with the diagnoses established by ocular fundus examination, fundus fluorescein angiography (FFA) and/or indocyanine green angiography (ICGA).</p><p><b>RESULTS</b>The patients included 15 men (68%) and 7 women (32%), with a mean age at the initial visit of 42 years, ranging from 25 to 64 years. Four patients (18%) received previously systemic corticosteroid therapy, and 2 of them used corticosteroids before retina detachment, 1 suffered progression of retinal detachment after corticosteroid therapy, and the other developed retinal detachment in the healthy eye during the therapy. Multifocal bullous retinal detachment was diagnosed as diffuse pigment epitheliopathy (DRPE) in 9 cases. Most of the 13 cases of big bullous retinal detachment had poor vision after operation and laser therapy.</p><p><b>CONCLUSION</b>Bullous retinal detachment occurs most frequently in mid-life and more often in men than women. Abnormal retinal pigment epithelium (RPE) and hyperpermeability of the choroid vessels are associated with its occurrence. Systemic corticosteroid therapy and mental stress may induce and aggravate this disease. Early medication and laser therapy are effective, and surgical intervention may save only part of the vision in advanced cases.</p>
Asunto(s)
Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fondo de Ojo , Desprendimiento de Retina , Diagnóstico , Patología , Terapéutica , Estudios RetrospectivosRESUMEN
<p><b>INTRODUCTION</b>Macular oedema is the main cause of visual impairment following retinal vein occlusion. The purpose of this study was to evaluate the anatomical and functional outcome of pars plana vitrectomy and internal limited membrane (ILM) peeling for macular oedema secondary to retinal vein occlusion.</p><p><b>CLINICAL PICTURE</b>This pilot study is a prospective nonrandomised series of 11 eyes of 11 patients with macular oedema secondary to retinal vein occlusion. The best-corrected visual acuity (BCVA), foveal thickness on optical coherence tomography, fundus fluorescein angiography (FFA) and multifocal electroretinography were evaluated.</p><p><b>TREATMENT AND OUTCOME</b>All 11 patients underwent pars plana vitrectomy with ILM peeling. The mean postoperative follow-up was 13.5 months (range, 1.5 to 24). The mean thickness at the foveal centre decreased from 794 +/- 276 microm preoperatively to 373 +/- 150 microm, 302 +/- 119 microm, 249 +/- 203 microm and 185 +/- 66 microm at 1 week, 1 month, 3 months and the final visit postoperatively, respectively (all P <0.001, paired t- test, compared to preoperative thickness). Postoperative FFA demonstrated markedly reduced leakage in the macular region. At the final visit, BCVA improved 2 lines or more in 72.7% (8/11) of patients and was unchanged in 27.3% (3/11) patients. Complications included cataract in 7 patients and vitreous haemorrhage, recurrence of macular oedema and visual field defect in 1 case each.</p><p><b>CONCLUSION</b>Pars plana vitrectomy and ILM peeling rapidly reduced the macular oedema caused by retinal vein occlusion, with improvement in BCVA.</p>
Asunto(s)
Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Membrana Epirretinal , Patología , Cirugía General , Edema Macular , Cirugía General , Pars Planitis , Patología , Cirugía General , Proyectos Piloto , Estudios Prospectivos , Oclusión de la Vena Retiniana , Agudeza Visual , VitrectomíaRESUMEN
NF-kappaB, a collective name of dimeric transcription factors, is composed of members of the Rel family proteins that recognize and bind a specific DNA sequence. It is normally sequestered in the cytoplasm of non-stimulated cells by associating with a family of inhibitor proteins called IkappaBs. Exposure of cells to a variety of extra-and intra-cellular stimuli leads to the rapid proteolytic degradation of IkappaBs, which frees NF-kappaBs allowing them to translocate to the nucleus where it regulates gene transcription. NF-kappaB is involved in a lot of physiological processes such as immunity, inflammation, cell proliferation, apoptosis and even tumorigenesis by regulating the transcription of a larger number of genes. This review introduces the various mechanisms of NF-kappaB activation including a recently reported alternative activation pathway mediated by lymphotoxin alpha/beta, B cell activating factor and CD40 ligand. The signal transduction pathway leading to NF-kappaB activation via IKK in response to proinflammatory factors like TNF-alpha and IL-1 is addressed in more detail concerning the regulation of IKK activity, mechanism of IkappaB degradation and regulation of transactivation activity of NF-kappaB on different levels. Considering the important role of NF-kappaB in cell proliferation and regulation of various genes participating in apoptosis, the involvement of NF-kappaB in tumorigenesis and drug screening is also discussed.
Asunto(s)
Animales , Humanos , Evaluación Preclínica de Medicamentos , Proteínas I-kappa B , Metabolismo , FN-kappa B , Metabolismo , Fisiología , Neoplasias , Transducción de Señal , Transcripción Genética , FisiologíaRESUMEN
Parkinson's disease(PD) is the most common neurodegenerative movement disorder and ?-synuclein plays an important role in its development.Using the genetically tractable Saccharomyces cere-visiae as a model system,the phenotypic repercussions and potential mechanisms of ?-synuclein-induced cytotoxicity are characterized through modulating its expression level and other cellular factors.Aggrega-tion-induced toxicity is more dramatic upon elevated expression of ?-synuclein than that induced at moder-ate levels of expression.The induced toxicity is also enhanced by reagents such as dimethyl sulfoxide,which increase intracellular levels of phospholipid and membrane,as well as ferrous ions and hydrogen peroxide,both of which cause oxidative stresses in yeast cells.In contrast,over-expression of yeast homologue of hu-man chaperone DJ-1,YDR533C,markedly alleviate the inhibition of growth afflicted by exogenous expres-sion of ?-synuclein.Taken together,the data presented suggest a role for protein folding machinery together with quality control system in dealing with the aggregation of ?-synuclein.